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2.
J Neurosurg Pediatr ; : 1-9, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31952041

RESUMO

OBJECTIVE: Extensive resection of a tumor in the posterior fossa in children is associated with the risk of neurological deficits. The objective of this study was to prospectively evaluate the short-term neurological morbidity in children after medulloblastoma surgery and relate this to the tumor's growth pattern and to the extent of resection. METHODS: In 160 patients taking part in the HIT-SIOP PNET 4 (Hyperfractionated Versus Conventionally Fractionated Radiotherapy in Standard Risk Medulloblastoma) trial, neurosurgeons prospectively responded to questions concerning the growth pattern of the tumor they had resected. The extent of resection (gross, near, or subtotal) was evaluated using MRI. The patients' neurological status before resection and around 30 days after resection was recorded. RESULTS: Invasive tumor growth, defined as local invasion in the brain or meninges, cranial nerve, or major vessel, was reported in 58% of the patients. After surgery almost 70% of all patients were affected by one or several neurological impairments (e.g., impaired vision, impaired extraocular movements, and ataxia). However, this figure was very similar to the preoperative findings. Invasive tumor growth implied a significantly higher number of impairments after surgery (p = 0.03) and greater deterioration regarding extraocular movements (p = 0.012), facial weakness (p = 0.048), and ataxia in the arms (p = 0.014) and trunk (p = 0.025) compared with noninvasive tumor growth. This deterioration was not dependent on the extent of resection performed. Progression-free survival (PFS) at 5 years was 80% ± 4% and 76% ± 5% for patients with invasive and noninvasive tumor growth, respectively, with no difference in the 5-year PFS for extent of resection. CONCLUSIONS: Preoperative neurological impairments and invasive tumor growth were strong predictors of deterioration in short-term neurological outcome after medulloblastoma neurosurgery, whereas the extent of resection was not. Neither tumor invasiveness nor extent of resection influenced PFS. These findings support the continuation of maximal safe resection in medulloblastoma surgery where functional risks are not taken in areas with tumor invasion.

3.
J Clin Oncol ; 38(1): 43-50, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31609649

RESUMO

PURPOSE: The identification of a heritable tumor predisposition often leads to changes in management and increased surveillance of individuals who are at risk; however, for many rare entities, our knowledge of heritable predisposition is incomplete. METHODS: Families with childhood medulloblastoma, one of the most prevalent childhood malignant brain tumors, were investigated to identify predisposing germline mutations. Initial findings were extended to genomes and epigenomes of 1,044 medulloblastoma cases from international multicenter cohorts, including retrospective and prospective clinical studies and patient series. RESULTS: We identified heterozygous germline mutations in the G protein-coupled receptor 161 (GPR161) gene in six patients with infant-onset medulloblastoma (median age, 1.5 years). GPR161 mutations were exclusively associated with the sonic hedgehog medulloblastoma (MBSHH) subgroup and accounted for 5% of infant MBSHH cases in our cohorts. Molecular tumor profiling revealed a loss of heterozygosity at GPR161 in all affected MBSHH tumors, atypical somatic copy number landscapes, and no additional somatic driver events. Analysis of 226 MBSHH tumors revealed somatic copy-neutral loss of heterozygosity of chromosome 1q as the hallmark characteristic of GPR161 deficiency and the primary mechanism for biallelic inactivation of GPR161 in affected MBSHH tumors. CONCLUSION: Here, we describe a novel brain tumor predisposition syndrome that is caused by germline GPR161 mutations and characterized by MBSHH in infants. Additional studies are needed to identify a potential broader tumor spectrum associated with germline GPR161 mutations.

