José Pimentel

A Pan-European Study of the C9orf72 Repeat Associated with FTLD: Geographic Prevalence, Genomic Instability, and Intermediate Repeats

We assessed the geographical distribution of C9orf72 G4C2 expansions in a pan‐European frontotemporal lobar degeneration (FTLD) cohort (n = 1,205), ascertained by the European Early‐Onset Dementia (EOD) consortium. Next, we performed a meta‐analysis of our data and that of other European studies, together 2,668 patients from 15 Western European countries. The frequency of the C9orf72 expansions in Western Europe was 9.98% in overall FTLD, with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of respectively 29.33% and 20.73%, but also Spain with 25.49%. In contrast, prevalence in Germany was limited to 4.82%. In addition, we studied the role of intermediate repeats (7–24 repeat units), which are strongly correlated with the risk haplotype, on disease and C9orf72 expression. In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss‐of‐function disease mechanism. Further, we observed a significantly increased frequency of short indels in the GC‐rich low complexity sequence adjacent to the G4C2 repeat in C9orf72 expansion carriers (P < 0.001) with the most common indel creating one long contiguous imperfect G4C2 repeat, which is likely more prone to replication slippage and pathological expansion.

Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis

BACKGROUND Recurrent medulloblastoma is a therapeutic challenge because it is almost always fatal. Studies have confirmed that medulloblastoma consists of at least four distinct subgroups. We sought to delineate subgroup-specific differences in medulloblastoma recurrence patterns. METHODS We retrospectively identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children (Toronto, ON, Canada) from 1994 to 2012 (cohort 1), and established molecular subgroups using a nanoString-based assay on formalin-fixed paraffin-embedded tissues or frozen tissue. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence, and survival after recurrence were assessed in a subgroup-specific manner. Two independent, non-overlapping cohorts (cohort 2: samples from patients with recurrent medulloblastomas from 13 centres worldwide, obtained between 1991 and 2012; cohort 3: samples from patients with recurrent medulloblastoma obtained at the NN Burdenko Neurosurgical Institute [Moscow, Russia] between 1994 and 2011) were analysed to confirm and validate observations. When possible, molecular subgrouping was done on tissue obtained from both the initial surgery and at recurrence. RESULTS Cohort 1 consisted of 30 patients with recurrent medulloblastomas; nine with local recurrences, and 21 with metastatic recurrences. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients with recurrent medulloblastoma. Subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs (five pairs from cohort 1 and 29 pairs from cohort 2 [15 SHH, five group 3, 14 group 4]). This finding was validated in 17 pairs from cohort 3. When analysed in a subgroup-specific manner, local recurrences in cohort 1 were more frequent in SHH tumours (eight of nine [89%]) and metastatic recurrences were more common in group 3 and group 4 tumours (17 of 20 [85%] with one WNT, p=0·0014, local vs metastatic recurrence, SHH vs group 3 vs group 4). The subgroup-specific location of recurrence was confirmed in cohort 2 (p=0·0013 for local vs metastatic recurrence, SHH vs group 3 vs group 4,), and cohort 3 (p<0·0001). Treatment with craniospinal irradiation at diagnosis was not significantly associated with the anatomical pattern of recurrence. Survival after recurrence was significantly longer in patients with group 4 tumours in cohort 1 (p=0·013) than with other subgroups, which was confirmed in cohort 2 (p=0·0075), but not cohort 3 (p=0·70). INTERPRETATION Medulloblastoma does not change subgroup at the time of recurrence, reinforcing the stability of the four main medulloblastoma subgroups. Significant differences in the location and timing of recurrence across medulloblastoma subgroups have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of patients with SHH tumours. Refinement of therapy for patients with group 3 or group 4 tumours should focus on metastases.

Intertumoral Heterogeneity within Medulloblastoma Subgroups

While molecular subgrouping has revolutionized medulloblastoma classification, the extent of heterogeneity within subgroups is unknown. Similarity network fusion (SNF) applied to genome-wide DNA methylation and gene expression data across 763 primary samples identifies very homogeneous clusters of patients, supporting the presence of medulloblastoma subtypes. After integration of somatic copy-number alterations, and clinical features specific to each cluster, we identify 12 different subtypes of medulloblastoma. Integrative analysis using SNF further delineates group 3 from group 4 medulloblastoma, which is not as readily apparent through analyses of individual data types. Two clear subtypes of infants with Sonic Hedgehog medulloblastoma with disparate outcomes and biology are identified. Medulloblastoma subtypes identified through integrative clustering have important implications for stratification of future clinical trials.

Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis

BACKGROUND Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours. METHODS We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling. FINDINGS Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95% CI 1·04-3·85; p=0·038) and 3·98 (1·71-9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes. INTERPRETATION An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours. FUNDING C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations.

Good interobserver and intraobserver agreement in the evaluation of the new ILAE classification of focal cortical dysplasias

Purpose:  An International League Against Epilepsy (ILAE) consensus classification system for focal cortical dysplasias (FCDs) has been published in 2011 specifying clinicopathologic FCD variants. The aim of the present work was to microscopically assess interobserver agreement and intraobserver reproducibility for FCD categories among an international group of neuropathologists with different levels of experience and access to epilepsy surgery tissue.

