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Until recently, diagnostics of brain tumors were almost solely based on morphology and immunohistochemical stainings for relatively unspecific lineage markers. Although certain molecular markers have been known for longer than a decade (combined loss of chromosome 1p and 19q in oligodendrogliomas), molecular biomarkers were not included in the WHO scheme until 2016. Now, the classification of diffuse gliomas rests on an integration of morphology and molecular results. Also, for many other central nervous system tumor entities, specific diagnostic, prognostic and predictive biomarkers have been detected and continue to emerge. Previously, we considered brain tumors with similar histology to represent a single disease entity. We now realize that histologically identical tumors might show alterations in different molecular pathways, and often represent separate diseases with different natural history and response to treatment. Hence, knowledge about specific biomarkers is of great importance for individualized treatment and follow-up. In this paper we review the biomarkers that we currently use in the diagnostic work-up of brain tumors., (© 2019 APMIS. Published by John Wiley & Sons Ltd.)

Meningiomas present as intracranial extra-axial lesions with dural attachment, which are primarily managed surgically. The extent of resection (EOR) may vary depending on patient- and tumor-related factors. The aim of this study is to identify preoperative predictive factors of EOR and to propose an estimation of the predicted gross total resection (GTR) based of patient- and tumor-characteristics. 1469 patients from a retrospectively (1990 to 2002) and prospectively managed (2003 to 2010) databank of Oslo University Hospital, Norway, totalling 11,414 patient-years of follow-up were included. Patients had a mean age at surgery of 64 ± 20.1 years with a female-to-male ratio was 2.4:1 and a mean KPS of 81.2 ± 12.1. Skull-base meningiomas represented 47% of all cases. WHO grades were I in 92.3%, II in 5.2%, and III in 2.2%. Bone infiltration was described in 18.7% of cases. 39.3% of patients had Simpson I resection, 34.3% had Simpson II, 5.4% had Simpson III, 20.6% had Simpson IV, and 0.5% had Simpson V. The risk factors for incomplete resection were: symptomatic presentation (OR 0.56 [0.43-0.72]), skull-base location (OR 0.79 [0.70-0.88]), and bone invasion (OR 0.85 [0.73-0.99]). Using a recursive partitioning analysis, we propose a classification-tree for the prediction of GTR rate based on preoperatively determinable patient- and tumor characteristics. The identification of preoperative predictors of poor GTR rate may aid clinicians managing meningioma patients. In selected cases were the predicted GTR rate is low, staged treatment with surgical debulking followed by adjuvant therapy may be favored in order to minimize postoperative morbidity and mortality.

Neuromuscular adverse events following cancer treatment with anti-programmed cell death protein 1 (PD-1) monoclonal antibodies are relatively rare, yet potentially fatal. We performed a systematic review to characterize the clinical presentation, diagnostic workup, and management of neuromuscular disorders (NMDs) in patients treated with nivolumab or pembrolizumab monotherapy or concurrent with other immunologic agents, such as ipilimumab. Sixty-one publications on 85 patients (mean age 66.9 years [range 34-86]; male/female 2.6:1; 59% metastatic melanoma) were identified from selected indexing databases until June 2018. Forty-eight patients had received nivolumab and 39 pembrolizumab. The mean number of PD-1 inhibitor treatment cycles prior to onset of symptoms was 3.6 (range 1-28). Symptoms included oculomotor (47%), respiratory (43%), bulbar (35%), and proximal weakness (35%), as well as muscle pain (28%). Diagnoses were categorized as myasthenia gravis (27%), neuropathy (23%), myopathy (34%), or a combination of these (16%). After a critical review of the data, however, evidence did not support the stated NMD diagnosis in 13% of cases, while up to 25% of patients had signs of additional NMDs. Cardiac complications occurred in more than 30% of patients diagnosed with myasthenia gravis or myositis. Mortality was high in these patients, despite adequate treatment strategies including corticosteroid, IV immunoglobulins, and plasma exchange. The clinical presentation of NMDs associated with PD-1 inhibitors is often atypical, with considerable overlap between myasthenia gravis and myopathy, and cardiac/respiratory complications are common., (© 2019 American Academy of Neurology.)

To identify differences between skull base meningiomas (SBM) and non-skull base meningiomas (NSBM). All adult patients (18.0-69.9 years) operated for intracranial meningiomas between 1990 and 2010 at our institution were investigated. Al-Mefty's definition was used to dichotomize tumors into SBM and NSBM. Overall, 1148 consecutive patients were identified. Median age at surgery was 54.2 years [18.1-69.9]. Median follow-up was 7.4 years [0.0-20.9]. There were 562 patients (49%) with SBM and 586 (51%) with NSBM. The two groups were similar with respect to patient age, follow-up time, and number of patients. Overall female-to-male ratio was 2.6:1, but 3.2:1 in SBM and 2.2:1 in NSBM (p < 0.005). With respect to presenting symptoms, SBMs had more often neurological deficits (risk ratio (RR) 1.4; p < 0.0001) and less often seizures (RR 0.4; p < 0.0001). Gross total resections were less frequent in SBM than NSBM (62 vs 84%) (RR 1.3; p < 0.0001). SBMs had a lower risk of WHO grades II and III histology (4.5 vs 9.5%) (RR 0.5; p < 0.001). Worsening of neurological function was more frequent in SBM (21 vs 121%) (RR 1.8; p < 0.001). Retreatment-free survival at 5, 10, and 15 years, respectively, was 80, 70, and 62% for SBM versus 90, 82, and 74% for NSBM (p < 0.0001). Overall survival at 5, 10, and 15 years, respectively, was 93, 85, and 78% for SBM and 96, 91, and 79% for NSBM (p = 0.14). Patients with SBMs had more new-onset neurological deficits and significantly shorter retreatment-free survivals, but this did not adversely affect the overall survival.

Diagnostics of tumours of the central nervous system has for decades been based entirely on microscopy. A con-siderable degree of diagnostic interobserver variability has been observed due to imprecise histological criteria. In the revised WHO classification for central nervous system tumours from 2016, several diagnoses are now defined by both histological and molecular features and constitute "integrated diagnoses". The development based on new technologies like next-generation sequencing and DNA methylation profiling is discussed in this review as well as its implication for daily diagnostics and the patient.

An intact and dynamic microtubule cytoskeleton is crucial for the development, differentiation, and maintenance of the mammalian cortex. Variants in a host of structural microtubulin-associated proteins have been identified to cause a wide spectrum of malformations of cortical development and alterations of microtubule dynamics have been recognized to cause or contribute to progressive neurodegenerative disorders. TBCD is one of the five tubulin-specific chaperones and is required for reversible assembly of the α-/β-tubulin heterodimer. Recently, variants in TBCD, and one other tubulin-specific chaperone, TBCE, have been identified in patients with distinct progressive encephalopathy with a seemingly broad clinical spectrum. Here, we report the clinical, neuroradiological, and neuropathological features in eight patients originating from the Faroe Islands, who presented with an early onset, progressive encephalopathy with features of primary neurodegeneration, and a homogenous clinical course. These patients were homozygous for a TBCD missense variant c.[3099C>G]; p.(Asn1033Lys), which we show has a high carrier frequency in the Faroese population (2.6%). The patients had similar age of onset as the previously reported patients (n = 24), but much shorter survival, which could be caused by either differences in supportive treatment, or alternatively, that shorter survival is intrinsic to the Faroese phenotype. We present a detailed description of the neuropathology and MR imaging characteristics of a subset of these patients, adding insight into the phenotype of TBCD-related encephalopathy. The finding of a Faroese founder variant will allow targeted genetic diagnostics in patients of Faroese descent as well as improved genetic counseling and testing of at-risk couples.

