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  • 1
    Keywords: POOR-PROGNOSIS ; BRAIN-TUMORS ; CHILDHOOD MEDULLOBLASTOMA ; RISK STRATIFICATION ; outcome prediction ; TP53 MUTATIONS ; PATHWAY ACTIVATION ; MOLECULAR SUBGROUPS ; NEUROTROPHIN RECEPTOR TRKC ; MYCN AMPLIFICATION
    Abstract: Purpose Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. Patients and Methods Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. Results Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. Conclusion Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.
    Type of Publication: Journal article published
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  • 2
  • 3
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  68. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), 7. Joint Meeting mit der Society of British Neurological Surgeons (SBNS); 20170514-20170517; Magdeburg; DOCDI.16.05 /20170609/
    Publication Date: 2017-06-09
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 4
    Keywords: PROTEIN ; CHILDHOOD ; HUMAN CANCERS ; MYC ; HEDGEHOG PATHWAY INHIBITOR ; ALPHA-SYNUCLEIN ; PARKINSONS-DISEASE ; COPY-NUMBER ALTERATION ; BETA FAMILY ; SYNPHILIN-1
    Abstract: Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4alpha. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-beta signalling in Group 3, and NF-kappaB signalling in Group 4, suggest future avenues for rational, targeted therapy.
    Type of Publication: Journal article published
    PubMed ID: 22832581
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  • 5
    ISSN: 1573-7373
    Keywords: progressive disease ; MB/PNET ; preradiation chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The overall prognosis in children with medulloblastoma/PNET has not significantly improved over the past decade. Intensive neoadjuvant chemotherapy has not yet adequately explored. We evaluated the short-term clinical results of an intensive chemotherapy regimen in high risk children with newly diagnosed MB/PNET, after surgery and before radiation. Twelve previously untreated patients with high-risk medulloblastoma/PNET, according to Chang's classification, were treated with the following chemotherapy regimen: high dose carboplatin 600 mg/m2/day on days 1 and 2; the same course was administered 4 weeks later. One month later, high dose cyclophosphamide 2 g/m2/day on days 1 and 2, followed by an identical course 4 weeks later. Vincristine 1,5 mg/m2 iv was given on the first day of each course. Systemic evaluation of the disease included imaging of the entire neuraxis, including MRI of the entire spine. Out of 12 enrolled, 7 patients were able to be evaluated for a residual disease after surgery. After two cycles of high dose carboplatin, we noted I CR, 4 PR and 2 MR. After the subsequent two cycles of high dose cyclophosphamide we observed an additional response in 4 cases. On the other hand, 4 patients clearly showed evidence of PD immediately after the first course of cyclophosphamide (2 cases) or following the second course. Three of the 4 patients had shown respectively 1 CR and 2 PR after the second course of carboplatin. Whereas it was confirmed that 2 courses of high dose carboplatin is effective in high risk MB/PNET children, we observed an unacceptable number of PD during the subsequent high dose cyclophosphamide therapy. A review from the literature also suggests that, in general, the longer radiotherapy is delayed, the higher the incidence of PD. In the search for the optimal drug combination in “sandwich chemotherapy” for children with high risk MB/PNET, PD must be reduced to an acceptable incidence, since a high number of PD may significantly lower the probability of long-term survival.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 0942-0940
    Keywords: Keywords: Craniopharyngioma; pediatric brain tumour; surgical therapy; recurrence.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Although histologically benign, craniopharyngioma can regrow either from macroscopic remnants of the tumour left behind at operation, or even after an apparently gross total removal. Recurrence rates vary significantly in the literature, depending on the efficacy of surgical treatment and also on the growth potential of the tumour itself. The main factor influencing tumour regrowth is obviously the extent of surgical resection, as total removal carries a much lesser risk of recurrence compared to subtotal or partial resections (although in such cases radiation therapy can lower this risk significantly). Other factors involved are the duration of follow-up and patient's age at operation, as children tend to relapse more frequently than adults. Even in the “microsurgery” era, characterized by high percentages of total resections, recurrences remain high and continue to represent a major problem of craniopharyngioma treatment. Twenty-seven children and adolescents were operated on for craniopharyngioma at the Department of Neurosurgery, Section of Pediatric Neurosurgery, Catholic University Medical School, Rome, between June 1985 and June 1997. Total tumour resection was achieved in 18 cases, subtotal in 7 and partial 2 instances. One patient died post-operatively. Post-operative neuroradiological investigations confirmed the operative findings, although 3 children with an apparently gross total removal showed a residual non-enhancing calcium fleck adherent to the hypothalamus (which remained stable at the following examinations). Three of the 9 patients with less than total removal underwent post-operative radiation therapy. Out of the 26 surviving patients 6 presented a recurrence of their craniopharyngioma, 2 after an apparently gross total removal and 4 after a subtotal or partial resection (one of them had received radiation therapy). The diagnosis was merely neuroradiological in 5 cases, as only one child presented a clinical picture suggestive of tumour regrowth. Surgery was the first therapeutic option in all cases. Total tumour resection was accomplished in 3 cases, subtotal in 2 and partial in the last one. One child died post-operatively. Four of the 5 survivors received radiation therapy. All the patients are presently alive and stable (mean follow-up: 5.6 yrs). The authors conclude that surgery should be the first therapeutic option in case of recurrent craniopharyngioma and that radiation therapy should also be considered but only as adjuvant therapy.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Acta neurochirurgica 142 (2000), S. 145-158 