4.
Acta Neuropathol ; 139(1): 175-192, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31473790

RESUMO

In search of novel genes associated with glioma pathogenesis, we have previously shown frequent deletions of the KIAA1797/FOCAD gene in malignant gliomas, and a tumor suppressor function of the encoded focadhesin impacting proliferation and migration of glioma cells in vitro and in vivo. Here, we examined an association of reduced FOCAD gene copy number with overall survival of patients with astrocytic gliomas, and addressed the molecular mechanisms that govern the suppressive effect of focadhesin on glioma growth. FOCAD loss was associated with inferior outcome in patients with isocitrate dehydrogenase 1 or 2 (IDH)-mutant astrocytic gliomas of WHO grades II-IV. Multivariate analysis considering age at diagnosis as well as IDH mutation, MGMT promoter methylation, and CDKN2A/B homozygous deletion status confirmed reduced FOCAD gene copy number as a prognostic factor for overall survival. Using a yeast two-hybrid screen and pull-down assays, tubulin beta-6 and other tubulin family members were identified as novel focadhesin-interacting partners. Tubulins and focadhesin co-localized to centrosomes where focadhesin was enriched in proximity to centrioles. Focadhesin was recruited to microtubules via its interaction partner SLAIN motif family member 2 and reduced microtubule assembly rates, possibly explaining the focadhesin-dependent decrease in cell migration. During the cell cycle, focadhesin levels peaked in G2/M phase and influenced time-dependent G2/M progression potentially via polo like kinase 1 phosphorylation, providing a possible explanation for focadhesin-dependent cell growth reduction. We conclude that FOCAD loss may promote biological aggressiveness and worsen clinical outcome of diffuse astrocytic gliomas by enhancing microtubule assembly and accelerating G2/M phase progression.

5.
Acta Neuropathol ; 139(2): 277-286, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31732806

RESUMO

Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly occurring in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. SMARCB1-mutant tumors in adolescents and adults are rare and may show uncommon histopathological and clinical features. Here we report seven SMARCB1-deficient intracranial tumors sharing distinct clinical, histopathological and molecular features. Median age of the four females and three males was 40 years (range 15-61 years). All tumors were located in the pineal region. Histopathologically, these tumors displayed spindled and epithelioid cells embedded in a desmoplastic stroma alternating with a variable extent of a loose myxoid matrix. All cases showed loss of nuclear SMARCB1/INI1 protein expression, expression of EMA and CD34 was frequent and the Ki67/MIB1 proliferation index was low in the majority of cases (median 3%). Three cases displayed heterozygous SMARCB1 deletions and two cases a homozygous SMARCB1 deletion. On sequencing, one tumor showed a 2 bp deletion in exon 4 (c.369_370del) and one a short duplication in exon 3 (c.237_276dup) both resulting in frameshift mutations. Most DNA methylation profiles were not classifiable using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-SNE analysis and hierarchical clustering analysis, however, all tumors grouped closely together and showed similarities with ATRT-MYC. After a median observation period of 48 months, three patients were alive with stable disease, whereas one patient experienced tumor progression and three patients had succumbed to disease. In conclusion, our series represents an entity with distinct clinical, histopathological and molecular features showing epigenetic similarities with ATRT-MYC. We propose the designation desmoplastic myxoid tumor (DMT), SMARCB1-mutant, for these tumors.

6.
J Cancer Res Clin Oncol ; 146(3): 659-670, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31754832

RESUMO

BACKGROUND: The use of alkylating chemotherapy versus bevacizumab for recurrent glioblastoma remains controversial. Here, we tested the hypothesis that the activity of alkylators, but not that of bevacizumab, would be associated with the O6-methylguanine DNA methyltransferase (MGMT) promoter methylation status. METHODS: We analyzed a cohort of patients treated at centers of the German Glioma Network or the University Hospital Zurich with alkylating agent-based chemotherapy (n = 260) or bevacizumab without or with irinotecan (n = 84) for first recurrence of glioblastoma. Outcome was stratified for O6-methylguanine DNA methyltransferase (MGMT) status and crossover to bevacizumab or alkylators at further progression. RESULTS: Median post-recurrence survival-1 (PRS-1) for patients receiving alkylating agents at first recurrence was longer than with bevacizumab (11.1 versus 7.4 months, p < 0.001). The use of alkylators was associated with longer PRS-1 for patients with a methylated versus unmethylated MGMT promoter (p = 0.017). For patients receiving bevacizumab, PRS-1 was not different with or without MGMT promoter methylation. PRS-1 was longer in patients receiving alkylating chemotherapy compared to bevacizumab for patients with methylated (p < 0.001) or unmethylated MGMT promoter (p = 0.034). For patients with alkylators at first recurrence receiving bevacizumab at any further recurrence, PRS-1 was longer than in patients receiving bevacizumab first and alkylators thereafter (p = 0.002). CONCLUSIONS: This study confirms limited value of bevacizumab in recurrent glioblastoma independent of MGMT status. Alkylating agents have activity in recurrent glioblastoma, especially in the context of MGMT promoter methylation.


