Search Results (203)

Introduction: Radiotherapy plays a critical role in the management of head and neck squamous-cell carcinoma (HNSCC); however, the influence of overall treatment time on patient outcomes remains an area of ongoing investigation. The use of radiation, either in conjunction with concurrent chemotherapy or on its own, is crucial when treating HNSCC. Despite the longstanding hypothesis that treatment gaps may adversely affect tumor response and overall survival, there is a paucity of literature on this particular area. This study aims to bridge the knowledge gap and assess the correlation of treatment gaps on recurrences in HNSCC patients. Materials and Methodology: This retrospective study is based on an analysis of data obtained from a single institution between 2017 and 2021. Patients were selected on the basis of the presence of treatment gaps. Data were extracted from medical records and analyzed to evaluate the association between overall treatment time and various patient and treatment-related factors. Various factors thought to contribute to treatment gaps, such as age, TNM Stage, radiation dose, and use of concurrent chemotherapy, were also examined. Results: A total of 212 patients with treatment gaps were evaluated. Of these, 80 individuals experienced recurrences. It was observed that compared to distant metastases, locoregional failure was more frequent (n = 2, 4.2% vs. n = 45, 95.74%). The patients underwent both adjuvant and definitive therapy and were treated with a dose range of 60–70 Gy and concurrent cisplatin chemotherapy. It was noticed that this cohort had a range of 4–43 days of treatment gaps. Notably, 19 out of 47 patients had treatment gaps ≤ 5 days, while 28 out of 47 had gaps exceeding 5 days. It was also observed that patients with treatment gaps of >5 days had poorer quality of life and overall survival. Conclusions: This study identified that the Overall Treatment Time (OTT) had a strong statistical correlation with the development of recurrences. Further, the age of the patient, presence of neutropenia and the duration of the treatment gap were also identified to significantly correlate with the chance of developing recurrences. Full article

Radiotherapy is an effective treatment for cancer; however, radioresistant cancer cells result in recurrence. Therefore, elucidating the mechanisms of radioresistance is urgently needed. Super-enhancers (SEs) are clusters of enhancers occupied by a high density of master transcription factors, mediators, and bromodomain protein BRD4. Recently, we reported that ΔNp63, an oncogenic transcription factor, promotes radioresistance in human head and neck squamous cell carcinoma (HNSCC) cells. As ΔNp63 establishes SEs in HNSCC cells, SEs may be involved in radioresistance. Here, we investigated the role of the SE component BRD4 in the radiation responses of HNSCC cells using a BRD4 degrader ARV-771 or BRD4 knockdown. First, Western blotting confirmed that ARV-771 decreased BRD4 protein expression. ARV-771 treatment resulted in reduced cell proliferation and enhanced apoptosis in irradiated HNSCC cells. Moreover, colony formation assays revealed that both ARV-771 and BRD4 knockdown enhanced the radiosensitivity of HNSCC cells, suggesting BRD4 contributes to the radioresistance of HNSCC cells. Furthermore, fluorescence immunostaining revealed distinct localization patterns of γH2AX, a marker of DNA double-strand breaks, compared with BRD4 and ΔNp63 in irradiated cells. Notably, ARV-771 and BRD4 knockdown decreased ΔNp63 and BRD4 protein expression, whereas ΔNp63 knockdown had minimal impact on BRD4 expression. Taken together, these findings suggest that BRD4-dependent maintenance of ΔNp63 expression may contribute, at least in part, to the regulation of radioresistance in HNSCC cells. Full article

The tumor microenvironment (TME) orchestrates tumor growth, immune evasion, and therapeutic response in head and neck squamous cell carcinoma (HNSCC). Current immune checkpoint inhibitors (ICIs) target the programmed death receptor-1/programmed death-ligand 1 (PD-1/PD-L1) axis and improve survival in recurrent, metastatic, and locally advanced HNSCC. Tumor cells produced exosomes directly suppress cytotoxic T-lymphocytes activity by modulating immune checkpoint pathways and disrupting T-cell receptor signaling. Cancer-associated fibroblast-derived exosomes (CAF-Exos) function indirectly by conditioning immune escape and tumor growth. Together, these exosomal populations cooperate to create an immunosuppressive niche that hinders the efficacy of immunotherapies. CAF-Exos induce TME changes that exclude CD8⁺ T-cells, promote regulatory T-cells (Tregs), and upregulate PD-L1 expression in tumor cells. The bidirectional transfer of microRNAs (miRNAs) between tumor cells and CAFs enhances epithelial–mesenchymal transition (EMT), suppresses cytotoxic lymphocytes, and undermines ICI efficacy. This review article summarizes recent publications about plasma-derived exosomes from HNSCC patients. These exosomes carry tumor and immune checkpoint markers, reflect tumor burden and treatment response, and strongly modulate immune cells by suppressing T- and B-cell activity and promoting immunosuppressive macrophages. We encourage functional and biomechanistic future studies in the field of HNSCC that examine how CAF subtypes exosomes achieve an immunoresistant TME. Full article