Purpose: Pediatric cancers are often difficult to classify and can be complex to treat. To ensure precise diagnostics and identify relevant treatment targets, we implemented comprehensive molecular profiling of consecutive pediatric patients with cancer relapse. We evaluated the clinical impact of extensive molecular profiling by assessing the frequency of identified biological onco-drivers, altered diagnosis, and/or identification of new relevant targeted therapies. Patients and Methods: Forty-six tumor samples (44 fresh-frozen; two formalin-fixed paraffin embedded), two bone marrow aspirates, three cerebrospinal fluid samples, and one archived DNA were obtained from 48 children (0-17 years; median 9.5) with relapsed or refractory cancer, where the disease was rapidly progressing in spite of their current treatment or they had exhausted all treatment options. The samples were analyzed by whole-exome sequencing (WES), RNA sequencing (RNAseq), transcriptome arrays, and SNP arrays. Final reports were available within 3-4 weeks after patient inclusion and included mutation status, a description of copy number alterations, differentially expressed genes, and gene fusions, as well as suggestions for targeted treatment. Results: Of the 48 patients, 33 had actionable findings. The most efficient method for the identification of actionable findings was WES (39%), followed by SNP array (37%). Of note, gene fusions were identified by RNAseq in 21% of the samples. Eleven findings led to clinical intervention, i.e., oncogenetic counseling, targeted treatment, and treatment based on changed diagnosis. Four patients received compassionate use targeted therapy. Six patients experienced direct benefits in the form of stable disease or response. Conclusion: The application of comprehensive genetic diagnostics in children with recurrent cancers allowed for discovery and implementation of effective targeted therapies and hereby improvement of outcome in some patients.

Background: To date, the traditional approach to intraspinal tumors has been open laminectomy or laminoplasty followed by microsurgical tumor resection. Recently, however, minimally invasive approaches have been attempted by some., Objective: To investigate the feasibility and safety of minimally invasive surgery (MIS) for primary intradural spinal tumors., Methods: Medical charts of 83 consecutive patients treated with MIS for intradural spinal tumors were reviewed. Patients were followed up during the study year, 2015, by either routine history/physical examination or by telephone consultation, with a focus on tumor status and surgery-related complications., Results: Mean age at surgery was 53.7 yr and 52% were female. There were 49 schwannomas, 18 meningeomas, 10 ependymomas, 2 hemangioblastomas, 1 neurofibroma, 1 paraganglioma, 1 epidermoid cyst, and 1 hemangiopericytoma. The surgical mortality was 0%. In 87% of cases, gross total resection was achieved. The complication rate was 11%, including 2 cerebrospinal fluid leakages, 1 asymptomatic pseudomeningocele, 2 superficial surgical site infections, 1 sinus vein thrombosis, and 4 cases of neurological deterioration. There were no postoperative hematomas, and no cases of deep vein thrombosis or pulmonary embolism. Ninety-three percent of patients were ambulatory and able to work at the time of follow-up., Conclusion: This study both demonstrates that it is feasible and safe to remove select, primary intradural spinal tumors using MIS, and augments the previous literature in favor of MIS for these tumors.

Introduction: In 2016, the WHO classification of diffuse astrocytoma began to include isocitrate dehydrogenase (IDH) mutation in addition to histology., Results: We here demonstrate a case where a 14-year-old boy presented with a parietal tumor with no histological evidence of neoplasia but with an IDH1 mutation. Due to the IDH1 R132H mutation, the patient was diagnosed with diffuse astrocytoma WHO grade II and underwent successful gross total resection of this near-eloquently located tumor., Conclusion: This case exemplifies how inclusion of immunohistochemistry in tumor classification alters surgical strategy and might improve accuracy and time to diagnosis.

Meningiomas are rare in children. They are highly complex, harboring unique clinical and pathological characteristics, and many occur in patients with neurofibromatosis type 2. Hereby, we present a case of a two-year-old boy presented with a diagnostically challenging intraventricular tumor. It was incompletely resected 6 times over 14 months but kept progressing and was ultimately deemed unresectable. Histologically, the tumor was initially classified as schwannoma, but extensive international review concluded it was most likely an atypical meningioma, WHO grade II. Comprehensive genomic profiling revealed a TFG-ROS1 fusion, suggesting that ROS1-signaling pathway alterations were driving the tumor growth. In light of this new information, the possibility of a diagnosis of inflammatory myofibroblastic tumor was considered; however the histopathological results were not conclusive. This specific molecular finding allowed the potential use of precision medicine and the patient was enrolled in the AcSé phase 2 trial with crizotinib (NCT02034981), leading to a prolonged partial tumor response which is persisting since 14 months. This case highlights the value of precision cancer medicine in children., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

We have previously identified two ALK rearrangements in a subset of ependymal tumors using a combination of cytogenetic data and RNA sequencing. The aim of this study was to perform an unbiased search for fusion transcripts in our entire series of ependymal tumors. Fusion analysis was performed using the FusionCatcher algorithm on 12 RNA-sequenced ependymal tumors. Candidate transcripts were prioritized based on the software's filtering and manual visualization using the BLAST (Basic Local Alignment Search Tool) and BLAT (BLAST-like alignment tool) tools. Genomic and reverse transcriptase PCR with subsequent Sanger sequencing was used to validate the potential fusions. Fluorescent in situ hybridization (FISH) using locus-specific probes was also performed. A total of 841 candidate chimeric transcripts were identified in the 12 tumors, with an average of 49 unique candidate fusions per tumor. After algorithmic and manual filtering, the final list consisted of 24 potential fusion events. Raw RNA-seq read sequences and PCR validation supports two novel fusion genes: a reciprocal fusion gene involving UQCR10 and C1orf194 in an adult spinal ependymoma and a TSPAN4-CD151 fusion gene in a pediatric infratentorial anaplastic ependymoma. Our previously reported ALK rearrangements and the RELA and YAP1 fusions found in supratentorial ependymomas were until now the only known fusion genes present in ependymal tumors. The chimeric transcripts presented here are the first to be reported in infratentorial or spinal ependymomas. Further studies are required to characterize the genomic rearrangements causing these fusion genes, as well as the frequency and functional importance of the fusions. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Pilocytic astrocytoma (PA) is one of the most common brain cancers among children and activation of the Mitogen-Activated Protein Kinase (MAPK) pathway is considered the hallmark. In the majority of cases, oncogenic BRAF fusions or BRAF V600E mutations are observed, while RAF1 or NF1 alterations are more rarely found. However, in some cases, no apparent cancer driver events can be identified. Here, we describe a novel fusion between the transcription factor nuclear factor 1A (NFIA) and Raf-1 proto-oncogene (RAF1) in a 5-year old boy with PA. The novel fusion was identified as part of a comprehensive genomic tumor profiling. We show that the NFIA:RAF1 fusion results in constitutive Raf1 kinase activity, leading to activation of downstream MEK1/2 cascade and increased proliferation of cancer cells. The NFIA:RAF1 fusion displayed distinct subcellular localization towards the plasma membrane indicative of Raf-1 activation, in contrast to both wild type NFIA and Raf-1, which were localized in the nucleus and cytoplasm, respectively. In conclusion, our data support the existence of rare oncogenic RAF1 fusions with constitutive Raf-1 activity. This highlights the need for broad genetic testing in order to refine diagnostics of PA and to unravel potential treatment options, e.g. with MEK inhibitors., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)," and "CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Flow diverter stents are new important tools in the treatment of large, giant, or wide-necked aneurysms. Their delivery and positioning may be difficult due to vessel tortuosity. Common adverse events include intracranial hemorrhage and ischemic stroke, which usually occurs within the same day, or the next few days after the procedure. We present a case where we encountered an unusual intracerebral complication several months after endovascular treatment of a large left internal carotid artery aneurysm, and where brain biopsy revealed foreign body reaction to hydrophilic polymer fragments distally to the stent site. Although previously described, embolization of polymer material from intravascular equipment is rare. We could not identify any other biopsy verified case in the literature, with this particular presentation of intracerebral polymer embolization--a multifocal inflammation spread out through the white matter of one hemisphere without hemorrhage or ischemic changes., (© The Author(s) 2015.)

