Spectrum of neuroimaging findings post-proton beam therapy in a large pediatric cohort

PURPOSE: Proton beam therapy (PBT) is now well established for the treatment of certain pediatric brain tumors. The intrinsic properties of PBT are known to reduce long-term negative effects of photon radiotherapy (PRT). To better understand the intracranial effects of PBT, we analyzed the longitudinal imaging changes in a cohort of children with brain tumors treated by PBT with clinical and radiotherapy dose correlations. MATERIALS AND METHODS: Retrospective imaging review of 46 patients from our hospital with brain tumors treated by PBT. The imaging findings were correlated with clinical and dose parameters. RESULTS: Imaging changes were assessed by reviewing serial magnetic resonance imaging (MRI) scans following PBT over a follow-up period ranging from 1 month to 7 years. Imaging changes were observed in 23 patients undergoing PBT and categorized as pseudoprogression (10 patients, 43%), white matter changes (6 patients, 23%), parenchymal atrophy (6 patients, 23%), and cerebral large vessel arteriopathy (5 patients, 25%). Three patients had more than one type of imaging change. Clinical symptoms attributable to PBT were observed in 13 (28%) patients. CONCLUSION: In accordance with published literature, we found evidence of varied intracranial imaging changes in pediatric brain tumor patients treated with PBT. There was a higher incidence (10%) of large vessel cerebral arteriopathy in our cohort than previously described in the literature. Twenty-eight percent of patients had clinical sequelae as a result of these changes, particularly in the large vessel arteriopathy subgroup, arguing the need for angiographic and perfusion surveillance to pre-empt any morbidities and offer potential neuro-protection

Beyond Survival - Cognition after Pediatric Brain Tumor

Background: Pediatric Brain Tumor (PBT) survivors suffer from cognitive sequelae, especially within the areas of cognitive tempo, attention, executive function and memory. The cognitive difficulties are often accentuated over the years, but knowledge about the long term trajectory is still scarce. Aim: The aim of this thesis was to examine cognitive sequelae after Pediatric Brain Tumor (PBT); risk factors, common difficulties, development and neuroimaging correlates. Methods: In study I, data from medical logs were used to examine characteristics of the patients who got access to neuropsychological services, compared to those who did not. In study II, data from 70 neuropsychological assessments were used to describe common cognitive impairments and to find risk factors. In study III, patients were invited to a follow-up study 10-13 years after diagnosis. Neuropsychological and neuroimaging data were collected and the two were compared. In study IV, longitudinal cognitive data from 173 patients were analyzed in order to describe development over time and to find risk factors for a negative development. Results: Study I: There were few differences between referred and non-referred patients. Study II: Patients had generally suppressed IQ and difficulties with executive function, memory, cognitive processing speed and attention. Risk factors were Whole-Brain Radiation Therapy (WBRT), large tumors, young age at diagnosis and male sex. Study III: Radiated as well as non-radiated patients had white matter abnormalities. Correlation between neuroimaging and cognition was low when group based statistics were used, but increased when a personalized method was used. Study IV: Most cognitive abilities showed a decline in age related scores over time unconsidered treatment given. Risk factors for impaired cognitive function at diagnosis were: male sex, WBRT, supratentorial lateral tumor, young age at diagnosis, larger tumor size and treatment with chemotherapy. Conclusions: A systematic neuropsychological follow-up is important. Risk factors for cognitive impairment and IQ decline are WBRT, large tumors, young age at diagnosis, male sex, supratentorial lateral tumor, and treatment with chemotherapy. A decline in IQ after PBT is common, unconsidered treatment given. Personalized methods of research would contribute significantly to our understanding of cognitive sequelae after PBT and its relation to neuroimaging

