Search Results (1,759)

Background/Objectives: Immune exclusion in head and neck squamous cell carcinoma (HNSCC) limits immunotherapy efficacy, yet the molecular determinants of stromal-immune organization remain incompletely characterized. The desmosomal cadherin DSG2 is highly expressed in squamous epithelium; its role in shaping the tumor microenvironment (TME) is unknown. Methods: We integrated bulk RNA-seq from 836 HNSCC patients (TCGA-HNSC n = 566, GSE65858 n = 270), single-cell RNA-seq (GSE139324, n = 26 patients, 133,308 cells), spatial transcriptomics (GSE208253, n = 12), proteomics (CPTAC-HNSCC, n = 108), and external validation cohorts (GSE41613, n = 97). CellChat ligand-receptor analysis, mediation analysis, Mendelian randomization (MR), LASSO-penalized Cox regression, HPV-stratified sensitivity analysis, and transcription factor (TF) correlation analysis were employed. Results: DSG2 exhibited epithelial-specific expression and showed consistent positive correlation with CXCL8 (IL-8; TCGA ρ = 0.228, p = 4.4 × 10⁻⁸) and myCAF activation across independent cohorts. Single-cell analysis revealed that 99.5% of CXCL8-producing cells have zero DSG2 expression, establishing the bulk correlation as compositional rather than cell-intrinsic. CellChat identified CXCL8-CXCR2 as the strongest tumor-stroma interaction in DSG2-high regions (probability = 0.821, 1.80-fold enrichment). Mediation analysis demonstrated 43.6% (95% CI [34.3–53.6%]) of DSG2’s tissue-level association with myCAF activation is mediated through CXCL8 (compositional mediation). Multi-instrument MR (IVW: Beta = −0.028, p = 0.028; I² = 0.0%) corroborated the compositional model. Protein-level validation in CPTAC-HNSCC confirmed DSG2-CD8A inverse correlation (Spearman ρ = −0.35, p = 2.2 × 10⁻⁴). Pan-squamous meta-analysis confirmed negative DSG2-cytolytic activity correlations (pooled ρ = −0.213, 95% CI [−0.296, −0.128], I² = 58.6%, 4 cohorts). DSG2 correlated with TIDE score (ρ = 0.176) and TGF-β exclusion subscore (ρ = 0.428). DepMap analysis identified CXCR2 inhibitor collateral sensitivity (ρ = −0.408, p < 0.0001). An eight-gene co-expression module was validated in two independent cohorts (GSE41613: HR = 3.09, p = 0.003; GSE65858: HR = 1.57, p = 0.032). Conclusions: DSG2 marks a stromal-immune organizational state characterized by CXCL8-CXCR2 paracrine signaling, myCAF activation, and immune exclusion, conserved across squamous malignancies. DSG2-high/PD-L1-high tumors (30.4% prevalence) exhibit the worst predicted ICI response and represent a candidate population for biomarker-selected CXCR2 inhibitor trials in combination with anti-PD-1 therapy. Full article

Objective: While advancements in radiotherapy and systemic agents have significantly improved survival rates in head and neck squamous cell carcinoma (HNSCC), managing long-term, treatment-induced toxicities remains a critical clinical challenge. This study aimed to develop a personalized, supervised machine learning-driven predictive model for multiple chronic toxicities by integrating clinical, dosimetric, and genetic data specifically evaluating the impact of the NBN gene rs1805794 (c.553G>C) polymorphism. Methods: This study enrolled 125 patients with HNSCC who received curative-intent radiotherapy and remained disease-free during follow-up with a median of 98 months. Comprehensive clinical and dosimetric data were collected, and chronic toxicities were recorded. Peripheral blood samples were analyzed for the NBN rs1805794 polymorphism using allele-specific PCR (AS-PCR). Following feature selection, four supervised machine learning classifiers were trained and evaluated to identify the optimal model for predicting multiple chronic toxicities. Results: The XGBoost algorithm emerged as the highest performing model. Baseline clinico-dosimetric predictors of multiple chronic toxicities included PTV70 volume, the addition of concurrent chemotherapy, advanced T and N stages, and continued smoking. Integrating the NBN rs1805794 genotype into the XGBoost architecture enhances its predictive capability. The final model accurately identified patients at high risk for multiple chronic toxicities, achieving an area under the curve (AUC) of 0.78, an accuracy of 0.77, a sensitivity of 0.74, and a specificity of 0.79. Conclusions: Integrating clinical, dosimetric, and genetic data within a machine learning framework effectively predicts multiple chronic toxicities in HNSCC. This approach enabled early risk stratification, providing the potential for personalized therapy. Full article

