Gliosarcoma with extensive extracranial metastatic spread and familial coincidence: A case report.

Gliosarcoma is a rare histopathological subtype of glioblastoma. Metastatic spreading is unusual. In this report, we illustrate a case of gliosarcoma with extensive extracranial metastases with confirmation of histological and molecular concordance between the primary tumor and a metastatic lesion of the lung. Only the autopsy revealed the extent of metastatic spread and the hematogenous pattern of metastatic dissemination. Moreover, the case bared a familial coincidence of malignant glial tumors as the patient's son was diagnosed with a high-grade glioma shortly after the patient's death. By molecular analysis (Sanger and next generation panel sequencing), we could confirm that both patient's tumors carried mutations in the TP53 gene. Interestingly, the detected mutations were located in different exons. Altogether, this case draws attention to the fact that sudden clinical aggravation could be caused by the rare phenomenon of metastatic spread and should therefore be always taken into consideration, even at an early disease stage. Furthermore, the presented case highlights the contemporary value of autoptic pathological examination.

Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters (DGONC) - a molecularly defined glioneuronal CNS tumour class displaying recurrent monosomy 14.

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.

Imaging Characteristics of Wingless Pathway Subgroup Medulloblastomas: Results from the German HIT/SIOP-Trial Cohort.

BACKGROUND AND PURPOSE: In addition to the 4 histopathologically defined entities of medulloblastoma, 4 distinct genetically defined subgroups have been included in the World Health Organization classification of 2016. The smallest subgroup is the medulloblastoma with activated wingless pathway. The goal of this study was to identify a typical MR imaging morphology in a larger number of pediatric patients with wingless pathway medulloblastoma. MATERIALS AND METHODS: From January 2001 to October 2017, of 75 patients with histologically confirmed and molecularly subgrouped wingless pathway medulloblastomas recruited to the German Pediatric Brain Tumor (HIT) trials, 38 patients (median age, 12.8 ± 4.6 years at diagnosis; 24 [63.2%] female) had preoperative imaging that passed the entry criteria for this study. Images were rated by the local standardized imaging criteria of the National Reference Center of Neuroradiology. Additionally, a modified laterality score was used to determine tumor localization and extension. RESULTS: Twenty-eight of 38 (73.7%) were primary midline tumors but with a lateral tendency in 39.3%. One extensively eccentric midline tumor was rated by the laterality score as in an off-midline position. Five tumors were found in the cerebellopontine angle; 3, in the deep white matter; and 2, in a cerebellar hemisphere. Leptomeningeal dissemination was rare (11.5%). In 60.5%, intratumoral blood-degradation products were found, and 26.3% showed cysts with blood contents. CONCLUSIONS: According to our observations, wingless pathway medulloblastomas are not preferentially off-midline tumors as postulated in previous studies with smaller wingless pathway medulloblastoma cohorts. Dense intratumoral blood-degradation products and cysts with blood contents are frequently found and might help to differentiate wingless pathway medulloblastoma from other medulloblastoma subtypes.

[Neuropathology of medulloblastomas and other CNS embryonal tumors : Precision diagnostics through the integration of genetic markers]. / Neuropathologie der Medulloblastome und anderer embryonaler Tumoren des ZNS : Präzisierung der Diagnostik durch Integration genetischer Marker.

The revised WHO classification of tumors of the central nervous system (CNS) in 2016 introduced the concept of the "integrated diagnosis." The definition of medulloblastoma entities now requires a combination of traditional histological information with additional molecular/genetic features. To define the histopathological component of the medulloblastoma diagnosis, tumors have to be assigned to one of the four histological entities: classic, desmoplastic/nodular (DNMB), extensive nodular (MBEN), or large cell/anaplastic (LC/A) medulloblastoma. The genetically defined component is one of the four entities: "WNT activated", "SHH activated and TP53 wildtype", "SHH activated and TP53 mutant", or "non-WNT/non-SHH medulloblastoma." Robust and validated methods are available that allow a precise diagnosis of these medulloblastoma entities according to the updated WHO classification and for differential diagnostic purposes. An immunohistochemical analysis of protein markers including ß­Catenin, Yap1, p75-NGFR, Otx2 and p53, in combination with targeted sequencing and chromosomal copy number assessment (such as FISH analysis for MYC genes), allows a precise stratification of patients for risk-adapted treatment. The group of other embryonic tumors of the central nervous system includes embryonic tumors with multilayered rosettes (ETMR), which frequently carry an amplification of the micro-RNA cluster C19MC and the (ganglio-)neuroblastomas of the CNS. These rare tumors can also be identified by characteristic genetic and immunophenotypic features.