Epileptic Seizures following Subcortical Infarcts

Stroke is one of the most frequent causes of seizures in adulthood. Subcortical infarcts have been associated with post-stroke epileptic seizures, although less frequently than cortical ischaemia. We studied 113 patients from a hospital stroke registry. The patients had subcortical non-lacunar infarcts (64 striatocapsular infarcts, 13 thalamic, 8 choroidal artery territory, 28 internal border zone and white matter medullary infarcts) and at least 1 year of follow-up. Only 4 patients (3.5%) with striatocapsular infarcts suffered an epileptic seizure. Two seizures occurred within the first 24 h, 1 within the first month and 1 within the first year of stroke onset. Emboligenic cardiac conditions were significantly more common in patients with seizures (difference 37%; 95% confidence intervals 2–72%). Subsequently to subcortical infarct, epileptic seizures are infrequent, tend to occur early after stroke and have a very low 1-year recurrence risk.

Genetic alterations in a papillary glioneuronal tumor

Papillary glioneuronal tumors (PGNTs) are rare lesions of the central nervous system, and no information exists on the genetic alterations in these neoplasms. The authors report on such a case in a child. Genetic studies revealed that the tumor was characterized by gains and structural alterations involving only chromosome 7 with breakpoints at 7p22. By using comparative genomic hybridization, the authors observed a high-level amplification region at 7p14~q12. Fluorescence in situ hybridization with a probe for EGFR revealed that this gene was not amplified. Similar to other patients with PGNTs, the patient in the present case fared well. From a genetic point of view the data in the present case are in accordance with previous findings of EGFR amplifications as uncommon in low-grade gliomas and gangliogliomas. Recurrent rearrangements of chromosome 7 have been noted in other mixed glioneuronal tumors. The data in this case suggest that genes located at chromosome 7 can also be involved in the pathogenesis of PGNT. In clinical terms it will be especially important to corroborate, through the analysis of further cases, the involvement of the chromosome 7p22 locus, a region where glial and neuronal linked genes (RAC1 and NXPH1) are known to be located.

Rosette-forming glioneuronal tumor: pathology case report.

OBJECTIVE Rosette-forming glioneuronal tumor is a newly described mixed glial and neuronal tumor. We describe two cases and review the literature to better characterize this entity. METHODS Patients were surgically treated, and tumors were diagnosed by light microscopy and immunohistochemistry using the avidin-biotin complex method. PubMed was searched for previously reported cases. RESULTS Patient 1 was a 38-year-old woman who presented with headaches and no neurological abnormality. Magnetic resonance imaging showed a solid mass in the fourth ventricle. Subtotal excision of the mass caused transient gait ataxia. Patient 2 was a 51-year-old woman with dizziness who fell and sustained head trauma. Magnetic resonance imaging revealed a right paramedian cerebellar cystic and nodular mass and a separate nodule in the vermis, which were excised gross totally with no morbidity. Microscopic examination showed neuroepithelial tumors composed of neurocytic cells focally forming well-defined rosettes that were immunopositive for neuronal markers and of elongated, glial fibrillary acidic protein-immunoreactive astrocytes. No histological anaplasia was present. Both patients were well 18 and 8 months after surgery, respectively. Eighteen rosette-forming glioneuronal tumors were identified with the literature search. CONCLUSION These are tumors of young adulthood (range, 12-59 yr) usually in or close to the fourth ventricle. Histologically, they are low-grade, although multiple foci or local extension may prevent total excision and account for some recurrences. On imaging, they are cystic, solid, or both, with minimal perilesional edema or mass effect. They are composed of neurocytic and glial elements, probably arising from a common progenitor in the subependymal plate, and need to be differentiated from a variety of glioneuronal tumors.

Epilepsy and physical exercise.

Epilepsy is one of the commonest neurologic diseases and has always been associated with stigma. In the interest of safety, the activities of persons with epilepsy (PWE) are often restricted. In keeping with this, physical exercise has often been discouraged. The precise nature of a persons seizures (or whether seizures were provoked or unprovoked) may not have been considered. Although there has been a change in attitude over the last few decades, the exact role of exercise in inducing seizures or aggravating epilepsy still remains a matter of discussion among experts in the field. Based mainly on retrospective, but also on prospective, population and animal-based research, the hypothesis that physical exercise is prejudicial has been slowly replaced by the realization that physical exercise might actually be beneficial for PWE. The benefits are related to improvement of physical and mental health parameters and social integration and reduction in markers of stress, epileptiform activity and the number of seizures. Nowadays, the general consensus is that there should be no restrictions to the practice of physical exercise in people with controlled epilepsy, except for scuba diving, skydiving and other sports at heights. Whilst broader restrictions apply for patients with uncontrolled epilepsy, individual risk assessments taking into account the seizure types, frequency, patterns or triggers may allow PWE to enjoy a wide range of physical activities.

Intramedullary neuroma of the cervical spinal cord: case report.

OBJECTIVE AND IMPORTANCE Intramedullary neuromas are rare tumors; only 37 cases have been described in the literature since 1931. CLINICAL PRESENTATION The case of a 36-year-old woman presenting with an 8-month history of a progressive cervical myelopathy is reported. A diagnosis of a cervical intramedullary tumor was made by magnetic resonance imaging. INTERVENTION A C3-C7 laminectomy and a near total resection were performed. Pathological examination revealed a neuroma; the various operative and pathological findings are presented. CONCLUSION The existence of intraparenchymal neuromas is difficult to explain. Various pathogenic hypotheses are discussed. Microsurgical resection is considered the therapeutic option of choice for these entities.