Background/Objectives: Frailty is increasingly recognized as a clinically relevant marker of reduced physiological reserve in surgical oncology. The modified 5-item frailty index (mFI-5) is simple and practical, but its clinical significance in oral squamous cell carcinoma (OSCC) remains incompletely defined. This study evaluated the association between mFI-5-defined frailty and postoperative complications, especially postoperative delirium, as well as survival outcomes in patients undergoing surgery for OSCC. Methods: We retrospectively analyzed 127 patients who underwent surgical resection for OSCC with postoperative high care unit (HCU) management between 2013 and 2021. Frailty was defined as an mFI-5 score of ≥2. Clinical characteristics, postoperative outcomes, HCU stay, length of hospital stay, overall survival (OS), and disease-free survival (DFS) were compared between frail and non-frail groups. Univariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for postoperative complications. An exploratory multivariable logistic regression analysis for postoperative delirium was performed using age ≥65 years and sex as covariates. Delirium was retrospectively assessed from clinical documentation considered consistent with DSM-5 criteria. Results: Twenty-one patients (16.5%) were classified as frail. Postoperative delirium occurred more frequently in frail patients than in non-frail patients (42.9% vs. 19.8%; p = 0.023). In a multivariable logistic regression model adjusted for age ≥65 years and sex, mFI-5-defined frailty was significantly associated with postoperative delirium (adjusted OR, 3.07; 95% CI, 1.08–8.60; p = 0.035). No significant association was observed for pneumonia, surgical site infection, or free-flap reoperation. Frailty was not significantly associated with HCU stay, length of hospital stay, OS, or DFS. Conclusions: mFI-5-defined frailty was associated with postoperative delirium but not with survival outcomes in this OSCC cohort. Because this retrospective study was limited by sample size, comorbidity-driven mFI-5 scoring, non-standardized delirium screening, and potential residual confounding, mFI-5 should be interpreted as a convenient screening marker rather than a stand-alone predictor. Comprehensive perioperative assessment incorporating frailty, nutrition, sarcopenia, cognition, tumor burden, and treatment-related factors may better identify patients at risk. Full article

Background and Clinical Significance: Oropharyngeal squamous cell carcinoma (OPSCC) and small-cell neuroendocrine carcinoma (SCNEC) are biologically distinct entities with markedly different prognostic and therapeutic implications. While HPV-negative OPSCC carries worse outcomes than HPV-positive disease, SCNEC is exceedingly rare, highly aggressive, and prone to early systemic dissemination. Their synchronous occurrence in the head and neck (HN) is exceptional and poses major diagnostic and therapeutic challenges. Case Presentation: A 54-year-old male, smoker and alcohol consumer, presented with a left tonsillar lesion and cervical lymphadenopathy. Biopsy confirmed p16-negative OPSCC. He underwent transoral robotic surgery with modified radical neck dissection. Histopathology unexpectedly revealed two distinct malignancies: keratinizing OPSCC in the tonsil and high-grade SCNEC in a cervical lymph node, confirmed by immunohistochemistry (synaptophysin, CD56, Ki-67 80%). Postoperative FDG-PET/CT performed within two months showed rapid systemic spread, including paravertebral, pulmonary, and pelvic nodal metastases. Despite recommendation for systemic therapy, the patient deteriorated quickly and died shortly thereafter. Conclusions: This study reports coexistence of p16-negative OPSCC and high-grade SCNEC in the HN. It highlights the diagnostic complexity, staging limitations, and therapeutic dilemmas of discordant histologies, while illustrating the fulminant clinical course typical of SCNEC of unknown origin. Early recognition, comprehensive pathology, and multidisciplinary management are essential, although prognosis remains dominated by the aggressive neuroendocrine component. Full article

