Search Results (3,262)

Objectives: To characterize the frequency and temporal patterns of anterior segment findings after radiotherapy for sinonasal and nasopharyngeal cancer, with particular focus on anterior segment neovascularization and its association with superselective intra-arterial cisplatin infusion with concurrent radiotherapy (RADPLAT). Methods: We retrospectively reviewed 113 patients treated with intensity-modulated radiotherapy between 2019 and 2022. Anterior segment findings were evaluated using the whole cohort as the denominator and among patients referred for ocular symptoms. Cumulative incidence was estimated with death as a competing risk using the Aalen–Johansen estimator and compared using Gray’s test. Results: Median follow-up was 1666 days. Forty-seven patients (41.6%) were referred to ophthalmology. Anterior segment findings occurred in 16/60 patients (26.7%) with nasal cavity cancer and 13/31 (41.9%) with maxillary sinus cancer (p = 0.16); 5-year cumulative incidences were 27.7% and 46.1%, respectively (p = 0.018). Anterior segment neovascularization occurred in 7/113 patients (6.2%), including 6/21 (28.6%) treated with RADPLAT and 1/92 (1.1%) without RADPLAT (p < 0.001); 5-year cumulative incidences were 31.4% and 1.4%, respectively (p < 0.001). Among patients with maxillary sinus cancer, neovascularization occurred in 5/19 RADPLAT-treated patients and 0/12 non-RADPLAT patients (p = 0.13); however, median follow-up was substantially shorter in the non-RADPLAT group (385 vs. 1784 days). Neovascularization developed late (median, 975 days), and four affected patients had final best-corrected visual acuity below 0.05. Conclusions: Anterior segment findings showed distinct temporal patterns after radiotherapy. Late, vision-threatening neovascularization was strongly associated with RADPLAT, although causality cannot be established because treatment selection was confounded by tumor site, disease extent, orbital invasion, and radiotherapy characteristics. These findings identify anterior segment neovascularization as an important safety signal warranting prospective evaluation. Standardized baseline ophthalmological assessment, long-term surveillance, and patient-level ocular dosimetry are needed to clarify mechanisms and define appropriate follow-up strategies. Full article

Background and Objectives: Basal cell carcinoma (BCC) is the most common non-melanoma skin cancer, and its global incidence rate constantly rises. However, there are no current epidemiological data for many regions, including Małopolska in southern Poland. This study aimed to characterize the clinical and histological profile of patients with BCC and to identify factors associated with local recurrence and the presence of multiple tumors. Materials and Methods: We performed a single-center, retrospective observational study consistent with STROBE guidelines at the Department of Dermatology and Allergology, University Hospital in Cracow. The included patients were adults with at least one histologically confirmed BCC treated between 2015 and 2025. Demographic, clinical, histopathological, and follow-up data were collected at patient and lesion levels. The results were evaluated using univariable tests, multivariable logistic regression, Kaplan–Meier survival analysis, and generalized estimating equations. Results: We included 108 patients (median age at first diagnosis, 73 years; 52% male) with 418 BCCs; the median follow-up duration was 84 months. Superficial BCC was the most common subtype among lesions with available histological subtype information (56%). The head and neck region was the most frequent anatomical site in this group (51%). Multiple BCCs were present in 62% of patients. Longer follow-up was independently associated with the presence of multiple BCCs. A history of actinic keratoses showed a positive but statistically nonsignificant association with multiple BCCs. Recurrence was observed in 15 lesions (3.6%). Female sex and H-zone involvement showed higher odds of recurrence. Conclusions: In this elderly cohort, multiple BCC tumors may reflect longer follow-up and cumulative actinic damage. Recurrence was relatively infrequent but associated with clinically relevant features, including H-zone involvement and female sex. These findings support an individualized, multifactorial approach to treatment and follow-up, taking into account age, sex, lesion burden, anatomical location, and histological subtype. Full article

