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We describe the management and clinical decision making in a cardiogenic shock patient with a free-floating left ventricular thrombus found during temporary mechanical support with an Impella CP. The management of these patients can be challenging because there are no guidelines or data to support any particular treatment strategy. (Level of Difficulty: Intermediate.), Graphical abstract, We describe the management and clinical decision making in a cardiogenic shock patient with a free-floating left ventricular thrombus found during temporary…

International audience; cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to evaluate and make practical recommendations on recent advances in the field of CNS tumor classification, particularly in light of the rapid progress in molecular insights into these neoplasms. For Round 2 of its deliberations, cIMPACT-NOW Working Committee 3 was reconstituted and convened in Utrecht, The Netherlands, for a meeting designed to review putative new CNS tumor types in advance of any future World Health Organization meeting on CNS tumor classification. In preparatory activities for the meeting and at the actual meeting, a list of possible entities was assembled and each type and subtype debated. Working Committee 3 recommended that a substantial number of newly recognized types and subtypes should be considered for inclusion in future CNS tumor classifications. In addition, the group endorsed a number of principles-relating to classification categories, approaches to classification, nomenclature, and grading-that the group hopes will also inform the future classification of CNS neoplasms.

Aims: DNA methylation-based central nervous system (CNS) tumour classification has identified numerous molecularly distinct tumour types, and clinically relevant subgroups among known CNS tumour entities that were previously thought to represent homogeneous diseases. Our study aimed at characterizing a novel, molecularly defined variant of glioneuronal CNS tumour. Patients and methods: DNA methylation profiling was performed using the Infinium MethylationEPIC or 450 k BeadChip arrays (Illumina) and analysed using the ‘conumee’ package in R computing environment. Additional gene panel sequencing was also performed. Tumour samples were collected at the German Cancer Research Centre (DKFZ) and provided by multinational collaborators. Histological sections were also collected and independently reviewed. Results: Genome-wide DNA methylation data from >25 000 CNS tumours were screened for clusters separated from established DNA methylation classes, revealing a novel group comprising 31 tumours, mainly found in paediatric patients. This DNA methylation-defined variant of low-grade CNS tumours with glioneuronal differentiation displays recurrent monosomy 14, nuclear clusters within a morphology that is otherwise reminiscent of oligodendroglioma and other established entities with clear cell histology, and a lack of genetic alterations commonly observed in other (paediatric) glioneuronal entities. Conclusions: DNA methylation-based tumour classification is an objective method of assessing tumour origins, which may aid in diagnosis, especially for atypical cases. With increasing sample size, methylation analysis allows for the identification of rare, putative new tumour entities, which are currently not recognized by the WHO classification. Our study revealed the existence of a DNA methylation-defined class of low-grade glioneuronal tumours with recurrent monosomy 14, oligodendroglioma-like features and nuclear clusters.

Embryonal tumours with multilayered rosettes (ETMRs) are aggressive paediatric embryonal brain tumours with a universally poor prognosis1. Here we collected 193 primary ETMRs and 23 matched relapse samples to investigate the genomic landscape of this distinct tumour type. We found that patients with tumours in which the proposed driver C19MC2–4 was not amplified frequently had germline mutations in DICER1 or other microRNA-related aberrations such as somatic amplification of miR-17-92 (also known as MIR17HG). Whole-genome sequencing revealed that tumours had an overall low recurrence of single-nucleotide variants (SNVs), but showed prevalent genomic instability caused by widespread occurrence of R-loop structures. We show that R-loop-associated chromosomal instability can be induced by the loss of DICER1 function. Comparison of primary tumours and matched relapse samples showed a strong conservation of structural variants, but low conservation of SNVs. Moreover, many newly acquired SNVs are associated with a mutational signature related to cisplatin treatment. Finally, we show that targeting R-loops with topoisomerase and PARP inhibitors might be an effective treatment strategy for this deadly disease.

