Christine Haberler

No tissue damage by chronic deep brain stimulation in Parkinson's disease

We report on the pathological findings in the brains of 8 Parkinsons disease patients treated with deep brain stimulation (DBS) of the thalamic ventral intermediate nucleus (6 cases) and subthalamic nucleus (2 cases). DBS was performed continuously for up to 70 months. All brains showed well‐preserved neural parenchyma and only mild gliosis around the lead track compatible with reactive changes due to surgical placement of the electrode. We conclude that chronic DBS does not cause damage to adjacent brain tissue. Ann Neurol 2000;48:372–376

Beta-catenin status in paediatric medulloblastomas: correlation of immunohistochemical expression with mutational status, genetic profiles, and clinical characteristics†

Medulloblastoma is the most frequent malignant paediatric brain tumour. The activation of the Wnt/β‐catenin pathway occurs in 10‐15% of medulloblastomas and has been recently described as a marker for favourable patient outcome. We report a series of 72 paediatric medulloblastomas evaluated for β‐catenin protein expression, CTNNB1 mutations, and comparative genomic hybridization. Gene expression profiles were also available in a subset of 40 cases. Immunostaining of β‐catenin showed extensive nuclear staining (>50% of the tumour cells) in six cases and focal nuclear staining (<10% of cells) in three cases. The other cases either exhibited a signal strictly limited to the cytoplasm (58 cases) or were negative (five cases). CTNNB1 mutations were detected in all β‐catenin extensively nucleopositive cases. The expression profiles of these cases documented strong activation of the Wnt/β‐catenin pathway. Remarkably, five out of these six tumours showed a complete loss of chromosome 6. In contrast, cases with focal nuclear β‐catenin staining, as well as tumours with negative or cytoplasmic staining, never demonstrated CTNNB1 mutation, Wnt/β‐catenin pathway activation or chromosome 6 loss. Patients with extensive nuclear staining were significantly older at diagnosis and were in continuous complete remission after a mean follow‐up of 75.7 months (range 27.5–121.2 months) from diagnosis. All three patients with focal nuclear staining of β‐catenin died within 36 months from diagnosis. Altogether, these data confirm and extend previous observations that CTNNB1‐mutated tumours represent a distinct molecular subgroup of medulloblastomas with favourable outcome, indicating that therapy de‐escalation should be considered. International consensus on the definition criteria of this distinct medulloblastoma subgroup should be achieved. Copyright

Immunohistochemical analysis of INI1 protein in malignant pediatric CNS tumors: Lack of INI1 in atypical teratoid/rhabdoid tumors and in a fraction of primitive neuroectodermal tumors without rhabdoid phenotype.

Immunohistochemical lack of nuclear INI1 protein expression has been recently described as characteristic finding in atypical teratoid/rhabdoid tumors (AT/RTs), and has been suggested as useful marker to distinguish AT/RTs from other malignant pediatric central nervous system (CNS) tumors. In this study, we examined a large series of malignant pediatric CNS tumors to determine the immunohistochemical expression of INI1 protein in different malignant pediatric tumor entities. Archival paraffin-embedded biopsy specimens of 289 malignant pediatric CNS tumors including medulloblastomas, supratentorial primitive neuroectodermal tumors, glioblastomas, anaplastic astrocytomas, anaplastic ependymomas, choroid plexus carcinomas, germ cell tumors, and AT/RTs were analyzed immunohistochemically for expression of nuclear INI1 protein. Positive INI1 staining was observed in 263 tumors. Lack of INI1 protein was detectable in 26 tumors. Seventeen of the 26 tumors showed morphologically characteristic features of AT/RTs, whereas 9 embryonal tumors did not display rhabdoid features. Tumors without rhabdoid phenotype but lack of INI1 showed an aggressive clinical course and poor response to conventional treatment regimens. In summary, immunohistochemical expression of INI1 protein is lacking in tumors displaying characteristic morphologic features of AT/RT. Furthermore, a certain number of embryonal tumors without rhabdoid features but lack of INI1 protein and aggressive biologic behavior can be detected. We conclude that INI1 protein analysis should be routinely performed in all malignant pediatric embryonal CNS tumors to detect cases with lack of INI1 protein, because patients with these tumors are likely to benefit from intensified treatment.

Incidence of atypical teratoid/rhabdoid tumors in children: a population-based study by the Austrian Brain Tumor Registry, 1996-2006.