Assuntos
Antineoplásicos Alquilantes/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/genética , Metilação de DNA/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Feminino , Glioblastoma/genética , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Intervalo Livre de Progressão , Regiões Promotoras Genéticas/genética , Estudos Retrospectivos , Proteínas Supressoras de Tumor/genética , Adulto Jovem
7.
Neuro Oncol ; 22(1): 116-127, 2020 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-31419298

RESUMO

BACKGROUND: The World Health Organization (WHO) adult glioma grading system is questionable in pediatric high-grade gliomas (pHGGs), which are biologically distinct from adult HGGs. We took advantage of the neuropathological review data obtained during one of the largest prospective randomized pHGG trials, namely HERBY (NCT01390948), to address this issue in children with newly diagnosed non-brainstem HGG. METHODS: HGG diagnosis was confirmed by pre-randomization, real-time central pathology review using WHO 2007 criteria, followed by a consensus review blinded to clinical factors and outcomes. We evaluated association between WHO 2007 grade and other clinical/radiological/biological characteristics and the prognostic value of WHO 2007 grade, midline location, and selected biomarkers (Ki-67 index/Olig2/CD34/EGFR/p53/H3F3A K27M mutation) on overall survival. RESULTS: Real-time central neuropathological review was feasible in a multicenter study, with a mean time of 2.4 days, and led to the rejection of HGG diagnosis in 20 of 163 cases (12.3%). The different grading criteria and resulting WHO grade were not significantly associated with overall survival in the entire population (n = 118) or in midline and non-midline subgroups. H3F3A K27M mutation was significantly associated with poor outcome. No significant prognostic value was observed for grade, even after regrading H3F3A K27M-mutated midline glioma as grade IV (WHO 2016). Midline location and a high Ki-67 index (≥20%) were associated with poor outcome (P = 0.004 and P = 0.04, respectively). A 10% increase in Ki-67 index was associated with a hazard ratio of 1.53 (95% CI: 1.27-1.83; P < 0.0001). CONCLUSION: Our findings suggest that WHO grade III versus IV has no prognostic value in pediatric HGG.

8.
Lancet Oncol ; 20(12): e715-e728, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31797797

RESUMO

The European Association of Neuro-Oncology (EANO) and EUropean RAre CANcer (EURACAN) guideline provides recommendations for the diagnosis, treatment, and follow-up of post-pubertal and adult patients with medulloblastoma. The guideline is based on the 2016 WHO classification of tumours of the CNS and on scientific developments published since 1980. It aims to provide direction for diagnostic and management decisions, and for limiting unnecessary treatments and cost. In view of the scarcity of data in adults with medulloblastoma, we base our recommendations on adult data when possible, but also include recommendations derived from paediatric data if justified. Our recommendations are a resource for professionals involved in the management of post-pubertal and adult patients with medulloblastoma, for patients and caregivers, and for health-care providers in Europe. The implementation of this guideline requires multidisciplinary structures of care, and defined processes of diagnosis and treatment.

9.
Nature ; 576(7786): 274-280, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31802000

RESUMO

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.

10.
Pediatr Res ; 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31756732

RESUMO

BACKGROUND: Glioblastoma (GBM) is the most aggressive form of glioma in adults and children and is associated with very poor prognosis. Pediatric tumors are biologically distinct from adult GBM and differ in response to current GBM treatment protocols. Regarding pediatric GBM, new drug combinations and the molecular background of chemotherapy effects need to be investigated, in order to increase patient survival outcome. METHODS: The expression of the RNA-binding protein Musashi1 (MSI1) in pediatric glioma samples of different WHO tumor grades was investigated on the protein (immunohistochemistry) and on the RNA level (publicly accessible RNA sequencing dataset). The impact of the chemotherapeutic temozolomide (TMZ) in combination with valproic acid (VPA) was tested in two pediatric glioblastoma-derived cell lines. The supportive effect of MSI1 expression against this treatment was investigated via transient knockdown and protein overexpression. RESULTS: MSI1 expression correlates with pediatric high-grade glioma (HGG). The combination of TMZ with VPA significantly increases the impact of drug treatment on cell viability in vitro. MSI1 was found to promote drug resistance to the combined treatment with TMZ and VPA. CONCLUSION: MSI1 expression is a potential marker for pediatric HGG and increases chemoresistance. Inhibition of MSI1 might lead to an improved patient outcome and therapy response.