Cross-sectional increase of adherence to multidisciplinary tumor board decisions.

BACKGROUND: Cancer research has made great progress in the recent years. With the increasing number of options in diagnosis and therapy the implementation of tumorboards (TUBs) has become standard procedure in the treatment of cancer patients. Adherence tests on tumor board decisions are intended to enable quality assurance and enhancement for work in tumor boards in order to continuously optimize treatment options for cancer patients. METHODS: Subject of this study was the adherence of the recommendations made in three of 14 tumorboards, which take place weekly in the Center for Integrated Oncology (CIO) at the University Hospital Bonn. In total, therapy recommendations of 3815 patient cases were checked on their implementation. A classification into four groups has been made according to the degree of implementation. A second classification followed regarding the reasons for differences between the recommendation and the therapy which the patient actually received. RESULTS: The study showed that 80.1% of all recommendations in the three TUBs were implemented. 8.3% of all recommendations showed a deviance. Most important reasons for the deviances were patient wish (36.5%), patient death (26%) and doctoral decision, due to the patient's comorbidities or side effects of the treatment (24.1%).Interestingly, deviance in all three tumor boards in total significantly decreased over time. CONCLUSIONS: Aim of the study was to clarify the use of tumor boards and find approaches to make them more efficient. Based on the results efficiency might be optimized by increased consideration of patients` preferences, improved presentation of patient-related data, more detailed documentation and further structuring of the tumor board meetings.

CNS embryonal tumours: WHO 2016 and beyond.

Embryonal tumours of the central nervous system (CNS) present a significant clinical challenge. Many of these neoplasms affect young children, have a very high mortality and therapeutic strategies are often aggressive with poor long-term outcomes. There is a great need to accurately diagnose embryonal tumours, predict their outcome and adapt therapy to the individual patient's risk. For the first time in 2016, the WHO classification took into account molecular characteristics for the diagnosis of CNS tumours. This integration of histological features with genetic information has significantly changed the diagnostic work-up and reporting of tumours of the CNS. However, this remains challenging in embryonal tumours due to their previously unaccounted tumour heterogeneity. We describe the recent revisions made to the 4th edition of the WHO classification of CNS tumours and review the main changes, while highlighting some of the more common diagnostic testing strategies.

Comparison of cryogenic low-pass filters.

Low-temperature electronic transport measurements with high energy resolution require both effective low-pass filtering of high-frequency input noise and an optimized thermalization of the electronic system of the experiment. In recent years, elaborate filter designs have been developed for cryogenic low-level measurements, driven by the growing interest in fundamental quantum-physical phenomena at energy scales corresponding to temperatures in the few millikelvin regime. However, a single filter concept is often insufficient to thermalize the electronic system to the cryogenic bath and eliminate spurious high frequency noise. Moreover, the available concepts often provide inadequate filtering to operate at temperatures below 10 mK, which are routinely available now in dilution cryogenic systems. Herein we provide a comprehensive analysis of commonly used filter types, introduce a novel compact filter type based on ferrite compounds optimized for the frequency range above 20 GHz, and develop an improved filtering scheme providing adaptable broad-band low-pass characteristic for cryogenic low-level and quantum measurement applications at temperatures down to few millikelvin.

Minimal methylation classifier (MIMIC): A novel method for derivation and rapid diagnostic detection of disease-associated DNA methylation signatures.