Quantitative Analysis of Radiation-Associated Parenchymal Lung Change

Radiation-induced lung damage (RILD) is a common consequence of thoracic radiotherapy (RT). We present here a novel classification of the parenchymal features of RILD. We developed a deep learning algorithm (DLA) to automate the delineation of 5 classes of parenchymal texture of increasing density. 200 scans were used to train and validate the network and the remaining 30 scans were used as a hold-out test set. The DLA automatically labelled the data with Dice Scores of 0.98, 0.43, 0.26, 0.47 and 0.92 for the 5 respective classes. Qualitative evaluation showed that the automated labels were acceptable in over 80% of cases for all tissue classes, and achieved similar ratings to the manual labels. Lung registration was performed and the effect of radiation dose on each tissue class and correlation with respiratory outcomes was assessed. The change in volume of each tissue class over time generated by manual and automated segmentation was calculated. The 5 parenchymal classes showed distinct temporal patterns We quantified the volumetric change in textures after radiotherapy and correlate these with radiotherapy dose and respiratory outcomes. The effect of local dose on tissue class revealed a strong dose-dependent relationship We have developed a novel classification of parenchymal changes associated with RILD that show a convincing dose relationship. The tissue classes are related to both global and local dose metrics, and have a distinct evolution over time. Although less strong, there is a relationship between the radiological texture changes we can measure and respiratory outcomes, particularly the MRC score which directly represents a patient’s functional status. We have demonstrated the potential of using our approach to analyse and understand the morphological and functional evolution of RILD in greater detail than previously possible

Quantifying effects of radiotherapy-induced microvascular injury; review of established and emerging brain MRI techniques

Microvascular changes are increasingly recognised not only as primary drivers of radiotherapy treatment response in brain tumours, but also as an important contributor to short- and long-term (cognitive) side effects arising from irradiation of otherwise healthy brain tissue. As overall survival of patients with brain tumours is increasing, monitoring long-term sequels of radiotherapy-induced microvascular changes in the context of their potential predictive power for outcome, such as cognitive disability, has become increasingly relevant. Ideally, radiotherapy-induced significant microvascular changes in otherwise healthy brain tissue should be identified as early as possible to facilitate adaptive radiotherapy and to proactively start treatment to minimise the influence on these side-effects on the final outcome. Although MRI is already known to be able to detect significant long-term radiotherapy induced microvascular effects, more recently advanced MR imaging biomarkers reflecting microvascular integrity and function have been reported and might provide a more accurate and earlier detection of microvascular changes. However, the use and validation of both established and new techniques in the context of monitoring early and late radiotherapy-induced microvascular changes in both target-tissue and healthy tissue currently are minimal at best. This review aims to summarise the performance and limitations of existing methods and future opportunities for detection and quantification of radiotherapy-induced microvascular changes, as well as the relation of these findings with key clinical parameters. (C) 2019 Elsevier B.V. All rights reserved

Survivors of Childhood Cerebellar Tumors: Atrophy, Lack of Lesion Specificity, and the Impact on Behavioral Performance

Research suggests that the cerebellum is involved in cognition, but its exact role is unclear. The efficiency theory posits that the cerebellum supports processing speed. Other researchers argue that the cerebellum is functionally heterogeneous, and damage to lobes of the cerebellum causes selective loss of cognitive functions. This study sought to determine whether selective impairment in motor, verbal fluency, or processing speed occurred depending on the lobe of the cerebellum that was lesioned. Lesion mapping was used to measure lesion size and volumetric methods were used to measure atrophy in 25 adult survivors of cerebellar tumors. Participants had too a high degree of heterogeneous cerebellar lesions and accompanying atrophy to explore specialization. However, total cerebellar atrophy negatively impacted written and oral processing speed to a greater degree than total cerebellar lesion size. Younger ages at diagnosis and radiation therapy were associated with greater cerebellar atrophy

Human induced pluripotent stem cell engineering establishes a humanized mouse platform for pediatric low-grade glioma modeling

A major obstacle to identifying improved treatments for pediatric low-grade brain tumors (gliomas) is the inability to reproducibly generate human xenografts. To surmount this barrier, we leveraged human induced pluripotent stem cell (hiPSC) engineering to generate low-grade gliomas (LGGs) harboring the two most common pediatric pilocytic astrocytoma-associated molecular alterations, NF1 loss and KIAA1549:BRAF fusion. Herein, we identified that hiPSC-derived neuroglial progenitor populations (neural progenitors, glial restricted progenitors and oligodendrocyte progenitors), but not terminally differentiated astrocytes, give rise to tumors retaining LGG histologic features for at least 6 months in vivo. Additionally, we demonstrated that hiPSC-LGG xenograft formation requires the absence of CD4 T cell-mediated induction of astrocytic Cxcl10 expression. Genetic Cxcl10 ablation is both necessary and sufficient for human LGG xenograft development, which additionally enables the successful long-term growth of patient-derived pediatric LGGs in vivo. Lastly, MEK inhibitor (PD0325901) treatment increased hiPSC-LGG cell apoptosis and reduced proliferation both in vitro and in vivo. Collectively, this study establishes a tractable experimental humanized platform to elucidate the pathogenesis of and potential therapeutic opportunities for childhood brain tumors