Medulloblastomas (MBs) are the most common brain tumors in children. Some are thought to originate from cerebellar granule neuron progenitors (GNPs) that fail to undergo normal cell cycle exit and differentiation. Because microRNAs regulate numerous aspects of cellular physiology and development, we reasoned that alterations in miRNA expression might contribute to MB. We tested this hypothesis using 2 spontaneous mouse MB models with specific initiating mutations, Ink4c −/−; Ptch1 +/− and Ink4c −/−; p53 −/−. We found that 26 miRNAs showed increased expression and 24 miRNAs showed decreased expression in proliferating mouse GNPs and MBs relative to mature mouse cerebellum, regardless of genotype. Among the 26 overexpressed miRNAs, 9 were encoded by the miR-17 ∼ 92 cluster family, a group of microRNAs implicated as oncogenes in several tumor types. Analysis of human MBs demonstrated that 3 miR-17 ∼ 92 cluster miRNAs ( miR-92 , miR-19a , and miR-20 ) were also overexpressed in human MBs with a constitutively activated Sonic Hedgehog (SHH) signaling pathway, but not in other forms of the disease. To test whether the miR-17 ∼ 92 cluster could promote MB formation, we enforced expression of these miRNAs in GNPs isolated from cerebella of postnatal (P) day P6 Ink4c −/−; Ptch1 +/− mice. These, but not similarly engineered cells from Ink4c −/−; p53 −/− mice, formed MBs in orthotopic transplants with complete penetrance. Interestingly, orthotopic mouse tumors ectopically expressing miR-17 ∼ 92 lost expression of the wild-type Ptch1 allele. Our findings suggest a functional collaboration between the miR-17 ∼ 92 cluster and the SHH signaling pathway in the development of MBs in mouse and man.

The accurate assessment of disease risk among children with medulloblastoma remains a major challenge to the field of paediatric neuro-oncology. In the current study we investigated the capacity of molecular abnormalities to increase the accuracy of disease risk stratification above that afforded by clinical staging alone. 41 primary medulloblastoma tumour samples were analysed for ErbB2 receptor expression using immunohistochemistry, and for aberrations of chromosome 17 and amplification of the MYC oncogene using fluorescence in situ hybridisation. The ErbB2 receptor and deletion of 17p were detected in 80% and 49% of tumours, respectively. 17p loss occurred either in isolation (20%), or in association with gain of 17q (29%), compatible with an isochromosome of 17q. Amplification of MYC was detected in only 2 tumours. Significant prognostic factors included, ‘metastatic disease’ (P = 0.0006), ‘sub-total tumour resection’ (P = 0.007), ‘high ErbB2 receptor expression’ (P = 0.003) and ‘isolated 17p loss’ (P = 0.003). Combined analysis of clinical and molecular factors enabled greater resolution of disease risk than clinical factors alone, identifying a sub-population of patients with particularly favourable disease outcome. These data support the hypothesis that a combination of clinical and molecular factors may afford a more reliable means of assigning disease risk in patients with medulloblastoma, thereby providing a more accurate basis for targeting therapy in children with this disease. © 2001 Cancer Research Campaign http://www.bjcancer.com

Background—Seven aVected members are described from a kindred with autosomal dominant familial Alzheimer’s disease associated with a novel mutation in the presenilin 1 (PS1) gene on chromosome 14 that results in a leucine to serine substitution at codon 250 (L250S). Method—Clinical information on the pedigree was collected directly from family members including aVected members and their carers and also from hospital records. Results—Detailed clinical information was available on five members. All had an early age at onset with a median age of 52 (95% confidence interval (95% CI) 49.4‐ 54.9). Age at onset varied between 49 and 56 years, with duration of illness varying between six years and 15 years. Myoclonus, depression, and psychosis were features of this pedigree;seizures were not reported. Conclusions—PS1 L250S familial Alzheimer’s disease is an early onset form of Alzheimer’s disease with clinical features similar to other reported familial Alzheimer’s disease pedigrees, except that seizures were absent. (J Neurol Neurosurg Psychiatry 1998;64:44‐49)