Background: Comorbidity is an important determinant of treatment selection and in-hospital complications in patients with head and neck cancer (HNC) and thyroid cancer (TC), yet population-based evidence on this relationship remains limited. Methods: We analyzed nationwide Diagnosis-Related Groups (DRG) data from 1,552,028 inpatient HNC and TC treatments of patients aged ≥30 years in Germany between 2005 and 2021. The aim was to characterize the association of comorbidity and severe treatment-related procedure-coded inpatient events (IEs) with gender, age, tumor subsite, and treatment type. Results: The largest proportion of treatments occurred in patients aged 60–69 years (33.5%). The most frequent tumor subsites were the oropharynx, thyroid gland, oral cavity, larynx, and hypopharynx, with 35.52, 33.84, 33.60, 26.12, and 15.76 treatments per 100,000 population per year, respectively. Overall, 38% of cases had a Charlson Comorbidity Index (CCI) ≥ 1, with the highest mean CCI observed for C14 (other sites of the lip, oral cavity and pharynx) and C12 (piriform sinus). IEs requiring additional in-hospital treatment occurred in 19.3% of cases. After adjustment for age, tumor location, and treatment type, men had a lower risk of IEs than women (OR 0.929; CI 0.919–0.939; p < 0.001). Increasing comorbidity was associated with a higher IE risk, reaching a plateau at CCI ≥ 4 (OR 2.135; CI 2.029–2.246; p < 0.001). IE risk was high during chemotherapy/immunotherapy (OR 29.527; CI 28.897–30.170; p < 0.001), followed by surgery (OR 3.465; CI 3.433–3.498; p < 0.001), whereas radiotherapy showed the lowest risk (OR 1.339; CI 1.313–1.366; p < 0.001). Conclusions: These findings highlight substantial heterogeneity in comorbidity and IE risk among patients with HNC or TC. Full article

Background/Objectives: Surgical pulmonary resection in lung cancer remains the cornerstone of curative treatment; however, it is associated with considerable postoperative pulmonary complications. Patients previously treated for head and neck cancer (HNC) have a significantly increased risk of developing second primary lung cancer (LC) and a higher incidence of adverse pulmonary outcomes after LC resective surgery due to increased baseline frailty. Methods: A retrospective observational longitudinal study was conducted on 1679 patients who underwent surgical resection with curative intent for LC at the Thoracic Surgery Department of Hospital Clínico San Carlos, Madrid, Spain, between December 1989 and December 2024. Patients were divided into two groups based on the presence or absence of prior HNC: 87 with HNC vs. 1592 without. Special attention was paid to respiratory complications, particularly bronchopleural fistula (BPF), empyema, atelectasis, and pneumonia. Variables significantly associated with BPF and HNC in univariate analyses (excluding those related to other complications to avoid collinearity), as well as clinically relevant baseline differences between groups, were included in a stepwise multivariable logistic regression modeling procedure to identify independent risk factors associated with BPF. Results: In comparison with the control group, significantly higher rates of postoperative BPF (12.6% vs. 3.6%), empyema (10.3% vs. 2.8%), atelectasis (14.9% vs. 8.3%) and need of reintervention (10.3% vs. 4.2%) were found in the HNC group under unadjusted approach and stratified by surgery period. Sex, history of HNC, chronic obstructive pulmonary disease (COPD) and length of preoperative hospital stay were independently associated with BPF according to several multivariable logistic regression fits, which showed a moderate discriminatory capacity (AUC values ranging from 0.723 to 0.732). In particular, the presence of HNC was significantly associated with BPF, with adjusted odds ratio (aOR) estimates ranging from 3.562 (95% CI: 1.773 to 7.156) to 3.789 (95% CI: 1.863 to 7.709). Conclusions: In our study, COPD, male sex, preoperative hospital stay as well as HNC history were found independently associated with an increased odds of BPF after surgical treatment for LC. In particular, patients previously treated for HNC had more than threefold higher odds of developing BPF than those without a history of HNC, with this association remaining consistent over the 35-year study period. Full article

