QuestionIs intratumoral delivery of NBTXR3 followed by definitive radiation therapy (RT) safe and effective for cisplatin-ineligible and cetuximab-ineligible patients with locally advanced head and neck squamous cell carcinoma (HNSCC)?FindingsIn this phase 1 dose-expansion nonrandomized clinical trial of 56 older patients with substantial comorbidities, intratumoral NBTXR3 followed by definitive RT was feasible with a preliminary signal in efficacy.MeaningIn this nonrandomized clinical trial, among a population with poor prognostic locally advanced HNSCC with limited treatment options, intratumoral NBTXR3 followed by RT was feasible and had a benefit-risk profile that supports further study in a randomized clinical trial. This nonrandomized clinical trial evaluates safety and preliminary efficacy of NBTXR3 followed by radiation therapy in patients with locally advanced head and neck squamous cell carcinoma ineligible to receive concurrent systemic therapy. ImportanceIntratumoral delivery of NBTXR3 radioenhancer followed by radiation therapy (RT) previously demonstrated safety and feasibility in cisplatin-ineligible and cetuximab-ineligible patients with locally advanced head and neck squamous cell carcinoma (HNSCC) in a dose-escalation phase 1 study.ObjectiveTo evaluate safety and preliminary efficacy of NBTXR3 followed by RT in patients with locally advanced HNSCC ineligible to receive concurrent systemic therapy.Design, Setting, and ParticipantsThis single-arm, phase 1 dose-expansion nonrandomized clinical trial was conducted across 20 centers in Europe between March 4, 2019, and January 10, 2022. Patients were ineligible for cisplatin and cetuximab per investigator's judgement and had unresectable T3-4 or overall stage III/IVA HNSCC (per the American Joint Committee on Cancer Staging Manual, eighth edition) of the oral cavity or oropharynx. Data were analyzed from July to August 2023.InterventionsPatients received a single intratumoral administration of NBTXR3 in the primary tumor at the recommended dose of 22% of estimated tumor volume (ETV) followed by RT (70 Gy over 35 fractions).Main Outcomes and MeasuresPrimary outcomes were safety and efficacy assessed by the objective response rate (ORR) of the NBTXR3-injected primary tumor. Other outcomes included ORR of all lesions (injected primary tumor and noninjected involved lymph nodes), progression-free survival, and overall survival.ResultsOf the 56 patients treated, the median (range) age was 72 (44-89) years, 40 (71%) were men, 34 (61%) were 70 years and older, and 36 (64%) had a substantial burden of comorbidities (age-adjusted Charlson Comorbidity Index score of 4 or greater). Median (range) follow-up was 33.0 (0.7-44.6) months. NBTXR3-related treatment-emergent adverse events occurred in 9 patients (16%), of which 6 (11%) were grade 3 or higher, the most frequent being stomatitis (2 [4%]). Objective tumor response was assessed in 44 patients, as 12 patients were unable to complete RT or did not have posttreatment tumor assessment. In this evaluable patient population, the ORR of the injected primary tumor and ORR of all lesions were 82% (95% CI, 67-92) and 80% (95% CI, 65-90), respectively. Among all 56 treated patients, the median progression-free survival was 11.4 months (95% CI, 6.7 to not reached), and the median overall survival was 18.1 months (95% CI, 9.7 to not reached).Conclusions and RelevanceThis dose-expansion phase 1 nonrandomized clinical trial demonstrated that intratumoral NBTXR3 followed by RT in a high-risk patient population unable to receive cisplatin or cetuximab was feasible and had a preliminary efficacy signal that supports a benefit-risk profile being evaluated in an ongoing randomized phase III trial.Trial RegistrationClinicalTrials.gov Identifier: NCT01946867

