Search Results (3,141)

Head and neck squamous cell carcinoma (HNSCC) remains a significant global health burden with limited survival improvement in locally advanced disease despite multimodal therapy. Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway have demonstrated substantial clinical benefit in recurrent or metastatic HNSCC, establishing PD-1 blockade as a standard of care. Similar approaches in locally advanced disease, including concurrent administration with chemoradiotherapy or use in the adjuvant setting, have not demonstrated improvement in survival outcomes across multiple randomized trials. Perioperative strategies incorporating neoadjuvant and adjuvant checkpoint inhibition have shown improved event-free and disease-free survival in resectable disease. Meta-analyses of concurrent and adjuvant approaches confirm limited benefit in unselected populations, with modest improvements restricted to biologically defined subgroups. Trial outcomes across disease settings demonstrate a consistent pattern in which therapeutic efficacy varies despite the use of similar agents. Rather than simply summarizing these clinical findings, this review integrates evidence across recurrent/metatstatic, unresected locally advanced and perioperative disease settings into a biologically focused framework to help explain the varying efficacies of immune checkpoint inhibition in HNSCC. Current evidence indicates that the effectiveness of immunotherapy in HNSCC is determined by the biologic context of treatment, including tumor antigen availability, host immune competence, and timing of immune activation. Administration of checkpoint blockade in the presence of intact tumor antigen and preserved immune function is associated with improved outcomes, whereas treatment delivered during or after cytotoxic therapy is limited by lymphopenia and reduced antigen exposure. By synthesizing randomized clinical evidence through this biologic framework, the review provides a conceptual perspective that may help explain previous trial outcomes and inform future biomarker-driven patient selection and treatment sequencing. Optimization of immunotherapy in HNSCC will depend on the integration of immune activation with disease context rather than an escalation of therapeutic intensity. Full article

The aim of this systematic survey was to evaluate the quality of clinical practice guidelines (CPGs) that provide recommendations for the detection, diagnosis, and treatment of oral cavity cancer (OCC). We conducted a systematic search in MEDLINE, EMBASE, Epistemonikos, CPG websites, and scientific societies to identify documents providing recommendations for the detection, diagnosis, and treatment of OCC. Two reviewers independently assessed the included CPGs using the AGREE II instrument. We calculated standardized scores for the six domains and provided a final recommendation for each CPG. We identified twenty-five CPGs published between 2019 and 2024. The mean scores (higher scores indicate better domain assessment) per domain were as follows: scope and purpose, 80.5 ± 11.6%; stakeholder involvement, 55.6 ± 16.7%; rigor of development, 48.3 ± 20.1%; clarity of presentation, 83.8 ± 8.2%; applicability, 33.6 ± 19.1%; and editorial independence, 57.3 ± 22.4%. The overall mean rate was 4.8 ± 0.8, with a maximum score of seven. Reviewers recommended five guidelines for use in practice, twelve were recommended with modifications, and eight were not recommended. The overall quality of CPGs on OCC was suboptimal. CPG developers should strengthen the use of systematic, transparent methodologies and frameworks for evidence synthesis and recommendation formulation, thereby improving the quality of recommendations and facilitating implementation across diverse clinical contexts. Full article

Introduction: The ecto-endodermal boundary in the human oral cavity remains debated. Rather than a distinct line, this transition forms a complex interface, especially in the developing mouth and pharynx. This ambiguity is clinically relevant, as, for example, HPV-induced tumors often arise where ecto- and endoderm meet. The boundary is generally placed at the posterior third of the tongue and behind the uvula, though its developmental basis remains unclear. This review summarizes the literature on the embryological development of the mouth and pharynx to trace origins and interactions of ectodermal and endodermal derivatives and identify potential tumor initiation regions. Methods: PubMed articles on oral structures were reviewed to approximate the ecto-endodermal border. Results: Teeth originate from ectoderm. The origin of salivary glands and papillae depends on their location. No study reports were found for the tonsils, incisive papilla, tubarial glands, and faucial pillars. Conclusions: A clear educational image of the origin of the structures of the human mouth is made to help identify regions of risk for oral cancer. Full article

