Feasibility and antitumour activity of the FGFR inhibitor erdafitnib in three paediatric CNS tumour patients.

Alterations of the fibroblast growth factor (FGF) signalling pathway are increasingly recognized as frequent oncogenic drivers of paediatric brain tumours. We report on three patients treated with the selective FGFR1-4 inhibitor erdafitinib. Two patients were diagnosed with a posterior fossa ependymoma group A (PFA EPN) and one with a low-grade glioma (LGG), harbouring FGFR3/FGFR1 overexpression and an FGFR1 internal tandem duplication (ITD), respectively. While both EPN patients did not respond to erdafitinib treatment, the FGFR1-ITD-harbouring tumour showed a significant decrease in tumour volume and contrast enhancement throughout treatment. The tumour remained stable 6 months after treatment discontinuation.

Targeting fibroblast growth factor receptors to combat aggressive ependymoma.

Ependymomas (EPN) are central nervous system tumors comprising both aggressive and more benign molecular subtypes. However, therapy of the high-risk subtypes posterior fossa group A (PF-A) and supratentorial RELA-fusion positive (ST-RELA) is limited to gross total resection and radiotherapy, as effective systemic treatment concepts are still lacking. We have recently described fibroblast growth factor receptors 1 and 3 (FGFR1/FGFR3) as oncogenic drivers of EPN. However, the underlying molecular mechanisms and their potential as therapeutic targets have not yet been investigated in detail. Making use of transcriptomic data across 467 EPN tissues, we found that FGFR1 and FGFR3 were both widely expressed across all molecular groups. FGFR3 mRNA levels were enriched in ST-RELA showing the highest expression among EPN as well as other brain tumors. We further identified high expression levels of fibroblast growth factor 1 and 2 (FGF1, FGF2) across all EPN subtypes while FGF9 was elevated in ST-EPN. Interrogation of our EPN single-cell RNA-sequencing data revealed that FGFR3 was further enriched in cycling and progenitor-like cell populations. Corroboratively, we found FGFR3 to be predominantly expressed in radial glia cells in both mouse embryonal and human brain datasets. Moreover, we detected alternative splicing of the FGFR1/3-IIIc variant, which is known to enhance ligand affinity and FGFR signaling. Dominant-negative interruption of FGFR1/3 activation in PF-A and ST-RELA cell models demonstrated inhibition of key oncogenic pathways leading to reduced cell growth and stem cell characteristics. To explore the feasibility of therapeutically targeting FGFR, we tested a panel of FGFR inhibitors in 12 patient-derived EPN cell models revealing sensitivity in the low-micromolar to nano-molar range. Finally, we gain the first clinical evidence for the activity of the FGFR inhibitor nintedanib in the treatment of a patient with recurrent ST-RELA. Together, these preclinical and clinical data suggest FGFR inhibition as a novel and feasible approach to combat aggressive EPN.

Influence of socioeconomic status on cognitive outcome after childhood arterial ischemic stroke.

AIM: To determine whether socioeconomic status (SES) is a stronger predictor for cognitive outcome after childhood arterial ischemic stroke compared to clinical factors. METHOD: We investigated perceptual reasoning, executive functions, language, memory, and attention in 18 children and adolescents (12 males, six females, median age at testing 13y 4mo, range 7y-17y 5mo) after arterial ischemic stroke; collected sociodemographic information (education of parents, household income); and used clinical information (initial lesion volume, residual lesion volume, age at stroke, time since stroke). Linear regression models were used to investigate the potential influence of SES and clinical parameters on cognitive abilities. RESULTS: SES had a moderate effect on all cognitive outcome parameters except attention by explaining 41.9%, 37.9%, 38.0%, and 22.5% of variability in perceptual reasoning, executive functions, language, and memory respectively. Initial lesion volume was the only clinical parameter that showed moderate importance on cognitive outcome (33.1% and 25.6% of the variability in perceptual reasoning and memory respectively). Overall, SES was a stronger predictor of cognitive outcome than clinical factors. INTERPRETATION: Future paediatric studies aiming at clinical predictors of cognitive outcome should control their analyses for SES in their study participants. The findings of the present study further point to the need for more attention to the treatment of children with low SES. WHAT THIS PAPER ADDS: Socioeconomic status (SES) explains up to 42% of variance in cognitive outcome after childhood arterial ischemic stroke. SES is a stronger predictor of outcome than clinical factors.