OBJECTIVE:Craniopharyngiomas are classified as adamantinomatous or papillary subtypes. Papillary craniopharyngiomas harbor BRAF V600E mutations and demonstrate high response rates to BRAF/MEK inhibition. Craniopharyngiomas involving the hypothalamus are common and carry high surgical morbidity, including endocrine, metabolic, and neurocognitive complications. Therefore, reliable preoperative identification of papillary hypothalamic tumors could support consideration of biopsy followed by targeted therapy, potentially avoiding high-risk surgery. DESIGN:This study is a single-center retrospective study. METHODS:We retrospectively analyzed 61 adult patients with hypothalamic craniopharyngiomas. We defined a novel MRI biomarker, the polystyrene beads sign, as an agglomerate of small, rounded, contrast-enhancing nodules on high-resolution T1-weighted post-contrast MRI. Six independent clinicians, blinded to histopathology, evaluated the presence of the sign. Diagnostic performance (sensitivity, specificity, accuracy) and intra- and interrater reliability were assessed. RESULTS:The polystyrene beads sign identified papillary tumors with 92% sensitivity, 98% specificity, and 96% overall diagnostic accuracy. Intrarater reliability across 2 separate readings was high, and interrater reliability among all 6 clinicians was excellent. After a brief calibration session, the sign was consistently recognizable and distinguishable from enhancement patterns observed in adamantinomatous tumors. CONCLUSIONS:The polystyrene beads sign is a simple and reproducible preoperative MRI marker that may help identify papillary hypothalamic craniopharyngiomas. These findings support further evaluation in multicenter studies before clinical implementation. Its recognition may contribute to imaging-based diagnostic strategies, including selection of patients for confirmatory biopsy, molecular testing, and subsequent targeted therapy in appropriate cases.

BACKGROUND AND PURPOSE:Postoperative target delineation after reconstructive surgery in head and neck cancer (HNC) is heterogeneous; whether to include the flap or focus on the native tissue-flap junction is debated. We quantified patterns of relapse relative to flaps and summarized practice, toxicity and function. MATERIALS AND METHODS:in the retrospective XFLAP1 cohort (2018-2023), patients with HNC underwent tumor resection with flap reconstruction and postoperative radiotherapy (PORT) ± concurrent chemotherapy. Competing-risks (Fine-Gray) estimated locoregional relapse (LRR) and metastases; overall survival (OS) used Kaplan-Meier. Flaps were contoured a posteriori on planning CTs, when available. RESULTS:Of 355 patients across eight centres, free flaps were used in 239 (67%) and regional pedicled flaps in 69 (33%). The entire flap body was encompassed in the CTVs in 66% of plans; median flap-body dose was 65.3 Gy and pedicle Dmax 67.5 Gy for the delineated flaps (N = 153). Median follow-up was 32.9 months, 120/355 (34%) patients relapsed, including 68 (19%) LRR and 71 (20%) metastases. Median time to LRR was 7.35 months; only 3 (1%) of relapses arose within the flap body. Two-year cumulative incidence was 15.8% for LRR and 16.7% for metastases; two-year OS was 74.6%. On multivariable analysis, pN2-3 predicted metastases; LRR, metastases, and ECOG ≥ 1 were associated with worse OS. CONCLUSIONS:relapses in the flap-body epicentre were rare; most local failures involved the native tissue-flap junction or non-flap sites. These data support junction-focused CTVs with reduced emphasis of the flap body to limit morbidity, pending prospective validation.

BACKGROUND:Aggressive evolution of PitNETs is rare; metastatic spread is even more. Defining aggressiveness and malignancy is challenging, subsequently hard to predict, and to understand. The aim was to provide a molecular definition of aggressiveness using genomic approaches. METHODS:PitNETs from 206 patients were included. Associations between 9 clinicopathological features of aggressiveness and PitNETs' omics were explored. Omics included transcriptome, DNA methylation, chromosomal alterations, and mutations. Clonal tumor evolution was monitored in 7 patients. RESULTS:Among the 9 clinicopathological features of aggressiveness, only rapid progression, progression after radiotherapy, Ki67/MIB1 proliferation index ≥10%, temozolomide treatment, metastases, and specific death were associated with specific omics signatures, while tumour maximal diameter ≥40 mm, cavernous, and sphenoid invasion were not. The omic signatures associated with these features of aggressiveness overlapped but remained distinct between corticotroph and mammo-somato-thyrotroph lineages. For each lineage, a common signature of aggressiveness was identified, associating a proliferative transcriptome signature and DNA hypermethylation. Alterations in specific genes were associated with aggressive features, including a novel PitNET gene, LRP1B, and known cancer genes (TP53, CDKN2A), while USP8 and GNAS alterations were not. Integration of gene alterations with methylome and transcriptome signatures isolated a subset of molecularly aggressive PitNETs. Molecular signatures were stable during the course of the disease, despite evolution toward aggressiveness and potential clonal divergence. CONCLUSION:This systematic analysis of clinicopathological features of aggressiveness using an integrated multiomic approach establishes a histomolecular definition of aggressiveness in PitNETs. Prospective cohort studies are needed to validate these molecular signatures and establish their prognostic value.