Malondialdehyde (MDA) is one of the main end-products of lipid peroxidation (LPO) and represents a widely investigated marker of oxidative stress (OS) and oxidative tissue damage. Beyond its role as a measurable byproduct of polyunsaturated fatty acid peroxidation, MDA can interact with proteins and nucleic acids, generating adducts that may contribute to mutagenic, genotoxic, and cytotoxic events involved in carcinogenesis and tumor progression. This narrative review summarizes current evidence on the role of MDA in cancers, including breast, lung, head and neck, colorectal, cervical, and cutaneous tumors. Across these cancer types, increased circulating or tissue MDA levels have frequently been associated with enhanced LPO, impaired antioxidant defenses, tumor burden, advanced disease stage, aggressive histopathological features, treatment-related oxidative injury, and, in selected studies, poorer clinical outcomes. MDA-derived DNA adducts may further reflect oxidative DNA damage and provide mechanistic insight into the relationship between chronic redox imbalance, inflammation, and malignant transformation. However, MDA remains a non-specific biomarker influenced by age, smoking, diet, metabolic disorders, systemic inflammation, comorbidities, treatment exposure, and analytical methodology. Current evidence therefore supports MDA as a biologically relevant indicator of oxidative damage rather than a validated stand-alone diagnostic, prognostic, or therapeutic biomarker. Larger prospective studies using standardized and specific analytical methods are needed to clarify its clinical utility and to integrate MDA within broader redox biomarker panels. Full article

This retrospective study characterizes the complex associations between serum 1H-NMR metabolomics, clinical nutritional status, and laboratory blood parameters in men with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) in relation to 3-year disease-free survival (DFS). A total of 536 serum samples from 67 patients, collected weekly during radiotherapy or chemoradiotherapy, were analyzed to characterize the metabolic-nutritional landscape. The patients with 3-year DFS exhibited stronger biological links between elevated levels of serum lipids, phosphocholine, branched-chain amino acids (BCAAs), and clinical markers such as BMI, albumin, and prealbumin compared to those with disease recurrence. Furthermore, our findings highlight a novel pattern of disrupted correlations (metabolic decoupling) between body fat distribution, overall obesity, and lipid metabolism, as well as the links between BCAAs and nutritional status, in patients with disease recurrence. This observed breakdown of internal coordination suggests that the survival advantage associated with body fat arises not just from adiposity, but from the body’s ability to metabolically coordinate fat and amino acid turnover with overall energy demands—a trait known as metabolic flexibility. In conclusion, we hypothesize that disease recurrence in men with LA-HNSCC is driven by failure of this system, manifested as a breakdown in the coordination between metabolic and nutritional profiles. The preserved metabolic-nutritional axis between fat turnover and nutrient availability is associated with 3-year disease-free survival in this patient group, although more research is required to fully elucidate the underlying mechanisms. Full article

APG157DS is a multi-component investigational drug which is currently the subject of multiple cancer trials. It has shown promising efficacy in patients with head and neck cancer. We report its immuno-modulatory effect in a syngeneic mouse model of glioblastoma (GBM). Long-term treatment with APG157DS led to durable tumor remission in 50% of mice, while all vehicle-treated mice reached humane endpoints within 42 days. Mechanistically, the drug induced selective repolarization of tumor-associated macrophages (TAMs) from an immunosuppressive Arg1^high/iNOS^low phenotype to a tumoricidal Arg1^low/iNOS^high state, accompanied by increased intratumoral recruitment of activated (NKp46+) natural killer cells and CD8+ cytotoxic T-cells. APG157DS also suppressed vascular endothelial growth factor (VEGF) and Hypoxia-inducible factor 1-alpha (HIF-1α) expression in tumors, further impairing tumor growth. Notably, APG157DS did not elicit off-target macrophage activation in peripheral tissues such as the spleen, highlighting its selective immune targeting. These findings provide a mechanistic rationale for further clinical development of APG157DS in GBM and potentially other immune-evasive cancers. Full article

Virus-based cancer therapy (virotherapy) is currently being researched as a novel form of immunotherapy and has already entered the clinical application phase. Among various types of virotherapy, oncolytic virotherapy involves infecting tumors with tumor-selective viruses, such as herpes simplex virus, adenoviruses, and vaccinia virus, and utilizing their replicative capacity to induce cell destruction within tumors. In addition, this therapy aims to enhance tumor immunity by changing the tumor microenvironment through viral infection. Genetic deletion in viruses is used to reduce their virulence and confer tumor selectivity, while the expression of foreign genes is utilized to enhance antitumor effects. Oncolytic viruses for head and neck cancer (HNC) are administered locally or systemically and are sometimes used as adjuvant therapy or in combination with immune checkpoint inhibitors. Another form of virotherapy involves non-replicating viruses, which are used to produce antitumor cytokines or as cancer vaccines expressing tumor antigens. Research on the efficacy of cancer vaccines in preventing postoperative recurrence is currently underway. A number of challenges have yet to be overcome for further advances in virotherapy, including the efficient delivery of viruses to tumor cells, avoiding viral inactivation in the bloodstream, ensuring efficient replication of the virus, and enhancing antitumor immunity. The development of effective strategies based on the findings of clinical studies will lead to improvements in virotherapy for HNC. Full article

