6120 Background: Sinonasal carcinomas (SNCs) are rare malignancies with poor prognosis. Multimodal treatments including induction chemotherapy (ICT), surgery and radiotherapy (RT) - modulated by histology and response to ICT - are often used, aiming to improve oncological outcome in terms of local control and survival. Two phase II clinical studies published in 2023 assessed the role of ICT in SNCs, SINTART1 and 2 for resectable and unresectable tumors, respectively [PMIDs: 37164774, 37163806]. The current work aims at reporting the long-term follow-up (FUP) data for both trials. Methods: The FUP was updated as of January 2026 for patients enrolled in both clinical studies. Median FUP was estimated with reverse Kaplan-Meier method. The following survival times were analyzed with Kaplan-Meier method in each cohort: overall survival (OS), disease-free survival (DFS), loco-regional-free survival (LRFS), distant metastasis-free survival (DMFS). Results: The updated median (m) survival times (in months) with their 95% confidence intervals (CI) and the event rates are detailed in Table 1. Pooling together the 2 studies, 30% of patients (18/60) were alive at last follow-up. Conclusions: SINTART 1 and 2 represent, to date, the largest prospective cohorts with long-term survival data in SNCs. With a median FUP exceeding 9 years, these results provide a robust benchmark for ICT-based multimodal strategies in this setting. Survival outcomes remain consistent with the initial reports, indicating that prognosis is largely determined within the first 2-3 years, when most deaths occur (approximately 70%). The near-overlap of mDFS and mLRFS identifies loco-regional failure as the predominant pattern of recurrence. Moreover, the short interval between relapse and death underscores the limited opportunity for salvage. These findings collectively emphasize the need for more effective local-intensification approaches and novel systemic agents. Additional analyses are underway to identify prognostic and predictive factors. Clinical trial information: NCT02099175 ; NCT02099188 . Resectable (SINTART1)N=35 Unresectable (SINTART2)N=25 mFUP (95% CI) 108.26 (97.37-129.84) 103.22 (91.68-NR) mOS (95% CI)Events 37.53 (21.97-98.36)66% 27.07 (11.28-65.03)76% mDFS (95% CI)Events 26.25 (15.43-80.43)71% 17.1 (7.89-37.76)80% mLRFS (95% CI)Events 26.25 (15.43-80.43)71% 18.95 (7.89-39.05)80% mDMFS (95% CI)Events 34.47 (21.84-96.32)69% 26.88 (9.31-46.78)76%

Background/Objectives. Head and neck mucosal melanoma (HNMM) is a rare, aggressive malignancy with poor outcomes and limited evidence to guide prognostication and treatment. A detailed assessment of long-term survival and prognostic factors is needed to inform clinical management and staging. This work aimed to describe outcomes and prognostic factors in HNMM patients treated over 45 years. Methods. This was a retrospective observational cohort study of consecutive patients treated at a tertiary referral center in Italy from 1975 to 2020. Random-forest-based screening informed covariate selection for Cox models. Endpoints were overall survival (OS), disease-free survival (DFS), and post-recurrence DFS (prDFS). Associations with clinical and pathological variables were evaluated using Kaplan-Meier estimates, log-rank tests, and multivariable Cox regression. Results. Among 112 patients (median follow-up, 121.1 months), 3-/5-year OS was 42.8%/28.0%, DFS 20.5%/13.2%, and 1-/3-year prDFS 36.7%/10.9%. Ulceration was associated with worse OS (HR 2.12; 95% CI 1.05-4.26) and DFS (HR 2.23; 95% CI 1.16-4.28). Male sex showed a trend toward poorer OS and DFS. Regional lymph-node treatment correlated strongly with OS and prDFS (overall p < 0.001), with neck dissection indicating unfavorable risk (OS HR 5.22; 95% CI 2.39-11.40). Conclusions. HNMM remains a high-mortality disease with frequent recurrence. Ulceration and nodal involvement were key adverse prognostic factors, while surgery was associated with improved survival. The findings support incorporating ulceration into future staging and highlight the potential for durable control through salvage surgery. Further investigation of treatment intensification, biomarkers, and multimodal strategies is warranted.