Proton therapy (PT), first delivered passively using the Double Scattering (DS) technique, has shifted to active delivery through the Pencil Beam technique (PBS). However, the biological effectiveness of DS versus PBS proton beams on cancer cells, remain largely unknown. Given that PBS-PT is now commonly used to treat young patients with Ewing sarcoma, this point is of major importance in clinical practice and raises the question of the same effectiveness of both proton modalities on tumor control. This study aims to compare the biological effects of clinical PBS vs. DS proton beams on various Ewing sarcoma cell lines. For this, we used a clinical Proteus 235 isochronous cyclotron capable of delivering both PBS and DS treatment modalities. Three different cancerous Ewing cell models were irradiated either in the plateau or in mid Spread-Out Bragg Peak (SOBP). We performed cell survival assays (2D monolayers and 3D spheroids), along with Reactive Oxygen Species (ROS) production (CellRox deep red assay) and quantification of 53BP1 foci 1 h and 18 h post-irradiation by immunofluorescence. No significant differences were observed in cell survival (either in 2D or in 3D) at the plateau or mid-SOBP between the two proton treatment modalities. However, higher ROS production and a greater number of residual 53BP1 foci were observed in PBS compared to DS technique. Both PBS and DS proton irradiation modalities exhibit the same in vitro biological effectiveness on Ewing sarcoma models. However, the question of the possible influence of the ROS/53BP1 increase on the onset of side effects or late toxicities when using the PBS irradiation technique, may arise.

Importance:Intratumoral delivery of NBTXR3 radioenhancer followed by radiation therapy (RT) previously demonstrated safety and feasibility in cisplatin-ineligible and cetuximab-ineligible patients with locally advanced head and neck squamous cell carcinoma (HNSCC) in a dose-escalation phase 1 study. Objective:To evaluate safety and preliminary efficacy of NBTXR3 followed by RT in patients with locally advanced HNSCC ineligible to receive concurrent systemic therapy. Design, Setting, and Participants:This single-arm, phase 1 dose-expansion nonrandomized clinical trial was conducted across 20 centers in Europe between March 4, 2019, and January 10, 2022. Patients were ineligible for cisplatin and cetuximab per investigator's judgement and had unresectable T3-4 or overall stage III/IVA HNSCC (per the American Joint Committee on Cancer Staging Manual, eighth edition) of the oral cavity or oropharynx. Data were analyzed from July to August 2023. Interventions:Patients received a single intratumoral administration of NBTXR3 in the primary tumor at the recommended dose of 22% of estimated tumor volume (ETV) followed by RT (70 Gy over 35 fractions). Main Outcomes and Measures:Primary outcomes were safety and efficacy assessed by the objective response rate (ORR) of the NBTXR3-injected primary tumor. Other outcomes included ORR of all lesions (injected primary tumor and noninjected involved lymph nodes), progression-free survival, and overall survival. Results:Of the 56 patients treated, the median (range) age was 72 (44-89) years, 40 (71%) were men, 34 (61%) were 70 years and older, and 36 (64%) had a substantial burden of comorbidities (age-adjusted Charlson Comorbidity Index score of 4 or greater). Median (range) follow-up was 33.0 (0.7-44.6) months. NBTXR3-related treatment-emergent adverse events occurred in 9 patients (16%), of which 6 (11%) were grade 3 or higher, the most frequent being stomatitis (2 [4%]). Objective tumor response was assessed in 44 patients, as 12 patients were unable to complete RT or did not have posttreatment tumor assessment. In this evaluable patient population, the ORR of the injected primary tumor and ORR of all lesions were 82% (95% CI, 67-92) and 80% (95% CI, 65-90), respectively. Among all 56 treated patients, the median progression-free survival was 11.4 months (95% CI, 6.7 to not reached), and the median overall survival was 18.1 months (95% CI, 9.7 to not reached). Conclusions and Relevance:This dose-expansion phase 1 nonrandomized clinical trial demonstrated that intratumoral NBTXR3 followed by RT in a high-risk patient population unable to receive cisplatin or cetuximab was feasible and had a preliminary efficacy signal that supports a benefit-risk profile being evaluated in an ongoing randomized phase III trial. Trial Registration:ClinicalTrials.gov Identifier: NCT01946867.