Rapid and reliable detection of disease-associated DNA methylation patterns has major potential to advance molecular diagnostics and underpin research investigations. We describe the development and validation of minimal methylation classifier (MIMIC), combining CpG signature design from genome-wide datasets, multiplex-PCR and detection by single-base extension and MALDI-TOF mass spectrometry, in a novel method to assess multi-locus DNA methylation profiles within routine clinically-applicable assays. We illustrate the application of MIMIC to successfully identify the methylation-dependent diagnostic molecular subgroups of medulloblastoma (the most common malignant childhood brain tumour), using scant/low-quality samples remaining from the most recently completed pan-European medulloblastoma clinical trial, refractory to analysis by conventional genome-wide DNA methylation analysis. Using this approach, we identify critical DNA methylation patterns from previously inaccessible cohorts, and reveal novel survival differences between the medulloblastoma disease subgroups with significant potential for clinical exploitation.

Imaging Biomarkers for Adult Medulloblastomas: Genetic Entities May Be Identified by Their MR Imaging Radiophenotype.

BACKGROUND AND PURPOSE: The occurrence of medulloblastomas in adults is rare; nevertheless, these tumors can be subdivided into genetic and histologic entities each having distinct prognoses. This study aimed to identify MR imaging biomarkers to classify these entities and to uncover differences in MR imaging biomarkers identified in pediatric medulloblastomas. MATERIALS AND METHODS: Eligible preoperative MRIs from 28 patients (11 women; 22-53 years of age) of the Multicenter Pilot-study for the Therapy of Medulloblastoma of Adults (NOA-7) cohort were assessed by 3 experienced neuroradiologists. Lesions and perifocal edema were volumetrized and multiparametrically evaluated for classic morphologic characteristics, location, hydrocephalus, and Chang criteria. To identify MR imaging biomarkers, we correlated genetic entities sonic hedgehog (SHH) TP53 wild type, wingless (WNT), and non-WNT/non-SHH medulloblastomas (in adults, Group 4), and histologic entities were correlated with the imaging criteria. These MR imaging biomarkers were compared with corresponding data from a pediatric study. RESULTS: There were 19 SHH TP53 wild type (69%), 4 WNT-activated (14%), and 5 Group 4 (17%) medulloblastomas. Six potential MR imaging biomarkers were identified, 3 of which, hydrocephalus (P = .03), intraventricular macrometastases (P = .02), and hemorrhage (P = .04), when combined, could identify WNT medulloblastoma with 100% sensitivity and 88.3% specificity (95% CI, 39.8%-100.0% and 62.6%-95.3%). WNT-activated nuclear ß-catenin accumulating medulloblastomas were smaller than the other entities (95% CI, 5.2-22.3 cm3 versus 35.1-47.6 cm3; P = .03). Hemorrhage was exclusively present in non-WNT/non-SHH medulloblastomas (P = .04; n = 2/5). MR imaging biomarkers were all discordant from those identified in the pediatric cohort. Desmoplastic/nodular medulloblastomas were more rarely in contact with the fourth ventricle (4/15 versus 7/13; P = .04). CONCLUSIONS: MR imaging biomarkers can help distinguish histologic and genetic medulloblastoma entities in adults and appear to be different from those identified in children.

Molecular characterization of disseminated pilocytic astrocytomas.

AIM: Pilocytic astrocytomas represent the most common paediatric tumours of the central nervous system. Dissemination through the ventricular system occurs rarely in patients with pilocytic astrocytomas; however, it is more common in infants with diencephalic tumours, and is associated with a poor outcome. Despite histological similarities with classic pilocytic astrocytomas, it is still unclear whether disseminated pilocytic astrocytomas may have specific molecular features. METHODS: Seventeen disseminated pilocytic astrocytomas were investigated using the molecular inversion probe array and screened for the presence of gene fusions (KIAA1549-BRAF) and mutations (BRAF, RAS and FGFR1). RESULTS: Along with evidence of a constitutive MAPK activation in all cases, the molecular inversion probe array, fluorescence in situ hybridization analysis and mutational study revealed KIAA1549-BRAF fusions in 66% and BRAF(V600E) mutations in 5% of cases. No KRAS, HRAS, NRAS or FGFR1 mutations were found. CONCLUSIONS: disseminated pilocytic astrocytomas showed genetic features similar to classic pilocytic astrocytoma, including a similar incidence of KIAA1549-BRAF fusions, BRAF mutations and a stable genetic profile. Given common activation of the MAPK pathway, the use of specific inhibitors can be hypothesized for the treatment of disseminated pilocytic astrocytomas, along with standard chemo- and/or radiotherapy.