Background: Recurrent and metastatic head and neck squamous cell carcinoma (R/M HNSCC) after immune checkpoint inhibitor (ICI) progression represents a major clinical challenge. Between 60 and 80% of patients develop resistance, and historical salvage regimens like cytotoxic chemotherapy or chemotherapy plus cetuximab rarely extend median overall survival (mOS) beyond one year. Scope of Review: This review examines systemic therapies evaluated specifically in the post-ICI setting, emphasizing agents advancing to Phase II and III trials. Classes include chemotherapy combinations, ICI-based approaches, small-molecule targeted combinations, bispecific antibodies, antibody-drug conjugates (ADCs), and next-generation vaccines. Results: Promising signals have emerged across multiple therapeutic modalities. Targeted combination strategies have demonstrated encouraging response rates and survival outcomes in difficult-to-treat, PD-1-resistant disease. Antibody-based platforms, including antibody-drug conjugates and bispecific antibodies, continue to show consistent clinical activity across diverse patient populations, offering disease control and prolonged survival. Novel immunotherapies and therapeutic vaccines are also generating durable responses, particularly in biologically defined subgroups, highlighting the potential of immune-based precision treatments in R/M HNSCC. Conclusions: Comparative analysis highlights distinct advantages and limitations: chemotherapy ensures rapid shrinkage but poor durability; biomarker-driven small molecules achieve strong survival gains in narrow niches; ADCs and bispecifics offer balanced efficacy in unselected patients; and vaccine platforms deliver durable benefit in defined subsets. Together, these data signal a paradigm shift toward biomarker-guided, mechanism-driven strategies as the path to closing the post-ICI therapeutic gap in R/M HNSCC. Full article

Background: Head and neck carcinomas represent a heterogeneous group of aggressive malignancies with often poor prognosis and high recurrence rates. In recent years, the identification and characterization of cancer stem cells (CSCs) within these tumors have profoundly reshaped our understanding of tumorigenesis, resistance mechanisms, and metastatic potential in this anatomical district. Cancer stem cells (CSCs) play a central role in therapeutic resistance, recurrence, and metastatic progression in head and neck squamous cell carcinoma (HNSCC), particularly within the anatomically complex maxillofacial region. This review has synthesized recent advances in CSC biology, including marker heterogeneity, stemness-associated pathways, and interactions with the tumor microenvironment. Methods: A narrative review of the available literature was conducted, focusing on studies dealing with cancer stem cells in head and neck carcinoma and their implications for maxillofacial surgery. Results: We have critically examined emerging systemic and locoregional CSC-targeted therapies, highlighting inhibitors of Notch, Wnt/β-catenin, Hedgehog, and Hippo/YAP pathways, ALDH and ABC transporter inhibitors, autophagy modulators, nanoparticle-based delivery systems, and CSC-directed immunotherapies. The implications of these approaches for surgical planning, resection margins, and postoperative disease control in maxillofacial oncology have been discussed. To enhance clarity and analytical value, we have incorporated two comprehensive tables summarizing CSC markers and therapeutic strategies. Collectively, the evidence indicates that integrating CSC-oriented diagnostics and therapeutics into multimodal management may improve long-term outcomes for patients with maxillofacial HNSCC. Conclusions: This review highlights the critical need for integrating CSC-focused research into clinical practice to develop more effective, personalized, and durable treatment strategies. Such an approach could enhance oncologic control, reduce recurrence, and improve functional outcomes for patients undergoing complex oncologic procedures in the maxillofacial region. Full article