Hand MRI and the Greulich-Pyle atlas in skeletal age estimation in adolescents.

OBJECTIVE: To evaluate the feasibility of hand MRI in age assessment in adolescents using the Greulich-Pyle (GP) atlas criteria. MATERIALS AND METHODS: Two radiologists, who were blinded to the study subjects' chronologic ages, semi-objectively evaluated 1.5-T MRIs of the left hands of ten patients (13.5 ± 2.6 years) who had left-hand radiographs and 50 healthy volunteers (15 ± 2 years). RESULTS: A coronal T1-weighted, volumetric, interpolated, breath-hold examination with water excitation (T1 VIBE-3D-WE) achieved the best image quality. The correlation between estimated patients' ages on radiographs and MRI was high. The average estimated age difference between the MRIs and radiographs was -0.05 years for reader 1 and -0.175 years for reader 2. The interclass coefficients (ICCs) showed high interobserver agreement (radiographs: ICC = 0.95, MRI: ICC = 0.97). The ICC, calculated separately for the male and female volunteers' estimated ages by MRI, also showed a high agreement between the two readers (male: ICC = 0.97, female: ICC = 0.95). Reader 1 estimated 94% of volunteers within 2 standard deviations (SD) and 62% within 1 SD. The results for reader 2 were 92% and 54%, respectively. Thirty-nine percent of girls and 27% of boys were estimated to be older using 1 SD. CONCLUSION: MRI of the left hand is a feasible alternative to hand radiographs for skeletal age estimation in adolescents using the GP criteria with 2 SD. Using 1 SD, the age of healthy volunteers tended to be estimated as higher than the chronologic age. Future studies should evaluate the results in a larger number of participants.

Intracranial hypertension in siblings with infantile hypercalcemia.

BACKGROUND: Idiopathic intracranial hypertension is a clinical condition with elevated intracranial pressure of uncertain etiology. Although various underlying causes are suspected and familial occurrence has also been reported, however, it still remains an unexplained phenomenon. CASE REPORT: We report the case of dizygotic siblings with a known CYP24A1 mutation resulting in chronic hypercalcemia and impairment of kidney function. At the same point in time both of them developed intracranial hypertension resistant to conservative therapy necessitating therefore ventriculoperitoneal shunt implantation. In both children magnetic resonance imaging showed slightly hypoplastic sinus transversus as the potential underlying cause. CONCLUSION: The simultaneous clinical presentation could be due to a genetic factor or might be a component of the underlying disease or the consequence of its treatment. Further cases and clinical experience are needed to clarify this issue.

MED20 mutation associated with infantile basal ganglia degeneration and brain atrophy.

UNLABELLED: Infantile movement disorders are rare and genetically heterogeneous. We set out to identify the disease-causing mutation in siblings with a novel recessive neurodegenerative movement disorder. Genetic linkage analysis and whole-exome sequencing were performed in the original family. A cohort of six unrelated patients were sequenced for further mutations in the identified candidate gene. Pathogenicity of the mutation was evaluated by in silico analyses and by structural modeling. We identified the first and homozygous mutation (p.Gly114Ala) in the Mediator subunit 20 gene (MED20) in siblings presenting with infantile-onset spasticity and childhood-onset dystonia, progressive basal ganglia degeneration, and brain atrophy. Mediator refers to an evolutionarily conserved multi-subunit RNA polymerase II co-regulatory complex. Pathogenicity of the identified missense mutation is suggested by in silico analyses, by structural modeling, and by previous reporting of mutations in four distinct Mediator subunits causing neurodegenerative phenotypes. No further MED20 mutations were detected in this study. CONCLUSION: We delineate a novel infantile-onset neurodegenerative movement disorder and emphasize the Mediator complex as critical for normal neuronal function. Definitive proof of pathogenicity of the identified MED20 mutation will require confirmation in unrelated patients.

Trabectedin has promising antineoplastic activity in high-grade meningioma.