Background: Oral cavity cancer is a clinically relevant subgroup of head and neck malignancies and is associated with substantial treatment burden and healthcare utilization. Hospital length of stay (LOS) is an important indicator of inpatient resource use and complexity of care, yet large multicenter data from Germany are limited. Methods: This retrospective multicenter analysis used anonymized inpatient administrative data from 49 German hospitals; eligible oral cavity cancer hospitalizations were contributed by 34 of these hospitals. Adult inpatient hospitalizations (≥18 years) with malignant neoplasms of the oral cavity, defined using ICD-10-GM codes C00–C06, recorded between January 1 2019 and 31 December 2024 were included. The primary outcome was hospital LOS in days. Multimorbidity was quantified using the van Walraven-weighted Elixhauser Comorbidity Score. Prolonged hospitalization was defined as LOS ≥ 7 days and LOS ≥ 14 days. Associations between demographic, clinical, and treatment-related variables and LOS were examined using multivariable Poisson regression models. Because overdispersion was present, a negative binomial mixed model was additionally fitted as a sensitivity analysis. To account for inter-hospital variability, hospital was included as a random intercept in all multivariable models. Associations with prolonged LOS were analyzed using multivariable logistic regression models. All analyses were performed at the hospitalization level. Results: A total of 3957 inpatient hospitalizations for oral cavity cancer were included. Mean age was 65.6 years, and 66.2% of hospitalizations involved male patients. The median LOS was 6 days (interquartile range [IQR] 3–13; mean 10.2 days, standard deviation 11.8). Overall, 49.4% of hospitalizations had an LOS ≥ 7 days and 23.5% had an LOS ≥ 14 days. Older age, particularly >80 years, and higher comorbidity burden were associated with longer LOS (adjusted Poisson rate ratio [RR] for age > 80 years 1.17, 95% CI 1.13–1.21; high comorbidity burden RR 1.58, 95% CI 1.54–1.63). Several treatment-related variables, including surgical procedures in the oral and facial region, lymphatic system operations, blood transfusions, and complex intensive care treatment, were associated with prolonged hospitalization (e.g., blood transfusion RR 1.80, 95% CI 1.76–1.85; complex intensive care RR 1.70, 95% CI 1.65–1.75). Chemotherapy-related hospitalizations were associated with shorter LOS. Conclusions: LOS varied substantially across inpatient hospitalizations for oral cavity cancer in Germany. Older age, higher comorbidity burden, and markers of more complex inpatient treatment were associated with extended hospital stay. These findings may help identify hospitalizations at increased risk of prolonged LOS and inform inpatient planning and resource allocation. Full article

Background/Objectives: Radiation-induced hypothyroidism (RIHT) is a frequent complication in head and neck cancer (HNC) patients following radiotherapy, significantly impacting quality of life. This study aimed to develop and validate an interpretable machine learning model for predicting RIHT, with a focus on providing individualized risk assessment. Methods: The study included a development cohort (n = 256) from the Second Affiliated Hospital of Harbin Medical University and an independent external validation cohort (n = 296) from the First Affiliated Hospital of Kunming Medical University. Using 18 predictive features, six machine learning algorithms—Random Forest, Support Vector Machine, Multi-Layer Perceptron, Logistic Regression, XGBoost, and LightGBM—were constructed. Model performance was evaluated using AUC, balanced accuracy, F1 score, PR-AUC, Brier score, and Brier skill score. SHapley Additive exPlanations (SHAP) was applied for model interpretability. Results: In internal validation, LightGBM achieved the highest performance (AUC = 0.872, balanced accuracy = 0.703, PR-AUC = 0.712, and Brier skill score = 0.371), outperforming logistic regression. In external validation, Random Forest achieved the highest AUC (0.769), while XGBoost and LightGBM achieved AUCs of 0.721 and 0.716, respectively. SHAP analysis identified pre-treatment thyroid volume, T-stage, tumor site, mean thyroid dose (Dmean), and V50 as the most influential features for model prediction. Notably, dose–volume parameters (V30–V60) were highly correlated (r = 0.75–0.98); therefore, they should be interpreted as a cluster rather than as independent predictors. We caution against overinterpreting individual Vx thresholds as rigid clinical cutoffs. Conclusions: Machine learning models, particularly tree-based ensemble methods (LightGBM and XGBoost), demonstrate good predictive performance for RIHT. Combined with SHAP analysis, these models provide transparent, individualized risk assessments. However, the dose–response relationship for RIHT is continuous, and no single dose threshold should be used as a rigid clinical cutoff. Model code is available from the corresponding author upon reasonable request. Future prospective studies with time-to-event analysis are needed to further validate clinical utility. Full article