11.
Acta Neuropathol Commun ; 7(1): 181, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31727173

RESUMO

INTRODUCTION: Risk stratification of children with ependymomas of the posterior fossa in current therapeutic protocols is mainly based on clinical criteria. We aimed to identify independent outcome predictors for this disease entity by a systematic integrated analysis of clinical, histological and genetic information in a defined cohort of patients treated according to the German HIT protocols. METHODS: Tumor samples of 134 patients aged 0.2-15.9 years treated between 1999 and 2010 according to HIT protocols were analyzed for histological features including mitotic activity, necrosis and vascular proliferation and genomic alterations by SNP and molecular inversion probe analysis. Survival analysis was performed by Kaplan-Meier method with log rank test and multivariate Cox regression analysis. RESULTS: Residual tumor after surgery, chromosome 1q gain and structural genomic alterations were identified as predictors of significantly shorter event-free (EFS) and overall survival (OS). Furthermore, specific histological features including vascular proliferation, necrosis and high mitotic activity were predictive for shorter OS. Multivariate Cox regression revealed residual tumor, chromosome 1q gain and mitotic activity as independent predictors of both EFS and OS. Using these independent predictors of outcome, we were able to build a 3-tiered risk stratification model that separates patients with standard, intermediate and high risk, and which outperforms current stratification procedures. CONCLUSION: The integration of defined clinical, histological and genetic parameters led to an improved risk-stratification model for posterior fossa ependymoma of childhood. After validation in independent cohorts this model may provide the basis for risk-adapted treatment of children with ependymomas of the posterior fossa.

12.
Int J Cancer ; 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31613986

RESUMO

Reports on pediatric low-grade glioma (LGG) of the caudal brainstem are retrospective with heterogeneous cohorts, variable treatments and inconsistent outcome data. We analyzed their natural history and asked whether brainstem location proved unfavorable for survival within the framework of the comprehensive SIOP-LGG 2004 management strategy. Within the prospectively registered, population-based German SIOP-LGG 2004 cohort 116 patients (age 0.2-16.5 years, 10% Neurofibromatosis NF1) were diagnosed with LGG of the pons (27%) and medulla oblongata (73%). After biopsy (23%), variable resection (63%) or radiologic diagnosis only (14%), 59 patients received no adjuvant treatment. Radiologic progression or severe neurologic symptoms prompted chemo- (n = 39) or radiotherapy (n = 18). After further progression (28/57), salvage treatments included multiple treatment lines for 12/28 patients. Five-years event-free survival dropped to 0.40, while 5-years overall survival was 0.95 (median observation time 6.8 years). Higher extent of resection yielded lower progression rate (p = 0.001), but at a cost of 21/100 patients suffering from new postsurgical complications including respiratory insufficiency. Central review confirmed pilocytic astrocytoma (56%), diffuse astrocytoma (8%) or glioneuronal histology (16%) (others 4%, no histology 17%). Malignant evolution was documented in five patients associated with Histone3 mutation in 2/5. Our treatment algorithm conveyed high overall survival for pediatric brainstem LGG. Extensive neurosurgical resection did increase additional postoperative neurologic deficits but not overall survival in this often-chronic disease. More than half of all patients can be safely followed by observation, while multimodal adjuvant treatment can control progressive tumors. Molecular assessment should confirm low-grade diagnosis and may detect patterns prognostic for malignant evolution.

13.
Int J Mol Sci ; 20(17)2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31480400

RESUMO

The insulin-like growth factor (IGF) pathway plays an important role in several brain tumor entities. However, the lack of inhibitors crossing the blood-brain barrier remains a significant obstacle for clinical translation. Here, we targeted the IGF pathway using ceritinib, an off-target inhibitor of the IGF1 receptor (IGF1R) and insulin receptor (INSR), in a pediatric patient with an unclassified brain tumor and a notch receptor 1 (NOTCH1) germline mutation. Pathway analysis of the tumor revealed activation of the sonic hedgehog (SHH), the wingless and integrated-1 (WNT), the IGF, and the Notch pathway. The proliferation of the patient tumor cells (225ZL) was inhibited by arsenic trioxide (ATO), which is an inhibitor of the SHH pathway, by linsitinib, which is an inhibitor of IGF1R and INSR, and by ceritinib. 225ZL expressed INSR but not IGF1R at the protein level, and ceritinib blocked the phosphorylation of INSR. Our first personalized treatment included ATO, but because of side effects, we switched to ceritinib. After 46 days, we achieved a concentration of 1.70 µM of ceritinib in the plasma, and after 58 days, MRI confirmed that there was a response to the treatment. Ceritinib accumulated in the tumor at a concentration of 2.72 µM. Our data suggest ceritinib as a promising drug for the treatment of IGF-driven brain tumors.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Fator de Crescimento Insulin-Like I/metabolismo , Neoplasias Neuroepiteliomatosas/tratamento farmacológico , Pirimidinas/uso terapêutico , Sulfonas/uso terapêutico , Adulto , Trióxido de Arsênio/farmacologia , Trióxido de Arsênio/uso terapêutico , Sequência de Bases , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Pré-Escolar , Aberrações Cromossômicas , Metilação de DNA/genética , Feminino , Mutação em Linhagem Germinativa/genética , Humanos , Terapia de Alvo Molecular , Neoplasias Neuroepiteliomatosas/patologia , Análise de Componente Principal , Pirimidinas/farmacologia , Receptor Notch1/metabolismo , Sulfonas/farmacologia , Transcriptoma/genética , Proteína Supressora de Tumor p53/genética
14.
J Neuropathol Exp Neurol ; 78(9): 791-797, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31373367