BACKGROUND: Meningiomas are common intracranial tumors arising from the meninges and usually are benign. However, a few meningiomas have aggressive behavior and, for such patients, effective treatment options are needed. Trabectedin is a novel, marine-derived, antineoplastic agent that has been approved and is used routinely as therapy for advanced soft tissue sarcoma and ovarian cancer. METHODS: The authors investigated the in vitro effects of trabectedin alone and in combination with hydroxyurea, cisplatin, and doxorubicin in primary cell cultures of benign (n = 9), atypical (n = 6), and anaplastic (n = 4) meningiomas using chemosensitivity assays (3-[4,5dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide [MTT]), Western blot analysis, cell cycle analysis, and immunofluorescent staining. RESULTS: Strong antimeningioma activity of trabectedin was observed and was characterized by distinct cell cycle arrest, down-regulation of multiple cyclins, deregulated expression of cell death-regulatory genes, and massive apoptosis induction. Cytotoxic activity was especially intense in higher grade meningiomas with a half-maximal inhibitory concentration <10 nM. Combination with trabectedin synergistically enhanced the antimeningioma activity of hydroxyurea but also enhanced the activity of doxorubicin and cisplatin. On the basis of these findings, trabectedin was given to 1 patient who had heavily pretreated, anaplastic meningioma, and a favorable response was observed with radiologic disease stabilization, marked reductions in brain edema and requirement for corticosteroids, and improvement of clinical symptoms. However, treatment had to be discontinued after 5 cycles because of adverse drug effects. CONCLUSIONS: The current results indicated that trabectedin may represent a promising new therapeutic option for patients with aggressive meningioma and should be evaluated in prospective clinical studies.

Antiangiogenic metronomic therapy for children with recurrent embryonal brain tumors.

BACKGROUND: Median survival time of recurrent embryonal brain tumors is short regardless of salvage chemotherapy used. An evolving alternative approach to conventional chemotherapy is to target neovascularization by interfering with tumor angiogenesis at various levels. PROCEDURE: From November 2006 to December 2010, 16 patients (median age: 9 years) with recurrent (9 first, 7 multiple) embryonal brain tumors were treated with an antiangiogenic multidrug combination regimen (bevacizumab, thalidomide, celecoxib, fenofibrate, etoposide, and cyclophophamide) and additional intraventricular therapy (etoposide and liposomal cytarabine). RESULTS: At a median of 33 months, 10/16 patients are alive. 4/4 patients with CNS primitive neuroectodermal tumors (CNS PNET) and 1/7 patients with medulloblastoma (MB) died of tumor progression during the first year. Another patient with MB died of an accident after 23 months, the remaining five patients with MB are alive for 12, 33, 33, 37, and 58 months. For the seven patients with MB, both overall survival (OS) and event free survival (EFS) after 6 months was 100%, after 12 months 85.7 ± 13%, and after 24 months 68.6 ± 19%. In contrast, for patients with CNS PNET, both OS and EFS after 6 months was 75.0 ± 22% and 0.0% and all patients had died by 12 months. Low-dose oral etoposide and cyclophosphamide was reduced after a median of 2 months and discontinued after a median of 11 months. Toxicities were manageable and therapy was generally well tolerated. CONCLUSION: Our results suggest that the chosen antiangiogenic drug combination is particularly beneficial for patients with MB and warrants further investigation.

Unique Finding of a Primary Central Nervous System Neuroendocrine Carcinoma in a 5-Year-Old Child: A Case Report.

Neuroendocrine tumors (NETs) are rare neoplasms predominantly arising in the gastrointestinal-tract or the lungs of adults. To date, only ten cases of primary central nervous system (CNS) NETs have been reported, with just three of them describing a neuroendocrine carcinoma (NECA) and none occurring in a child. We report on a previously healthy 5-year-old boy, who presented with headaches, nausea and vomiting, and was diagnosed with a left cerebellar solid mass with a cystic component. After gross-total resection, histology revealed a neuroendocrine carcinoma. Molecular analysis of the tumor tissue showed a KRAS-splice-site mutation (c451-3C > T). The KRAS-mutation was discovered to be a maternal germline mutation, previously described as likely benign. After extensive search for an extracranial primary tumor, including Ga-68 DOTANOC-PET-CT, the diagnosis of a primary CNS NECA was established, and proton irradiation was performed. Unfortunately, the patient developed an in-field recurrence just 5 weeks after the end of radiotherapy. The tumor was re-resected with vital tumor tissue. Six cycles of chemotherapy were initiated, consisting of cisplatin, carboplatin, etoposide and ifosfamide. The patient remains disease free 22 months after the end of treatment, supporting the beneficial effect of platinum- and etoposide-based chemotherapy for this tumor entity.