It is well established that inherited human aldehyde dehydrogenase 2 (ALDH-2) deficiency reduces the risk for alcoholism. Kudzu plants and extracts have been used for 1,000 years in traditional Chinese medicine to treat alcoholism. Kudzu contains daidzin, which inhibits ALDH-2 and suppresses heavy drinking in rodents. Decreased drinking due to ALDH-2 inhibition is attributed to aversive properties of acetaldehyde accumulated during alcohol consumption. However not all of the anti-alcohol properties of diadzin are due to inhibition of ALDH-2. This is in agreement with our earlier work showing significant interaction effects of both pyrozole (ALDH-2 inhibitor) and methyl-pyrozole (non-inhibitor) and ethanol's depressant effects. Moreover, it has been suggested that selective ALDH 2 inhibitors reduce craving for alcohol by increasing dopamine in the nucleus accumbens (NAc). In addition there is significant evidence related to the role of the genetics of bitter receptors (TAS2R) and its stimulation as an aversive mechanism against alcohol intake. The inclusion of bitters such as Gentian & Tangerine Peel in Declinol provides stimulation of gut TAS2R receptors which is potentially synergistic with the effects of Kudzu. Finally the addition of Radix Bupleuri in the Declinol formula may have some protective benefits not only in terms of ethanol induced liver toxicity but neurochemical actions involving endorphins, dopamine and epinephrine. With this information as a rationale, we report herein that this combination significantly reduced Alcohol Use Disorders Identification Test (AUDIT) scores administered to ten heavy drinkers (M=8, F=2; 43.2 ± 14.6 years) attending a recovery program. Specifically, from the pre-post comparison of the AUD scores, it was found that the score of every participant decreased after the intervention which ranged from 1 to 31. The decrease in the scores was found to be statistically significant with the p-value of 0.00298 (two-sided paired test; p-value = 0.00149 for one-sided test). Albeit this being a small pilot, we are encouraged about these significant results, and caution any interpretation until larger controlled studies are executed.

Medulloblastoma (MB) is the most common brain tumor in children. Recent studies have demonstrated a relationship between specific signaling pathway abnormalities, a tendency to more favorable outcomes, and a histopathological feature: nodular growth patterns. In this work we present a new segmentation scheme which requires minimal user interaction to segment nodules on MB histopathological sections. Our segmentation scheme consists of two steps: (1) color reduction using Hierarchical Normalized Cuts (HNCut), (2) Random Walker (RW) segmentation within the reduced HNCut color space. Across a cohort of 18 nodular MB images, our integrated HNCut and RW scheme yielded nodule segmentations with a Dice coefficient of 83:55 ± 12:4% and Predictive Positive Value (PPV) of 93:71 ± 9:0%.

Deregulated expression of genes encoding members of the S100 family of calcium-binding proteins has been associated with the malignant progression of multiple tumour types. Using a pharmacological expression reactivation approach, we screened 16 S100 genes for evidence of epigenetic regulation in medulloblastoma, the most common malignant brain tumour of childhood. Four family members (S100A2, S100A4, S100A6 and S100A10) demonstrated evidence of upregulated expression in multiple medulloblastoma cell lines, following treatment with the DNA methyltransferase inhibitor, 5′-aza-2′-deoxycytidine. Subsequent analysis revealed methylation of critical CpG sites located within these four genes in an extended cell line panel. Assessment of these genes in the non-neoplastic cerebellum (from which medulloblastomas develop) revealed strong somatic methylation affecting S100A2 and S100A4, whereas S100A6 and S100A10 were unmethylated. Assessed against these normal tissue-specific methylation states, S100A6 and S100A10 demonstrated tumour-specific hypermethylation in medulloblastoma primary tumours (5 out of 40 and 4 out of 35, respectively, both 12%) and cell lines (both 7 out of 9, 78%), which was associated with their transcriptional silencing. Moreover, S100A6 hypermethylation was significantly associated with the aggressive large cell/anaplastic morphophenotype (P=0.026). In contrast, pro-metastatic S100A4 displayed evidence of hypomethylation relative to the normal cerebellum in a significant proportion primary tumours (7 out of 41, 17%) and cell lines (3 out of 9, 33%), which was associated with its elevated expression. In summary, these data characterise complex patterns of somatic methylation affecting S100 genes in the normal cerebellum and demonstrate their disruption causing epigenetic deregulation of multiple S100 family members in medulloblastoma development. Epigenetic events affecting S100 genes have potential clinical utility and merit further investigation as molecular biomarkers for this disease.