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) remains a challenging complication of bisphosphonate therapy because jaw extraction sockets exposed to bisphosphonates represent impaired wound environments rather than ordinary bone defects. This narrative review summarizes clinical, cellular, animal, and biomaterial evidence on the mechanisms that limit BRONJ repair and discusses how these pathological barriers can inform local material design. Current evidence suggests that BRONJ repair is constrained by impaired osteoclast-mediated remodeling, osteocyte and osteoblast dysfunction, oxidative stress, unresolved inflammation, angiogenic insufficiency, microbial challenge, mucosal instability, and changes in bone material properties. Biomaterial strategies investigated to date include local delivery of regenerative factors, restoration of remodeling activity, extracellular vesicles, nucleic acid nanostructures, platelet-derived matrices, antibacterial and ion-releasing hydrogels, angiogenic or lymphangiogenic systems, and mechanically adaptive scaffolds. Most studies remain preclinical and are based on rodent extraction or mandibular defect models, and few establish a direct causal link between a specific material property and durable BRONJ resolution. Future materials should be judged not only by their ability to enhance bone formation, but also by whether they can re-establish a sealed, vascularized, immune-balanced, and remodeling-competent socket capable of sustained jawbone repair. Full article

In this paper, we propose a new flexible modification of the Lomax distribution within the Bilal-G family generated through the T-X framework, referred to as the Lomax–Bilal distribution. The proposed model offers greater flexibility for modeling-skewed and heavy-tailed phenomena that frequently arise in survival and reliability studies. A comprehensive set of statistical properties is derived, as moments, order statistics, reliability measures, the quantile function, stochastic ordering, and maximum likelihood estimation. Furthermore, several information measures are obtained to characterize the uncertainty structure of the distribution, namely Shannon entropy, Rényi entropy, extropy, cumulative residual extropy, and generalized weighted extropy. Also, the Lorenz, Bonferroni, Zenga curves and Gini index are presented. The practical applicability and effectiveness of the proposed distribution are illustrated through analyses of two real datasets: survival times of patients with head and neck cancer treated with chemotherapy and radiation therapy, and repair times of an airborne communication transceiver. The empirical results showed that the Lomax–Bilal distribution consistently provides a better fit than several well-established lifetime distributions according to goodness-of-fit statistics and information criteria, particularly in modeling tail behavior. These findings suggest that the Lomax–Bilal distribution constitutes a flexible and competitive alternative for analyzing complex lifetime data in reliability engineering and medical survival studies. Full article

Background: Radiotherapy-induced xerostomia is a prevalent and disabling complication in patients with head and neck cancer, leading to persistent oral pain, impaired salivary function, and substantial deterioration in quality of life. Photobiomodulation (PBM) has emerged as a supportive therapeutic strategy with potential anti-inflammatory, analgesic, and tissue-preserving effects; however, its clinical effectiveness remains incompletely defined. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials evaluating PBM for the management of radiotherapy-induced xerostomia in adults with head and neck cancer. MEDLINE (PubMed), Embase, Scopus, and Web of Science were searched from inception to October 2025. Eligible studies assessed intraoral and/or extraoral PBM using predefined laser parameters and reported outcomes related to oral pain, salivary flow, or xerostomia-related quality of life. Risk of bias was assessed using the Cochrane RoB 2.0 tool. Random-effects meta-analyses were performed using the Paule–Mandel estimator. Certainty of evidence was appraised using the GRADE framework. Results: Seven randomized trials were included. PBM significantly reduced oral pain compared with control interventions (mean difference [MD] −0.76; 95% CI −1.33 to −0.20), with moderate heterogeneity. For stimulated and unstimulated salivary flow, pooled estimates favored PBM but did not reach statistical significance, and heterogeneity was considerable (I² > 90%). Substantial variability in laser wavelength, energy density, treatment frequency, anatomical targeting, and radiation exposure of salivary glands contributed to inconsistent effects across studies. The certainty of evidence was rated as moderate for pain reduction and low to very low for salivary flow outcomes. Conclusions: Photobiomodulation provides a clinically meaningful reduction in radiotherapy-related oral pain and may confer symptomatic benefit in xerostomia; however, its effect on salivary flow restoration remains uncertain. Standardized PBM protocols, improved methodological rigor, and adequately powered trials are required to clarify its role in supportive care for head and neck cancer patients. Full article

