Introduction A hallmark of pediatric low-grade glioma (pLGG) is aberrant signaling of the mitogen activated protein kinase (MAPK) pathway. Hence, inhibition of MAPK signaling using small molecule inhibitors such as MEK inhibitors (MEKi) may be a promising strategy. Methods In this multi-center retrospective centrally reviewed study, we analyzed 18 patients treated with the MEKi trametinib for progressive pLGG as an individual treatment decision between 2015 and 2019. We have investigated radiological response as per central radiology review, molecular classification and investigator observed toxicity. Results We observed 6 partial responses (PR), 2 minor responses (MR), and 10 stable diseases (SD) as best overall responses. Disease control rate (DCR) was 100% under therapy. Responses were observed in KIAA1549:BRAF- as well as neurofibromatosis type 1 (NF1)-driven tumors. Median treatment time was 12.5 months (range: 2 to 27 months). Progressive disease was observed in three patients after cessation of trametinib treatment within a median time of 3 (2–4) months. Therapy related adverse events occurred in 16/18 patients (89%). Eight of 18 patients (44%) experienced severe adverse events (CTCAE III and/or IV; most commonly skin rash and paronychia) requiring dose reduction in 6/18 patients (33%), and discontinuation of treatment in 2/18 patients (11%). Conclusions Trametinib was an active and feasible treatment for progressive pLGG leading to disease control in all patients. However, treatment related toxicity interfered with treatment in individual patients, and disease control after MEKi withdrawal was not sustained in a fraction of patients. Our data support in-class efficacy of MEKi in pLGGs and necessity for upfront randomized testing of trametinib against current standard chemotherapy regimens.

Background. We sought to determine the value of diffusion-weighted (DW) magnetic resonance imaging (MRI) for characterization of benign and malignant peripheral nerve sheath tumors (PNSTs) in patients with neurofibromatosis type 1 (NF1). Methods. Twenty-six patients with NF1 and suspicion of malignant transformation of PNSTs were prospectively enrolled and underwent DW MRI at 3T. For a set of benign (n = 55) and malignant (n = 12) PNSTs, functional MRI parameters were derived from both biexponential intravoxel incoherent motion (diffusion coefficient D and perfusion fraction f) and monoexponential data analysis (apparent diffusion coefficients [ADCs]). A panel of morphological MRI features was evaluated using T1-and T2-weighted imaging. Mann-Whitney U-test, Fisher's exact test, and receiver operating characteristic (ROC) analyses were applied to assess the diagnostic accuracy of quantitative and qualitative MRI. Cohen's kappa was used to determine interrater reliability. Results. Malignant PNSTs demonstrated significantly lower diffusivity (P < 0.0001) compared with benign PNSTs. The perfusion fraction f was significantly higher in malignant PNSTs (P < 0.001). In ROC analysis, functional MRI parameters showed high diagnostic accuracy for differentiation of PNSTs (eg, ADC mean, 92% sensitivity with 98% specificity, AUC 0.98; D mean, 92% sensitivity with 98% specificity, AUC 0.98). By contrast, morphological imaging features had only limited sensitivity (18-94%) and specificity (18-82%) for identification of malignancy. Interrater reliability was higher for monoexponential data analysis. Conclusion. DW imaging shows better diagnostic performance than morphological features and allows accurate differentiation of benign and malignant peripheral nerve sheath tumors in NF1. Key Points 1. DWI allows sensitive and specific identification of malignancy in NF1. 2. Morphological features have limited accuracy for identifying malignant transformation. Well et al. Diffusion-weighted imaging in NF1 Neuro-Oncology Keywords diffusion-weighted imaging | intravoxel incoherent motion analysis | morphological features | neurofibromatosis type 1 | peripheral nerve sheath tumor

The utility of nanobodies and conventional antibodies for in vivo imaging is well known, but optimum dosing and timing schedules for one versus the other have not been established. We aimed to improve specific tumor imaging in vivo with nanobodies and conventional antibodies using near-infrared fluorescence (NIRF) imaging. We used ARTC2 expressed on lymphoma cells as a model target antigen. ARTC2-specific nanobody s+16a and conventional antibody Nika102 were labeled with NIRF-dye AF680. In vivo NIRF-imaging of ARTC2-positive and ARTC2-negative xenografts was performed over 24 h post-injection of 5, 10, 25, or 50 µg of each conjugate. Specific target-binding and tissue-penetration were verified by NIRF imaging ex vivo, flow cytometry and fluorescence microscopy. NIRF-imaging of s+16a(680) in vivo revealed a six times faster tumor accumulation than of Nika102(680). Using 50 µg of s+16a(680) increased the specific signals of ARTC2-positive tumors without increasing background signals, allowing a tumor-to-background (T/B) ratio of 12.4 ± 4.2 within 6 h post-injection. Fifty micrograms of Nika102(680) increased specific signals of ARTC2-positive tumors but also of ARTC2-negative tumors and background, thereby limiting the T/B ratio to 6.1 ± 2.0. Ten micrograms of Nika102(680) only slightly reduced specific tumor signals but dramatically reduced background signals. Ex vivo analyses confirmed a faster and deeper tumor penetration with s+16a(680). Using nanobody s+16a allowed same-day imaging with a high T/B ratio, whereas antibody Nika102 gave optimal imaging results only 24 h post injection. Nanobody s+16a required a high dose, whereas antibody Nika102 had the best T/B-ratio at a low dose. Therefore, timing and dosage should be addressed when comparing nanobodies and conventional antibodies for molecular imaging purposes.