Purpose To analyze the clinical and molecular characteristics of malignant transformation (MT) of low-grade glioma (LGG) in children. Patients and Methods The clinical, radiologic, and histologic characteristics of children treated at our institution who experienced MT of LGG were reviewed. Molecular alterations in these tumors were analyzed by fluorescent in situ hybridization, immunohistochemistry, and TP53 sequencing. Cumulative incidence estimate and risk factors for MT were determined for 65 patients with grade 2 astrocytoma treated at our institution during the study interval. Results Eleven patients who experienced MT were identified (median age at diagnosis of LGG, 13.3 years). Initial diagnoses were grade 2 astrocytoma (n = 6) and other grade 1/2 gliomas (n = 5). The median latency of MT was 5.1 years. Histologic diagnoses after MT were glioblastoma (n = 7) and other high-grade gliomas (n = 4). The 15-year cumulative incidence estimate of MT among 65 patients with grade 2 astrocytoma was 6.7% ± 3.9%; no risk factor analyzed, including radiotherapy, was associated with MT. Tissue was available for molecular analysis in all patients, including nine with samples obtained before and after MT. TP53 overexpression was more common after MT. Deletions of RB1 and/or CDKN2A were observed in 71% of LGGs and in 90% of tumors after MT. PTEN pathway abnormalities occurred in 76% of patients. One of five oncogenes analyzed (PDGFRA) was amplified in one patient. Conclusion The molecular abnormalities that occur during MT of LGG in children are similar to those observed in primary and secondary glioblastoma in adults.

Background and objectives Ependymomas are the third most common CNS tumours in childhood, and account for 9–12% of CNS neoplasms in all age groups. However, the prognosis for cases not completely excised is poor and the underlying biology of their development and progression is poorly understood. The few studies published to date have suggested that specific chromosomal abnormalities may be associated with the development of a significant proportion of these tumours. We set out to screen a large series of intracranial and spinal ependymomas for genetic imbalances, and to correlate these with histology and clinical behaviour. Methods Comparative genomic hybridisation (CGH) was used to detect chromosome imbalances on 86 ependymomas from 77 patients, of which 22 were children under 16, treated at one of three UK centres (Newcastle, Nottingham, Southampton). Cases were first analysed without reference to histology or clinical features, and were then divided up according to anatomical location, histology and age at presentation. Results Chromosomal imbalances were detected in tumours from 63/77 patients (82%). The majority involved entire chromosomes or chromosome arms, many showing patterns of gains suggestive of intermediate ploidy. Of previously reported abnormalities in ependymoma, the most frequent findings were gain of 1 q, seen in 13 cases (17%), and loss of 22 in 20 (26%). Whereas 1 q gain was seen mainly in posterior fossa tumours and was restricted to those with classic and anaplastic histology, loss of 22 was rarely observed in tumours from this location and their histology was predominantly classic or myxopapillary. In contrast to previous studies, loss of 6q was found in only 6 cases (8%) and in only one child. Out of 7 tumours biopsied at presentation and relapse, 4 revealed imbalances and 3 of these demonstrated progression of abnormalities at relapse. Conclusions Chromosomal imbalance is common in ependymoma and patterns of abnormality are emerging that are associated with histology or location. Further studies are needed to establish the prognostic significance of these abnormalities.

Cerebellar liponeurocytoma, a rare, newly identified CNS neoplasm of adults, is characterized by advanced neuronal/neurocytic and focal lipomatous differentiation, low proliferative potential and a favorable clinical prognosis. Despite the different age distribution and benign biological behavior, the cerebellar liponeurocytoma shares several features with the cerebellar medulloblastoma, which may include an origin from the periventricular matrix of the fourth ventricle or the external granular layer of the cerebellum. To establish the genetic profile of cerebellar liponeurocytomas, we have formed an international consortium and collected tumor samples from 20 patients. DNA sequencing revealed TP53 missense mutations in 4 (20%) of 20 cerebellar liponeurocytomas, a frequency higher than in medulloblastomas. There was no case with PTCH, APC, or beta-catenin mutations, each of which may be present in subsets of medulloblastomas. Isochromosome 17q, a genetic hallmark of classic medulloblastomas, was not observed in any of the cases investigated by FISH analysis. cDNA array analyses were carried out on 4 cerebellar liponeurocytomas, 4 central neurocytomas, and 4 classic medulloblastomas. Cluster analysis of the cDNA expression data of 1176 genes grouped cerebellar liponeurocytomas close to central neurocytomas, but distinct from medulloblastomas. These results suggest cerebellar liponeurocytoma as a distinct tumor entity that is genetically different from medulloblastoma. Furthermore, the cDNA expression array data suggest a relationship to central neurocytomas, but the presence of TP53 mutations, which are absent in central neurocytomas, suggests that their genetic pathways are different.