Treatment of recurrent primitive neuroectodermal tumors (PNET) in children and adolescents with high-dose chemotherapy (HDC) and stem cell support: results of the HITREZ 97 multicentre trial.

Early studies with high-dose chemotherapy for treatment of relapsed cerebral PNET had shown modest efficacy but considerable toxicity. The HIT97 national trial tested a nonrandomized but stratified relapse protocol using either intensive chemotherapy, potentially high dose, or oral chemotherapy. 72 patients (59 disseminated) whose primary treatment had been surgery (97 %), radiotherapy (88 %), and/or chemotherapy (95 %) were enrolled in the intensive chemotherapy arm at diagnosis of relapse or resistance. As a window for this study they received two courses of a 96-hour infusion with carboplatin and etoposide. A response (complete or partial remission) was documented by MRI. Responders received two more cycles of this therapy and stem cell collection, before they received HDC (carboplatin, etoposide, thiotepa) and stem cell support. All possibilities of local therapy were to be explored and applied. After two courses of chemotherapy there was a 52 % response rate (41/72 patients). The median PFS and OS for all 72 patients were 11.6 and 21.1 months. Patients with medulloblastoma had a longer PFS and OS (12.6 and 22.6 months) than those with other PNETs (3.1 and 12.3 months). Favourable prognostic features were no new signs of clinical impairment and localised disease at relapse diagnosis. For the 27 patients who received HDC the median PFS and OS were 8.4 and 20.2 months, respectively. HDC did not benefit patients with resistant cerebral PNET and was associated with profound haematological and mucosal toxicity (90-100 % grade III, IV), infections (50 % grade III and IV) and severe ototoxicity (50 % grade III, 12.5 % grade IV). Treatment related mortality was 8 %. There was low long-term survival and only 2/72 patients are in continuous remission. Adding HDC in patients who responded to the initial courses of chemotherapy did not improve survival. Patients with relapsed cerebral PNET who respond to conventional chemotherapy do not profit from further augmentation to HDC.

MRI characteristics of ependymoblastoma: results from 22 centrally reviewed cases.

BACKGROUND AND PURPOSE: Ependymoblastoma is a malignant embryonal tumor that develops in early childhood and has a dismal prognosis. Categorized by the World Health Organization as a subgroup of CNS-primitive neuroectodermal tumor, ependymoblastoma is histologically defined by "ependymoblastic rosettes." Because it is so rare, little is known about specific MR imaging characteristics of ependymoblastoma. We systematically analyzed and discussed MR imaging features of ependymoblastoma in a series of 22 consecutive patients. MATERIALS AND METHODS: Ependymoblastoma cases were obtained from the database of the German multicenter HIT trials between 2002 and 2013. All cases within this study were centrally reviewed for histopathology, MR imaging findings, and multimodal therapy. For systematic analysis of initial MR imaging scans at diagnosis, we applied standardized criteria for reference image evaluation of pediatric brain tumors. RESULTS: Ependymoblastomas are large tumors with well-defined tumor margins, iso- to hyperintense signal on T2WI, and diffusion restriction. Contrast enhancement is variable, with a tendency to mild or moderate enhancement. Subarachnoid spread is common in ependymoblastoma but can be absent initially. There was a male preponderance (1.75:1 ratio) for ependymoblastoma in our cohort. Mean age at diagnosis was 2.1 years. CONCLUSIONS: With this study, we add the largest case collection to the limited published database of MR imaging findings in ependymoblastoma, together with epidemiologic data. However, future studies are needed to systematically compare MR imaging findings of ependymoblastoma with other CNS-primitive neuroectodermal tumors and ependymoma, to delineate imaging criteria that might help distinguish these pediatric brain tumor entities.

Childhood craniopharyngioma - changes of treatment strategies in the trials KRANIOPHARYNGEOM 2000/2007.