    ISSN: 0942-0940
    Keywords: Keywords: AVM; paediatric.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary ¶ In spite of their congenital origin, only 18–20% of cerebral AVMs are diagnosed during infancy and childhood. Intracranial haemorrhage is the presenting clinical manifestation in 75–80% of paediatric patients and is associated with a high morbidity and mortality. The natural history of untreated cerebral AVMs in children is worse than in adults, in relation to a longer life expectation, a higher annual risk of AVM bleeding (3.2% vs. 2.2%) and a higher incidence of posterior fossa and basal ganglia AVMs, most of which present with massive haemorrhages. The surgical excision remains the treatment of choice for parenchymal AVMs in children; AVM complete removal is currently achieved in 70–90% of the patients. With the advent of new agents for endovascular management, preoperative AVM embolization has further improved surgical results. Stereotactic radiosurgery appears to be a successful treatment option in small or moderate sized AVMs. Recent studies have demonstrated low complication rates with this technique in paediatric patients.  We reviewed our experience with 37 paediatric AVMs treated at the Section of Paediatric Neurosurgery of the Catholic University of Rome between 1980 and 1997. Twenty-three patients underwent surgery as the only treatment modality; endovascular embolization was combined with the surgical treatment in a further four cases. Radiosurgery was utilized as the only treatment in three patients and in combination with other techniques in an other three children (with surgery in one case and with AVM embolization in the remaining two subjects). No treatment was carried out in three patients because of excessively critical condition on admission; endovascular embolization failed in a further patient because of the anatomical complexity of the malformation. Previous studies have demonstrated a quite strict correlation between AVM complexity based on Spetzler and Martin's grading system and patients outcome. A less direct relationship has been observed in the present study. In our experience the factors which were more closely predictive of patients' outcome were the occurrence of an AVM bleeding and the neurological status on admission. In spite of the low number of cases in the single subsets of patients this study seems to support the role of AVM embolization and radiosurgery as effective adjuvant techniques in the management of cerebral AVMs in children.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-1203
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Jackson-Weiss syndrome is a rare skeletal disorder characterized by craniosynostosis associated with foot malformations. This condition is inherited as an autosomal dominant trait with complete penetrance and wide phenotypic heterogeneity. Mutations in the fibroblast growth factor receptor 2 (FGFR2) gene have been recently identified as causes of this syndrome and of at least four other craniosynostotic disorders, namely the Apert, Beare-Stevenson cutis gyrata, Crouzon and Pfeiffer syndromes. We report two novel FGFR2 missense mutations associated with phenotypes consistent with Jackson-Weiss syndrome. Both nucleotide changes predict a serine for cysteine-342 substitution in the second half of the third immunoglobulin-like domain. The replacement of Cys-342 with arginine has previously been reported in one of the three Jackson-Weiss cases investigated. Interestingly, both Cys342Ser and Cys342Arg substitutions have been found to be associated with the Crouzon and Pfeiffer phenotypes; a phenotypic heterogeneity, Crouzon vs Jackson-Weiss clinical features, has been also observed for Gln289Pro and Ala344Gly amino-acid changes. This finding indicates the genetic homogeneity of the “heterogeneous” Jackson-Weiss phenotype and a common molecular basis for these apparently “clinically distinct” craniosynostotic disorders.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1433-0350
    Keywords: Key words Children ; Head injury ; Hyperglycaemia ; Outcome
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Fifty children with head injury were evaluated in an attempt to estabilish a correlation between post-traumatic hyperglycaemia and long-term outcome. In all the patients, the blood glucose level was measured on admission and on the days following the trauma (threshold of normal value set at 150 mg/dl). Hyperglycaemia was seen more frequently in children with severe head injury than in those with mild and moderate head injury. It was present in 87.5% of the patients with a Glasgow Coma Score (GCS) ≤8 (the average blood glucose level on admission was 237.8±92 mg/dl), in 60% of the patients with a GCS of 9–12 (178±78.7 mg/dl) and only in 25% of those with a GCS of 13–15 (131.5±39 mg/dl). A close correlation was also seen between the outcome and the blood glucose level. In fact, the blood glucose on admission was higher in the patients with a poor outcome, i.e. in those having a Glasgow Outcome Score (GOS) of 2 or 3 and in those who died (GOS 1), than in the patients with a good outcome (GOS of 4 or 5). Finally, hyperglycaemia persisted beyond the first 24 h after trauma in all the children who died or who survived with a poor outcome. Hyperglycaemia, and especially its persistence over time, appears to be an important negative prognostic factor in children with head injury.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Child's nervous system 16 (2000), S. 837-837 
    ISSN: 1433-0350
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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