The tryptophan (TRP) to kynurenine (KYN) metabolic pathway is now firmly established as a key regulator of innate and adaptive immunity. A plethora of preclinical models suggests that this immune tolerance pathway – driven by the key and rate-limiting enzymes indoleamine-2,3-dioxygenase and TRP-2,3-dioxygenase – is active in cancer immunity, autoimmunity, infection, transplant rejection, and allergy. Drugs targeting this pathway, specifically indoleamine-2,3-dioxygenase, are already in clinical trials with the aim at reverting cancer-induced immunosuppression. In the past years, there has been an increase in our understanding of the regulation and downstream mediators of TRP metabolism, such as the aryl hydrocarbon receptor as a receptor for KYN and kynurenic acid. This more detailed understanding will expand our opportunities to interfere with the pathway therapeutically on multiple levels. Here, we discuss the perspective of targeting TRP metabolism at these different levels based on reviewing recent insight into the regulation of TRP metabolism and its downstream effectors.

Background To assess changes of the craniocervical junction (CCJ), computed tomography (CT) is considered the reference standard. Recent advances in bone depiction on magnetic resonance imaging (MRI) enable high‐quality visualization of osseous structures. Consequently, MRI may serve as an alternative to CT, without the use of ionizing radiation. Purpose To compare two MRI sequences optimized for bone visualization to the CT reference standard in the assessment of the osseous CCJ. Study Type Prospective. Population/Subjects Twenty‐seven decedents and five healthy volunteers. Field Strength/Sequence 3T/ultrashort‐echo time gradient echo (UTE) and optimized 3D‐multiecho in‐phase gradient echo sequences (FRACTURE). Assessment All decedents were scanned with both MRI sequences and CT. Three observers rated degeneration to obtain a score for the upper (atlanto‐dental and left/right atlanto‐occipital joint) and for the lower part of the CCJ (left and right atlanto‐axial joint). Two reader rated the following quantitative parameters: basion‐axial‐interval, atlanto‐dental‐interval, atlanto‐occipital‐interval, Powers‐ratio, and signal/contrast‐to‐noise‐ratio. As a proof of concept, five healthy volunteers were scanned with both MRI sequences. Statistical Tests Degeneration was assessed on a Likert scale by three independent observers. Interrater and intermodality reliability were calculated using an intraclass correlation coefficient. To compare distance measurements between examination methods, a Friedman test, between‐degenerative ratings, and a Kruskal–Wallis test were performed. Results Degenerative ratings of the CCJ between MRI sequences and CT showed a good interrater and intermodality agreement. MRI sequences tended to underestimate the degree of degeneration compared to CT, and this became more marked with increasing degeneration severity. There were no significant relationships between distance measurements and the degree of degeneration (PCT = 0.62, PUTE = 0.64, PFRACTURE = 0.67). The in vivo examination proved the feasibility of both MRI methods in a clinical setting. Data Conclusion Quantitative and qualitative ratings on MR images were comparable to CT images; thus, MRI may be a valid alternative to CT assessing the CCJ. Level of Evidence 1. Technical Efficacy Stage 3.

Background Radiation therapy is an integral part of the multimodal primary therapy of glioblastomas. As the overall prognosis in this tumor entity remains unfavorable, current research is focused on additional drug therapies, which are often accompanied by increases in toxicity. By using proton beams instead of photon beams, it is possible to protect large parts of the brain which are not affected by the tumor more effectively. An initial retrospective matched-pair analysis showed that this theoretical physical benefit is also clinically associated with a reduction in toxicity during therapy and in the first few months thereafter. Methods/design The GRIPS trial is a multicenter, prospective, open-label, randomized, two-arm, phase III study using either intensity modulated photon radiation techniques (standard arm) or proton beam radiotherapy (experimental arm). Additionally, patients are stratified according to "fractionation scheme" (normofractionated/hypofractionated), "subventricular zone involvement" (yes/no) and concurrent chemotherapy (yes/no) and the planned case number is 326 patients. Radiation therapy is performed with a dose of 30 × 2 Gy(RBE) or 33 × 1.8 Gy(RBE), or for patients treated according to the hypofractionation protocol with 15 × 2.67 Gy(RBE). A possible administration of additional chemotherapy (concurrent or adjuvant) or tumor treating fields is applied in dosage and frequency according to the therapy standard outside of this study. The primary endpoint is the cumulative rate of toxicity CTC grade 2 and higher in the first 4 months. Secondary endpoints include overall survival, progression-free survival, quality of life, and neurocognition. Discussion Aim of the GRIPS study is to prospectively assess whether the theoretical physical advantage of proton beam radiotherapy will translate into a clinical reduction of toxicity during and in the first months after therapy. Trial registration ClinicalTrials (NCT): NCT04752280.