Background/Objectives: Head and neck squamous cell carcinomas (HNSCC) are a heterogenous group of tumors, which are usually treated with surgery and radiotherapy, while chemotherapy (e.g., cisplatin), anti-EGFR, or immune checkpoint inhibitors are used to treat locoregionally advanced and recurrent cases. However, survival outcomes are still unsatisfactory, and novel augmenting treatments are required. Recently, histone lysine demethylases (KDMs) emerged as promising anti-cancer targets. In order to further characterize KDM4–6 as pharmacological targets in HNSCC, we evaluated changes in KDM4/5/6 expression in HNSCC patients, and we experimentally assessed the biological effects of inhibitors of KDM4/5/6 in HNSCC cell lines. Methods: We used online tools (TIMER, GEPIA3, UALCAN) to analyze TCGA data from HNSCC patients. Then, we used resazurin assay to assess the effect of ML324, GSK-J4, and JIB-04 (the inhibitors of KDM4, KDM6, and KDM4–6, respectively) on cell viability in two-dimensional (2D) and three-dimensional (3D) culture of FaDu, SCC-152, and Detroit-562 cells. The potential for cisplatin sensitization was also assessed. Gene/protein expression was evaluated by qPCR and antibody array. Results: We found that the majority of the analyzed KDMs were overexpressed in HNSCC, except KDM4C, KDM5D, and KDM6A. All three studied inhibitors significantly reduced cell viability in 2D and 3D cell cultures. Moreover, the pre-treatment of cells with KDM inhibitors showed moderate potential for cisplatin sensitization. In addition, the chemicals significantly reduced the expression of pluripotency markers, especially SOX2. Conclusions: In conclusion, KDM4–6 inhibitors significantly affected HNSCC cell growth, and exerted the potential for epigenetic priming in combination with cisplatin. Full article

Background: Death-associated protein kinase 1 (DAPK1) is a key regulator of apoptosis and immune responses; however, its prognostic significance in oral cancer remains insufficiently characterized. This study investigated the prognostic relevance of DAPK1 in oral squamous cell carcinoma (OSCC) and examined its associations with immune infiltration and apoptosis-related signaling pathways. Methods: A retrospective translational study design was employed, integrating TCGA-based expression and methylation analyses of 528 head and neck squamous cell carcinoma (HNSCC) tumors, UALCAN epigenetic profiling, GeneMANIA protein–protein interaction mapping, TIMER 2.0 immune correlation analyses in 422 HPV-negative HNSCC patients, and multiplex immunofluorescence validation using a tissue microarray cohort of 82 patients with histologically confirmed OSCC, of whom 75 were eligible for the final analysis at Kaohsiung Veterans General Hospital, Taiwan. Results: In vitro validation using Western blot analysis in FaDu cells showed that epidermal growth factor receptor (EGFR) inhibition with gefitinib induced upregulation of DAPK1 protein expression at 10 μM and increased total caspase-3 expression. Higher DAPK1 signal in whole-field quantification was associated with increased CD4+ and CD8+ T-cell infiltration and enrichment of apoptosis-related pathways. Patients with high DAPK1 expression demonstrated a consistent protective trend for overall survival in a pre-specified fully adjusted primary model (adjusted HR = 0.51, 95% CI: 0.21–1.21, p = 0.126), and exhibited significantly improved survival in a secondary parsimonious model (adjusted HR = 0.41, 95% CI: 0.18–0.91, p = 0.029). Multiplex immunofluorescence further confirmed stronger DAPK1 and caspase-3 staining, along with denser lymphocytic infiltration within the tumor microenvironment. Conclusions: Collectively, these findings suggest that DAPK1 is associated with apoptosis-related signaling, increased immune-cell infiltration, and favorable clinical outcomes in OSCC, although its independent prognostic value requires validation in larger cohorts. Full article