BACKGROUND: Prognosis in childhood cranio-pharyngioma, is frequently impaired due to sequelae. Radical surgery was the treatment of choice for decades. Even at experienced facilities radical surgery can result in hypothalamic disorders such as severe obesity. OBJECTIVE: We analyzed, whether treatment strategies for childhood craniopharyngioma patients recruited in GPOH studies have changed during the last 12 years. MATERIALS AND METHODS: We compared the grade of pre-surgical hypothalamic involvement, treatment, degree of resection and grade of surgical hypothalamic lesions between patients recruited in KRANIOPHARYNGEOM 2000 (n=120; 2001-2007) and KRANIOPHARYNGEOM 2007 (n=106; 2007-2012). RESULTS: The grade of initial hypothalamic involvement was similar in patients treated 2001-2007 and 2007-2012. The realized treatment was more radical (p=0.01) in patients recruited 2001-2007 (38%) when compared with patients treated 2007-2012 (18%). In patients with pre-surgical involvement of anterior/posterior hypothalamic areas, the rate of hypothalamus-sparing operations resulting in no (further) hypothalamic lesions was higher (p=0.005) in patients treated 2007-2012 (35%) in comparison with the 2001-2007 cohort (13%). Event-free-survival rates were similar in both cohorts. CONCLUSIONS: A trend towards less radical surgical approaches is observed, which was accompanied by a reduced rate of severe hypothalamic lesions. Radical surgery is not an appropriate treatment strategy in patients with hypothalamic involvement. Despite previous recommendations to centralize treatment at specialized centers, a trend towards further decentralization was seen.

NDRG1 prognosticates the natural course of disease in WHO grade II glioma.

There is a lack of relevant prognostic and predictive factors in neurooncology besides mutation of isocitrate dehydrogenase 1, codeletion of 1p/19q and promoter hypermethylation of O (6) -methylguanine-DNA-methyltransferase. More importantly, there is limited translation of these factors into clinical practice. The cancer genome atlas data and also clinical correlative analyses suggest a pivotal role for the epidermal growth factor receptor /protein kinase B/mammalian target of rapamycin (mTOR) pathway in both biology and the clinical course of gliomas. However, attempts to stratify gliomas by activating alterations in this pathway have failed thus far. The tumors of 40 patients with WHO grade II gliomas without immediate postoperative genotoxic treatment and known progression and survival status at a median follow-up of 12.2 years were analyzed for expression of the mTOR complex 2 downstream target N-myc downstream regulated gene (NDRG)1 using immunohistochemistry. Baseline characteristics for NDRG1 absent/low versus moderate/high patients were similar. Time to reintervention was significantly longer in the NDRG1 group (P = 0.026). NDRG1 may become a novel biomarker to guide the decision which WHO°II glioma patients may be followed without postsurgical intervention and which patients should receive genotoxic treatment early on. Validation of this hypothesis will be possible with the observational arm of the RTOG 9802 and the pretreatment step of the EORTC 22033/26032 trials.

High-dose chemotherapy (HDCT) with auto-SCT in children with atypical teratoid/rhabdoid tumors (AT/RT): a report from the European Rhabdoid Registry (EU-RHAB).

A retrospective analysis of data from the European Rhabdoid Registry (EU-RHAB) was performed to describe the outcome of children with atypical teratoid/rhabdoid tumors (AT/RT) who underwent high-dose chemotherapy (HDCT) with auto-SCT. Nineteen patients (male, n=15; median age at diagnosis 21 months) were identified. Nine patients presented with metastatic disease at diagnosis. A partial or subtotal resection was achieved in 11, a total resection in five and a biopsy in three patients. Patients received a median of six chemotherapy cycles prior to HDCT. Additional radiotherapy was performed in 14 patients (first-line, n=9; following progression, n=5). Six patients underwent tandem auto-SCT. Disease status before HDCT was CR in six, PR in eight, stable disease in two and progressive disease (PD) in two patients (data missing, n=1). With a median follow-up of 16 months, 14 patients progressed. Estimated progression-free and OS at 2 years were 29% (±11%) and 50% (±12%), respectively. At last follow-up, eight patients were alive (first CR, n=4; second CR, n=2; PR, n=1; PD, n=1). Eleven patients died of PD. Median time-to-progression was 14 months. Selected patients with AT/RT might benefit from HDCT with radiotherapy. The definitive impact of this treatment modality has to be evaluated prospectively in a randomized trial.