Medulloblastoma arises in the cerebellum and is the most common malignant brain tumour of childhood, however its molecular basis is not well understood. To assess the role of aberrant epigenetic events in medulloblastoma and identify critical genes in its development, we profiled the promoter methylation status of 11 candidate tumour-suppressor genes (TSGs; p14 ARF , p15 INK4b , p16 INK4a , CASP8, HIC1, EDNRB, TIMP3, TP73, TSLC1, RIZI and RASSFIA) in medulloblastoma cell lines, primary tumours and the normal cerebellum. Gene-specific TSG methylation was a significant feature of both medulloblastomas and the cerebellum. Extensive hypermethylation of RASSFIA was detected frequently in medulloblastomas but not in the normal cerebellum (41/44 primary tumours versus 0/5 normal cerebella). In contrast, complete methylation of HIC1 and CASP8 in a subset of primary tumours (17/44 and 14/39) occurred against a consistent background of partial methylation in the normal cerebellum. These data therefore indicate that extensive methylation of RASSFIA, HIC1 and CASP8 are tumour-specific events in medulloblastoma. Moreover, methylation of these genes in medulloblastoma cell lines was associated with their epigenetic transcriptional silencing and methylation-dependent re-expression following treatment with the DNA methyl-transferase inhibitor, 5-aza-2'-deoxycytidine. The remaining genes studied showed either low frequency methylation (p14 ARF , p16 INK4a , RIZI

Conventional treatment of childhood medulloblastoma is associated with a significant incidence of failure and long-term side-effects. It is hoped that recent advances in our understanding of medulloblastoma biology will lead to the development of curative non-toxic therapies for all children with this disease. In this article David Ellison reviews the current histopathological classification system for medulloblastoma and Steve Clifford highlights recent advances in our understanding of the molecular genetics of medulloblastoma. Amar Gajjar discusses state-of-the-art clinical management of medulloblastoma and Richard Gilbertson concludes with a review of how future efforts in this disease will seek to translate knowledge of disease biology into clinical practice. 1. Histopathology of medulloblastoma

CRA9501 Background:Aberrant signaling in SHH pathway is implicated in causing medulloblastoma in approximately 20% of children with this disease. GDC-0449 is an orally active agent that binds to the SMO receptor and prevents downstream signaling through GLI. Preclinical murine models predict efficacy of an SMO antagonist to treat tumors dependent on the SHH pathway. Adult studies have documented the efficacy of this compound against recurrent medulloblastoma and basal cell carcinoma. A phase I pharmacokinetic trial of GDC 0449 was conducted in children with recurrent or refractory medulloblastoma to select, based on safety and pharmacokinetics, one of two dosages to recommend for a pediatric phase II trial. We also used immunonistochemistry (IHC) and in situ hybridization (ISH) on paraffin-embedded tissue to determine which tumors belonged to the SHH subtype. Methods: GDC 0449 was administered once daily for 28 days dose levels of (1) 85 mg/m2/dose and (2) 170 mg/m2/dose. A course was defined as 28 days in duration. PK analysis was performed during the first course and steady-state concentrations were obtained prior to each subsequent course (day 21). MRI scans of the knees were obtained at baseline and 3 mos to assess abnormalities in bone development. Results: To date 11 eligible patients have been enrolled on the trial (10 males, median age 11.6 years (range 4.4–20.9). All patients were fully evaluable for toxicity. 1 DLT, grade 3 gamma-Glutamyl transpeptidase, occurred in a patient enrolled at 170 mg/m2/dose. There were no grade 4 toxicities. The median (range) steady-state day 21 concentration at 85 mg/m2 (n=5) is 10.15 μ M (9.10–18.99 μ M) and at 170 mg/m2 (n=2) is 14.50 μ M (14.43–14.57 μ M). The steady-state GDC-0449 clearance (n=7) is 0.86 (0.44 – 1.17 L/h/m2). At steady state (day 21), the ratio of GDC-0449 CSF to plasma is 1.3%, which is an estimate of the CSF penetration of GDC-0449. Conclusions: GDC 0449 is well-tolerated in children with recurrent or refractory medulloblastoma. The phase I study estimating the recommended phase II dose of GDC 0449 is ongoing; final results including medulloblastoma subgroup data will be presented. [Table: see text]