Assessment of skeletal tumor load in metastasized castration-resistant prostate cancer patients: A review of available methods and an overview on future perspectives

Metastasized castration-resistant prostate cancer (mCRPC), is the most advanced form of prostate neoplasia, where massive spread to the skeletal tissue is frequent. Patients with this condition are benefiting from an increasing number of treatment options. However, assessing tumor response in patients with multiple localizations might be challenging. For this reason, many computational approaches have been developed in the last decades to quantify the skeletal tumor burden and treatment response. In this review, we analyzed the progressive development and diffusion of such approaches. A computerized literature search of the PubMed/Medline was conducted, including articles between January 2008 and March 2018. The search was expanded by manually reviewing the reference list of the chosen articles. Thirty-five studies were identified. The number of eligible studies greatly increased over time. Studies could be categorized in the following categories: automated analysis of 2D scans, SUV-based thresholding, hybrid CT-and SUV-based thresholding, and MRI-based thresholding. All methods are discussed in detail. Automated analysis of bone tumor burden in mCRPC is a growing field of research; when choosing the appropriate method of analysis, it is important to consider the possible advantages as well as the limitations thoroughly

Adult genetic leukoencephalopathies: identifying new entities using advanced MRI techniques, next generation sequencing and clinical profiling

Genetic leukoencephalopathies are considered rare in the adult population. However, several lines of evidence suggest that there is a larger than expected number of adult patients with genetic leukoencephalopathies who are currently not diagnosed. The study of leukoencephalopathies - either genetically-proven or unsolved - relies greatly on MRI pattern-recognition, which allowed the characterization of the majority of genetic white matter disorders. The advent of next generation sequencing (NGS) revolutionized the field, by disclosing new phenotypes associated to known genetic white matter conditions and identifying novel genes responsible for unsolved leukoencephalopathies. The goals of my study were1.the application of advanced neuroimaging tools to define and characterize white matter abnormalities of known and novel genetic leukoencephalopathies2.the clinical and demographic characterization of subjects with adult genetic leukoencephalopathies3.the identification of genes responsible for new forms of hereditary white matter disorders, using NGS techniques.We applied an integrated approach which combined clinical phenotyping with MRI pattern-recognition and NGS data. This work led to a) the description of a cohort of 68 adult subjects with leukoencephalopathy of probable genetic origin, 59 of which were included in our study, b) the identification of the causal mutations (16 in total, 11 novel) in genes known to be associated with leukoencephalopathies in 14/59 subjects (23.7%), and c) the broadening of clinical and imaging phenotypes of known disorders: POLR3-related disorders, vanishing white matter disease, Krabbe disease, MTFMT-related disorders. We demonstrated that MRI family studies can be crucial in adult leukoencephalopathies to define the modality of transmission of unclear white matter disorders within families. In conclusion, we documented that adult genetic leukoencephalopathies are an emerging problem in clinical neurosciences. MRI family studies and the recognition of disease-specific MRI features are critical to guide the diagnostic process. Despite the access to NGS techniques, more than 70% of our subjects remain without a diagnosis. The international sharing of MRI and NGS on adult leukoencephalopathies will allow the identification of subjects with same phenotypes or mutated genes and ultimately lead to the description of new genetic entities.Les leucoencéphalopathies génétiques sont considérées rares dans la population adulte. Cependant, plusieurs sources de données suggèrent qu'il existe un nombre plus élevé qu'attendu de patients adultes atteints par une leucoencéphalopathie qui n'ont pas encore de diagnostic. L'étude des leucoencéphalopathies – autant confirmées génétiquement que non résolues – dépend grandement de l'identification de caractéristiques diagnostiques obtenues par IRM, qui permettent la caractérisation de la majorité des maladies génétiques de la substance blanche. L'avènement du séquençage de dernière génération (NGS) a révolutionné ce domaine, en permettant la découverte de nouveaux phénotypes associés à des maladies génétiques connues de la substance blanche et l'identification de nouveaux gènes responsables pour des formes non résolues. Les objectifs de mon étude ont été1.l'application de techniques de neuroimagerie avancées dans le but de définir et caractériser les anomalies de la substance blanche de leucoencéphalopathies connues et nouvelles ;2.la caractérisation clinique et démographique des sujets adultes atteints de leucoencéphalopathies génétiques ;3.l'identification de gènes responsables de nouvelles formes de maladies héréditaires de la substance blanche, en utilisant des techniques NGS.Nous avons appliqué une approche intégrée combinant phénotypage clinique et identification de critères obtenus par IRM et données générées par NGS. Cette étude a permis l'obtention de données concernant a) la description d'une cohorte de 68 sujets adultes atteints d'une leucoencéphalopathie d'origine supposée génétique, dont 59 ont été inclus dans notre étude, b) l'identification de mutations causales (16 au total, dont 11 nouvelles) dans des gènes connus pour être associés à des leucoencéphalopathies dans 14/59 sujets (23.7%), c) l'expansion des phénotypes cliniques et radiologiques de leucoencéphalopathies connues: les désordres associés à POLR3, maladie VWM (Vanishing White Matter disease), maladie de Krabbe, les désordres associés à MTFMT. Nous avons démontré que les études familiales par IRM sont un outil crucial dans le domaine des leucoencéphalopathies adultes pour la définition de la modalité de transmission – quand cette dernière était jusqu'à lors inconnue.En conclusion, nous avons documenté que les leucoencéphalopathies génétiques chez les patients adultes sont un problème émergeant dans les neurosciences cliniques. Les études familiales par IRM et l'identification de caractéristiques IRM spécifiques de chaque maladie sont déterminantes pour guider le processus diagnostique. Malgré l'accès aux techniques NGS, une grande majorité (plus de 70%) de nos sujets demeure sans diagnostic. Le partage de données IRM et NGS de leucoencéphalopathies adultes dans des réseaux internationaux permettra l'identification de sujets avec les mêmes phénotypes ou gènes mutés, et portera finalement à la description de nouvelles entités génétiques

