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Magnetic resonance thermometry (MRT) can measure in-vivo 3D-temperature changes in real-time and noninvasively. However, for the oropharynx region and the entire head and neck, motion potentially introduces large artifacts. Considering long treatment times of 60–90 min, this study aims to evaluate whether MRT around the oropharynx is clinically feasible for hyperthermia treatments and quantify the effects of breathing and swallowing on MRT performance. A 3D-ME-FGRE sequence was used in a phantom cooling down and around the oropharynx of five volunteers over ∼75 min. The imaging protocol consisted of imaging with acceleration (ARC = 2), number of image averages (NEX = 1,2 and 3). For volunteers, the acquisitions included a breath-hold scan and scans with deliberate swallowing. MRT performance was quantified in neck muscle, spinal cord and masseter muscle, using mean average error (MAE), mean error (ME) and spatial standard deviation (SD). In phantom, an increase in NEX leads to a significant decrease in SD, but MAE and ME were unchanged. No significant difference was found in volunteers between the different scans. There was a significant difference between the regions evaluated: neck muscle had the best MAE (=1.96 °C) and SD (=0.82 °C), followed by spinal cord (MAE = 3.17 °C, SD = 0.92 °C) and masseter muscle (MAE = 4.53 °C, SD = 1.16 °C). Concerning the ME, spinal cord did best, then neck muscle and masseter muscle, with values of −0.64 °C, 1.15 °C and −3.05 °C respectively. Breathing, swallowing, and different ways of imaging (acceleration and NEX) do not significantly influence the MRT performance in the oropharynx region. The ROI selected however, leads to significant differences.

Abstract Background Radiotherapy (RT) is the standard of care for most advanced head and neck squamous cell carcinoma (HNSCC) and results in an unfavorable 5-year overall survival of 40%. Despite strong biological rationale, combining RT with immune checkpoint inhibitors does not result in a survival benefit. Our hypothesis is that the combination of these individually effective treatments fails because of radiation-induced immunosuppression and lymphodepletion. By integrating modern radiobiology and innovative radiotherapy concepts, the patient’s immune system could be maximally retained by (1) increasing the dose per fraction so that the total dose and number of fractions can be reduced (HYpofractionation), (2) redistributing the radiation dose towards a higher peak dose within the tumor center and a lowered elective lymphatic field dose (Dose-redistribution), and (3) using RAdiotherapy with protons instead of photons (HYDRA). Methods The primary aim of this multicenter study is to determine the safety of HYDRA proton- and photon radiotherapy by conducting two parallel phase I trials. Both HYDRA arms are randomized with the standard of care for longitudinal immune profiling. There will be a specific focus on actionable immune targets and their temporal patterns that can be tested in future hypofractionated immunoradiotherapy trials. The HYDRA dose prescriptions (in 20 fractions) are 40 Gy elective dose and 55 Gy simultaneous integrated boost on the clinical target volume with a 59 Gy focal boost on the tumor center. A total of 100 patients (25 per treatment group) will be recruited, and the final analysis will be performed one year after the last patient has been included. Discussion In the context of HNSCC, hypofractionation has historically only been reserved for small tumors out of fear for late normal tissue toxicity. To date, hypofractionated radiotherapy may also be safe for larger tumors, as both the radiation dose and volume can be reduced by the combination of advanced imaging for better target definition, novel accelerated repopulation models and high-precision radiation treatment planning and dose delivery. HYDRA’s expected immune-sparing effect may lead to improved outcomes by allowing for future effective combination treatment with immunotherapy. Trial registration The trial is registered at ClinicalTrials.gov; NCT05364411 (registered on May 6th, 2022).

Neuroblastoma is a childhood malignancy and in the majority of patients, the primary tumor arises in one of the adrenal glands. Neuroblastoma cells highly express the disialoganglioside GD2, which is the primary target for the development of neuroblastoma immunotherapy. Anti-GD2 mAbs have shown clinical efficacy and are integrated into standard treatment for high-risk neuroblastoma patients. We previously reported synergy between the HDAC inhibitor Vorinostat and anti-GD2 mAbs in a heterotopic, subcutaneous growing neuroblastoma model. Additionally, we have previously developed an orthotopic intra-adrenal neuroblastoma model showing more aggressive tumor growth. Here, we report that anti-GD2 mAb and Vorinostat immunocombination therapy is even more effective in suppressing neuroblastoma growth in the aggressive orthotopic model, resulting in increased animal survival. Intra-adrenal tumors from mice treated with Vorinostat were highly infiltrated with myeloid cells, including macrophages, displaying increased MHCII and Fc-receptor expression. Collectively, these data provide a strong rationale for clinical testing of anti-GD2 mAbs with concomitant Vorinostat in neuroblastoma patients.