[18F]mFBG PET-CT for detection and localisation of neuroblastoma: a prospective pilot study

Purpose Meta-[F-18]fluorobenzylguanidine ([F-18]mFBG) is a positron emission tomography (PET) radiotracer that allows for fast and high-resolution imaging of tumours expressing the norepinephrine transporter. This pilot study investigates the feasibility of [F-18]mFBG PET-CT for imaging in neuroblastoma. Methods In a prospective, single-centre study, we recruited children with neuroblastoma, referred for meta-[I-123]iodobenzylguanidine ([I-123]mIBG) scanning, consisting of total body planar scintigraphy in combination with single-photon emission computed tomography-CT (SPECT-CT). Within two weeks of [I-123]mIBG scanning, total body PET-CTs were performed at 1 h and 2 h after injection of [F-18]mFBG (2 MBq/kg). Detected tumour localisations on scan pairs were compared. Soft tissue disease was quantified by number of lesions and skeletal disease by SIOPEN score. Results Twenty paired [I-123]mIBG and [F-18]mFBG scans were performed in 14 patients (median age 4.9 years, n = 13 stage 4 disease and n = 1 stage 4S). [F-18]mFBG injection was well tolerated and no related adverse events occurred in any of the patients. Mean scan time for [F-18]mFBG PET-CT (9.0 min, SD 1.9) was significantly shorter than for [I-123]mIBG scanning (84.5 min, SD 10.5), p < 0.01. Most tumour localisations were detected on the 1 h versus 2 h post-injection [F-18]mFBG PET-CT. Compared to [I-123]mIBG scanning, [F-18]mFBG PET-CT detected a higher, equal, and lower number of soft tissue lesions in 40%, 55%, and 5% of scan pairs, respectively, and a higher, equal, and lower SIOPEN score in 55%, 30%, and 15% of scan pairs, respectively. On average, two more soft tissue lesions and a 6-point higher SIOPEN score were detected per patient on [F-18]mFBG PET-CT compared to [I-123]mIBG scanning. Conclusion Results of this study demonstrate feasibility of [F-18]mFBG PET-CT for neuroblastoma imaging. More neuroblastoma localisations were detected on [F-18]mFBG PET-CT compared to [I-123]mIBG scanning. [F-18]mFBG PET-CT shows promise for future staging and response assessment in neuroblastoma.Analysis and Stochastic

Heterogeneous clinical phenotypes and cerebral malformations reflected by rotatin cellular dynamics

Recessive mutations in RTTN, encoding the protein rotatin, were originally identified as cause of polymicrogyria, a cortical malformation. With time, a wide variety of other brain malformations has been ascribed to RTTN mutations, including primary microcephaly. Rotatin is a centrosomal protein possibly involved in centriolar elongation and ciliogenesis. However, the function of rotatin in brain development is largely unknown and the molecular disease mechanism underlying cortical malformations has not yet been elucidated. We performed both clinical and cell biological studies, aimed at clarifying rotatin function and pathogenesis. Review of the 23 published and five unpublished clinical cases and genomic mutations, including the effect of novel deep intronic pathogenic mutations on RTTN transcripts, allowed us to extrapolate the core phenotype, consisting of intellectual disability, short stature, microcephaly, lissencephaly, periventricular heterotopia, polymicrogyria and other malformations. We show that the severity of the phenotype is related to residual function of the protein, not only the level of mRNA expression. Skin fibroblasts from eight affected individuals were studied by high resolution immunomicroscopy and flow cytometry, in parallel with in vitro expression of RTTN in HEK293T cells. We demonstrate that rotatin regulates different phases of the cell cycle and is mislocalized in affected individuals. Mutant cells showed consistent and severe mitotic failure with centrosome amplification and multipolar spindle formation, leading to aneuploidy and apoptosis, which could relate to depletion of neuronal progenitors often observed in microcephaly. We confirmed the role of rotatin in functional and structural maintenance of primary cilia and determined that the protein localized not only to the basal body, but also to the axoneme, proving the functional interconnectivity between ciliogenesis and cell cycle progression. Proteomics analysis of both native and exogenous rotatin uncovered that rotatin interacts with the neuronal (non-muscle) myosin heavy chain subunits, motors of nucleokinesis during neuronal migration, and in human induced pluripotent stem cell-derived bipolar mature neurons rotatin localizes at the centrosome in the leading edge. This illustrates the role of rotatin in neuronal migration. These different functions of rotatin explain why RTTN mutations can lead to heterogeneous cerebral malformations, both related to proliferation and migration defects.Genetics of disease, diagnosis and treatmen

A SUMO Extension for Norm based Traffic Control Systems

Autonomous vehicles will most likely participate in traffic in the near future. The advent of autonomous vehicles allows us to explore innovative ideas for traffic control such as norm based control systems. A norm is a violable rule that describes correct behavior. Norm based traffic control systems monitor traffic and effectuate sanctions in case vehicles violate norms. In this paper we present an extension of SUMO that enables the user to apply norm based control systems to traffic simulations. In our extension, vehicles are capable of making an autonomous decision on whether to comply with the norms or not. We provide a description of the extension, a summary on its implementation and an experimental evaluation