Extracranial metastases from glioblastoma are rare. We report two patients with extracranial metastases from glioblastoma. Case 1 concerns a 59-year-old woman with multiple metastases that spread early in the course of disease. What makes this case unusual is that the tumor had grown into the falx close to the straight sinus and this might be an explanation to the early and extensive metastases. Case 2 presents a 60-year-old man with liver metastasis found at autopsy, and, in this case, it is more difficult to find an explanation. This patient had two spontaneous intracerebral bleeding incidents and extensive bleeding during acute surgery with tumor removal, which might have induced extracranial seeding. The cases presented might have hematogenous spreading in common as an explanation to extracranial metastases from GBM.

A 17-year-old female with migraine with aura complained of fatigue and was diagnosed with anemia. Three years later, changes in her headache pattern prompted hospital referral. Brain MRI showed a bi-lobed extra-axial intracerebral tumor encroaching both parieto-occipital regions. The resection specimen yielded a rare diagnosis of primary intracranial angiomatoid fibrous histiocytoma (AFH). Tumor removal resulted in cessation of her migraine and anemia. AFH may cause systemic symptoms--in this case fatigue and anemia--long before focal neurological symptoms are present. This is the first report of an intracranial AFH presenting as migraine with visual aura and anemia., (© International Headache Society 2015.)

Background: We have previously characterized 19 ependymal tumors using Giemsa banding and high-resolution comparative genomic hybridization. The aim of this study was to analyze these tumors searching for fusion genes., Methods: RNA sequencing was performed in 12 samples. Potential fusion transcripts were assessed by seed count and structural chromosomal aberrations. Transcripts of interest were validated using fluorescence in situ hybridization and PCR followed by direct sequencing., Results: RNA sequencing identified rearrangements of the anaplastic lymphoma kinase gene (ALK) in 2 samples. Both tumors harbored structural aberrations involving the ALK locus 2p23. Tumor 1 had an unbalanced t(2;14)(p23;q22) translocation which led to the fusion gene KTN1-ALK. Tumor 2 had an interstitial del(2)(p16p23) deletion causing the fusion of CCDC88A and ALK. In both samples, the breakpoint of ALK was located between exons 19 and 20. Both patients were infants and both tumors were supratentorial. The tumors were well demarcated from surrounding tissue and had both ependymal and astrocytic features but were diagnosed and treated as ependymomas., Conclusions: By combining karyotyping and RNA sequencing, we identified the 2 first ever reported ALK rearrangements in CNS tumors. Such rearrangements may represent the hallmark of a new entity of pediatric glioma characterized by both ependymal and astrocytic features. Our findings are of particular importance because crizotinib, a selective ALK inhibitor, has demonstrated effect in patients with lung cancer harboring ALK rearrangements. Thus, ALK emerges as an interesting therapeutic target in patients with ependymal tumors carrying ALK fusions., (© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Methods: Ten consecutive children (0-18 years) who underwent primary tumor resection for a spinal ependymoma between 1980 and 2011 were included in this retrospective study. Gross motor function and activities of daily life were scored according to the Barthel Index., Conclusion: Three out of six pediatric patients treated for spinal myxopapillary ependymoma are disease-free after 11 to 33 years of follow-up. The other three have progressive disease, after relapses occurring after 4.5, 7, and 20 years, respectively. One out of two patients with grade II ependymoma had progressive disease from 10 years after initial surgery but is in full-time work in spite of widespread metastatic disease after 32 years. One of the two children with grade III tumor died from progressive disease 17 years from primary diagnosis, while the last one is tumor-free after 19 years. The quality of life is good for three of the four patients with widespread disease, and they are managed conservatively aiming at symptomatic treatment intervention if necessary. We strongly advocate lifelong follow-up for children treated for spinal ependymomas.

Object: The authors delineate the long-term results of surgical treatment for pediatric low-grade midbrain glioma., Methods: A series of 15 consecutive patients (age range 0-15 years) who underwent primary tumor resection for a low-grade midbrain glioma during the years 1989-2010 were included in this retrospective study on surgical morbidity, mortality rate, academic achievement, and/or work participation. Gross motor function and activities of daily living were scored according to the Barthel Index., Results: Of the 15 patients, 10 were in their 1st decade (age 0-9 years) and 5 were in their 2nd decade of life (age 10-15 years) at the time of surgery. The male/female ratio was 0.50 (5:10). No patients were lost to follow-up. One patient died in the postoperative period (32 days posttreatment). Another 2 patients died during follow-up. One patient succumbed to acute bleeding in the resection cavity 8 months after surgery, and the other died of shunt failure 21 years after initial treatment. Twelve patients are alive at the time of this writing, with follow-up periods from 3 to 24 years (median 8 years). Among the 12 survivors, the Barthel Index scores were normal (100) in 11 patients and 80 in 1 patient. A total of 25 tumor resections were performed. In 1 patient, further resection was performed 5 days after initial resection due to MRI-confirmed residual tumor. Another 5 patients underwent repeat tumor resection after MRI-confirmed progressive tumor disease and clinical deterioration ranging from 3 months to 4 years after the initial operation. Three of these 5 patients also underwent a third resection, and 1 of the 3 underwent a fourth operation. Six children received adjuvant therapy: local radiotherapy in 2 patients, chemotherapy in 3 patients, and both in 1 patient. Twelve (80%) of the 15 patients needed treatment for persistent hydrocephalus., Conclusions: Selected cases of low-grade midbrain gliomas may clearly benefit from resection with favorable results, even for prolonged periods. Three patients in the present series died, one of whom had a prolonged survival period of 21 years. Among the 12 survivors, stable long-term results appeared obtainable in at least 9. One patient died of acute hemorrhage 8 months after initial resection; otherwise, rapid tumor progression and death were not observed. Forty percent of the patients received adjuvant treatment, with local radiotherapy, chemotherapy, or both.