Extensive pleural and pericardial effusion in chronic myeloid leukemia during treatment with dasatinib at 100 mg or 50 mg daily.

Dasatinib is considered an effective drug in imatinib-resistant chronic myeloid leukemia. Although reported to be well-tolerated, severe events such as pleural or pericardial effusion have been reported at 140 mg daily. We examined our chronic myeloid leukemia patients treated with dasatinib at 100 mg or 50 mg daily and identified 4 of 13 patients who developed marked effusion formation. In 2 patients, grade III/IV pleural and/or pericardial effusions were recorded. All 4 patients had received previous anti-leukemia therapy but none had pre-existing cardiac or pulmonary diseases. In 3 patients, dasatinib had to be discontinued despite treatment with diuretics and glucocorticosteroids. In conclusion, dasatinib-treated chronic myeloid leukemia patients are at risk for the development of pleural and pericardial effusions even when the drug is administered at 100 mg or 50 mg daily. Therefore, all patients should be examined for pre-existing comorbidity and risk factors before starting dasatinib and all should have repeated chest X-rays during long-term dasatinib therapy.

Lethal Encephalopathy in an Infant with Hypophosphatasia despite Enzyme Replacement Therapy.

Hypophosphatasia (HPP) is an inborn error of metabolism caused by loss-of-function mutations in the biomineralization-associated alkaline phosphatase gene, encoding tissue-nonspecific alkaline phosphatase (TNSALP). Symptoms include skeletal hypomineralization and extra-skeletal manifestations such as pyridoxine (B6)-responsive seizures due to impaired cerebral B6 passage. Since the introduction of enzyme replacement therapy (ERT), skeletal manifestations and B6-responsive seizures were reported to improve significantly. Nevertheless, there is an increasing evidence of B6-independent neurological manifestation of HPP including HPP-associated encephalopathy. Here, we present for the first time the brain alterations of an infant with neonatal HPP who died of neurological complications at the age of 5 months despite early initiation of ERT. CSF analysis showed normal concentrations of biogenic amines reflecting sufficient intracellular B6 availability. Postmortem histopathology revealed severe, localized affection of the cerebral cortex including cortical lesions in layers 2 and 3 in direct proximity to TNSALP-expressing neurons and hippocampal sclerosis. Our findings confirm that TNSALP deficiency may lead to a severe encephalopathy. We hypothesize that HPP-associated encephalopathy resistant to currently available ERT may develop in addition and probably independently of typical B6-responsive seizures in some patients. Prospective, controlled studies with close neurological follow-up including brain imaging are needed to identify patients at risk for severe neurological symptoms despite ERT.

Novel Insights into Diagnosis, Biology and Treatment of Primary Diffuse Leptomeningeal Melanomatosis.

Primary diffuse leptomeningeal melanomatosis (PDLMM) is an extremely rare and aggressive cancer type for which best treatment strategies remain to be elucidated. Herein, we present current and prospective diagnostic strategies and treatment management of PDLMM. Against the background of an extensive literature review of published PDLMM cases and currently employed therapeutic strategies, we present an illustrative case of a pediatric patient suffering from PDLMM. We report the first case of a pediatric patient with PDLMM who received combination treatment including trametinib and everolimus, followed by intravenous nivolumab and ipilimumab with concomitant intensive intraventricular chemotherapy, resulting in temporary significant clinical improvement and overall survival of 7 months. Following this clinical experience, we performed a comprehensive literature review, identifying 26 additional cases. By these means, we provide insight into current knowledge on clinical and molecular characteristics of PDLMM. Analysis of these cases revealed that the unspecific clinical presentation, such as unrecognized increased intracranial pressure (present in 67%), is a frequent reason for the delay in diagnosis. Mortality remains substantial despite diverse therapeutic approaches with a median overall survival of 4 months from diagnosis. On the molecular level, to date, the only oncogenic driver reported so far is mutation of NRAS (n = 3), underlining a close biological relation to malignant melanoma and neurocutaneous melanosis. We further show, for the first time, that this somatic mutation can be exploited for cerebrospinal fluid liquid biopsy detection, revealing a novel potential biomarker for diagnosis and monitoring of PDLMM. Last, we use a unique patient derived PDLMM cell model to provide first insights into in vitro drug sensitivities. In summary, we provide future diagnostic and therapeutic guidance for PDLMM and first insights into the use of liquid biopsy and in vitro models for this orphan cancer type.