RESUMO

Adult spinal cord ependymomas are typically low grade and have a relatively favorable clinical course following gross total resection. We report 4 cases of anaplastic spinal cord ependymoma with MYCN amplification, an exceptionally rare finding. All cases occurred in the spinal cord of adolescent and young adult women and had morphological and immunohistochemical features of anaplastic ependymomas (World Health Organization grade III). Chromosomal microarray analysis demonstrated amplification of 2p24 (including MYCN) in all cases. One patient died 6 months after surgery. Another patient recently had removal of metastatic nodules in the thoracic region, following gross total resection and adjuvant radiation therapy of a lumbar ependymoma 1 year previously. One patient responded well after chemotherapy but died after multiple relapses 82 months after diagnosis. We found MYCN amplification reported in 2 other ependymomas, both anaplastic and arising in the spinal cord of adult females (Brain Pathol 2001;11:133-43). One patient had multiple recurrences in the spinal cord and an intracranial metastasis. Although MYCN amplification is rare in ependymomas, the current and previously reported cases suggest that this is associated with higher-grade histology, spinal location, and often unfavorable prognosis. The clinical significance and therapeutic implications of MYCN amplification in ependymomas require further evaluation.

15.
Oncotarget ; 10(43): 4449-4465, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31320997

RESUMO

Glioblastoma multiforme is an aggressive cancer type with poor patient outcomes. Interestingly, we reported previously a novel association between the little studied paucimannosidic N-linked glycoepitope and glioblastoma. Paucimannose has only recently been detected in vertebrates where it exhibits a very restricted tumor-specific expression. Herein, we demonstrate for the first time a very high protein paucimannosylation in human grade IV glioblastoma and U-87MG and U-138MG glioblastoma cells. Furthermore, we revealed the involvement of paucimannosidic epitopes in tumorigenic processes including cell proliferation, migration, invasion and adhesion. Finally, we identified AHNAK which is discussed as a tumor suppressor as the first paucimannose-carrying protein in glioblastoma and show the involvement of AHNAK in the observed paucimannose-dependent effects. This study is the first to provide evidence of a protective role of paucimannosylation in glioblastoma, a relationship that with further in vivo support may have far reaching benefits for patients suffering from this often fatal disease.

16.
Cancers (Basel) ; 11(6)2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31226836

RESUMO

Gap junctions have recently been shown to interconnect glioblastoma cells to a multicellular syncytial network, thereby allowing intercellular communication over long distances as well as enabling glioblastoma cells to form routes for brain microinvasion. Against this backdrop gap junction-targeted therapies might provide for an essential contribution to isolate cancer cells within the brain, thus increasing the tumor cells' vulnerability to the standard chemotherapeutic agent temozolomide. By utilizing INI-0602-a novel gap junction inhibitor optimized for crossing the blood brain barrier-in an oncological setting, the present study was aimed at evaluating the potential of gap junction-targeted therapy on primary human glioblastoma cell populations. Pharmacological inhibition of gap junctions profoundly sensitized primary glioblastoma cells to temozolomide-mediated cell death. On the molecular level, gap junction inhibition was associated with elevated activity of the JNK signaling pathway. With the use of a novel gap junction inhibitor capable of crossing the blood-brain barrier-thus constituting an auspicious drug for clinical applicability-these results may constitute a promising new therapeutic strategy in the field of current translational glioblastoma research.