Ependymomas are rare tumors of the central nervous system (CNS). They are classified based on tumor histology and grade, but the prognostic value of the WHO grading system remains controversial. Treatment is mainly surgical and by radiation. An improved knowledge of ependymoma biology is important to elucidate the pathogenesis, to improve classification schemes, and to identify novel potential treatment targets. Only 113 ependymoma karyotypes with chromosome aberrations are registered in the Mitelman database. We present the first study of ependymoma genomes combining karyotyping and high resolution comparative genomic hybridization (HR-CGH). Nineteen tumor samples were collected from three pediatric and 15 adult patients treated at Oslo University Hospital between 2005 and 2012. Histological diagnoses included subependymoma and myxopapillary ependymoma (WHO grade I), ependymoma (WHO grade II) and anaplastic ependymoma (WHO grade III). Four tumors were intraspinal and 15 were intracranial. Seventeen samples were successfully karyotyped, HR-CGH analysis was undertaken on 17 samples, and 15 of 19 tumors were analyzed using both methods. Twelve tumors had karyotypic abnormalities, mostly gains or losses of whole chromosomes. Structural rearrangements were found in four tumors, in two of which 2p23 was identified as a breakpoint region. Twelve tumors displayed genomic imbalances by HR-CGH analysis with loss of material at 6q as the most common. 6q loss, which was detected by one or both methods in seven of 12 (58%) abnormal tumors, and 5p gain (observed in five tumors; 42%) were the most common genomic aberrations in this series.

Purpose: To retrospectively evaluate the performance of an automatic support vector machine (SVM) routine in combination with perfusion-based dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) for preoperative survival associations in patients with gliomas and compare our results to traditional MRI., Materials and Methods: The study was approved by the Ethics Committee and informed consent was signed. Structural, diffusion- and perfusion-weighted MRI was performed at 1.5-T preoperatively in 94 adult patients (49 males, 45 females, 23-82 years; mean 51 years) later diagnosed with a primary glioma. Patients were randomly assigned in training and test datasets and the resulting DSC-based survival associations by SVM were compared to traditional MRI features including contrast-agent enhancement, perfusion- and diffusion-weighted imaging, tumor size, and location. The results were adjusted for age, neurological status, and postoperative factors associated with survival, including surgery and adjuvant therapy., Results: For 1- (26/33 alive, 11/14 deceased), 2- (15/21, 21/26), 3- (12/16, 27/31) and 4- (12/15, 28/32) year survival associations in the test dataset (47 patients), the SVM routine was the only biomarker to consistently associate with survival (Cox; P < 0.001)., Conclusion: The automatic machine learning routine presented in our study may provide the operator with a reliable instrument for assessing survival in patients with glioma., (© 2013 Wiley Periodicals, Inc.)

Background: To study patient characteristics, prognostic factors and overall survival (OS) in a consecutive, surgical series of WHO grade III anaplastic astrocytomas (AA)., Methods: Patients were identified from a prospective tumor database at Oslo University Hospital, Norway, and patients undergoing surgery for an AA from 2005-2012 were included. Patients' medical charts were retrospectively reviewed for data collection., Results: A total of 99 adult patients with histologically verified AA were included. Median age was 52 years (20-81). Biopsy was conducted in 33 % and resection in 67 %. Adjuvant treatment with radiation therapy + temozolomide or radiation therapy only was given in 63 % and 26 %, respectively. The thirty-day mortality rate was 3 %. Median OS was 19 months (95 % CI 11-27 months). Age ≥ 65 years, KPS < 70, biopsy as opposed to resection, and no adjuvant treatment were confirmed negative prognostic factors in multivariate analysis. For patients undergoing resection, presence of postoperative contrast-enhanced tumor, not volume of residual tumor, had significant impact on OS in adjusted analysis., Conclusions: Median OS following surgery was 19 months, though much variable outcome was observed among subgroups of AA (95 % CI 11-27 months). Age ≥65 years, KPS < 70, biopsy as opposed to resection, and no adjuvant treatment were confirmed negative prognostic factors for OS.

Aim: To describe patients diagnosed with limb girdle muscular dystrophy 2I (LGMD2I) in our paediatric departments between 2004 and 2012., Methods: The hospital charts of 17 patients presenting for evaluation at a mean age of 7.8 years (range 1-13 years) were retrospectively reviewed., Results: With one exception, all patients were homozygous for the common mutation c.826C>A in the FKRP gene. Three patients experienced transient pronounced weakness as toddlers. Fatigue and muscle pain were most prominent, weakness less so, in children presenting at an older age. The degree of severity varied substantially. In certain cases, increased creatine kinase was an incidental finding. All walked independently by 18 months. When last evaluated at a mean age of 14.3 years (range 3.5-18 years), five patients were part-time wheelchair users. One patient was then treated for a cardiomyopathy. Creatine kinase was consistently increased, except presymptomatic in one patient. Muscle biopsies showed focal acute and chronic myopathic changes and pathological expression of α-dystroglycan. No consistent relationship between clinical function and the degree of morphological pathology was found., Conclusion: LGMD2I is a relevant differential diagnosis when creatine kinase is increased in children presenting with fatigue, muscle pain and sometimes weakness., (©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Object: The object of this study was to delineate long-term results of the surgical treatment of pediatric CNS tumors classified as oligodendroglioma (OD) or oligoastrocytoma (OA) WHO Grade II or III., Methods: A cohort of 45 consecutive patients 19 years or younger who had undergone primary resection of CNS tumors originally described as oligodendroglial during the years 1970-2009 at a single institution were reviewed in this retrospective study of surgical morbidity, mortality, and academic achievement and/or work participation. Gross motor function and activities of daily living were scored using the Barthel Index (BI)., Results: Patient records for 35 consecutive children and adolescents who had undergone resection for an OA (17 patients) or OD (18 patients) were included in this study. Of the 35 patients, 12 were in the 1st decade of life at the first surgery, whereas 23 were in the 2nd decade. The male/female ratio was 1.19 (19/16). No patient was lost to follow-up. The tumor was localized to the supratentorial compartment in 33 patients, the posterior fossa in 1 patient, and the cervical medulla in 1 patient. Twenty-four tumors were considered to be WHO Grade II, and 11 were classified as WHO Grade III. Among these latter lesions were 2 tumors initially classified as WHO Grade II and later reclassified as WHO Grade III following repeat surgery. Fifty-four tumor resections were performed. Two patients underwent repeat tumor resection within 5 days of the initial procedure, after MRI confirmed residual tumor. Another 10 patients underwent a second resection because of clinical deterioration and progressive disease at time points ranging from 1 month to 10 years after the initial operation. Six patients underwent a third resection, and 1 patient underwent a fourth excision following tumor dissemination to the spinal canal. Sixteen (46%) of the 35 children received adjuvant therapy: 7, fractionated radiotherapy; 4, chemotherapy; and 5, both fractionated radiotherapy and chemotherapy. One patient with primary supratentorial disease experienced clinically malignant development with widespread intraspinal dissemination 9 years after initial treatment. Only 2 patients needed treatment for persistent hydrocephalus. In this series there was no surgical mortality, which was defined as death within 30 days of resection. However, 12 patients in the study, with follow-up times from 1 month to 33 years, died. Twenty-three patients, with follow-up times from 4 to 31 years, remained alive. Among these survivors, the BI was 100 (normal) in 22 patients and 80 in 1 patient. Nineteen patients had full- or part-time work or were in normal school programs., Conclusions: Pediatric oligodendroglial tumors are mainly localized to the supratentorial compartment and more often occur in the 2nd decade of life rather than the 1st. Two-thirds of the patients remained alive after follow-ups from 4 to 31 years. Twelve children succumbed to their disease, 9 of them within 3 years of resection despite combined treatment with radio- and chemotherapy. Three of them remained alive from 9 to 33 years after primary resection. Among the 23 survivors, a stable, very long-term result was attainable in at least 20. Five-, 10-, 20-, and 30-year overall survival in patients with Grade II tumors was 92%, 92%, 92%, and 88%, respectively.