Background/Objectives: Metatypical basal cell carcinoma (MTBCC) is a rare and aggressive variant of non-melanoma skin cancer (NMSC) characterised by overlapping histological features of basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC). Owing to its increased propensity for local invasion, recurrence, and metastasis, MTBCC poses diagnostic and therapeutic challenges. This study aimed to characterise the epidemiological, histopathological, and clinical features of MTBCC and to evaluate temporal changes in tumour characteristics and aggressiveness before, during, and after the COVID-19 pandemic. Methods: A retrospective cohort study was conducted on 129 histologically confirmed MTBCC lesions diagnosed in the Pathology Department of the Mures Clinical County Hospital, Targu Mures, Romania, between January 2017 and December 2025. Demographic data, tumour location, histological subtypes, differentiation of the squamous component, aggressiveness parameters, and volumetric measurements of tumours and excision specimens were analysed. Volumetric analyses were restricted to cases with complete three-dimensional measurements. Statistical comparisons were performed across demographic variables and the following three time periods: pre-pandemic, pandemic, and post-pandemic. Results: The median age at diagnosis was 71 years, with a slight male predominance (p = 0.25) and a significant predominance of patients from urban areas (p < 0.001). Most tumours were located in the head and neck region. Mixed-type MTBCC was significantly associated with higher tumour aggressiveness (p = 0.0019) and with high-risk histological subtypes, particularly micronodular and adenoid–cystic variants. Tumour volume showed a significant inverse correlation with year of diagnosis (p = 0.0139; r = (−) 0.50), whereas excision specimen volume differed significantly according to year of diagnosis (p = 0.0425). Neither tumour volume nor excision specimen volume was associated with histopathological aggressiveness. Conclusions: Metatypical basal cell carcinoma is a rare skin malignancy in which biological behaviour appears to be determined primarily by histopathological architecture rather than tumour size. Mixed-type lesions were associated with significantly higher aggressiveness, underscoring the need for accurate histopathological assessment. These findings support a pathology-driven approach to management and emphasise the importance of adequate surgical treatment and long-term follow-up in patients with MTBCC. Full article

Background: Squamous cell carcinomas (SCCs) share squamous differentiation and may engage the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway, although their causes, biology, and treatment differ by anatomical site. We evaluated tumor response, short-term survival, and grade 3–4 adverse events after neoadjuvant immune-checkpoint blockade, with or without chemotherapy, followed by surgery. Methods: A comprehensive search of PubMed, Embase, the Cochrane Library, and clinical trial registries was conducted from inception to October 2024. Prospective and retrospective studies evaluating neoadjuvant immunotherapy, with or without chemotherapy, before surgery in patients with SCC were included. In mixed-histology studies, data were eligible only when SCC outcomes could be extracted separately. Pooled proportions and 95% confidence intervals (CIs) were estimated with random-effects models. Results: A total of 44 studies involving 2586 patients with six anatomical SCC groups were included. The pooled objective response rate (ORR) was 0.70 (95% CI, 0.59–0.80), clinical complete response (cCR) rate was 0.17 (95% CI, 0.10–0.28), and pathological complete response (pCR) rate was 0.30 (95% CI, 0.27–0.34). The pooled 1-year progression-free survival (PFS), disease-free survival (DFS), and overall survival (OS) rates were 0.82 (95% CI, 0.79–0.86), 0.86 (95% CI, 0.75–0.92), and 0.92 (95% CI, 0.90–0.93), respectively. The pooled incidence of grade 3–4 adverse events was 0.18 (95% CI, 0.14–0.23). Because the PD-L1 subgroup contained only one study for most outcomes, checkpoint-target subgroup findings were considered exploratory. Conclusions: Existing predominantly single-arm evidence suggests antitumor activity of neoadjuvant immune-checkpoint blockade, with or without chemotherapy, in selected patients with resectable SCC. Because esophageal SCC accounted for most studies and clinical heterogeneity was substantial, these pooled proportions should not be interpreted as comparative effects or as evidence of uniform benefit across SCC sites. Full article