PURPOSE:To quantitatively assess how microvascular conditions estimated via a non-invasive method can predict acute side effects after radiotherapy in patients with breast, prostate, and head and neck cancers. MATERIALS AND METHODS:We studied 314 patients, assessing their MicroVascular Health Score (MVHS) before radiotherapy using a sublingual microscope that records videos of red blood cells in microvessels, analyses the microvasculature's functional and geometric properties, and calculates the MVHS. The MVHS was incorporated into a logistic model to predict the risk of developing acute radio-induced both alone and in combination with dose. RESULTS:A clear quantitative association between MVHS and side effects was observed in the overall population (OR = 0.68, p = 0.001). A 1-unit decrease in MVHS was associated with a 31.9% increased risk of radiation-induced symptoms across cancer sites. In the breast subgroup, dose factors significantly affected side effect risk (OR for D200cc to the skin: 1.05 per 1 Gy; OR for D20cc: 1.14 per 1 Gy; OR for V20Gy: 1.01 per 1 cc; all p < 0.05). The D20cc model had the highest AUC (0.69), and adding MVHS further improved it to 0.76. CONCLUSION:The study strongly linked microvascular health to the risk of acute radio-induced symptoms, suggesting that this could inform predictive models and customise treatments based on patient vascular status.

This study presents a personalized computational framework for modeling the vascular microenvironment in head-and-neck cancer patients and evaluating the impact of microvasculature on radiotherapy outcomes. We first perform a population-based calibration of a microvascular model using data collected with a sublingual microscope from 62 patients, creating synthetic networks that capture microvascular features with a population-based approach. The calibrated models accurately reproduce key physiological parameters, such as red blood cells velocity, aligning with clinical data. Next, we personalize the model for nine patients, demonstrating that digital patient-specific microvascular networks can replicate individual vascular beds' structural and functional characteristics. Simulations highlight that, while morphological features improve with vascularization, red blood cells velocity is less predictable, revealing the limitations of using capillary density alone to describe microvascular complexity. We then integrate these microvascular models into a 3D virtual microenvironment to simulate oxygen delivery and radiotherapy response. Our results show that higher vascularization enhances oxygenation and reduces hypoxic regions, which correlates with improved tumor control probability. Additionally, our findings demonstrate how the properties of microvascular networks, radiosensitivity, and treatment parameters affect predicted radiotherapy outcomes. Our workflow supports the creation of microvascular digital twins, initialized using patient data from sublingual microscopy.

Background and purpose:Optimizing head and neck cancer (HNC) plans with single-energy proton beams that fully traverse the patient (transmission beams) can improve robustness and delivery efficiency, complementing conventional approaches. Materials and Methods:Experimental measurements, validated with Monte Carlo (MC) simulations, were carried out on a uniform water-equivalent plastic phantom (RW3) containing a metal component (2-Euro coins) irradiated with a single high energy proton field (228.6 MeV) to verify the transmission beam concept. 28 nasopharyngeal cancer (NPC) intensity modulated proton therapy (IMPT) were then optimized with nine coplanar single-energy fields (228.6 MeV), positioning the Bragg peaks well beyond the patient body, so called transmission beam mode. These plans (IMPT-TB) were compared to conventional IMPT and volumetric modulated arc therapy (VMAT) photon plans in terms of dose distributions quality, expected organ at risk (OAR) toxicity, robustness and delivery time. Results:Transmission beams minimized dose perturbation by metal objects (∼7% max relative variation at 18 cm depth). IMPT-TB plans achieved comparable dose distribution and expected toxicities to IMPT, increasing the dose bath (+96 % vs. IMPT) but remaining significantly lower than VMAT (-31.4 %). For 94 % of patients (N = 26), IMPT-TB met at least one additional dose constraint that the corresponding IMPT plan failed to satisfy. Moreover, in the analyzed subgroup (N = 5), IMPT-TB plans delivered with our synchrotron exhibit a 67 % reduction in beam time compared to IMPT plans. Conclusions:IMPT-TB plans demonstrated enhanced robustness and significantly faster delivery compared to IMPT. Transmission beams could be clinically implemented, also in conjunction with standard IMPT, for proton radiation treatment of NPC.