Bilateral striatal necrosis in two subjects with Aicardi-Goutières syndrome due to mutations in ADAR1 (AGS6)

Aicardi-Goutières syndrome (AGS) is a genetic inflammatory disease. The classic neuroradiological picture mimics that of congenital infections in that Aicardi-Goutières syndrome is characterized by leukoencephalopathy, brain atrophy and intracranial calcifications. To date, bilateral striatal necrosis has not been reported in patients with AGS. We report on two patients with clinical diagnosis of Aicardi-Goutières syndrome in which brain MRI and CT scans demonstrated bilateral striatal necrosis. The diagnosis of Aicardi-Goutières syndrome in these two patients was genetically confirmed after the recent discovery that mutations in the ADAR1 (AGS6) gene may cause Aicardi-Goutières syndrome. This is the first report of bilateral striatal necrosis in association with Aicardi-Goutières syndrome. These results expand the neuroradiological phenotype of Aicardi-Goutières syndrom

Spectrum of visual disorders in children with cerebral visual impairment.

Cerebral visual impairment is a visual function deficit caused by damage to the retrogeniculate visual pathways in the absence of any major ocular disease. It is the main visual deficit in children in the developed world. Preperinatal hypoxic-ischemic damage is the most frequent cause of cerebral visual impairment, but the etiology is variable. The authors set out to evaluate the presence of visual disorders not attributable to any major ocular pathology in a sample of children with central nervous system disease and to describe the clinical picture of cerebral visual impairment in this cohort. One hundred twenty-one patients with central nervous system damage and visual impairment underwent a protocol developed at the authors' center that included neurologic, neurophthalmologic, and neuroradiologic assessments (brain magnetic resonance imaging). Reduced visual acuity was found in 105 of 121 patients, reduced contrast sensitivity in 58, abnormal optokinetic nystagmus in 88, and visual field deficit in 7. Fixation was altered in 58 patients, smooth pursuit in 95, and saccadic movements in 41. Strabismus was present in 88 patients, and abnormal ocular movements were found in 43 patients. Of the 27 patients in whom they could be assessed, visual-perceptual abilities were found to be impaired in 24. Fundus oculi abnormalities and refractive errors were frequently associated findings. This study confirms that the clinical expression of cerebral visual impairment can be variable and that, in addition to already well-documented symptoms (such as reduced visual acuity, visual field deficits, reduced contrast sensitivity), the clinical picture can also be characterized by oculomotor or visual-cognitive disorders. Cerebral visual impairment is often associated with ophthalmologic abnormalities, and these should be carefully sought. Early and careful assessment, taking into account both the neurophthalmologic and the ophthalmologic aspects, is essential for a correct diagnosis and the development of personalized rehabilitation programs

Different mutations in three prime repair exonuclease 1 and ribonuclease H2 genes affect clinical features in Aicardi-Goutieres syndrome.

none9Aicardi-Goutières syndrome is a rare encephalopathy of mutational origin characterized by increased levels of interferon alpha in cerebrospinal fluid. The aim of this study was to explore the influence of different Aicardi-Goutières syndrome genotypes on the clinical course of patients, seeking to identify specific gene expression profiles able to explain Aicardi-Goutières syndrome phenotype differences. We detected the occurrence of Aicardi-Goutières syndrome mutations in 21 patients and compared microarray gene-expression data of cerebrospinal fluid lymphocytes with clinical variables. The levels of interferon alpha in cerebrospinal fluid were high in all patients; we found differences in the expression of genes encoding for Toll-like receptor, endogenous RNases, T lymphocyte activation, angiogenesis inhibition, and peripheral interferon alpha production. These results indicate that further to interferon alpha production in the central nervous system, a variety of other pathogenic mechanisms is activated in Aicardi-Goutières syndrome to various degrees in different patients, thus explaining the interindividual difference in Aicardi-Goutières syndrome course.A. Izzotti;M. Longobardi;C. Cartiglia;F. Anzuini;P. Arrigo;E. Fazzi;S. Orcesi;R. L. Piana;A. PullieroIzzotti, Alberto; Longobardi, Mariagrazia; Cartiglia, Cristina; F., Anzuini; P., Arrigo; E., Fazzi; S., Orcesi; R. L., Piana; Pulliero, Alessandr