Object: The objective of this study was to delineate the long-term results of surgical treatment of pediatric low-grade cerebellar astrocytoma., Methods: One hundred consecutive children and adolescents (0-19 years old) who underwent primary tumor resection for a low-grade cerebellar astrocytoma during the years 1980-2011 were included in this retrospective study on surgical morbidity, mortality rate, academic achievement, and/or work participation. Gross motor function and activities of daily living were scored according to the Barthel Index., Results: Of the 100 patients, 61 children were in the 1st decade, and 39 were 10-19 years old. The male/female ratio was 1.13:1 (53 males, 47 females). No patients were lost to follow-up. There were no deaths in this series and all 100 patients are currently alive. In 29 patients, the follow-up duration was less than 10 years, in 37 it was between 10 and 19 years, and in 34 it was between 20 and 31 years. The Barthel Index was 100 (normal) in 97 patients, 90 in 2 patients, and 40 in the last patient. A total of 113 tumor resections were performed. Two patients underwent further tumor resection due to MRI-confirmed residual tumor demonstrated on the immediate postoperative MR image (obtained the day after the initial procedure). Furthermore, 9 children underwent repeat tumor resection after MRI-confirmed progressive tumor recurrence up to 10 years after the initial operation. Two of these patients also underwent a third resection, without subsequent radiation therapy, and have experienced 8 and 12 years of tumor-free follow-up thereafter, respectively. A total of 15% of the patients required treatment for persistent hydrocephalus., Conclusions: Low-grade cerebellar astrocytoma is a surgical disease, in need of long-term follow-up, but with excellent long-term results. Nine percent of the children in this study underwent repeated surgery due to progressive tumor recurrence, and 15% were treated for persistent hydrocephalus.

Object: Recently the relevance of Simpson resection grade as a prognostic factor for recurrence of WHO Grade I meningiomas was challenged, contradicting many previous scientific reports and traditional neurosurgical teaching. The objective of this study was to determine whether the predictive value of Simpson resection grade is outdated or remains valid with respect to meningioma recurrence and overall survival., Methods: All patients at least 16 years old who underwent primary craniotomies for convexity meningiomas at Oslo University-affiliated hospitals (Rikshospitalet and Ullevål University Hospitals) in the period between January 1, 1990, and January 27, 2011, were included. Overall survival and retreatment-free survival rates were correlated with patient- and surgery-specific factors., Results: Three hundred ninety-one consecutive patients were included in the study. The median patient age was 60.1 years (range 19-92 years). The female-to-male ratio was 2.1:1. The WHO grades were Grade I in 353 (90.3%), Grade II in 22 (5.6%), and Grade III in 16 (4.1%). The follow-up rate was 100%. Median follow-up time was 7.1 years (range 0.0-20.9 years) and total observation time was 3147 patient-years. The 1-, 5-, and 10-year overall survival rates were 96%, 89%, and 78%, respectively. Age, sex, WHO grade, and Simpson grade were significantly associated with overall survival. The 1-, 5-, and 10-year retreatment-free survival rates were 99%, 94%, and 90%, respectively. Simpson resection grade and WHO grade were significantly associated with retreatment-free survival. The hazard ratios for retreatment after combined Simpson resection Grades II+III and IV+V were 4.9- and 13.2-times higher than after Simpson Grade I resection, respectively., Conclusions: Simpson Grade I resection should continue to be the goal for convexity meningiomas.

Background: Methylation of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene promoter is a favorable prognostic factor in glioblastoma patients. However, reported methylation frequencies vary significantly partly due to lack of consensus in the choice of analytical method., Method: We examined 35 low- and 99 high-grade gliomas using quantitative methylation specific PCR (qMSP) and pyrosequencing. Gene expression level of MGMT was analyzed by RT-PCR., Results: When examined by qMSP, 26% of low-grade and 37% of high-grade gliomas were found to be methylated, whereas 97% of low-grade and 55% of high-grade gliomas were found methylated by pyrosequencing. The average MGMT gene expression level was significantly lower in the group of patients with a methylated promoter independent of method used for methylation detection. Primary glioblastoma patients with a methylated MGMT promoter (as evaluated by both methylation detection methods) had approximately 5 months longer median survival compared to patients with an unmethylated promoter (log-rank test; pyrosequencing P = .02, qMSP P = .06). One third of the analyzed samples had conflicting methylation results when comparing the data from the qMSP and pyrosequencing. The overall survival analysis shows that these patients have an intermediate prognosis between the groups with concordant MGMT promoter methylation results when comparing the two methods., Conclusion: In our opinion, MGMT promoter methylation analysis gives sufficient prognostic information to merit its inclusion in the standard management of patients with high-grade gliomas, and in this study pyrosequencing came across as the better analytical method., (© 2012 Håvik et al; licensee BioMed Central Ltd.)

We analyzed the relationships among clinical variables, histology, 1p/19q status, and outcome in 95 patients with oligodendroglial tumors. The study enrolled adult patients who underwent first-time surgery for a supratentorial oligodendroglial tumor at Oslo University Hospital, Rikshospitalet. Tumors were: 27 oligodendrogliomas, WHO grade II; 32 oligoastrocytomas, WHO grade II; 16 anaplastic oligodendrogliomas, WHO grade III; 14 anaplastic oligoastrocytomas, WHO grade III; and 6 glioblastomas with a major oligodendroglial component, WHO grade IV. The clinical files were reviewed. Three neuropathologists evaluated the histological slides independently. Loss-of-heterozygosity analysis for 1p and 19q was performed by PCR. Favorable prognostic factors from univariate analyses included seizures as presenting symptom, female sex, location in the frontal lobe, low WHO grade, classic histology, absence of gemistocytic cells, and combined 1p/19q loss. Solitary 19q loss was a negative prognostic marker. 1p/19q status was of prognostic significance in both tumors with classic and nonclassic oligodendroglial histology. In the multivariate analysis, WHO grade II (P< .001), frontal tumor location (P= .002), and combined 1p/19q loss (P< .001) remained favorable prognostic variables. Our results suggest that tumor location, WHO grade, and 1p/19q status are important independent variables associated with survival in oligodendroglial tumors. The study suggests that solitary 19q loss is a negative prognostic variable and that 1p/19q loss is associated with prolonged survival also in oligodendroglial tumors without classic histology.

The current classification of diffuse low-grade gliomas is based mainly on histopathological criteria, which cannot accurately predict the highly variable clinical course observed in patients with such tumors. In an attempt to increase pathogenetic understanding of these tumors, we investigated 38 WHO Grade II astrocytomas, oligodendrogliomas, and oligoastrocytomas using a combination of G-band chromosome analysis and high-resolution comparative genomic hybridization (HR-CGH). Abnormal karyotypes were found in 41% of tumors. Karyotypes of astrocytomas and oligodendrogliomas were near-diploid whereas oligoastrocytomas also displayed near-tetraploid clones. The most common aberrations were losses of chromosomes X, Y, 3, 4, 6, and 11 and gains of chromosomes 8 and 12. The only recurrent structural rearrangement was del(6)(q21). HR-CGH analysis verified karyotyping findings but also revealed frequent losses at 1p, 17q, and 19q and gains of 7q, 10p, 11q, and 20p. Among the tumors were two gemistocytic astrocytomas, a subgroup of diffuse astrocytomas with a particular predisposition for progression but not studied cytogenetically before; one showed a near-diploid, complex karyotype with structural aberrations of chromosomes 1, 3, and 11 whereas both displayed simple aberrations including loss of 11p by HR-CGH. Our findings suggest that within diffuse low-grade gliomas are genetically distinct entities that do not fit the currently used classification. In addition, tumors with complex chromosomal aberrations had a higher tendency for aggressive tumor behavior (shorter progression-free survival) than tumors displaying simple aberrations only (P = 0.07). This could help identify genetic subsets of patients with low-grade glioma who might benefit from early antineoplastic therapy., (Copyright © 2011 Wiley-Liss, Inc.)