Multidelay ASL of the pediatric brain

Arterial spin labeling (ASL) is a powerful noncontrast MRI technique for evaluation of cerebral blood flow (CBF). A key parameter in single-delay ASL is the choice of postlabel delay (PLD), which refers to the timing between the labeling of arterial free water and measurement of flow into the brain. Multidelay ASL (MDASL) utilizes several PLDs to improve the accuracy of CBF calculations using arterial transit time (ATT) correction. This approach is particularly helpful in situations where ATT is unknown, including young subjects and slow-flow conditions. In this article, we discuss the technical considerations for MDASL, including labeling techniques, quantitative metrics, and technical artefacts. We then provide a practical summary of key clinical applications with real-life imaging examples in the pediatric brain, including stroke, vasculopathy, hypoxic-ischemic injury, epilepsy, migraine, tumor, infection, and metabolic disease

Diffusion and Perfusion MRI in Paediatric Posterior Fossa Tumours

Brain tumours in children frequently occur in the posterior fossa. Most undergo surgical resection, after which up to 25% develop cerebellar mutism syndrome (CMS), characterised by mutism, emotional lability and cerebellar motor signs; these typically improve over several months. This thesis examines the application of diffusion (dMRI) and arterial spin labelling (ASL) perfusion MRI in children with posterior fossa tumours. dMRI enables non-invasive in vivo investigation of brain microstructure and connectivity by a computational process known as tractography. The results of a unique survey of British neurosurgeons’ attitudes towards tractography are presented, demonstrating its widespread adoption and numerous limitations. State-of-the-art modelling of dMRI data combined with tractography is used to probe the anatomy of cerebellofrontal tracts in healthy children, revealing the first evidence of a topographic organization of projections to the frontal cortex at the superior cerebellar peduncle. Retrospective review of a large institutional series shows that CMS remains the most common complication of posterior fossa tumour resection, and that surgical approach does not influence surgical morbidity in this cohort. A prospective case-control study of children with posterior fossa tumours treated at Great Ormond Street Hospital is reported, in which children underwent longitudinal MR imaging at three timepoints. A region-of-interest based approach did not reveal any differences in dMRI metrics with respect to CMS status. However, the candidate also conducted an analysis of a separate retrospective cohort of medulloblastoma patients at Stanford University using an automated tractography pipeline. This demonstrated, in unprecedented spatiotemporal detail, a fine-grained evolution of changes in cerebellar white matter tracts in children with CMS. ASL studies in the prospective cohort showed that following tumour resection, increases in cortical cerebral blood flow were seen alongside reductions in blood arrival time, and these effects were modulated by clinical features of hydrocephalus and CMS. The results contained in this thesis are discussed in the context of the current understanding of CMS, and the novel anatomical insights presented provide a foundation for future research into the condition

Aspects of monoclonal antibody technology in diagnosis and therapy of neoplastic meningitis

This study includes an introductory review of current diagnostic, clinical and therapeutic aspects of neoplastic meningitis. Emphasis is placed on the importance of early detection of leptomeningeal tumour, as current therapeutic strategies are more effective against minimal disease. The enhancement of conventional diagnostic cytology by the addition of monoclonal antibody immunocytochemistry is discussed and, subsequently illustrated in a study of 12 patients with neoplastic meningitis. The use of monoclonal antibodies in radioimmunoassay methods is then demonstrated by the development of an immunoradiometric assay for the detection of Polymorphic Epithelial Mucin (PEM) in cerebrospinal fluid (CSF). This high molecular weight glycoprotein has not been previously assayed for in CSF and its potential value as a new diagnostic biochemical marker for carcinomatous meningitis is assessed. Finally, in a study of 15 patients with neoplastic meningitis, the potential therapeutic application of monoclonal antibodies as vectors of targeted radiation is explored. Monoclonal antibodies labelled with I-131 were administered directly into ventricular CSF, and demonstrable therapeutic responses were seen in 3/15 patients. Toxicity was seen in the form of bone marrow suppression in 3/15 patients and epilepsy in 2/15 patients