Gross total but not incomplete resection of glioblastoma prolongs survival in the era of radiochemotherapy.

BACKGROUND: This prospective multicenter study assessed the prognostic influence of the extent of resection when compared with biopsy only in a contemporary patient population with newly diagnosed glioblastoma. PATIENTS AND METHODS: Histology, O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, and clinical data were centrally analyzed. Survival analyses were carried out with the Kaplan-Meier method. Prognostic factors were assessed with proportional hazard models. RESULTS: Of 345 patients, 273 underwent open tumor resection and 72 biopsies; 125 patients had gross total resections (GTRs) and 148, incomplete resections. Surgery-related morbidity was lower after biopsy (1.4% versus 12.1%, P = 0.007). 64.3% of patients received radiotherapy and chemotherapy (RT plus CT), 20.0% RT alone, 4.3% CT alone, and 11.3% best supportive care as an initial treatment. Patients ≤60 years with a Karnofsky performance score (KPS) of ≥90 were more likely to receive RT plus CT (P < 0.01). Median overall survival (OS) (progression free survival; PFS) ranged from 33.2 months (15 months) for patients with MGMT-methylated tumors after GTR and RT plus CT to 3.0 months (2.4 months) for biopsied patients receiving supportive care only. Favorable prognostic factors in multivariate analyses for OS were age ≤60 years [hazard ratio (HR) = 0.52; P < 0.001], preoperative KPS of ≥80 (HR = 0.55; P < 0.001), GTR (HR = 0.60; P = 0.003), MGMT promoter methylation (HR = 0.44; P < 0.001), and RT plus CT (HR = 0.18, P < 0.001); patients undergoing incomplete resection did not better than those receiving biopsy only (HR = 0.85; P = 0.31). CONCLUSIONS: The value of incomplete resection remains questionable. If GTR cannot be safely achieved, biopsy only might be used as an alternative surgical strategy.

Cerebellar location may predict an unfavourable prognosis in paediatric high-grade glioma.

BACKGROUND: High-grade glioma (HGG) of the cerebellum accounts for only 5% of paediatric HGG. Since little is known about these tumours, the present study aimed at their further characterisation. METHODS: Twenty-nine paediatric patients with centrally reviewed cerebellar HGG were identified from the HIT-GBM/HIT-HGG database. Clinical and epidemiological data were compared with those of 180 paediatric patients with cortical HGG. RESULTS: Patients with cerebellar tumours were younger (median age of 7.6 vs 11.7 years, P=0.028), but both groups did not differ significantly with regard to gender, tumour predisposing syndromes, secondary HGG, primary metastasis, tumour grading, extent of tumour resection, chemotherapy regimen, or radiotherapy. Except for an increased incidence of anaplastic pilocytic astrocytoma (APA) in the cerebellar subset (20.7% vs 3.3%; P<0.001), histological entities were similarly distributed in both groups. As expected, tumour grading had a prognostic relevance on survival. Compared with cortical HGG, overall survival in the cerebellar location was significantly worse (median overall survival: 0.92 ± 0.02 vs 2.03 ± 0.32 years; P=0.0064), and tumour location in the cerebellum had an independent poor prognostic significance as shown by Cox-regression analysis (P=0.019). CONCLUSION: High-grade glioma represents a group of tumours with an obviously site-specific heterogeneity associated with a worse survival in cerebellar location.

Radiotherapy in pediatric pilocytic astrocytomas. A subgroup analysis within the prospective multicenter study HIT-LGG 1996 by the German Society of Pediatric Oncology and Hematology (GPOH).