Forebrain development in fetal MRI: evaluation of anatomical landmarks before gestational week 27.

INTRODUCTION: Forebrain malformations include some of the most severe developmental anomalies and require early diagnosis. The proof of normal or abnormal prosencephalic development may have an influence on further management in the event of a suspected fetal malformation. The purpose of this retrospective study was to evaluate the detectability of anatomical landmarks of forebrain development using in vivo fetal magnetic resonance imaging (MRI) before gestational week (gw) 27. METHODS: MRI studies of 83 singleton fetuses (gw 16-26, average +/- sd: gw 22 +/- 2) performed at 1.5 Tesla were assessed. T2-weighted (w) fast spin echo, T1w gradient-echo and diffusion-weighted sequences were screened for the detectability of anatomical landmarks as listed below. RESULTS: The interhemispheric fissure, ocular bulbs, corpus callosum, infundibulum, chiasm, septum pellucidum (SP), profile, and palate were detectable in 95%, 95%, 89%, 87%, 82%, 81%, 78%, 78% of cases. Olfactory tracts were more easily delineated than bulbs and sulci (37% versus 18% and 8%), with significantly higher detection rates in the coronal plane. The pituitary gland could be detected on T1w images in 60% with an increasing diameter with gestational age (p = 0.041). The delineation of olfactory tracts (coronal plane), chiasm, SP and pituitary gland were significantly increased after week 21 (p < 0.05). Pathologies were found in 28% of cases. CONCLUSION: This study provides detection rates for anatomical landmarks of forebrain development with fetal MRI before gw 27. Several anatomical structures are readily detectable with routine fetal MRI sequences; thus, if these landmarks are not delineable, it should raise the suspicion of a pathology. Recommendations regarding favorable sequences/planes are provided.

An adolescent with herpes simplex encephalitis, presenting with mild symptoms and rapid deterioration: A case report.

Headaches in children are a common, but unspecific symptom that can have many underlying causes, ranging from unspecific tension headache through migraine and up to encephalitis and intracranial hypertension. We present the case of a 14-year-old boy who presented to our emergency department with headache, nausea as well as vomiting and developed seizures later on. The initial diagnosis was complicated by a magnetic resonance imaging which did not show any signs of inflammation, but was of limited informative value due to orthodontic appliances. Despite the unremarkable imaging, prophylactic antiviral and antibiotic treatment was started after lumbar puncture. Herpes simplex virus as well as human herpes virus 7 were confirmed in the cerebrospinal fluid. Although both viruses are ubiquitous, severe infections are a rare complication. Immunodeficiency syndromes are predisposing factors for serious complications and genetic analysis of UNC93B and TLR-3 might be helpful for decision-making. No genetic or immunologic predisposition was found in our patient. The patient's condition deteriorated rapidly, so he had to be admitted to the pediatric intensive care unit, where he was intubated and his antiviral treatment with acyclovir was extended by foscarnet. After prolonged mechanical ventilation, he slowly improved. With intensive neurorehabilitation, he could finally return to his daily life activities 3 months after diagnosis. Despite headaches being an unspecific symptom, the possibility of a herpes simplex virus encephalitis should always kept in mind, especially in patients presenting with additional symptoms such as vomiting, altered mental status and/or focal neurological deficits. An initial magnetic resonance imaging might be misleading if orthodontic appliances are in place. Initiation of treatment without delay is crucial for neurologic outcome of herpes simplex virus encephalitis.

Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma.