Background: Radiotherapy is essential for skull base tumor management but carries the risk of radiation-induced brain injury (RIBI). This spectrum ranges from transient radiation-induced contrast enhancement (RICE) to irreversible necrosis. Distinguishing these entities from tumor progression is critical, particularly with the increasing adoption of proton therapy. Methods: A comprehensive narrative review of the peer-reviewed literature was conducted up to October 1, 2025. The search strategy focused on adult patients treated for skull base malignancies, synthesizing data on dose–volume metrics, incidence rates, and modality-specific toxicity profiles. Results: RIBI represents a pathophysiological continuum. (a) Descriptive imaging patterns: In prospective proton therapy series, focal RICE occured in 15% of patients, typically at a median of 12 months, and often resolved spontaneously. (b) Modality comparison: Although proton therapy reduces integral brain dose versus photon therapy, elevated linear energy transfer (LET) at the distal Bragg peak may contribute to focal radiation-associated image changes (RAIC), particularly in the temporal lobes. (c) Risk stratification and diagnosis: Risk increased when >1% of the healthy brain received >57.6 Gy (Relative Biological Energy (RBE)) or when V67Gy exceeded 0.17 cc. Advanced MRI and amino acid positron emission tomography (PET) improved differentiation between radiation effects and tumor recurrence. Conclusions: Post-radiation imaging changes are common and often benign. Distinguishing RICE from progression requires multimodal imaging and adherence to specific dose constraints. Management should prioritize surveillance for asymptomatic lesions.

Background:Recent advances in understanding the biology of cancer have resulted in an extensive armamentarium of new therapeutic agents, most often tested on various tumor types at the earliest stages of drug development. However, the clinical impact of these therapies on patients with head and neck cancer (HNC) remains underexplored and requires further evaluation. Objectives:To investigate the clinical outcomes and toxicity profiles of patients with HNC enrolled in phase I trials (Ph1t) at a tertiary referral center over the last decade. Design:A retrospective cohort study was conducted, analyzing data from HNC patients enrolled in phase I trials at the Curie Institute between October 2011 and January 2024. Methods:Data on baseline characteristics, hematologic biomarkers, and outcomes were extracted from medical records. Objective response rate (ORR) and Kaplan-Meier estimates of progression-free survival (PFS) and overall survival (OS) were analyzed. A Cox model was used for the identification of prognostic factors. Results:One hundred and thirty patients were enrolled in Ph1t for recurrent/metastatic (R/M) setting (66.9%), including 20.8% of patients being treated with more than two lines of therapy, followed by locally advanced (LA) treated with radical surgery or exclusive chemo/radiotherapy (17.7%), neoadjuvant (10.0%), and adjuvant (5.4%) Ph1t. Patients were treated with immunotherapy (53.8%), targeted therapy (23.1%), bispecific antibody (8.5%), antibody-drug conjugate (4.6%), and other agents (10.0%). In 122 patients evaluable for response, ORR were 16.5%, 87.0%, and 92.3% in R/M, LA, and neoadjuvant Ph1t, respectively. Median PFS/OS rates were 2.0/8.3, 21.5/38.3, and 20.0/27.4 months in R/M, LA, and neoadjuvant Ph1t, respectively.At multivariable analysis, lower lymphocytes (HR = 0.144; 95% CI: 0.052-0.399; p < 0.001) and lower albumin levels (HR = 0.922; 95% CI: 0.879-0.966; p < 0.001) remained associated with poorer OS. Grade 3-4 adverse events were recorded in 27/130 patients (20.8%). The most frequent were hematologic and gastrointestinal disorders. No treatment-related deaths occurred. Conclusion:HNC Ph1t show encouraging results in terms of early efficacy signals and safety profiles, emphasizing their value across a variety of clinical settings.

OBJECTIVE:Radiotherapy plays a relevant role in uncontrolled pituitary neuroendocrine tumors (PitNETs). Radiotherapy controls tumor progression in most cases, but not always. Prognostic factors for tumor progression after radiotherapy remain poorly defined. The aim was to evaluate tumor progression after radiotherapy, to identify risk factors, and to report management and outcomes in a cohort of PitNETs with uncontrolled progression. DESIGN:This was a retrospective, single-center, observational study. METHODS:In total, 123 consecutive patients who underwent radiotherapy for PitNETs and were followed at Cochin Hospital between 2000 and 2022 were included. Indication for radiotherapy was uncontrolled tumor progression (80%), adjuvant (9%), or uncontrolled secretion (11%). The median follow-up after radiotherapy was 10.0 years. RESULTS:Tumor progression after radiotherapy was observed in 28/123 (23%) patients. Higher risk of progression was associated with lactotroph and corticotroph tumor types (HR [95% CI] 12.0 [1.2-117.1] and 9.3 [1.3-69.6], respectively), male sex (3.7 [1.6-8.4]), and necrotic-hemorrhagic changes before radiotherapy on magnetic resonance imaging (3.1 [1.1-8.4]). Surgery, temozolomide, and re-irradiation were the most frequent treatments for the management of patients with tumor progression after radiotherapy, used in 18/28(64%), 16/28(57%), and 8/28(29%) cases, respectively. The most common complication of radiotherapy was the new onset of pituitary deficits, observed in 41% of cases; other complications, including radiation-induced neuroinflammation, cerebrovascular events, and second brain tumors, were rare. Three patients developed metastases, and 6 patients died because of tumor progression. CONCLUSIONS:Lactotroph and corticotroph PitNETs, in male patients, and/or with necrotic-hemorrhagic changes are at higher risk of progression after radiotherapy. Patients with progression after radiotherapy require additional heavy treatments with variable outcome.