Background/Objectives: Functional p53 is critical for anti-tumor activity of mitomycin-C. In wild-type TP53 human papillomavirus (HPV)-positive squamous cell carcinoma (SCC) cell lines, mitomycin-C repressed E6 oncoprotein expression and induced p53, p21, and Bax, resulting in apoptosis. In mutant TP53 HPV-negative SCC cell lines, mitomycin-C was inactive. The primary aim of this trial was to determine the objective response rate (ORR) with mitomycin-C among patients with HPV-positive (cohort A) and HPV-negative (cohort B) platinum-refractory, recurrent or metastatic head and neck SCC (RM-HNSCC). Methods: Patients with platinum-refractory RM-HNSCC received mitomycin-C (10 mg/m² on day one every five weeks) until discontinuation criteria were met. Tumor response was assessed by RECIST1.1. We hypothesized an ORR of ≥30% (H₁) with mitomycin-C (vs. H₀ ORR of ≤10%). Using a two-stage Simon phase 2 design for each cohort, 2 or more responses among 12 evaluable patients were required to enroll 23 additional patients. H₁ was accepted if 6 or more responses occurred among 35 evaluable patients (power 0.90; one-sided α = 0.10). Results: Forty-seven patients were treated with mitomycin-C: 34 in cohort A and 13 in cohort B. Tumor response occurred in 3 of 33 evaluable patients in cohort A (ORR 9.1%, 95%CI: 0–19.4) and in 0 of 12 evaluable patients in cohort B. The duration of tumor responses in cohort A was 2.3, 2.5, and 4.5 months. The most common treatment-related AEs of any grade were anemia (96%), fatigue (62%), and thrombocytopenia (40%). No treatment-related deaths occurred. Conclusions: Mitomycin-C had limited activity in HPV-positive, and no activity in HPV-negative, platinum-refractory RM-HNSCC. Full article

Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCC) represent a distinct subgroup of head and neck squamous cell carcinoma (HNSCC) characterized by better prognosis and increased radiosensitivity compared to HPV-negative OPSCC. However, current diagnostic and monitoring methods, including tissue biopsies and imaging, are insufficient for precise risk stratification and early detection of recurrence, leading to challenges in treatment de-escalation and surveillance strategies. Circulating tumor HPV DNA (ctHPV-DNA) has emerged as a promising minimally invasive biomarker that offers tumor-specific detection and monitoring capabilities, potentially transforming the management of HPV-related OPSCC through early disease detection, treatment response assessment, recurrence surveillance stratification, and disease monitoring. Despite encouraging results from early clinical studies, current use is limited to trial settings. Large-scale prospective studies are needed to validate its clinical utility and determine whether early ctHPV-DNA testing can improve patient outcome while reducing treatment related morbidity. This review outlines the biological rationale, technological approaches, and current clinical evidence for ctHPV-DNA in HPV-related OPSCC, emphasizing its potential role in treatment monitoring and surveillance. Full article

Head and neck squamous cell carcinoma (HNSCC) is often diagnosed at advanced stages. Due to pronounced intratumoral heterogeneity (ITH), reliable risk stratification and prediction of treatment response remain challenging. This study aimed to identify peptide signatures in HNSCC tissue that are associated with treatment outcomes in HPV-negative, advanced-stage HNSCC patients undergoing 5-fluorouracil/platinum-based chemoradiotherapy (CDDP-CRT). We integrated matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) of tryptic peptides with univariate statistics and machine learning approaches to uncover potential prognostic patterns. Formalin-fixed, paraffin-embedded whole tumor sections from 31 treatment-naive, HPV-negative HNSCC patients were digested in situ with trypsin, and the generated peptides were analyzed using MALDI-MSI. Clinical follow-up revealed recurrence or progression (RecPro) in 20 patients, while 11 patients showed no evidence of disease (NED). Classification models were developed based on the recorded peptide profiles using both unrestricted and feature-restricted approaches, employing either the full set of m/z features or a subset of the most discriminatory m/z features, respectively. The unrestricted model achieved a balanced accuracy of 71% at the patient level (75% sensitivity, 66% specificity), whereas the feature-restricted model reached a balanced accuracy of 72%, showing increased specificity (92%) but reduced sensitivity (52%) in the CDDP-CRT cohort. In order to assess treatment specificity, models trained on the CDDP-CRT cohort were tested on an independent patient cohort treated with mitomycin C-based CRT (MMC-CRT). Neither model demonstrated prognostic performance in the MMC-CRT patient cohort, suggesting specificity for platinum-based therapy. Presented findings highlight the potential of MALDI-MSI–based proteomic profiling to identify patients at elevated risk of recurrence following CDDP-CRT. This approach may support more personalized risk assessment and treatment planning, ultimately contributing to improved therapeutic outcomes in HPV-negative HNSCC. Full article