Background/Objectives: Individualized treatment selection for head and neck cancer requires survival models that use routine clinical variables while accounting for censored time-to-event outcomes. This study developed an interpretable Cox proportional hazards baseline and a DeepSurv framework to estimate mortality risk and explore treatment-specific predictions among radiotherapy-based options. Methods: Clinical data were obtained from the RADCURE collection in The Cancer Imaging Archive. After preprocessing, stage harmonization, exclusion of sparse treatment categories, missing-data assessment, one-hot encoding, and standardization, 3266 patients were analyzed. Cox regression and DeepSurv were evaluated using a held-out 80%/20% split, paired bootstrap confidence intervals for C-index differences, and five-fold cross-validation. For treatment recommendation, treatment modality was hypothetically varied across radiotherapy alone, chemoradiotherapy, and radiotherapy plus epidermal growth factor receptor inhibitor while other covariates were held fixed. Results: On the held-out test set, Cox achieved a C-index of 0.684 and DeepSurv achieved a C-index of 0.695. The absolute difference was 0.011, with a paired bootstrap 95% CI of −0.010 to 0.030, indicating no statistically significant improvement. Five-fold cross-validation showed mean C-index values of 0.688 for Cox and 0.707 for DeepSurv. Cox regression identified older age and advanced tumor stage as higher-risk factors, whereas former and non-smoking status were associated with lower hazard than current smoking. Conclusions: DeepSurv provided only a modest numerical gain over the Cox baseline. The recommendation framework illustrates how survival models can generate treatment-specific risk estimates, but these outputs should be interpreted as decision-support signals rather than causal treatment effects. External validation and prospective evaluation are needed before clinical use. Full article

Head and neck cancer (HNC) comprises a heterogeneous group of tumours, most often of squamous cell origin, characterized by both high morbidity and mortality rates. It is the seventh most common form of cancer diagnosed in humans, accounting for approximately 4.7% of all cancers. Among HNCs, neck squamous cell carcinoma (HNSCC) is predicted to become the most common form of human cancer. Some sources include oesophagus (ESCC) in this group due to their similar histology, being described as upper aerodigestive tract cancers (UADT). Unfortunately, 60–70% of cases are diagnosed late, i.e., at clinical stages III-IV. As a result, despite modern surgical techniques and oncological treatments, the survival rate remains below 40–60% due to frequent lymph node metastases and local tumour recurrence. There is a growing concern that diet and inflammatory dietary components may influence the initiation and development of HNSCC. The inflammatory potential of diets can be quantified by the Dietary Inflammatory Index (DII). The DII was derived from an analysis of 45 dietary constituents that either increase or decrease inflammation. Several recent clinical studies have noted a significant relationship between DII score and many inflammation-associated chronic diseases, such as obesity, cardiovascular and neurodegenerative disorders, and diabetes, and the incidence of various human cancers, i.e., prostate, ovarian, breast, colorectal cancer, and HNC. However, few studies have investigated the relationship between DII and HNSCC, with most being limited to observational, case-control, and cross-sectional studies. Therefore, the aim of this narrative review is to present the substantial oncological aspects of DII, discuss the use of DII and its modification, the Energy-Adjusted Dietary Inflammatory Index (E-DII), as indicators of HNSCC risk. It also introduces key diet-induced pro- and anti-inflammatory mechanisms and the cellular molecular signalling pathways determining the carcinogenesis of HNSCC. It provides a comprehensive overview of the current literature, including key opinion-forming systematic reviews, as well as molecular, observational, cross-sectional and case-control studies, all of which are accessible via scholarly databases such as PubMed/EMBASE/Web of Science. Thus, the work serves as a compendium of up-to-date knowledge on the relationship between DII/ED-II score and HNSCC etiopathogenesis and the influence of a diet-induced persistent inflammatory microenvironment. Full article