Targeting oncogenic fusion-genes in pediatric high-grade gliomas (pHGG) with entrectinib has emerged as a highly promising therapeutic approach. Despite ongoing clinical studies, to date, no reports on the treatment of cerebrospinal fluid (CSF) disseminated fusion-positive pHGG exist. Moreover, clinically important information of combination with other treatment modalities such as intrathecal therapy, radiotherapy and other targeted agents is missing. We report on our clinical experience of entrectinib therapy in two CSF disseminated ROS1/NTRK-fusion-positive pHGG cases. Combination of entrectinib with radiotherapy or intrathecal chemotherapy appears to be safe and has the potential to act synergistically with entrectinib treatment. In addition, we demonstrate CSF penetrance of entrectinib for the first time in patient samples suggesting target engagement even upon CSF dissemination. Moreover, in vitro analyses of two novel cell models derived from one case with NTRK-fusion revealed that combination therapy with either a MEK (trametinib) or a CDK4/6 (abemaciclib) inhibitor synergistically enhances entrectinib anticancer effects. In summary, our comprehensive study, including clinical experience, CSF penetrance and in vitro data on entrectinib therapy of NTRK/ROS1-fusion-positive pHGG, provides essential clinical and preclinical insights into the multimodal treatment of these highly aggressive tumors. Our data suggest that combined inhibition of NTRK/ROS1 and other therapeutic vulnerabilities enhances the antitumor effect, which should be followed-up in further preclinical and clinical studies.

Personalized Treatment of H3K27M-Mutant Pediatric Diffuse Gliomas Provides Improved Therapeutic Opportunities.

Diffuse gliomas with K27M histone mutations (H3K27M glioma) are generally characterized by a fatal prognosis, particularly affecting the pediatric population. Based on the molecular heterogeneity observed in this tumor type, personalized treatment is considered to substantially improve therapeutic options. Therefore, clinical evidence for therapy, guided by comprehensive molecular profiling, is urgently required. In this study, we analyzed feasibility and clinical outcomes in a cohort of 12 H3K27M glioma cases treated at two centers. Patients were subjected to personalized treatment either at primary diagnosis or disease progression and received backbone therapy including focal irradiation. Molecular analyses included whole-exome sequencing of tumor and germline DNA, RNA-sequencing, and transcriptomic profiling. Patients were monitored with regular clinical as well as radiological follow-up. In one case, liquid biopsy of cerebrospinal fluid (CSF) was used. Analyses could be completed in 83% (10/12) and subsequent personalized treatment for one or more additional pharmacological therapies could be recommended in 90% (9/10). Personalized treatment included inhibition of the PI3K/AKT/mTOR pathway (3/9), MAPK signaling (2/9), immunotherapy (2/9), receptor tyrosine kinase inhibition (2/9), and retinoic receptor agonist (1/9). The overall response rate within the cohort was 78% (7/9) including one complete remission, three partial responses, and three stable diseases. Sustained responses lasting for 28 to 150 weeks were observed for cases with PIK3CA mutations treated with either miltefosine or everolimus and additional treatment with trametinib/dabrafenib in a case with BRAFV600E mutation. Immune checkpoint inhibitor treatment of a case with increased tumor mutational burden (TMB) resulted in complete remission lasting 40 weeks. Median time to progression was 29 weeks. Median overall survival (OS) in the personalized treatment cohort was 16.5 months. Last, we compared OS to a control cohort (n = 9) showing a median OS of 17.5 months. No significant difference between the cohorts could be detected, but long-term survivors (>2 years) were only present in the personalized treatment cohort. Taken together, we present the first evidence of clinical efficacy and an improved patient outcome through a personalized approach at least in selected cases of H3K27M glioma.

Quantification and detectability of in-stent stenosis with CT angiography and MR angiography in arterial stents in vitro.

OBJECTIVE: The purpose of this study was to compare CT angiography (CTA) and MR angiography (MRA) for the detectability of 75% and 95% stenoses in phantoms using six different stents. MATERIALS AND METHODS: Six different stents (Expander, Hemobahn, SelfX, Smart, Symphony, and Wallstent) were inserted into tubes filled with contrast agent (ioversol or gadoteric acid). To mimic stenoses of 75% and 95% of the patent lumen, 8-mm-diameter nylon cylinders were bored in the central axis (2 mm and 4 mm, respectively) and placed into the stent lumen. Intensity profiles across stenoses on 2-mm coronal reformatted sections of CTA or MRA were compared, and the detectability of the residual lumen was assessed using a subjective score. RESULTS: CTA showed relative in-stent signal attenuation for the in-stent stenoses of the tested stents ranging from 75% to 100% of the signal intensity of the control. SelfX and Symphony showed further shading of the residual lumen due to beam-hardening artifacts. Overestimation of stenosis was associated with low-grade stenoses in which the border of the lumen was closer to the stent struts. MRA showed relative in-stent signal attenuation of the in-stent stenoses ranging from 30% to 100% of the signal intensity of the control. Strut thickness tended to correlate with higher attenuation at CT. CONCLUSION: CTA may be more suitable for differentiation between 95% stenosis and occlusion; MRA has higher sensitivity in detecting 75% stenoses. Strut thickness and mesh size did not prove to be significant predictors for signal attenuation or overall image quality.