Fanconi anemia (FA) is a genetic disorder characterized by congenital anomalies, bone marrow failure, and cancer predisposition. Among other solid cancers, head and neck squamous cell carcinoma (FA HNSCC) is the most common cancer type in individuals with FA. The FA pathway is required for the complete repair of DNA interstrand crosslinks (ICLs), and unresolved ICLs result in cell cycle arrest, apoptosis, or complex chromosomal rearrangements due to chromosome breaks, ultimately leading to tumorigenesis. FA HNSCCs present earlier (median age of onset in the 30s) and exhibit a more aggressive course with frequent recurrence and second primaries, and entail a poorer survival rate compared to sporadic HNSCC. FA HNSCCs are mostly human papillomavirus (HPV)-negative and frequently carry somatic copy number variations (CNVs), which amplify oncogenes implicated in sporadic HNSCC, but single-nucleotide variants or small insertions and deletions are less frequent than in HPV-negative sporadic HNSCC. A subset of sporadic HNSCC carries pathogenic mutations or promoter methylation in FA genes, which also harbor characteristic somatic CNVs, suggesting shared molecular underpinnings with FA HNSCC. Heightened inflammation from genomic instability and transcriptional activation of retrotransposons contribute to tumorigenesis and increased invasiveness by the epithelial-to-mesenchymal transition. Due to heightened sensitivity to DNA crosslinking agents in patients with FA, platinum-based chemotherapy is generally avoided, which presents a significant hurdle for treatment and thereby leaves limited therapeutic options. Surgical management is the mainstay of therapy if possible, and targeted therapy has been increasingly studied in HNSCC in FA. Full article

The survival rate of patients with advanced laryngeal cancer has not substantially improved over time. RNA sequencing analysis identified Keratin-1 (KRT1) as a gene potentially associated with cancer recurrence. This study investigated the association between KRT1 expression and recurrence in advanced laryngeal cancer. RNA sequencing was performed to identify candidate genes associated with recurrence. The effects of KRT1 expression on clinical outcomes were evaluated in patients with laryngeal cancer. Multiple experimental techniques were utilized. RNA sequencing of patient samples demonstrated higher KRT1 gene expression in the recurrence group than in non-recurrent cases. Patients with KRT1-positive immunostaining exhibited trends of worse overall survival (OS) and recurrence-free survival (RFS). In vitro studies showed that KRT1 knockdown suppressed tumor cell invasion, cell migration, and expression of epithelial–mesenchymal transition (EMT)-related genes in human head and neck squamous cell carcinoma (HNSCC) cell lines. KRT1 knockdown enhanced tumor cell apoptosis and exhibited synergistic effects with conventional radiation and chemotherapy treatments. KRT1 may serve as a biomarker for predicting advanced laryngeal cancer recurrence and assist with selecting patients to receive concurrent chemoradiotherapy (CCRT). Further molecular investigations are warranted to determine its effects, but KRT1 has potential as a therapeutic target. Full article

Immune checkpoint inhibitors (ICIs) have transformed the landscape of cancer therapy by reactivating immune surveillance mechanisms against tumor cells. In the context of oral squamous cell carcinoma (OSCC) and broader head and neck squamous cell carcinoma (HNSCC), agents such as pembrolizumab, durvalumab, and ipilimumab target PD-1, PD-L1, and CTLA-4, respectively. This review comprehensively examines their clinical efficacy, safety profiles, mechanisms of action, and therapeutic potential in OSCC management, with an emphasis on strategies to overcome therapeutic resistance. A systematic analysis of the literature was conducted, focusing on clinical outcomes, ongoing trials, and emerging combination therapies. Pembrolizumab has demonstrated significant improvements in overall survival (OS) and progression-free survival (PFS) in OSCC patients. Durvalumab, mainly utilized in locally advanced or recurrent disease, has shown survival benefit, particularly in combination or maintenance settings. Ipilimumab exhibits durable responses in advanced OSCC, with enhanced efficacy observed when used alongside nivolumab in dual checkpoint blockade regimens. Although both pembrolizumab and nivolumab target PD-1, they differ in clinical indications and regulatory approvals. Notably, ICIs are associated with immune-related adverse events (irAEs), requiring careful monitoring. Collectively, these agents represent promising therapeutic options in oral cancer, though future studies must prioritize the identification of predictive biomarkers and the development of optimized combination strategies to maximize therapeutic benefit while minimizing toxicity. Full article

Background/Objectives: This single-cohort follow-up study describes the median overall survival (OS) in patients with unresectable head and neck squamous cell carcinoma (HNSCC) due to invasion of vital structures, which is under-represented in the current literature. Secondarily, subgroups were evaluated according to the type of presentation, in order to identify clinical characteristics and contribute to developing an appropriate treatment plan and managing patient’s expectations. Methods: This single-cohort observational study analysed the OS of 39 patients from the Otolaryngology Department with advanced-stage head and neck cancer with invasion of vital anatomical structures considered ineligible for surgical treatment. Secondarily, subgroups were evaluated according to type of presentation and various clinical characteristics. Results: A total of 39 patients radiologically classified as having unresectable HNSCC (i.e., unsuitable for surgical resection), with a mean age of 66.87 years, were included during a 24-month follow-up. By the end of the study, 56.4% of the patients had died. The median OS was 16.09 months. Statistically significant differences were observed when comparing human papilloma virus (HPV)-positive and -negative status and when comparing initial and recurrent tumours. Conclusions: The invasion of anatomical structures such as the skull base, internal carotid artery, and prevertebral space was associated with a marked decrease in survival, with an OS time of 16 months. This study provides valuable evidence in patients with unresectable HNSCC, highlighting tumour recurrence and HPV-negative status as important indicators of poor prognosis. Full article