PURPOSE: We evaluated clinical outcomes in the subset of patients who underwent radiotherapy (RT) due to progressive pilocytic astrocytoma within the Multicenter Treatment Study for Children and Adolescents with a Low Grade Glioma HIT-LGG 1996. PATIENTS AND METHODS: Eligibility criteria were fulfilled by 117 patients. Most tumors (65 %) were located in the supratentorial midline, followed by the posterior fossa (26.5 %) and the cerebral hemispheres (8.5 %). Median age at the start of RT was 9.2 years (range 0.7-17.4 years). In 75 cases, external fractionated radiotherapy (EFRT) was administered either as first-line nonsurgical treatment (n = 58) or after progression following primary chemotherapy (n = 17). The median normalized total dose was 54 Gy. Stereotactic brachytherapy (SBT) was used in 42 selected cases. RESULTS: During a median follow-up period of 8.4 years, 4 patients (3.4 %) died and 33 (27.4 %) experienced disease progression. The 10-year overall (OS) and progression-free survival (PFS) rates were 97 and 70 %, respectively. No impact of the RT technique applied (EFRT versus SBT) on progression was observed. The 5-year PFS was 76 ± 5 % after EFRT and 65 ± 8 % after SBT. Disease progression after EFRT was not influenced by gender, neurofibromatosis type 1 (NF1) status, tumor location (hemispheres versus supratentorial midline versus posterior fossa), age or prior chemotherapy. Normalized total EFRT doses of more than 50.4 Gy did not improve PFS rates. CONCLUSION: EFRT plays an integral role in the treatment of pediatric pilocytic astrocytoma and is characterized by excellent tumor control. A reduction of the normalized total dose from 54 to 50.4 Gy appears to be feasible without jeopardizing tumor control. SBT is an effective treatment alternative.

Bone involvement in atypical teratoid/rhabdoid tumors of the CNS.

SUMMARY: Destruction of the bony structures of the skull is rare in primary tumors of the CNS. In low-grade gliomas, modeling of the skull is caused by slow growth and chronic pressure. Bony destruction is exceptional even in highly malignant gliomas. Atypical teratoid/rhabdoid tumors of the CNS are highly malignant neoplasms diagnosed with an increasing frequency, mainly in young children. On imaging, these tumors exhibit distinct though not specific morphologic features including peripheral cysts, bleeding residues, and a distinct bandlike, wavy pattern of enhancement. A combination of these single characteristics together with a predilection for young age is suggestive of an atypical teratoid/rhabdoid tumor. We present 5 children with an atypical teratoid/rhabdoid tumor affecting the adjacent bone. These 5 patients were collected in our imaging data base for childhood atypical teratoid/rhabdoid tumor consisting of 91 children at the time of this evaluation and thus representing 6.6%. The mean age of children with bone involvement (4.8 years) was above the average age (2 years) of all children in the data base. We add this rare feature to the list of typical features in MR imaging and CT morphology of atypical teratoid/rhabdoid tumor.

What's in a name? Intracranial peripheral primitive neuroectodermal tumors and CNS primitive neuroectodermal tumors are not the same.

BACKGROUND: Intracranial peripheral primitive neuroectodermal tumors (P-PNET) are extremely rare. They can be easily misdiagnosed as central nervous system primitive neuroectodermal tumors (CNS-PNET) or meningiomas. Little is known about the optimal treatment and prognosis of these tumors. PATIENTS AND METHODS: We evaluated the treatment and outcome of 17 patients with intracranial, nonmetastatic, genetically confirmed P-PNET. Three patients were treated at our institutions. Thirteen other cases providing sufficient treatment and follow-up information were extracted from the literature. RESULTS: The median age at diagnosis was 17 years. All patients underwent initial surgery. Complete resection was achieved in 9 of the 17 cases (53 %). Combined adjuvant treatment consisting of radiotherapy (focal, n = 10; craniospinal, n = 1) and chemotherapy was administered to 11 of the 17 patients (59 %). The median follow-up time was 1.4 years. In 8 of the 17 patients (47 %), the disease progressed; 4 of the 17 patients (24 %) died. The 2-year progression-free and overall survival rates were 64 % and 76 %, respectively. CONCLUSION: The differential diagnosis for intracranial, meningeal-based, small, round-cell tumors should include P-PNET. It is highly probable that complete resection has a positive impact on survival--as previously reported for extracranial P-PNET--but this cannot be shown by our data. Intensive adjuvant treatment consisting of radiotherapy and chemotherapy seems to be essential. A statistically grounded recommendation for the appropriate target volume and radiation dose is not yet possible. However, in most case reports of primary intracranial P-PNET published to date, patients were treated with focal irradiation. The optimal chemotherapy regimen has yet to be established, with both the Ewing tumor and CNS-PNET protocols being promising candidates for effective treatment.