Background and Importance: As a consequence of the increased use of endovascular coiling of intracranial aneurysms, a growing number of case reports on complications are being reported. This article presents a case with a previously undescribed complication of coil treatment: a reactive, noninfectious process after coiling of an unruptured intracranial aneurysm, Clinical Presentation: A 60-year-old hypertensive woman with hypoxic encephalopathy after respiratory arrest following a total thyroidectomy had extensive intentional myoclonus and reduced quality of life as sequelae. An asymptomatic 15-mm internal carotid artery bifurcation aneurysm was discovered on magnetic resonance imaging (MRI) 6 months after the thyroidectomy. After documented growth, the aneurysm was treated endovascularly with bare platinum Guglielmi detachable coils. Three months later, an expansion in the right frontal lobe cranially to the coiled aneurysm was observed. The lesion had grown at the 12-month postcoil MRI and, because of its increasing mass effect, was resected through a craniotomy 2 years after the coiling. As a result of lesion regrowth and cyst formation, she underwent a new craniotomy 5 years later with excision of the now 21-mm large coiled aneurysm, internal carotid artery clip reconstruction, and lesionectomy. Five months postoperatively, the process had not recurred. No signs of malignancy or infection were observed during the histological evaluation of the resected tissue. The tissue is described as a reactive, noninfectious process, most likely resulting from the coils acting as a foreign body., Conclusion: This article presents a case with a reactive expansive intracerebral process as a complication to endovascular coil treatment of an unruptured intracranial aneurysm.

Background: In order to weigh the risks of surgery against the presumed advantages, it is important to have specific knowledge about complication rates., Objective: To study the surgical mortality and rate of reoperations for hematomas and infections after intracranial surgery for brain tumors in a large, contemporary, single-institution consecutive series., Methods: All adult patients from a well-defined population of 2.7 million inhabitants who underwent craniotomies for intracranial tumors at Oslo University Hospital from 2003 to 2008 were included (n = 2630). The patients were identified from our prospectively collected database and their charts studied retrospectively. Follow-up was 100%., Results: The overall surgical mortality, defined as death within 30 days of surgery, was 2.3% (n = 60). The mortality rates for high- and low-grade gliomas, meningiomas, and metastases were 2.9%, 1.0%, 0.9%, and 4.5%, respectively. Age >60 (odds ratio 1.84, P < 0.05) and biopsy compared with resection (odds ratio 4.67, P < 0.01) were significantly positively associated with increased surgical mortality. Hematomas accounted for 35% of the surgical mortality. Postoperative hematomas needing evacuation occurred in 2.1% (n = 54). Age >60 was significantly correlated to increased risk of postoperative hematomas (odds ratio 2.43, P < 0.001). A total of 39 patients (1.5%) were reoperated for postoperative infection. Meningiomas had an increased risk of infections compared with high-grade gliomas (odds ratio 4.61, P < 0.001)., Conclusion: The surgical mortality within 30 days of surgery was 2.3%, with age >60 and biopsy vs resection being the 2 factors significantly associated with increased mortality. Postoperative hematomas caused about one third of the surgical mortality.

We have investigated a family where two siblings had a developmental disorder associated with polycystic dysplastic kidney disease that was incompatible with postnatal survival. Additional features observed were ductal plate malformation in the liver, dysplasia of the pancreas, and (in one individual) complete situs inversus and polymicrogyria of the cingulate gyri. The autopsy findings were compatible with renal-hepatic-pancreatic dysplasia, a condition with unknown genetic cause at the time of autopsy but with similarities to the Meckel-Gruber/Joubert group of recessive ciliopathies. Consanguinity between the parents made it likely that the mutated gene (with known or potential function in cilia) was located within a rather large region of homozygosity in the affected individuals (identical by descent). Using genetic markers (50K single nucleotide polymorphism microarrays), we found a single large homozygous region of 21.16 Mb containing approximately 200 genes on the long arm of chromosome 3. This region contained two known ciliopathy genes: NPHP3 (adolescent nephronophthisis) and IQCB1 (NPHP5), which is associated with Senior-Löken syndrome. In NPHP3, homozygosity for a deletion of the conserved splice acceptor dinucleotide (AG) preceding exon 20 was found. Our finding confirms the recent report that NPHP3-null mutations cause renal-hepatic-pancreatic dysplasia. Also, our case illustrates that genes for rare and genetically heterogeneous recessive conditions may be identified by homozygosity mapping using single nucleotide polymorphism arrays in the routine clinical setting.

Screening the whole glioblastoma multiforme (GBM) genome for aberrations is a good starting point when looking for molecular markers that could potentially stratify patients according to prognosis and optimal treatment. We investigated 80 primary untreated GBM using both G-banding analysis and high-resolution comparative genomic hybridization (HR-CGH). Abnormal karyotypes were found in 83% of the tumors. The most common numerical chromosome aberrations were +7, -10, -13, -14, -15, +20, and -22. Structural abnormalities most commonly involved chromosomes 1 and 3, and the short arm of chromosome 9. HR-CGH verified these findings and revealed additional frequent losses at 1p34-36, 6q22-27, and 19q12-13 and gains of 3q26 and 12q13-15. Although most karyotypes and gain/loss patterns were complex, there was also a distinct subset of tumors displaying simple karyotypic changes only. There was a statistically significant association between trisomy 7 and monosomy 10, and also between +7/-10 as putative primary aberrations and secondary losses of 1p, 9p, 13q, and 22q. The low number of tumors in the rarer histological tumor subgroups precludes definite conclusions, but there did not seem to be any clear-cut cytogenetic-pathological correlations, perhaps with the exception of ring chromosomes in giant cell glioblastomas. Our findings demonstrate that although GBM is a pathogenetically very heterogeneous group of diseases, distinct genomic aberration patterns exist., ((c) 2009 Wiley-Liss, Inc.)

We present a 67-year-old non-diabetic male who presented with muscle cramps, paresis, atrophy and fasciculations in the left leg, followed by rapidly progressive muscle stiffness and superimposed spasms which subsequently also affected the right leg and the trunk. GAD65 autoantibodies were elevated in serum and CSF, compatible with systemic and intrathecal synthesis of oligoclonal and high-avidity autoantibodies, and GAD65 specific T cells were clonally expanded in the CSF. The patient did not respond to GABAergic and immunomodulatory treatment or plasma exchange, and died from respiratory failure after 18 months. Autopsy revealed unilateral axonal swelling, chromatolysis and vacuolisation of anterior horn cells of the lower spinal cord, accompanied by microglia proliferation and discrete infiltration of CD8+ cytotoxic T cells. No CD4+ T helper cells, B cells or complement deposition were detected. To our knowledge, this is the first report of stiff person syndrome with lower motor signs restricted to a lower limb, and also the first attempt to characterize the infiltrating T cells. The finding of CD8+ cytotoxic T cells in the absence of B cells in the inflamed area of the spinal cord suggests that the intrathecal synthesis of GAD65 autoantibodies takes place in areas of the CNS not strictly related to the clinically relevant lesions.