Atypical teratoid/rhabdoid tumors are highly malignant embryonal central nervous system (CNS) tumors that were defined as an entity in 1996. As compared with other malignant CNS tumors, their biological behavior is particularly aggressive, but patients may benefit from an intensified treatment. Atypical teratoid/rhabdoid tumors display a complex histomorphology, which renders them prone to misdiagnosis. They occur predominantly in young children, with an estimated prevalence of 1% to 2% among all pediatric CNS tumors. However, population‐based data on the incidence of these tumors are not yet available.

Vascular-endothelial-growth-factor (VEGF) expression and possible response to angiogenesis inhibitor bevacizumab in metastatic alveolar soft part sarcoma

Alveolar soft part sarcoma is a rare tumour of unknown histogenesis. Although tumour growth is slow and often asymptomatic, vascular invasion and metastatic dissemination (especially to the brain and lung) take place early in the course of disease. Resection is the treatment of choice and could lead to complete remission. If complete resection is not possible, the prognosis of alveolar soft part sarcoma is poor, since conventional cytotoxic chemotherapy regimens have little effi cacy in most patients. Therefore, alternative treatment approaches are needed. We report tumour regression in a patient with disseminated alveolar soft part sarcoma during antiangiogenic treatment with the antibody against vascular endothelial growth factor (VEGF), bevacizumab. An 8-year-old boy presented with a 2-week history of headaches in July, 2003. The boy was in good general condition, but physical examination revealed minor gait ataxia, dysdiadochokinesis, bilateral pyramidal signs, papilloedema, and homonymous hemianopsia. MRI of the brain detected three solid contrast-enhancing lesions in the left cerebellum (3·2×3·7 cm), left occipital lobe (4·8×3·7×5·2 cm), and left parietal lobe (1·3×1 cm). Digital subtraction angiography showed all lesions to be highly vascularised. No notable fi ndings were seen in MRI of the spinal cord. A multislice CT of the thorax and abdomen revealed 15 intra pulmonary lesions (the largest measur ing 2·7×2·8 cm). Whole-body MRI detected a lesion (2·4×1·2 cm) in the left psoas muscle, which was regarded as the primary site. Resection of the infratentorial tumour was undertaken to prevent brain-stem compression. Histopathological examination of the tissue revealed tumour cells arranged in solid nests and separated by thin sinusoidal vessels, characteristic of alveolar soft part sarcoma (fi gure 1A). The Lancet Oncol 2006; 7: 521–23

Comparative analysis of NeuN immunoreactivity in primary brain tumours: conclusions for rational use in diagnostic histopathology

Aims : NeuN is considered to be a marker of neuronal differentiation in brain tumours. Our aim was to perform, for the first time, a systematic and comparative analysis of NeuN expression in all major brain tumour subtypes to provide guidance for the rational use of NeuN immunohistochemistry in diagnostic histopathology.

Antiangiogenic metronomic therapy for children with recurrent embryonal brain tumors

Median survival time of recurrent embryonal brain tumors is short regardless of salvage chemotherapy used. An evolving alternative approach to conventional chemotherapy is to target neovascularization by interfering with tumor angiogenesis at various levels.

Histopathologic assessment of hot-spot microvessel density and vascular patterns in glioblastoma: Poor observer agreement limits clinical utility as prognostic factors: a translational research project of the European Organization for Research and Treatment of Cancer Brain Tumor Group.

Hot‐spot microvessel density (MVD) and vascular patterns have been reported as histopathologic factors that influence prognosis in retrospective series of malignant gliomas. To investigate clinical utility, the authors systematically studied observer agreement on MVD and vascular patterns and the influence of repeatedly assessed data on patient outcomes in 2 independent glioblastoma series.

Immunohistochemical Analysis of Platelet-derived Growth Factor Receptor-α, -β, c-kit, c-abl, and Arg Proteins in Glioblastoma: Possible Implications for Patient Selection for Imatinib Mesylate Therapy

