Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) poses a significant health challenge, especially among elderly patients, who are often underrepresented in clinical trials. Transoral robotic surgery (TORS) has emerged as a promising alternative to non-surgical strategies such as chemoradiotherapy (CRT), but its effectiveness in older adults is not well-studied. Methods: A structured narrative review of studies on TORS for elderly HNSCC patients was conducted using the PubMed/MEDLINE database. Studies were selected according to predefined eligibility criteria based on the PICOS framework. PRISMA reporting principles were applied to document study identification and selection. Results: The available evidence suggests that, in carefully selected elderly patients, TORS is associated with disease-specific (DSS) and disease-free survival (DFS) outcomes comparable to those reported in younger cohorts, while overall survival (OS) appears more strongly influenced by comorbidities than chronological age. TORS may facilitate treatment de-escalation in selected cases, potentially reducing exposure to adjuvant therapies and limiting treatment-related toxicity. Functional outcomes, particularly swallowing function and long-term gastrostomy dependence, may be favorable in selected elderly patients; however, comparative data with non-surgical approaches remain limited, heterogeneous, and are partly derived from mixed-age cohorts. Conclusions: TORS represents a viable treatment option for selected elderly HNSCC patients, providing encouraging oncologic outcomes and potential functional advantages. Nevertheless, the current evidence base is predominantly retrospective and heterogeneous. Careful patient selection is essential, and further prospective elderly-specific studies are needed to better define functional and oncologic benefits.

Agreement between two pathologists

CosMx protein panel showing stainings in MGC

Immunohistochemistry for representative Visium markers

Background: Radiosensitivity biomarkers hold promise for personalized radiotherapy but their clinical maturity and acceptability remain uncertain in head and neck cancer (HNC). This study assessed expert consensus on the potential integration of radiosensitivity testing and Normal Tissue Complication Probability (NTCP) modeling to inform therapeutic and supportive decisions. Material and methods: A Delphi consensus survey was conducted among HNC specialists to evaluate perceptions of clinical applicability, validation requirements, and integration of radiosensitivity testing to guide therapeutic interventions, including test-guided treatment modifications and combination with NTCP models. Results: A clear distinction emerged between supportive-care interventions and radiosensitivity test-guided treatment adaptations. Experts agreed that the current level of maturity of radiosensitivity biomarkers and NTCP modeling does not support major changes to primary treatment decisions outside clinical trials. Ten statements reached consensus, including IMRT as standard, individualized nutritional follow-up, and posttreatment surveillance as routine practice; one reached rejection. Partial agreement was observed for radiosensitivity testing in complex cases and for proton referral in high-risk patients, while preventive gastrostomy showed no consensus. Supportive-care measures were consistently considered acceptable in routine practice, whereas biomarker-guided treatment adaptations were mainly supported within clinical trials. External validation confirmed high concordance for supportive-care items and moderate support for trial-based biomarkerguided strategies. Conclusions: Experts considered radiosensitivity testing and NTCP modeling as promising yet not ready for routine therapeutic decision-making. Supportive-care interventions are widely accepted in routine HNC practice, whereas radiosensitivity test-guided treatment adaptations remain investigational and should currently be evaluated within clinical trials.

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

Transoral robotic surgery (TORS) for head and neck cancers has developed since 2005, following the pioneering work of the University of Pennsylvania team. Since then, numerous publications have demonstrated its clinical feasibility and safety, while several clinical trials have confirmed favorable oncologic and functional outcomes. Today, robotic surgery is routinely used as an alternative to conventional transoral approaches for tumors that are difficult to expose, as an alternative to external open approaches for tumors that are not amenable to transoral exposure, and as an alternative to non-surgical treatments when robotic surgery is expected to provide oncologic or quality-of-life benefits. The most common head and neck tumor sites treated with robotic surgery are HPV-positive oropharyngeal carcinomas, followed by HPV-negative oropharyngeal carcinomas, supraglottic laryngeal tumors, and other less frequent locations. In oropharyngeal carcinoma, published data have demonstrated oncologic outcomes at least equivalent to those achieved with other therapeutic and surgical strategies, while allowing de-escalation of adjuvant treatments in patients with low- or intermediate-risk disease. Evidence remains more limited for other tumor sites, particularly the larynx, hypopharynx, parapharyngeal spaces, and salvage surgery, where robotic surgery may be reserved for carefully selected indications and patients and performed by experienced teams. This article summarizes the current evidence regarding indications, oncologic and functional outcomes, and future perspectives of robotic surgery within the framework of personalized multimodal treatment strategies.

Quantification of TILs, CD68-positive mononuclear macrophages and tumor grade

CosMx 64-plex human immuno-oncology protein panel

Representative video of an isolated MGC in oral cavity SCC from GR cohort

This table provides the DEG for the seven main clusters of the Visium experiment

Performances of the deep-learning cell detection model in TCGA cohorts (oral cavity, uterine cervix and larynx SCC) and GR cohorts (oral cavity SCC)

Background: Cancer-related sarcopenia (CRS) is a significant complication of head and neck carcinoma (HNC), characterised by muscle degeneration and poor clinical outcomes. Although various dietary and therapeutic interventions have been explored, most of them remain empirical, and the molecular mechanisms underlying CRS are not yet fully understood. Methods: Transcription profiles of muscle fragments from 29 HNC patients and 8 control donors were analysed by bulk RNA sequencing (6/29 and 3/8) and/or RT-qPCR (29/29 and 5/8). In parallel, differentiating human myoblasts (AB1190) were subjected to indirect co-culture with two types of effector cells: HNC cells (FaDu) or control epithelial cells (NHEK). The contactless effects of effector cells on target myoblasts were investigated using cell imaging to assess muscular differentiation, RT-qPCR and Western blot to assess gene expression. Results: Bulk RNA sequencing identified 789 differentially expressed transcripts between HNC and control samples. Subsequent RT-qPCR analysis focused on IL32 and BIRC3 mRNAs (up-regulated in HNC samples) and ACE1 mRNA (down-regulated). Among male HNC patients, the IL32/ACE1 mRNA ratio was significantly elevated in CRS cases (p = 0.0001, effect size r = 0.57) and correlated with the severity of muscle atrophy (negative correlation with the Skeletal Muscle Index at a threshold of 10%: p = 0.093, r = -0.41). In contrast, no such trend was observed for the BIRC3/ACE1 ratio. Exposure of human myoblasts to HNC cells induced inhibition of myogenesis and strong up-regulation of IL32 mRNA and protein. In contrast, these effects were absent or much smaller under exposure to NHEK controls. Conclusions: IL32 is a potential biomarker for CRS in HNC patients. In addition, the HNC-myoblast co-cultivation model provides a promising in vitro system to study CRS mechanisms, potentially reducing the reliance on animal models.

Clinical Tables and Statistical Analyses

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.

Association between keratin, MGC and clinical outcome

Representative video of granulomas made of multiple MGC in oral cavity SCC from GR cohort

This table provides the DEG between MGC spots and non-MGC spots