AIM:To assess the value of biologically enriched Normal Tissue Complication Probability (NTCP) models integrating clinical, dosimetric, and biological markers, specifically the RadioDtect© assay based on phosphorylated ATM (Ataxia-Telangiectasia Mutated, pATM) quantification. METHODS:We considered 67 patients with head-and-neck cancer receiving curative-intent radiotherapy. We developed logistic NTCP models for severe acute/late toxicities (grade ⩾3) using (i) the pATM-based RadioDtect test, (ii) clinical-dosimetric variables, and (iii) a combined model. Model performance was evaluated using AUC (Area Under the receiver operating characteristic Curve), calibration, and Net Reclassification Improvement (NRI), with internal validation via bootstrapping/permutation. RESULTS:Acute and late toxicity occurred in 70% and 15% of patients. The RadioDtect test alone yielded moderate performance for late toxicity (AUC=0.65) and low discriminatory power for acute toxicity (AUC=0.57). Clinical-dosimetric models for acute toxicity demonstrated substantial predictive value (AUC=0.77), primarily driven by doses to the pharyngeal constrictor muscles and parotid glands. Integrating RadioDtect modestly improved discrimination for acute toxicity (AUC=0.82) but added no clinical utility (NRI=0%). Conversely, for late toxicity, doses showed poor association and discrimination for the occurrence of severe side effects. The biological refined NTCP model showed improved discrimination (AUC=0.76) and meaningful clinical utility (NRI=46.3%). CONCLUSIONS:The RadioDtect assay adds limited value for predicting acute toxicity in clinical settings entailing large volumes of organs at risk irradiated at high doses, but enhances NTCP models for late toxicity prediction.

AIM:To evaluate the outcomes of combining carbon ion radiotherapy boost (CIRTb) with photons (Ph) or protons (PT) for locally advanced salivary gland and sinonasal cancers (SGCs and SNCs). MATERIALS AND METHODS:Sixty-nine patients with SGCs and SNCs received CIRTb to high-risk CTV and Ph or PT to low-risk CTV (LR-CTV) from October 2014 to September 2022. Two-year local relapse-free survival (LRFS) was analyzed with Kaplan-Meier. Toxicity according to Common Terminology Criteria for Adverse Events v5. Variables affecting toxicities were analyzed with chi-squared and Mann-Whitney U tests. RESULTS:Patients received a median CIRTb dose of 15 Gy RBE, with 24 (35%) receiving Ph and 45 (65%) receiving PT. With a median follow-up of 1805 months, 2-year LRFS achieved 89% (95% CI: 81-98). Female (p = 0.045) reported better 2-year LRFS rates: 95% (95% CI: 87-100) versus 84% (95% CI: 72-98). Acute and late G2+ toxicity were, respectively, 80% and 60%. Ph (p = 0.004) and smaller LR-CTV (p = 0.004) reduced acute and late toxicities. No G4 late toxicity was reported. CONCLUSIONS:CIRT combined with Ph or PT seems a valuable option for locally advanced SGCs and SNCs. Prospective studies are needed to select the best treatment combination.

BACKGROUND:Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer-related deaths worldwide, with HPV-negative cases being particularly aggressive. These cases often show poor prognosis and low responsiveness to radiotherapy. Improved prognostic tools and treatment strategies are needed to enhance outcomes. AIM:To evaluate the prognostic value of various gene expression signatures in predicting survival outcomes in HPV-negative HNSCC patients receiving radiotherapy and to compare their accuracy against the current TNM staging system. METHODS:This observational cohort study used data from the European BD2Decide project, systematically analyzing gene expression in loco-regionally advanced, non-metastatic HPV-negative HNSCC patients (stage III-IVa/b) treated with curative radiotherapy (post-operative or definitive) between 2008 and 2017. The primary outcome was overall survival (OS), with secondary outcomes including disease-free survival (DFS), distant metastasis-free survival (DMFS), and loco-regional recurrence-free survival (LRRFS). The prognostic performance of selected gene expression signatures was evaluated using receiver operating characteristic (ROC) curves and hazard ratios (HR) from Cox models. RESULTS:The study included 783 patients, with a median age of 63 years, mostly male (68 %), with significant tobacco (84 %) and alcohol (69 %) exposure. The 172-gene signature (172GS) showed the highest prognostic accuracy, outperforming the TNM system in predicting OS, DFS, DMFS, and LRRFS. Multivariable analysis confirmed its independent prognostic value. CONCLUSIONS:The 172GS gene signature offers superior prognostic information compared to TNM staging, supporting its potential use for better risk stratification and personalized treatment planning in HPV-negative HNSCC. Future trials should consider tumor biology and gene signatures for better patient selection. TRIAL REGISTRATION:NCT02832102.