Head and neck squamous cell carcinomas (HNSCCs) that develop from the mucosal epithelium in the oral cavity, pharynx, and larynx are a heterogeneous group of malignant tumors. A lack of appropriate screening and diagnostic methods leads to late diagnoses, with the majority of patients having locally advanced disease, which is associated with a high risk of local recurrence and a poor prognosis and is usually treated with combination therapies. Biomarkers for predicting the therapy response and risk of recurrence in HNSCC patients are urgently needed. Liquid biopsy, e.g., the profiling of circulating biomarkers in bodily fluids, is a promising approach with increasing utility in the early detection and diagnosis of cancer, monitoring cancer progression, patient stratification and treatment selection, detecting minimal residual disease (MRD), and predicting recurrence across different cancer types, including HNSCC. Among liquid biomarkers, circulating tumor DNA (ctDNA), which is based on detecting tumor-specific mutations, insertions/deletions, copy number alterations, and methylation, is the most promising transformative tool in cancer management and personalized cancer treatment. In this review, we provide an update of recent data on the role of non-viral ctDNA in the management of HNSCC patients. Accumulating data suggests the enormous potential of ctDNA profiling by serial sampling during and after definitive therapy in detecting MRD and predicting recurrence in HNSSC patients treated with a single treatment modality (surgery or radiotherapy) or with combination therapies, including immune-checkpoint-inhibitor-based immunotherapy. By incorporating the latest immunotherapy trials and organizing the data by the treatment modality, this review offers a novel perspective not found in previous surveys. Full article

Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous malignancy characterized by a complex tumor microenvironment (TME) that plays a critical role in disease progression and therapeutic resistance. Tumor-infiltrating immune cells, including T lymphocytes, macrophages, dendritic cells, and myeloid-derived suppressor cells, exhibit dual functions, either promoting or suppressing tumor growth depending on their phenotype and interactions within the TME. The presence of immune evasion mechanisms, such as the loss of human leukocyte antigen (HLA) expression, upregulation of immune checkpoint molecules, and metabolic reprogramming (hypoxia-induced glycolysis and lactate accumulation), further contributes to immune suppression and poor treatment responses. While immune checkpoint inhibitors (ICIs) have revolutionized the treatment of recurrent/metastatic HNSCC, response rates remain highly variable, underscoring the need for biomarker-driven patient selection and combinatorial therapeutic strategies. This review provides a comprehensive analysis of the role of immune cells in the TME of HNSCC, discusses the mechanisms underlying immune escape, and explores emerging immunotherapeutic and epigenetic-targeting approaches aimed at enhancing antitumor immune responses and improving clinical outcomes. Full article

Head and neck squamous cell carcinoma (HNSCC) remains challenging to treat despite multimodal therapeutic approaches. Cisplatin treatment is effective and cost-efficient, although chemoresistance and disease recurrence limit its efficacy. Understanding the mechanisms of cisplatin resistance and the identification of compounds to target resistant tumor cells are critical for improving patient outcomes. We have demonstrated that cisplatin-induced senescent HN30 HNSCC cells can be eliminated by ABT-263 (navitoclax), a BCL-2/BCL-X_L inhibitor that has senolytic properties. Here, we report the development of a cisplatin-resistant cell line (HN30R) for the testing of ABT-263 and the PROTAC BET degraders ARV-825 and ARV-771. ABT-263 was ineffective in sensitizing HN30R cells to cisplatin, largely due to a lack of senescence induction. However, the BET degraders in combination with cisplatin promoted apoptotic cell death in both HN30 and HN30R cells. The effectiveness of ARV-825 did not appear to depend on the cells entering into senescence, indicating that it was not acting as a conventional senolytic. ARV-825 treatment downregulated BRD4 and its downstream targets, c-Myc and Survivin, as well as decreased the expression of RAD51, a DNA repair marker. These results suggest that the BET degraders ARV-825 and ARV-771 may be effective in improving the response of chemoresistant head and neck cancer to cisplatin treatment. Full article