Background: Myositis-specific antibodies (MSA) are autoantibodies that are almost exclusively detected in idiopathic inflammatory myopathies (IIM). This article provides an overview of these autoantibodies and how they can be used clinically to identify subgroups of IIM., Material and Methods: The article is based on a non-systematic literature review and our own experience., Results: MSA can be detected in up to 50 % of patients with IIM. Patients with anti-synthetase antibodies have a constellation of clinical findings termed "the anti-synthetase syndrome", in which interstitial lung disease dominates the clinical picture. Anti-Mi2 antibodies is another myositis-specific antibody. Patients with anti-Mi2 antibodies often have classical dermatomyositis, while the anti-SRP antibody identifies patients with severe myopathy, poor response to treatment with corticosteroids and histological findings of muscle cell necrosis - often lacking inflammatory infiltrates. The newly detected anti-CADMp140 appears to be associated with amyopathic or hypomyopathic dermatomyositis, previously called dermatomyositis sine myositis. Anti-p155 antibodies are most often found in patients who also have cancer., Interpretation: Myositis-specific antibodies may be useful for identification of clinical subgroups of IIM and can thereby affect the choice of medical treatment.

Background and Purpose: Inclusion of oligodendroglial tumors may confound the utility of MR based glioma grading. Our aim was, first, to assess retrospectively whether a histogram-analysis method of MR perfusion images may both grade gliomas and differentiate between low-grade oligodendroglial tumors with or without loss of heterozygosity (LOH) on 1p/19q and, second, to assess retrospectively whether low-grade oligodendroglial subtypes can be identified in a population of patients with high-grade and low-grade astrocytic and oligodendroglial tumors., Materials and Methods: Fifty-two patients (23 women, 29 men; mean age, 52 years; range, 19-78 years) with histologically confirmed gliomas were imaged by using dynamic susceptibility contrast MR imaging at 1.5T. Relative cerebral blood volume (rCBV) maps were created, and 4 neuroradiologists defined the glioma volumes independently. Averaged over the 4 observers, a histogram-analysis method was used to assess the normalized histogram peak height of the glioma rCBV distributions., Results: Of the 52 patients, 22 had oligodendroglial tumors. The histogram method was able to differentiate high-grade gliomas (HGGs) from low-grade gliomas (LGGs) (Mann-Whitney U test, P < .001) and to identify low-grade oligodendroglial subtypes (P = .009). The corresponding intraclass correlation coefficients were 0.902 and 0.801, respectively. The sensitivity and specificity in terms of differentiating low-grade oligodendroglial tumors without LOH on 1p/19q from the other tumors was 100% (6/6) and 91% (42/46), respectively., Conclusion: With histology as a reference, our results suggest that histogram analysis of MR imaging-derived rCBV maps can differentiate HGGs from LGGs as well as low-grade oligodendroglial subtypes with high interobserver agreement. Also, the method was able to identify low-grade oligodendroglial tumors without LOH on 1p/19q in a population of patients with astrocytic and oligodendroglial tumors.

The advantages of predictive modeling in glioma grading from MR perfusion images have not yet been explored. The aim of the current study was to implement a predictive model based on support vector machines (SVM) for glioma grading using tumor blood volume histogram signatures derived from MR perfusion images and to assess the diagnostic accuracy of the model and the sensitivity to sample size. A total of 86 patients with histologically-confirmed gliomas were imaged using dynamic susceptibility contrast (DSC) MRI at 1.5T. Histogram signatures from 53 of the 86 patients were analyzed independently by four neuroradiologists and used as a basis for the predictive SVM model. The resulting SVM model was tested on the remaining 33 patients and analyzed by a fifth neuroradiologist. At optimal SVM parameters, the true positive rate (TPR) and true negative rate (TNR) of the SVM model on the 33 patients was 0.76 and 0.82, respectively. The interobserver agreement and the TPR increased significantly when the SVM model was based on an increasing sample size (P < 0.001). This result suggests that a predictive SVM model can aid in the diagnosis of glioma grade from MR perfusion images and that the model improves with increasing sample size., ((c) 2008 Wiley-Liss, Inc.)

Purpose: To retrospectively compare the diagnostic accuracy of an alternative method used to grade gliomas that is based on histogram analysis of normalized cerebral blood volume (CBV) values from the entire tumor volume (obtained with the histogram method) with that of the hot-spot method, with histologic analysis as the reference standard., Materials and Methods: The medical ethics committee approved this study, and all patients provided informed consent. Fifty-three patients (24 female, 29 male; mean age, 48 years; age range, 14-76 years) with histologically confirmed gliomas were examined with dynamic contrast material-enhanced 1.5-T magnetic resonance (MR) imaging. CBV maps were created and normalized to unaffected white matter (normalized CBV maps). Four neuroradiologists independently measured the distribution of whole-tumor normalized CBVs and analyzed this distribution by classifying the values into area-normalized bins. Glioma grading was performed by assessing the normalized peak height of the histogram distributions. Logistic regression analysis and interobserver agreement were used to compare the proposed method with a hot-spot method in which only the maximum normalized CBV was used., Results: For the histogram method, diagnostic accuracy was independent of the observer. Interobserver agreement was almost perfect for the histogram method (kappa = 0.923) and moderate for the hot-spot method (kappa = 0.559). For all observers, sensitivity was higher with the histogram method (90%) than with the hot-spot method (55%-76%)., Conclusion: Glioma grading based on histogram analysis of normalized CBV heterogeneity is an alternative to the established hot-spot method, as it offers increased diagnostic accuracy and interobserver agreement., ((c) RSNA, 2008.)

Background: The incidence of primary central nervous system lymphoma (PCNSL) appears to be increasing in some countries, whereas it is stable in others. Many reports the last decades have suggested that there have been improvements in the treatment of PCNSL. The objective of this study was to analyze time trends in the incidence, clinical features, histologic diagnosis, treatment, and outcome of nonacquired immunodeficiency syndrome (non-AIDS) PCNSL in Norway from 1989 to 2003., Methods: Patients were identified by a chart review of all patients who had a recorded diagnosis of PCNSL from 1989 to 2003 in The Norwegian Cancer Registry. The histologic and cytologic material from each patient was re-examined by pathologists. Time trends were analyzed according to year of diagnosis grouped into 3 5-year periods: 1989-1993, 1994-1998, and 1999-2003., Results: There were 98 patients who had confirmed, newly diagnosed non-AIDS PCNSL in Norway from 1989 to 2003. The incidence rate increased during the consecutive 5-year periods from 0.89 per million during 1989 to 1993, to 1.74 per million during 1994 to 1998, and to 1.82 per million during 1999 to 2003 (P = .013). Diagnostic delay and overall survival did not improve with time. Survival decreased from 1999 to 2003 compared with survival from 1994 to 1998, which was explained in part by reduced performance status and fewer patients receiving combined chemotherapy and radiotherapy during 1999 to 2003. In multivariate analysis, age

Intravascular lymphomatosis is a rare disease, characterized by occlusion of small arterioles and veins by malignant lymphoma cells. It often affects the central and peripheral nervous system and the skin. This case report illustrates the diagnostic challenge. Most patients develop rapidly progressive dementia combined with focal neurological symptoms. No relevant clinical, radiological or laboratory tests are available to diagnose the disease. Blood samples and bone marrow are usually normal. Diagnosis is often delayed and made post mortem. Brain biopsy could be diagnostic. The prognosis is poor, but early aggressive chemotherapy can potentially prolong the life span and in a few cases be curative. Intravascular lymphomatosis should be considered in patients with a combination of rapidly developing encephalopathy and focal neurological signs.