Childhood onset temporal lobe epilepsy: Beyond hippocampal sclerosis.

OBJECTIVE: Hippocampal Sclerosis (HS) is widely recognized as a significant underlying cause of drug-resistant temporal lobe epilepsy (TLE) in adults. In contrast, HS is a rare finding in pediatric surgical series, and a higher incidence of HS associated with cortical dysplasia (i.e. FCD type IIIa according to the new ILAE classification) than in adult series has been reported. Data about the electro-clinical characteristics of this subgroup are scarce. METHODS: We studied 15 children and adolescents with drug-resistant TLE and HS who had anterior temporal lobe resection at our center with regard to electroclinical characteristics, MRI features and histopathology. Children in whom histopathology was consistent with Focal Cortical Dysplasia (FCD) type IIIa (n = 7) were compared with those who had HS only (n = 8). RESULTS: Clinical characteristics associated with this highly selective subset of patients with FCD type IIIa were: the presence of febrile seizures during infancy, a shorter duration of active epilepsy and a lower age at epilepsy surgery. In addition, there were non-significant trends towards more extended abnormalities on both EEG and neuroimaging. We were, however, not able to find group differences with respect to neuropathologic subtyping of the HS. CONCLUSION: We present the first detailed description and comprehensive data analysis of children with FCD type IIIa. According to our results, this patient group seems to show a distinct clinical phenotype.

CT-MR image data fusion for computer-assisted navigated surgery of orbital tumors.

PURPOSE: To demonstrate the value of multidetector computed tomography (MDCT) and magnetic resonance imaging (MRI) in the preoperative assessment of orbital tumors, and to present, particularly, CT and MR image data fusion for surgical planning and performance in computer-assisted navigated surgery of orbital tumors. MATERIALS AND METHODS: In this retrospective case series, 10 patients with orbital tumors and associated complaints underwent MDCT and MRI of the orbit. MDCT was performed at high resolution, with a bone window level setting in the axial plane. MRI was performed with an axial 3D T1-weighted (w) gradient-echo (GE) contrast-enhanced sequence, in addition to a standard MRI protocol. First, MDCT and MR images were used to diagnose tumorous lesions compared to histology as a standard of reference. Then, the image data sets from CT and 3D T1-w GE sequences were merged on a workstation to create CT-MR fusion images that were used for interventional planning and intraoperative image guidance. The intraoperative accuracy of the navigation unit was measured, defined as the deviation between the same landmark in the navigation image and the patient. Furthermore, the clinical preoperative status was compared to the patients' postoperative outcome. RESULTS: Radiological and histological diagnosis, which revealed 7 benign and 3 malignant tumors, were concordant in 7 of 10 cases (70%). The CT-MR fusion images supported the surgeon in the preoperative planning and improved the surgical performance. The mean intraoperative accuracy of the navigation unit was 1.35mm. Postoperatively, orbital complaints showed complete regression in 6 cases, were ameliorated notably in 3 cases, and remained unchanged in 1 case. CONCLUSION: CT and MRI are essential for the preoperative assessment of orbital tumors. CT-MR image data fusion is an accurate tool for planning the correct surgical procedure, and can improve surgical results in computer-assisted navigated surgery of orbital tumors.

Diagnostic pitfalls in fetal brain MRI.

Recent technological advances in fetal magnetic resonance imaging (MRI) and increased reliability of MRI in depicting abnormalities and lesions, especially in the central nervous system, are increasingly bringing up challenging issues with regard to accurate diagnosis. There are also pitfalls not only attributable to image acquisition but also in clinical interpretation. The misinterpretation of findings because of insufficient knowledge about fetal brain development as visualized by MRI may also be regarded as an important limitation of fetal MRI. We provide an overview of the most common pitfalls experienced in fetal MRI in routine practice, demonstrate how to identify some of the factors that lead to imaging misinterpretation, and suggest ways to tackle these problems, with an emphasis on MR techniques and image calibration.