Head and neck squamous cell carcinoma (HNSCC) continues to be an important health problem worldwide, with high morbidity and mortality and considerable biological variability among tumors. Although clinicopathological features remain essential in clinical practice, they do not fully explain differences in tumor behavior or treatment response. The growing availability of molecular data has therefore increased interest in multi-omics strategies for HNSCC. Genomic, transcriptomic, epigenomic, proteomic, and metabolomic analyses provide different, but complementary, views of tumor biology. Genomic alterations, including recurrent changes in TP53 and PIK3CA, help define the molecular landscape of HNSCC, while transcriptomic biomarkers such as PD-L1 expression and epithelial–mesenchymal transition (EMT)-related signatures provide insights into tumor–microenvironment interactions, immune evasion, and treatment resistance. Epigenetic alterations further regulate gene expression, whereas proteomic and metabolomic biomarkers provide information more closely related to cellular function, metabolic reprogramming, and disease progression. More recently, single-cell and spatial approaches have allowed tumors to be studied according to their cellular composition and tissue organization. Artificial intelligence and machine learning are also being explored to combine these large datasets and identify biomarkers related to prognosis or therapeutic response. This review critically discusses the principal multi-omics biomarkers investigated in HNSCC, including biomarkers associated with genomic instability, immune regulation, EMT, and metabolic reprogramming, highlighting their potential clinical applications and the current barriers limiting their incorporation into routine practice. Full article

Background/Objectives: Cutaneous squamous cell carcinoma (cSCC) is the second most common non-melanoma skin cancer (NMSC) and represents the leading cause of NMSC-related deaths. Despite its growing global burden, comprehensive epidemiological and clinicopathological data from Easter Europe remains limited. This study aimed to evaluate the epidemiological, clinical, histopathological, and surgical characteristics of cSCC diagnosed before, during and after the COVID-19 pandemic. Methods: We conducted a retrospective, descriptive observational study including 332 lesions diagnosed between January 2017 and December 2025 at the Clinical Pathology Department of the Mureș Clinical County Hospital. Demographic, epidemiological, topographic, histopathologic, surgical, and volumetric parameters were analyzed. Tumours were stratified into low-, high-, and very-high-risk categories according to the National Comprehensive Cancer Network (NCCN) criteria. Results: The cohort demonstrated a significant male predominance (n = 193 vs. n = 139; p = 0.0355), with females presenting a higher median age (77 vs. 75; p = 0.0489). Lesions were predominantly located in the head and neck region (n = 216; p < 0.0001), which was significantly associated with very-high-risk tumours (p = 0.0051). Low-risk tumours accounted for 62.35% of cases, while high-risk and very-high-risk lesions comprised 19.88% and 17.77%, respectively (p < 0.0001). Ulcerations were strongly associated with very-high-risk tumours (p < 0.0001). Poor differentiation was more frequent outside the head and neck region (p < 0.0001) and varied significantly across the pandemic periods (p = 0.0349). Tumoral and excision volumes were higher in very-high-risk (p = 0.0070; p = 0.0004) and ulcerated tumours (p < 0.001), with a peak in volume during the COVID-19 period (p < 0.0001). A decrease through the years of diagnosis was observed in tumoral volumes (r = −0.2295; p < 0.0001) and patients showed a weak positive correlation with diagnosis year (r = +0.13; p = 0.019). Conclusions: The study provides an epidemiological and clinicopathological characterization of cSCC within one of the largest Romanian cohorts to date. Tumour aggressiveness was primarily driven by histopathological and topographical features rather than demographic factors. While the COVID-19 pandemic did not induce persistent changes in tumour risk profiles or surgical outcomes, it influenced diagnosis timing and tumour burden. These findings highlight the importance of incorporating temporal and emerging systemic factors, such as pandemics, and infectious events, into future epidemiological models to improve preparedness, early detection, future treatment schemes, and risk stratification in cSCC. Full article