Background/Objectives: Pediatric nasopharyngeal carcinoma (NPC) is a very rare childhood cancer strongly associated with Epstein–Barr virus (EBV) infection. We investigated the prognostic value of EBV DNA on staging and outcome in pediatric NPC from two large study centers, the Children’s Oncology Group (COG) in North America and the German Society of Pediatric Oncology and Hematology (GPOH) in Europe. Methods: Samples collected from NPC patients treated on the COG study ARAR0331 between 2006 and 2012 and the GPOH NPC protocol between 2003 and 2021 were retrospectively analyzed for the level of available plasma (P-EBV) or whole-blood EBV DNA (WB-EBV), both pre-treatment and post-induction chemotherapy. Patients were dichotomized into high and low groups based on the median pre-treatment EBV value. Results: Pre-treatment EBV DNA levels from 102 patients (50 and 23 P-EBV DNA from the COG and GPOH, respectively, and 29 WB-EBV from GPOH) and post-induction EBV DNA levels from 61 patients (31 and 12 P-EBV DNA from the COG and GPOH, respectively, and 18 WB-EBV DNA from GPOH) were evaluated. Patient characteristics, including age and disease stage, were not associated with high and low P-EBV values in any cohort. Disease stage correlated with high EBV levels in the WB-EBV GPOH cohort (p = 0.014). Pre-treatment P-EBV and WB-EBV levels showed no significant association with 5-year event-free survival (EFS: COG p = 0.65, GPOH P-EBV: p = 0.08, GPOH WB-EBV: p = 0.75) or 5-year overall survival (OS: COG p = 0.90, GPOH P-EBV p = 0.17, GPOH WB-EBV p = 0.19). Conclusions: Our study could not establish a significant correlation between outcome and pre-treatment EBV DNA in pediatric NPC patients from non-endemic areas. Full article

Background and Objectives: Functional sequelae following head and neck cancer (HNC) treatment frequently impair swallowing, mouth opening, speech, cervical and shoulder mobility, and overall quality of life. Although rehabilitation is increasingly recognized as an essential component of multidisciplinary care, evidence has largely focused on isolated functional impairments rather than providing a comprehensive evaluation across rehabilitation domains. To systematically evaluate the effectiveness of rehabilitation and physiotherapy interventions for preventing and treating functional sequelae in adults with head and neck cancer. Materials and Methods: A systematic review and meta-analysis of randomized controlled trials was conducted according to PRISMA 2020 guidelines. PubMed/MEDLINE, Embase, Cochrane Library, and PEDro were searched from inception to June 2026. Studies involving adult patients with head and neck cancer receiving conservative rehabilitation interventions were included. Random-effects meta-analyses were performed for clinically homogeneous intervention contrasts within the mouth-opening and trismus domains. Distinct comparisons involving intervention timing, additional therapeutic components, or delivery strategies were analysed separately. Results: Twenty-seven publications representing 21 independent randomized trials were included. Quantitative synthesis was restricted to clinically homogeneous intervention contrasts. Compared with usual care, preventive jaw rehabilitation favoured greater mouth opening across three independent trials (mean difference = 2.85 mm; conventional 95% CI: 0.38–5.32), although the modified Hartung–Knapp sensitivity interval included no effect (95% CI: −2.58–8.27). The pooled estimate for trismus across three independent trials also favoured rehabilitation, although both conventional and small-sample-adjusted confidence intervals included no effect (RR = 0.87; conventional 95% CI: 0.53–1.42; modified Hartung–Knapp 95% CI: 0.25–2.98). Postoperative swallowing rehabilitation after oral-cancer surgery and free-flap reconstruction favoured rehabilitation in both sequential cohorts (adjusted difference in change = 10.06 points; 95% CI: 7.68–12.44; GEE group-by-time β = 7.29 points; 95% CI: 4.11–10.47). Additional timing, support, enhancement, and delivery comparisons were analysed separately. Conclusions: Targeted rehabilitation interventions produced favourable estimates for mandibular mobility and postoperative swallowing function in adults with head and neck cancer. Preventive jaw rehabilitation favoured greater mouth opening, although the result was inconclusive after small-sample adjustment; the trismus estimate also favoured rehabilitation but remained imprecise. Full article