BACKGROUND:Plasma Epstein Barr Virus (EBV)-DNA is an established biomarker for endemic EBV-related nasopharyngeal carcinoma (NPC). Its relevance in non-endemic regions is less understood. This study longitudinally assessed plasma EBV-DNA (LEA study) throughout the curative management of non-endemic EBV-related NPC to evaluate its prognostic value. MATERIALS AND METHODS:Between 2012 and 2023, patients with non-endemic, non-metastatic, histologically confirmed EBER+ NPC treated at a tertiary center were retrospectively analyzed. Plasma EBV-DNA levels were measured at pre-treatment (T1), early (T2a, ≤6 weeks) and late (T2b, ≤14 weeks) post-treatment, during follow-up (T3), and after induction chemotherapy (T4), when applicable. EBV-DNA was analyzed for its association with recurrence-free survival (RFS). RESULTS:At a median follow-up of 60 months (range: 9-134), 167 patients were included. Median age was 50 years (range: 22-75), with 72 % male; 84 % had stage III-IV disease (TNM VIII Edition). Pre-treatment EBV-DNA was detected in 96 % of patients, with no predictive cut-off (median RFS: 43 vs. 62 months for detectable vs. undetectable EBV-DNA). Post-treatment undetectable EBV-DNA correlated with better RFS, also with no cut-off. Follow-up EBV-DNA anticipated recurrence in 71 % of cases by a median of 38 days (range: 11-365). Persistently negative follow-up EBV-DNA was observed in 91 % of non-recurrent patients; isolated positive spikes lacked prognostic significance. Post-induction chemotherapy EBV-DNA demonstrated a 92 % negative predictive value for recurrence. CONCLUSIONS:Plasma EBV-DNA is a valuable prognostic biomarker for non-endemic NPC. Pre- and post-treatment undetectable EBV-DNA holds a positive prognostic value. Post-induction EBV-DNA is the most informative timepoint. Longitudinal EBV-DNA monitoring is warranted in clinical practice.

Purpose/Objective The rising incidence of Human Papilloma Virus (HPV) related oropharyngeal squamous cell carcinoma (OPC) in the older population has been confirmed by recent epidemiologic reports. An increase of over 50% is expected in the population aged older than 65 years in the next decade. Some authors have focused their investigations on the “late” elderly subgroup defined as patients (pts) aged 75 years or older, still underrepresented in clinical trials. Indeed, there is a significant lack of data on their disease trajectory. The purpose of our experience was to evaluate the pattern of clinical practice in this specific subgroup of pts within the Italian Association of Radiotherapy and Clinical Oncology (AIRO). Material/Methods An observational retrospective study was conducted over a 6-year period (2015-2021). Consecutive patients older than 75 years at diagnosis with a histologically-confirmed HPV positive (p16 immunohistochemistry/HPV DNA-in situ hybridization) OPC eligible for a curatively-intended treatment were included. Overall survival (OS) was defined as the time from OPC diagnosis to last follow-up or death from any cause. Progression-free survival (PFS) was defined as the time from the last day of curative-intended treatment to disease progression or death from any cause. Median OS and PFS was estimated by the Kaplan-Meyer method. A log-rank test was employed to test different variables: smoking history, presence of caregiver, employed treatment modality and age (< or > 80 years) correlated with longer OS. Hazard ratios (HR) for the association between the variables of interest and the risk of death were obtained by univariate Cox regression analysis. A p-value <0.05 was considered statistically significant. Acute toxicity was evaluated according to CTCAE v. 5.0 Results A cohort of 95 pts was included in our analysis. The median age was 78 years (table 1). ECOG PS 0-1 and locally advanced disease were reported for the vast majority of patients, 92.6% and 89.4% (in stage III/IV according to TNM 7thedition) respectively. As expected, exclusive radiotherapy (RT) was the most common adopted strategy. After a median follow- up of 25 months (range: 0-116), 64 patients were alive (67.3%). The one and two-year PFS were 75% and 67%, the median PFS was not reached (Figure 1a). The one and two-year OS rates were 83% and 75%, respectively, whereas the median OS was not reached. Among the tested variables, belonging to the group of age >80 years was associated with a worse OS (p=0.0429; HR for death, 2.15, 95% CI 1.00-4.60, Figure 1b), whereas no impact on survival was associated to the smoking history (p=.011), treatment modality (p=0.32) and presence of caregiver (p=0.65). The toxicity profile was acceptable (>G3 toxicity of 29.4%), although 6 patients (6.3%) died due to potential treatment-related complications. Further analyses on radiation dose, target volumes and pattern of failure will be reported Conclusion To the best of our knowledge, our series represents one of the largest to date on “late” elderly population with non-metastatic HPV positive OPC treated with a curatively-intended, RT-based approach. Thanks to the appropriate selection of pts, an optimal survival outcome can be achieved with standard treatment options, in line with data reported for the younger population. Further prospective studies investigating larger series of older pts are warranted in order to confirm our conclusions.