Background/Objectives: To evaluate whether automated three-dimensional volumetric body composition metrics from the Body and Organ Analysis (BOA) algorithm provide prognostic information beyond body mass index (BMI) for overall survival (OS) in surgically treated head and neck squamous cell carcinoma (HNSCC), and to compare cervical (C1–C7) measurements with thoracic and abdominal regional comparators. Methods: This single-center retrospective cohort study included 391 surgically treated HNSCC patients (2010–2019). Pretreatment CT scans were processed using the open-source BOA algorithm to obtain volumetric muscle, bone, and adipose measurements across cervical (C1–C7), thoracic, and abdominal regions. Composite indices—Sarcopenia Index (SI = Muscle/Bone) and Myosteatotic Fat Index (MFI = IMAT/TAT)—were derived; Cerv SI denotes the volumetric C1–C7 ratio. The predefined primary Cox model adjusted for age, sex, tumor site, UICC stage, treatment, HN-CCI, and secondary malignancy. Results: Of 391 patients (91% male, median follow-up 5.0 years, 141 deaths), BMI was not independently associated with OS (HR 0.88, p = 0.15). Cerv SI was associated with OS in the minimally adjusted model (HR 0.71, 95% CI 0.58–0.88, p = 0.002) and remained independent in the primary clinically adjusted model (HR 0.72, 95% CI 0.58–0.90, p = 0.004; C-index 0.67). When BMI and Cerv SI were entered together, Cerv SI remained independently associated (HR 0.72, p = 0.006) while BMI was null (HR 1.01, p = 0.95). Conclusions: BOA-derived cervical volumetric body composition is associated with overall survival beyond BMI and is obtainable from routine head and neck CT. Prospective validation and comparison with established two-dimensional C3/L3 methods are warranted before clinical use. Full article

Oral squamous cell carcinoma (OSCC) accounts for most head-and-neck cancers, and effective biological adjuvants remain limited. Gingival mesenchymal stem cells (GMSCs) exhibit anti-tumour paracrine activity, but the underlying molecular mechanisms and their relevance in patient cohorts remain incompletely understood. Consensus apoptosis–reactive oxygen species (ROS) effectors were identified through integrated transcriptomic analyses of TCGA-HNSC and three GEO cohorts. Candidate genes were evaluated in primary OSCC cells exposed to GMSC-conditioned medium or indirect Transwell co-culture. Findings were further examined using patient-cohort validation, single-cell ligand–receptor analysis, pathway and transcription-factor activity inference, and drug-repurposing approaches. Computational analyses identified an apoptosis–ROS network centred on BAX, BCL2, CASP3, CASP9, NOX1, and GPX1. Indirect GMSC co-culture reduced intracellular ROS, increased early apoptosis, and induced G2/M accumulation, whereas conditioned medium produced inconsistent effects, suggesting a requirement for live bidirectional paracrine signalling. BAX was the only consistently up-regulated effector. The axis demonstrated concordant differential expression across independent HPV-negative OSCC cohorts but was not independently prognostic under leakage-free cross-validation or external validation. Pathway analyses supported ROS suppression, apoptosis activation, and altered stromal–tumour communication. Drug-repurposing analyses identified HSP90 inhibitors and the FDA-approved TOP2 inhibitor mitoxantrone as candidate therapeutic agents. GMSC paracrine activity targets a biologically interpretable apoptosis–ROS axis in OSCC that is reproducibly expressed across patient cohorts but does not constitute an independent prognostic biomarker. The identified therapeutic candidates warrant further experimental investigation. Full article

Background: Head and neck squamous cell carcinoma (HNSCC) remains a major global health challenge due to the lack of effective and non-invasive diagnostic tools, often resulting in late-stage detection of cancer. Small extracellular vesicles (sEVs) have emerged as promising biomarkers for early cancer detection and disease monitoring due to their omnipresence and stability in bodily fluids, such as blood plasma. In addition, cancer-derived sEVs specifically carry cargo reflective of oncogene-derived molecular alterations. In summary, these characteristics position sEVs as a potential platform for non-invasive testing of HNSCC. Methods: Plasma-derived sEVs from HNSCC patients (n = 71) and benign subjects (n = 25) were isolated using size exclusion chromatography. Proteomic profiling via liquid chromatography-tandem mass spectrometry identified potential candidate biomarkers, followed by ELISA validation. Results: Proteomic analyses revealed a significant enrichment of multiple proteins in HNSCC-derived sEVs compared to sEVs derived from non-cancer individuals. The von Willebrand factor (vWF) was significantly higher in HNSCC patient-derived sEVs compared to those derived from benign individuals. A validation cohort confirmed that sEV-associated vWF (sEV-vWF) effectively distinguished HNSCC patients from benign subjects, demonstrating strong diagnostic performance, specifically in laryngeal HNSCC (AUC = 0.82) and oropharyngeal HNSCC (AUC = 0.96) patient cohorts. Moreover, postoperative reductions and recurrence-associated increases in sEV-vWF levels corresponded with clinical outcomes, indicating its potential as a dynamic disease indicator. Conclusions: These findings highlight sEV-vWF as a novel and non-invasive biomarker with potential applications in early detection and real-time monitoring of HNSCC, supporting advancement toward precision liquid biopsy strategies in head and neck oncology. Full article