Background: Hypoxia and oxidative stress are central features of cutaneous melanoma biology. Body mass index (BMI) and smoking, both of which can influence systemic hypoxia, inflammation, and oxidative stress, have shown inconsistent associations with melanoma. We investigated the association of the hypoxia-inducible factor-1 alpha gene (HIF1A) rs11549465 (1772 C>T; Pro582Ser) polymorphism, alone and in combination with overweight/obesity or smoking habits, with cutaneous melanoma susceptibility and clinicopathological characteristics. Methods: This observational case–control study included 132 Caucasian Italian patients with cutaneous melanoma and 312 healthy controls. The rs11549465 polymorphism was genotyped by genomic DNA restriction fragment analysis. Logistic regression provided age- and sex-adjusted and mutually adjusted estimates. Results: Genotype and allele frequencies did not differ between patients and controls. Within the melanoma cohort, smoking for ≥20 years remained associated with metastatic disease after adjustment for BMI ≥ 25 kg/m², age at diagnosis, and sex (aOR = 3.12, p = 0.006), whereas BMI did not (aOR = 1.23, p = 0.612). Compared with healthy controls, metastatic melanoma was independently associated with BMI ≥ 25 kg/m² (aOR = 2.26, p = 0.010) and smoking for ≥20 years (aOR = 3.85, p < 0.001). Mean pack-years were higher in melanoma patients than controls (9.4 ± 16.7 vs. 5.1 ± 12.2; p = 0.002), and ≥10 and ≥20 pack-years remained associated after age- and sex-adjustment (aOR = 2.19, p = 0.001 and aOR = 3.31, p < 0.001, respectively). Mean pack-years were higher in MetM than NMetM (13.1 ± 21.0 vs. 5.9 ± 10.0; p = 0.013), and ≥20 pack-years was associated with MetM (OR = 3.05, p = 0.017). Adjusted associations with head/neck melanoma (n = 13) were observed for CC plus BMI ≥ 30 kg/m² (aOR = 9.07, p < 0.001), ≥20 cigarette/day (aOR = 5.96, p = 0.004), ≥20 years smoking (aOR = 6.64, p = 0.003), and other smoking measures. Conclusions: To our knowledge, this is the first report on the interplay between the rs11549465 polymorphism and cutaneous melanoma. HIF1A rs11549465 was not independently associated with melanoma susceptibility. Associations involving smoking, BMI, joint genotype–lifestyle exposures, and anatomical localization had wide confidence intervals and were exploratory; small subgroups and multiple comparisons require cautious interpretation and independent validation. Full article

Background: Tumor hypoxia is a major determinant of radioresistance, limiting oxygen-mediated fixation of radiation-induced DNA damage and promoting metabolic adaptation, tumor aggressiveness, and treatment failure. Nitroimidazole derivatives and related hypoxia-targeting compounds have been investigated as radiosensitizers because of their oxygen-mimetic properties and selective activation under low-oxygen conditions. Methods: A structured narrative review was conducted to evaluate recent evidence on hypoxia-targeting strategies and nitroimidazole-based radiosensitizers combined with radiotherapy. PubMed and Scopus were searched in March 2026 using terms related to radiotherapy and nitroimidazoles. Studies published within the last five years were included if they investigated hypoxia-targeting compounds, radiosensitization strategies, or dose–response relationships relevant to radiotherapy. Preclinical, computational, and clinical studies were considered. Results: Sixteen studies were included, comprising preclinical, computational, and clinical investigations. Most studies were preclinical and evaluated in vitro cell lines, murine tumor models, or xenografts across multiple tumor types, including head and neck cancer, glioblastoma, breast cancer, colorectal cancer, cervical cancer, renal carcinoma, pancreatic cancer, and ovarian-related models. Nitroimidazole-based and related hypoxia-targeting strategies generally enhanced radiation response under hypoxic conditions, with sensitizer enhancement ratio values ranging from approximately 1.09 to 1.65. In vivo studies reported reductions in tumor growth or tumor volume when radiosensitizers were combined with radiotherapy. Clinical evidence, mainly in head and neck squamous cell carcinoma, showed variable effects on locoregional outcomes. Conclusions: Current evidence supports the biological relevance of hypoxia-targeting strategies for improving radiotherapy response. Nitroimidazole-based compounds show consistent radiosensitizing effects in preclinical models, but clinical translation remains heterogeneous. Future studies should integrate hypoxia imaging, standardized endpoints, advanced drug delivery systems, and clinically relevant radiotherapy models to better define their role in modern radiation oncology. Full article