Background: Metronomic chemotherapy (MCT), understood as continuous, low-dose cytotoxic administration without prolonged drug-free intervals, has become an established strategy in several solid tumors, acting primarily through antiangiogenic, immunomodulatory, and direct cytostatic mechanisms rather than replication-dependent cytotoxicity. Despite an expanding evidence base, including positive randomized trials, validated predictive biomarkers of response remain unavailable. Methods: We searched PubMed/MEDLINE, Embase, and ClinicalTrials.gov (January 2000 to July 2026) for phase II/III randomized trials, prospective cohorts, and selected retrospective analyses of MCT in breast cancer, head and neck squamous cell carcinoma, NSCLC, and mCRC, and extracted biomarker data from embedded translational substudies of eligible trials. Results: In breast cancer, phase III SYSUCC-001 (adjuvant metronomic capecitabine, improved DFS in TNBC) and MECCA (metronomic capecitabine plus aromatase inhibitor in HR+/HER2− disease) provide the strongest evidence, supported by randomized phase II data for the VEX regimen (METEORA-II) and MCT-anti-PD-1 combinations. TEMPO LUNG established metronomic vinorelbine as effective in platinum-unfit NSCLC, while CAIRO3 confirmed metronomic capecitabine–bevacizumab as an effective mCRC maintenance therapy. Most recently, the phase III TMC-I trial extended positive randomized evidence to head and neck cancer. Candidate biomarkers span angiogenic, immune, tumor proliferative, molecular, pharmacodynamic cytokine, on-treatment clinical (adverse-event-based), and gut–microbiome domains, with FOXC1, circulating endothelial cell kinetics, VEGF pathway markers, and regulatory T-cell dynamics among the most promising; however, none has been prospectively validated in a dedicated confirmatory trial. Conclusions: MCT has moved from empirical use to an evidence-based strategy across multiple tumor types, but the lack of validated predictive biomarkers limits informed patient selection. Future trials should incorporate biomarker-driven designs, particularly FOXC1, endothelial cell kinetics, and immune profiling as co-primary objectives. Defining an MCT-sensitive biological phenotype remains the key translational challenge for the field. Full article

Salivary microbiome profiling may represent a promising non-invasive approach for characterizing OSCC-associated microbial patterns and longitudinal microbiome dynamics during patient management. This exploratory pilot study aimed to longitudinally assess salivary microbiota profiles in patients with oral squamous cell carcinoma (OSCC) before and after tumor resection using Oxford Nanopore Technology. Unstimulated saliva samples were collected from 16 patients with OSCC at two time points (before and after tumor resection) and from 10 OSCC-free reference subjects. Microbial DNA was extracted using the QIAamp DNA Blood Kit (QIAGEN GmbH, Hilden, Germany) and subjected to long read metagenomic sequencing using the Oxford Nanopore MinION platform (v. 20.06.4, Oxford Nanopore Technologies, Oxford, UK). Taxonomic profiling was performed to longitudinally characterize salivary microbiota composition within patients and to provide descriptive comparisons with the OSCC-free reference cohort. Longitudinal analysis identified differences in salivary microbiota profiles between pre- and post-resection samples. Before surgery, an increased relative abundance of Neisseria subflava and Leptotrichia buccalis was observed. Post-surgical samples showed higher levels of Glaesserella parasuis, Streptomyces anulatus, and Lactobacillus species. Distinct microbial patterns were also descriptively observed between OSCC patients and OSCC-free controls, suggesting disease-associated dysbiosis. This exploratory longitudinal pilot study suggests differences in salivary microbiota profiles between samples collected before and after tumor resection in patients with OSCC, including changes in taxonomic composition and reduced alpha diversity. Given the limited sample size and the potential influence of unmeasured perioperative factors, these findings should be considered hypothesis-generating. Larger, well-controlled longitudinal studies incorporating standardized oral health assessment and detailed perioperative metadata are required to clarify the biological and clinical relevance of these observations. Full article