17.
Klin Padiatr ; 231(3): 107-135, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31108561

RESUMO

Low grade gliomas (LGGs) constitute the largest, yet clinically and (molecular-) histologically heterogeneous group of pediatric brain tumors of WHO grades I and II occurring throughout all pediatric age groups and at all central nervous system (CNS) sites. The tumors are characterized by a slow growth rate and may show periods of growth arrest. Around 40% of all LGG patients can be cured by complete neurosurgical resection and are followed by close observation. In case of relapse, second resection often is possible. Following incomplete resection observation is recommended, as long as there is no radiologic tumor growth and the patient does not suffer from significant, tumor-related symptoms. This also applies to patients with a diagnosis of LGG on the basis of radiological criteria. By contrast, clinical worsening and / or radiologic progression are an indication to treatment with either chemo- or radiotherapy. Overall survival is around 90%, and many patients survive with residual tumor, i. e. they suffer from chronic disease. All patients need comprehensive neuro-oncological care, the principles and details of which are summarized in the current guidelines. These represent standard of care for diagnostic work-up (including neuroimaging and neuropathology), and for therapeutic decisions (including the indications to non-surgical treatment) as well as concepts for neurosurgical intervention, chemotherapy and radiotherapy as well as surveillance and rehabilitation. The current treatment algorithm was compiled by members of the LGG working group of the SIOP-E brain tumor group (SIOP-E-BTG) and is based upon the results of previous European LGG studies and international reports.


Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/terapia , Glioma/diagnóstico , Glioma/terapia , Guias de Prática Clínica como Assunto , Adolescente , Criança , Progressão da Doença , Humanos , Recidiva Local de Neoplasia , Sociedades Médicas
18.
Acta Neuropathol Commun ; 7(1): 78, 2019 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-31109382

RESUMO

The recently described malignant neuro-epithelial tumors with histone H3F3A point mutations at G34 (NET-H3-G34) occur most often in cerebral hemispheres of teenagers and young adults, and have a generally adverse prognosis. These tumors have been histologically classified as glioblastoma or primitive neuroectodermal tumor (PNET) in the past, and have not been defined as a separate entity in the revised WHO classification of tumors of the CNS 2016. Here, we report two cases of NET-H3-G34 with glial and dysplastic ganglion cell components affecting teenagers. Patients were treated with surgery and radiochemotherapy with temozolomide. One patient underwent partial resection and deceased 21 months after diagnosis, while the other patient is alive without evidence of disease 15 months after total resection. So far, a dysplastic ganglion cell component has not been described in NET-H-G34, and its presence raises a possible relation to (anaplastic) gangliogliomas. Genome-wide copy number analysis did not provide unequivocal evidence that these tumors represent anaplastic variants of gangliogliomas, as opposed to NET-H3-G34. Our observations expand the morphologic spectrum of NET-H3-G34. Further cases of NET-H3-G34 with dysplastic ganglion cells should be clinically followed to find differences or similarities in their biological behavior, as compared to NET-H3-G34 and anaplastic gangliogliomas.

20.
Eur J Cancer ; 114: 27-35, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31022591

RESUMO

PURPOSE: Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive paediatric brain tumour with fatal outcome. The Individualised Therapy For Relapsed Malignancies In Childhood (INFORM) registry study offers comprehensive molecular profiling of high-risk tumours to identify target alterations for potential precision therapy. We analysed molecular characteristics and clinical data after brainstem biopsy of all enrolled newly diagnosed DIPGs. PATIENTS AND METHODS: From -February 2015 to February 2018, 21 subsequent primary DIPG cases were enrolled in the nation-wide multicentre INFORM registry study after brainstem biopsy. Whole-genome, whole-exome sequencing and DNA methylation analysis were performed, and RNA-sequencing was added in case of sufficient material. Clinical data were obtained from standardised questionnaires and the INFORM clinical data bank. RESULTS: Tumour material obtained from brainstem biopsy was sufficient for DNA analysis in all cases and RNA analysis in 16 of 21 cases. In 16 of 21 cases (76%), potential targetable alterations were identified including highly relevant MET and NTRK1 fusions as well as an EZH2 alteration not previously described in DIPG. In 5 of 21 cases, molecular information was used for initiation of targeted treatment. The majority of patients (19/21) presented with neurological deficits at diagnosis. Newly arising or worsening of neurological deficits post-biopsy occurred in nine patients. Symptoms were reversible or improved notably in eight cases. CONCLUSION: In this multicentre study setting, brainstem biopsy of DIPG was feasible and yielded sufficient material for comprehensive molecular profiling. Relevant molecular targets were identified impacting clinical management in a substantial subset. Death or severe bleeding occurred in none of the cases. One of 20 patients experienced unilateral paraesthesia possibly related to biopsy.

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