SummaryInhibition of tyrosine kinase (TK) receptors by synthetic small molecules has become a promising new therapy option in oncology. The TK inhibitor imatinib mesylate selectively targets PDGFR-α, -β, c-kit, c-abl and arg and has proven successful in the treatment of chronic myeloid leukaemia. In recurrent glioblastoma, phase II therapy trials using imatinib mesylate have been initiated. As only a fraction of patients seems to benefit from imatinib mesylate therapy and due to potential side effects and high costs of imatinib mesylate therapy, selection of the right patients is important. The goal of our study was to assess systematically immunohistochemical expression of the major TKs targeted by imatinib mesylate in glioblastoma, as expression of these factors could be used to select patients for imatinib mesylate therapy.In a cohort of 101 glioblastoma patients, anti-PDGFR-α, -β, c-kit, c-abl and arg protein immunohistochemistry was performed. Expression of these proteins was assessed semi-quantitatively and correlated with patient survival.PDGFR-α and arg expression in tumor cells was widespread in 1/101 cases, respectively. Focal PDGFR-α, -β, c-kit, c-abl and arg immunolabeling was detected in 25/101, 19/101, 4/101, 7/101 and 31/101 cases, respectively. Statistical analysis did not reveal any correlation between expression of the TKs and patient survival.We show here for the first time in a large series of glioblastomas that PDGFR-α, -β, c-kit, c-abl and arg expression is immunohistochemically detectable in a fraction of cases. The value of anti-tyrosine kinase immunolabeling as predictive factor for patient selection remains to be clarified by comparative analysis of tumor tissue of therapy-responders versus non-responders.

Malignant glioma: neuropathology and neurobiology.

ZusammenfassungMaligne Gliome können in jedem Lebensalter auftreten. Am häufigsten jedoch bei Erwachsenen, die das 40. Lebensjahr bereits überschritten haben. Männer sind häufiger betroffen als Frauen. Maligne Gliome beinhalten ein Spektrum von Tumoren mit verschiedenen Subtypen. Im Wesentlichen handelt es sich um Glioblastome, anaplastische Astrozytome / Oligoastrozytome / Oligodendrogliome, die gemeinsam durch ein diffus infiltrierendes, rasches Wachstum und durch eine fatale Prognose mit wenigen Monaten oder Jahren gekennzeichnet sind. Invasion ist eine der Hauptursache für das geringe therapeutische Ansprechen, was auch eine komplette chirurgische Resektion unmöglich macht. Die Invasion durch Tumorzellen benötigt eine Interaktion mit extrazellulärer Matrix und benachbarten Zellen des normalen Gehirns. Vaskuläre Proliferationen und Gewebsnekrosen sind charakteristische Merkmale, insbesondere des Glioblastoms. Diese Veränderungen sind wahrscheinlich die Konsequenz rasch wachsender, schlecht oxygenierten, Tumorgewebes. Häufige genetische Veränderungen wie P53, EGFFR und RB pathway scheinen auch pathogenetisch relevant. Bei Patienten mit Glioblastomen ist der Methylguaninemethyltransferase (MGMT) Promoter Methylierungs Status und bei Patienten mit anaplastischen Oligodendrogliomen der 1p19q Status relevant für das Ansprechen auf Chemotherapie. Die Rolle der Neuropathologie und Neurobiologie in der Neuroonkologie besteht erstens in der klinisch relevanten Klassifizierung von Hirntumoren auf der Basis pathobiologischer Faktoren und zweitens in der Klärung der Ätiologie und Pathogenese von Hirntumoren und drittens das Übertragen von klinisch relevanten molekularen Parametern in die klinische Praxis.SummaryMalignant gliomas may manifest at any age including congenital and childhood cases. Peak incidence is, however, in adults older than 40 years. Males are more frequently affected than females. The sole unequivocal risk factor is therapeutic ionizing irradiation. Malignant gliomas comprise a spectrum of different tumor subtypes. Within this spectrum, glioblastoma, anaplastic astrocytoma and anaplastic oligodendroglioma share as basic features preferential location in cerebral hemispheres, diffuse infiltration of brain tissue, fast tumor growth with fatal outcome within months or years. Invasion is regarded as one of the main reasons for poor therapeutic success, because it makes complete surgical removal of gliomas impossible. Invasion of glioma cells requires interaction with the extracellular matrix and with surrounding cells of the healthy brain tissue. Vascular proliferates and tissue necrosis are characteristic features of malignant gliomas, in particular glioblastoma. These features are most likely the consequence of rapidly increasing tumor mass that is inadequately oxygenized by the preexisting vasculature. In malignant glioma, distinct molecular pathways including the p53 pathway, the RB pathway and the EGFR pathway show frequent alterations that seem to be pathogenetically relevant. Methylguanine-methyltransferase (MGMT) promoter methylation status in glioblastoma and 1p19q deletion status in anaplastic oligodendroglioma are associated with response to chemotherapy. The role of neuropathology and neurobiology in neurooncology is 1. to provide a clinically meaningful classification of brain tumors on basis of pathobiological factors, 2. to clarify etiology and pathogenesis of brain tumors as rational basis for development of new diagnostic tests and therapies, and 3. to translate testing for new clinically relevant molecular parameters into clinical application.