Combined loss of heterozygosity (LOH) on 1p and 19q is reported in 50% to 90% of oligodendroglial tumors and has emerged as a strong and favorable prognostic factor. Fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) are the most widely used techniques. The aim of this study was to evaluate the reliability of FISH to predict LOH at 1p and 19q when performed on touch preparations from 40 oligodendroglial tumors, even if the majority of the nuclei showed chromosomal imbalance. PCR was used as the gold standard. The presence of none or one target signal was reported as FISH-LOH, whereas all other losses were defined as FISH-imbalance. The sum of nuclei with FISH-LOH and imbalance was calculated in each case (FISH-sum) and cut-off values were defined as the mean FISH-sum value in controls plus 3 standard deviations; 27.7% for 1p and 33.2% for 19q. These corresponded well with the optimal cut-off values for our data, calculated using the minimum error rate classification procedure (35.6% for 1p and 33.1% for 19q). Concurrent FISH and PCR results were encountered in 95% for 1p and 87.5% for 19q. FISH-sum was the best and simplest discriminating variable for correct classification of LOH status. Under these conditions, even a dominant population of nuclei showing FISH-imbalance represented an LOH status in the tumor cells. FISH on touch preparations is a quick and reliable method for 1p/19q testing, does not require normal DNA and can be easily performed in an immunohistochemistry unit.

Objective: To examine fetal brain injury in the Göttingen minipig following intrauterine asphyxia and infection/inflammation induced at 3/4 of gestational length., Methods: We performed laparotomy after anesthesia in six pregnant sows. We randomized 29 fetuses to one of four groups: pretreatment with saline or endotoxin followed by 30 min of umbilical cord occlusion or no occlusion. After 48 h we performed a re-laparotomy and examined the fetal brains., Results: After total asphyxia, brain stem injury was present in the group pretreated with saline (P < 0.01 vs. controls) and with endotoxin (P < 0.005 vs. controls). Microglia activation was more marked in the brain stem (P < 0.05) and posterior white matter (P < 0.05) in the asphyxia group than in controls. Two of five fetuses in the asphyxia group had white matter injury, while no white matter lesions were found in the asphyxia/inflammation or endotoxin only groups., Conclusions: In this Göttingen minipig model, a species closer to humans than animals commonly used in experimental studies of perinatal brain injuries, intrauterine asphyxia following pretreatment with saline caused brain stem and white matter injury. This model can be further developed to study the impact of other intrauterine exposures on brain injury.

It has been reported that the incidence of meningioma increased in several industrialized countries in the late 1970s and early 1980s. The aim of this study was to evaluate the time trends in incidence of meningiomas in Denmark, Finland, Norway and Sweden, with emphasis on the age distribution and sex ratio. Information about cases of meningiomas in people aged 15-84 years was obtained from the cancer registries of these Nordic countries for the years 1968-1997, and estimates of person-years at risk were calculated from information provided by the national population registries. Age-specific incidence rates per 100,000 and incidence rate ratios were calculated for 3-year periods. The female:male ratios were also evaluated. The combined incidence among men increased from 1.4 to 1.9 per 100,000 during the follow-up period, the corresponding rates for women were 2.6 and 4.5. The female:male ratio increased over time for several age groups and was as high as 3.5:1 in the group aged 40-44 years in the latest follow-up period (1993-1997). In summary, our results provide some support for the idea that the introduction of computed tomography in the late 1970s has had an impact on the detection of cases in people aged 60 and over. The decrease in the rate or detection postmortem has affected the incidence time trend, but it also coincides with widespread use of new imaging technologies. The increasing trend shown for the female:male ratio in the group aged 35-59 years is consistent with the possibility that increasing use of hormones may affect the incidence of meningiomas in women., (Copyright 2005 Wiley-Liss, Inc)

Unlabelled: The objective of this retrospective study was to present long-term follow-up data for 110 consecutive children and young adults treated for a benign cerebellar astrocytoma at our institution between 1960 and 2001. Mean age at presentation was 8.9 years. The total surgical mortality was 9%, but declined from 16% in 1960-1977 to 0% in 1988-2001. At the close of the study 97/110 patients were still alive. Nine deaths were surgery related, 2 patients died of shunt-related causes and 2 patients died due to tumor recurrence. Five-, 10- and 25-year survival were 90, 89 and 85%, respectively. Multiple Cox regression analysis showed that tumor infiltration of the brain stem and the time period of surgery were the only explanatory variables significantly associated with survival. Five-year survival improved from 79% in the time period of 1960-1977 to 100% in the time period of 1988-2001. Tumor recurrence after total tumor resection was observed in 5 of 76 (7%) evaluable patients. Growth of residual tumor after subtotal tumor resection was observed in 7 of 26 (27%) evaluable patients. Recent followup MR revealed regression of residual tumor in 14 of 16 patients. Only 5 of these patients had received radiotherapy. Thus, spontaneous regression of residual tumor is a more frequent event than growth of residual tumor. The functional outcome was favorable in 82% of the patients [Karnofsky performance index (KPI) > or = 90]. Eighteen percent of the patients had moderate to severe disabilities (KPI 50-80)., Conclusions: Benign cerebellar astrocytoma is a surgical disease where the prognosis with respect to both survival and functional outcome is favorable. Spontaneous regression of residual tumor is frequently encountered, allowing for observation of residual tumors instead of performing a second resection in cases where a second resection carries a high risk of neurological sequelae., (Copyright 2002 S. Karger AG, Basel)

Background and Purpose: Accelerated radiotherapy (ART) and intracavity brachytherapy (ICBT) have been introduced in the primary treatment of glioblastoma. Our objective was to determine total treatment costs, hospitalisation time, and treatment outcome in these two experimental therapies compared to standard treatment., Materials and Methods: In the time period 1985 to 1st May 1999, a total of 174 patients with histologically confirmed glioblastoma multiforme were given postoperative radiotherapy according to three different treatment schedules at three different time intervals. A conventional regime of external radiotherapy (54Gy/30 fractions) was given to 58 patients (group I), 75 patients were treated with ART (48Gy/twice daily 30 fractions) (group II), and 41 patients were given ICBT (60Gy/ten fractions) (group III). Treatment costs including surgery, hospital stay, hospital hotel stay, and radiotherapy were calculated., Results: The total mean costs employing the three treatment alternatives were calculated to $25,618 (group I), $23,442 (group II), and $14,534 (group III). Total mean stay in hospital for the whole primary treatment was 48.8, 41.6, and 19 days for groups I, II, and III respectively. Median survival figures were 16, 14, and 13 months for groups I, II, and III, respectively., Conclusions: The total cost of postoperative radiotherapy in glioblastoma is comparable to other health care services. ART did not improve the total treatment cost or influence the need for hospitalisation compared to standard treatment. ICBT seemed to have economic benefits with less need for hospitalisation.