Perineural invasion (PNI) is a distinct route of cancer spread associated with neuropathic pain, local recurrence, and poor survival across many solid tumours. Increasing evidence shows that PNI is not only a structural pattern of invasion but also a dynamic biological process involving neurodegeneration, nociceptor sensitisation, and marked local immunosuppression. This narrative review synthesises experimental, translational, and clinical data on the molecular, neurological, and immunological mechanisms of PNI in solid malignancies. PNI arises through complex crosstalk between tumour cells, Schwann cells, macrophages, fibroblasts, and neurotrophic pathways, leading to peripheral nerve remodelling, axonal degeneration, and abnormal regeneration. These changes promote neuropathic pain through ion-channel dysregulation, neurotrophin-driven sensitisation, and pathological neuroplasticity. At the same time, PNI creates an immunosuppressive microenvironment enriched in Tregs, M2 macrophages, and myeloid-derived suppressor cells, shaped by cholinergic, adrenergic, and neuropeptidergic signalling, which may contribute to immune exclusion and resistance to immunotherapy. We propose that PNI should be understood as a neuro-immuno-metabolic process and that recognising the PNI–pain–immunosuppression triad may support the development of targeted neuroprotective, analgesic, and immunomodulatory therapies. Full article

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer of the oral cavity, pharynx, larynx and upper airway. HNSCC is subdivided into distinct clinical entities based on the presence or absence of high-risk human papillomavirus (HPV) infection. While HPV-positive HNSCC patients respond better to conventional and targeted therapies than HPV-negative cases, recurrence is more frequent in HPV-negative cases with limited treatment options. Ferroptosis is a form of iron-based programmed cell death caused by excessive lipid peroxide accumulation. Biomarkers of ferroptosis have proven useful for identifying and triggering ferroptosis in models of treatment-resistant cancers. Identifying and understanding ferroptosis biomarker function in HPV-negative HNSCC allows the possibility for more effective treatment strategies. Methods: Literature searches combined with the public online ferroptosis database FerrDB V3 were utilized for the objective identification and classification of established and non-established ferroptosis biomarkers in HPV-negative HNSCC. Additional novel biomarkers were identified based on known roles in HNSCC oncogenesis. Results: A total of 30 ferroptosis biomarkers were identified associated with HPV-negative disease. Biomarkers were grouped according to shared biological functions, with each marker summarized for prognostic and mechanistic roles in HNSCC ferroptosis. Conclusions: The described biomarkers present a means for stratifying tumors for ferroptotic induction, with several offering potential novel methods for overcoming refractory HPV-negative disease. These biomarkers may warrant further investigation into devising future patient-tolerant strategies that selectively activate ferroptosis in HPV-negative HNSCC. Full article

Background and Objectives: Head and neck cancer in patients aged 40 years or younger represents a rare and heterogeneous entity with conflicting data regarding prognosis and risk factors. This study aimed to evaluate oncological outcomes and independent prognostic factors in young patients treated with radio(chemo)therapy. Materials and Methods: This retrospective multi-center analysis included patients aged ≤ 40 years with histologically confirmed HNC who received definitive or adjuvant radio(chemo)therapy between 2002 and 2023 at the University Hospital Regensburg and affiliated partner hospitals. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method. Independent prognostic factors were identified by Cox proportional hazard regression with backward stepwise elimination. Results: A total of 88 patients were included. The median age at diagnosis was 38.2 years (IQR 35.8–39.8). Median OS was 91.0 months in the adjuvant and 23.7 months in the definitive treatment group. In multivariate analysis, four independent predictors of OS were identified: nicotine abuse (HR 2.887; p = 0.004), pre-existing comorbidities (HR 2.871; p = 0.005), absence of complete remission 12 weeks after radiotherapy (HR 25.676; p < 0.001), and locoregional recurrence or distant metastases (HR 8.183; p < 0.001). Failure to achieve complete remission was the sole independent predictor of PFS (HR 4.479; p < 0.001). Conclusions: In young HNC patients, early treatment response and disease recurrence are the strongest determinants of survival, alongside modifiable lifestyle factors and comorbidity burden. These findings support the need for intensified response monitoring and tailored follow-up strategies in this patient population. Full article