Purpose/Objective Plasma Epstein Barr virus (EBV)-DNA is employed as a biomarker for EBER (EBV-encoded RNA) positive nasopharyngeal cancer (NPC) patients. In Europe, the use of plasma EBV-DNA is limited by the lack of harmonization among different European Conformity (CE)-marked EBV-DNA detection methods and BamHI-W, the latter being the gold standard assay in endemic areas. Our Institution demonstrated that three CE-marked (i.e., ELITech, Abbott, Artus) and BamHI-W assays significantly agreed in plasma EBV-DNA quantification in non-endemic NPC (1). In this setting, the role of plasma EBV-DNA was better defined only before curative treatment, (2) with undetectable baseline plasma EBV-DNA levels holding a positive prognostic significance in terms of disease-free survival (DFS) and overall survival (OS) (2). However, the value of CE-marked assays in Longitudinal assessment of plasma EBV-DNA (LEA) -alongside the curative management and follow-up of non-endemic NPC - is still lacking (1; 2). Herein, we present the results of the LEA study (Ethics Comittee n. 150/23) concerning the dynamics of plasma EBD-DNA viral load in a single-Institution cohort of non-endemic NPC patients. Material/Methods From 2012 to 2023 we retrospectively collected data of all EBER-positive NPC patients treated with curative intent at our Institution. All subjects underwent plasma EBV-DNA quantification at the following time-points: 1) pre-treatment (within 1 month since treatment start); 2) post-treatment (2A, early post-treatment, within 6 weeks after treatment completion and/or 2B, late post-treatment, within 16 weeks after treatment end); 3) follow-up phase. EBV-DNA results were classified as negative (if EBV-DNA was not detected) or positive (if EBV-DNA was detected and quantifiable or detected but not quantifiable) and were expressed as log IU/ml. Descriptive statistics were performed on all available data. The role of pre-treatment EBV-DNA as predictive factor for disease recurrence was assessed by estimating the Receiver Operating Characteristic (ROC) curve at different cut-offs. The predictive value of post-treatment (2A, 2B) EBV-DNA load was assessed considering its ability to forecast recurrence. For patients with both 2A and 2B available samples, the 2B value was considered for post-treatment analyses. Results At the data cut-off (Aug, 07th, 2023), 169 EBV-related NPC patients were identified. Median age at diagnosis was 50 years (range: 22-75). Most of them were male (72%) and staged as III/IV (84%) according to AJCC classification (VIII Ed.). Only two patients presented oligo-metastatic disease at distant sites, and they were not included in the final analyses on the predictive value of EBV-DNA. At a median follow-up of 66 months (range: 9-134), 41 patients (24.2%) recurred and 139 (82.2%) were still alive. Out of 167 evaluable patients, median viral load of pre-treatment plasma EBV-DNA was of 2.59 log IU/ml (range: 1.59-5.11), while it was undetectable only in six (3.5%) patients who did not recur. All 41 recurrences occurred in patients with pre-treatment detectable EBV-DNA. In addition, subjects with undetectable baseline EBV-DNA had almost significantly (p=0.07) higher DFS with respect to those who showed detectable baseline values (DFS: 66 vs. 47 months, respectively). For pre-treatment plasma EBV-DNA, the best cut-off in terms of disease recurrence prediction was not identified within total population (area under curve, AUC: 0.56) and in early (at 1-y) recurrent patients (n=20) (AUC: 0.58). Regarding the predictive value of post-treatment EBV-DNA measurement (2A, 2B; within 16 weeks), its accuracy, sensitivity, specificity were 78%, 61%, and 80%, respectively, with regards to recurrence detection at any time-point during the follow-up. Moreover, its negative predictive value (NPV) was 94%, which resulted stable across the first three years of follow-up (93% at 1st-y, 95% at 2nd-y, 95% at 3rd-y). On the other hand, its overall positive predictive value (PPV) was 27%, which progressively decreased during follow-up (40% at 1st-y, 34% at 2nd-y, 30% at 3rd-y). Conclusion To our knowledge, this is the largest longitudinal evaluation of plasma EBV-DNA quantification in non-endemic EBV-related NPC patients. Undetectable pre-treatment plasma EBV-DNA confirmed its positive prognostic role. NPV of post-treatment (within 16 weeks since curative therapy end) plasma EBV-DNA was 94%, remaining stable during follow-up time (first 3 years) whereas its sensitivity and PPV were lower - 61% and 27%, respectively. The LEA study provides additional data on the significance of plasma EBV-DNA in non-endemic curable NPC, which can also guide clinicians towards a standardization of the timing of plasma EBV-DNA assessment in this setting.