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

Background: Human papillomavirus (HPV) infection defines a distinct subtype of head and neck squamous cell carcinoma (HNSCC). Although HPV-positive (HPV+) HNSCC generally shows better overall survival than HPV-negative (HPV−) disease, it is frequently associated with cervical lymph node metastasis. However, the epithelial cell states and viral gene-associated mechanisms underlying HPV−related metastatic progression remain incompletely understood. This study aimed to identify metastasis-associated epithelial subpopulations in HPV+ HNSCC and explore the potential role of HPV16 E7 in regulating metastatic programs. Methods: Public single-cell RNA-sequencing datasets from paired primary and metastatic HNSCC samples were integrated and analyzed to characterize malignant epithelial subpopulations. Copy number variation (CNV) inference, clustering, pathway enrichment, stemness scoring, and trajectory analysis were performed to define metastasis-associated epithelial states. TCGA transcriptomic data and tissue-based validation were used to support candidate gene screening. In vitro functional assays were performed using SERPINB3-knockdown and HPV16 early gene-overexpressing CAL27 cell models. Results: Single-cell analysis identified stem-like metastatic epithelial subpopulations in HPV+ and HPV− HNSCC. In HPV+ metastatic lesions, an ALDH2+/LAMB3+ epithelial subpopulation showed elevated epithelial–mesenchymal transition activity and stem-like features. SERPINB3 displayed a dynamic expression pattern during HPV+ metastatic progression. Functional assays showed that SERPINB3 knockdown enhanced CAL27 cell migration and invasion and was associated with activation of MYC- and epithelial–mesenchymal transition-related transcriptional programs. Among HPV16 early genes, E5, E6, E6*, and E7 showed different degrees of SERPINB3 suppression, while E7-expressing cells exhibited distinct transcriptional alterations associated with epithelial plasticity and metastatic-related programs. Conclusions: This study identifies a stem-like metastatic epithelial state in HPV-associated HNSCC and suggests a potential HPV16 early gene-SERPINB3-MYC-related regulatory mechanism involved in metastatic epithelial plasticity. 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

Background: Cetuximab-based therapies continue to play an important role in the management of recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) despite the increasing use of immunotherapy. However, data regarding treatment outcomes and prognostic factors remain limited. This study aimed to evaluate treatment outcomes and prognostic factors associated with survival in patients with R/M HNSCC treated with cetuximab-based regimens. Methods: This retrospective single-center cohort study included patients with recurrent/metastatic HNSCC who received cetuximab-based systemic therapy at the Department of Medical Oncology, Manisa Celal Bayar University Faculty of Medicine, between May 2012 and September 2025. Demographic, clinical, laboratory, and PET/CT data were retrospectively analyzed. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method and compared using the log-rank test. Prognostic factors associated with survival were evaluated using univariable and multivariable Cox proportional hazards regression analyses. Results: A total of 57 patients were included in the study. The median age was 65 years, and 91.2% of patients were male. Most patients had ECOG performance status 0–1 (94.7%) and stage IV disease (71.9%). The larynx was the most common primary tumor site (50.9%), while distant lymph node metastasis (63.2%) and lung metastasis (61.4%) were the predominant metastatic sites. Median PFS and OS were 4.6 months and 13.8 months, respectively. Kaplan–Meier analysis demonstrated that patients with a body mass index (BMI) > 25 had longer OS, whereas chronic kidney disease (CKD), primary tumor localization, and best response to first-line treatment were significantly associated with survival. In multivariable Cox regression analysis, chronic kidney disease (CKD) (HR: 5.15, p = 0.004), oral cavity primary tumor localization (HR: 2.55, p = 0.013), progressive disease as the best response to first-line treatment (HR: 4.44, p < 0.001) and the absence of grade 1–2 cetuximab-related dermatologic toxicity (HR: 3.20, p = 0.027) remained independent adverse prognostic factors. BMI was not independently associated with survival in multivariable analysis. Conclusions: Cetuximab-based therapy demonstrated clinically meaningful activity in patients with R/M HNSCC. Comorbidities, primary tumor localization, the absence of grade 1–2 cetuximab-related dermatologic toxicity and treatment response appear to substantially influence survival outcomes. Larger prospective studies are warranted to validate these findings. Full article