Surgical (SS) and non-surgical strategies (NSS) are both considered as valid options in the therapeutic management of oropharyngeal squamous cell carcinoma (OPSCC) because of the absence of randomized control trial. The objective of this retrospective cohort study was to compare the efficacy of SS versus NSS on overall survival (OS) and disease-free survival (DFS) in non-metastatic OPSCC. The study included patients treated in two centers between 2012 and 2020 treated by upfront surgery in SS group and other therapies in NSS. A Cox model allowed to estimate hazard ratios and 95

PURPOSE:This study evaluates the efficacy of a previously published [18F]-FDG PET radiomic signature in predicting locoregional failure locations post-reirradiation in head and neck cancer (HNC) patients, using an independent cohort from a different institution. MATERIALS AND METHODS:Among the 66 patients reirradiated for recurrent HNC at Massachusetts General Hospital between 2012 and 2022, 31 underwent pre-reirradiation PET, constituting the external cohort for this analysis. These patients were characterized using the same radiomic features as the original model (Intensity_histogram_min, Kurtosis, Correlation, and Contrast), projected as a supplementary individual onto the published first principal component, and assigned to one of two groups using the published cutoff. The cutoff was then optimized for the external cohort to determine the loss of performance due to technical or population shifts. RESULTS:Among the 31 patients, 22 experienced a second locoregional failure, distributed between 12 "in-field" and 10 "outside" recurrences. With the original cutoff, the model achieved a BA of 70% and a positive predictive value (PPV) of 86% for detecting "in-field" recurrences. After recalibrating the cutoff, the model achieved a BA of 78% and a PPV of 89%, close to the 84.5% BA obtained in the original article. CONCLUSION:The study validates the ability of the previously established PET radiomic signature to predict "in-field" relapses following reRT with a high PPV. These results support the potential of PET radiomics in identifying patients who may benefit from "in-field" dose escalation in reRT schemes. The model is freely available through the user-friendly LIFEx software.

Magnetic resonance imaging (MRI) often demonstrates alterations following cranial radiotherapy (RT), which may result in clinical symptoms and diagnostic uncertainty, and thus potentially impact treatment decisions. The potential differences in MRI alterations after proton and photon RT, has raised concerns regarding the relative biological effectiveness of proton therapy. To provide an overview of MRI alterations in the brain post-RT and to explore differences between photon and proton RT, a systematic review adhering to the PRISMA guidelines was conducted, focusing on the assessment methods and definitions across studies. A systematic search of three electronic databases was performed using the concepts 'normo-fractionated radiotherapy ', 'MRI alterations' and 'brain, skull base or head and neck tumours in adult and paediatric populations'. Data extraction and quality assessment was performed on articles meeting the predefined criteria by two independent reviewers. Out of 5887 screened studies, 94 met the inclusion criteria. These studies were categorized based on confinement of the MRI alterations to temporal lobe, brainstem, or across the entire brain. Additional subclassification was performed based on MRI sequences evaluated or by the nature of the alterations, with pseudoprogression generally reserved for glioma patients. While many papers exist on MRI alterations in the brain after RT, this review highlights significant inconsistencies in the terminology and definitions, limiting the comparability of findings across studies. Our results highlight the need for and facilitate the development of a standardized framework for describing MRI alterations after RT.

Advances in radiation therapy techniques that allow for better normal tissue sparing have made reirradiation (reRT) a more viable option for managing locoregional recurrences in various cancers. However, severe toxicity and a high risk of second recurrence persist, emphasizing the need for improved patient selection and treatment planning. This scoping review, registered in the PROSPERO database (CRD42023387364), followed PRISMA guidelines. A thorough search was conducted from 2012 to December 2023 in MEDLINE (via PubMed) and BioMed Central databases, focusing on studies that reported the value of multimodal imaging in enhancing patient selection and optimizing reRT planning. Inclusion criteria targeted studies involving MRI and PET imaging, with exclusions based on relevance, language, and quality. Of 363 records identified, 29 studies met inclusion criteria. Most focused on high-grade glioma (HGG, 48