Joachim M. Baehring

Paraneoplastic anti-N-methyl -D -aspartate receptor encephalitis associated with ovarian teratoma

To report the autoantigens of a new category of treatment‐responsive paraneoplastic encephalitis.

Genomic Analysis of Non-NF2 Meningiomas Reveals Mutations in TRAF7, KLF4, AKT1, and SMO

Genetic Clues to Meningioma Meningiomas are the most common primary brain tumors in adults. Located within the layer of tissue covering the brain, these tumors are usually slow-growing and benign but can cause serious neurological complications. About half of these tumors have mutations in the neurofibromin 2 gene (NF2). To identify other genes that contribute to meningioma pathogenesis, Clark et al. (p. 1077, published online 24 January) performed genome sequence analysis on 300 tumors. Meningiomas fell into two general classes: benign tumors located at the skull base—which tend to harbor mutations in the TRAF7, KLF4, AKT1, and SMO genes—and higher-grade tumors located in the cerebral and cerebellar hemispheres harbor mutations in NF2. The mutational profiles of meningiomas, a common type of brain tumor, correlate with their anatomical location and clinical status. We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1E17K, a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive—nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.

Evidence for antibody-mediated pathogenesis in anti-NMDAR encephalitis associated with ovarian teratoma

We report the immunopathological analysis of the brain and tumor of two patients who died of anti-NMDAR-associated encephalitis, and of the tumor of nine patients who recovered. Findings included prominent microgliosis and deposits of IgG with rare inflammatory infiltrates in the hippocampus, forebrain, basal ganglia, and spinal cord. Detection of cells expressing markers of cytotoxicity (TIA, granzyme B, perforin and Fas/Fas ligand) was extremely uncommon. All tumors showed NMDAR-expressing neurons and inflammatory infiltrates. All patients’ NMDAR antibodies were IgG1, IgG2, or IgG3. No complement deposits were observed in any of the central nervous system regions examined. Overall, these findings coupled with recently reported in vitro data showing that antibodies downregulate the levels of NMDA receptors suggest that the antibody immune-response is more relevant than cytotoxic T-cell mechanisms in the pathogenesis of anti-NMDAR-associated encephalitis.

Associations among Magnetic Resonance Spectroscopy, Apparent Diffusion Coefficients, and Image-guided Histopathology with Special Attention to Radiation Necrosis

OBJECTIVE:In patients with malignant glioma previously treated with surgery, radiation, and chemotherapy, clinical and radiographic signs of recurrent disease often require differentiation between radiation necrosis and recurrent tumor. Published work suggests that although magnetic resonance spectroscopy (MRS) can reliably differentiate pure tumor, pure necrosis, and spectroscopically normal tissues, it may not be particularly helpful because most patients have mixed histological findings comprised of necrosis and tumor. To improve our clinical ability to discriminate among these histological entities, we have analyzed MRS in conjunction with apparent diffusion coefficient (ADC) sequences derived from magnetic resonance imaging. METHODS:In 18 patients, spectroscopic and diffusion-weighted images were obtained before surgery for suspected recurrent neoplastic disease. Spectral data for pure tumor, pure necrosis, and mixed tumor and necrosis were derived from 65 spectroscopic observations in patients with previously treated gliomas (n = 16) and metastatic tumors (n = 2). Spectral data for choline (Cho), N-acetylaspartate (NAA), creatine (Cr), and lipid-lactate were analyzed separately and in conjunction with ADCs in all patients (15 observations of pure tumor, 33 observations of pure necrosis, and 13 observations of mixed tumor and necrosis). Histological specimens were obtained stereotactically at the time of surgery (<48 h after image acquisition) for recurrent disease and digitally co-registered with MRS data. RESULTS:ADC values for pure tumor, pure necrosis, and mixed tumor and necrosis were 1.30, 1.60, and 1.42, respectively. Cho/NAA less than 0.20, NAA/normal Cr greater than 1.56, and NAA/Cho greater than 1.32 increase the odds that a tissue biopsy will be pure necrosis versus mixed tumor and necrosis. Although various values of all MRS ratios analyzed may provide positive correlations for histopathological differentiation of tissue between that of pure tumor and that of pure necrosis, the addition of ADC values to only NAA/Cho and NAA/normal Cr increases the odds of correct differentiation between pure tumor and pure necrosis. The addition of ADC values does not provide additional information beyond that of MRS in distinguishing specimens of mixed tumor and necrosis from either pure tumor or pure necrosis. CONCLUSION:It has been demonstrated that MRS ratio analysis may allow for the clinical discrimination between specimens of pure tumor and pure necrosis, and the addition of ADC data into this analysis may enhance this specific differentiation. However, although a trend toward correlation between ADC values and the various histopathological features was noted, the direct addition of ADC data does not seem to allow further discrimination, beyond that provided by MRS, among specimens of mixed tumor and necrosis and either pure tumor or pure necrosis.

Malignant peripheral nerve sheath tumor The clinical spectrum and outcome of treatment

Malignant peripheral nerve sheath tumors (MPNST) are derived from Schwann cells or pluripotent cells of the neural crest. Delay of diagnosis is common, especially in lesions affecting proximal parts of the peripheral nervous system. Presented is a series of 54 patients with MPNST seen at a single institution over a 10-year period. In this series, tumor diameter of <5 cm, gross total resection of the tumor, and younger age were favorable prognostic variables.

Primary CNS lymphoma

Non-Hodgkins lymphoma invades the brain, the vitreous body and nerves of the eye, the meninges, and the nerve roots of brain and spine, leading to the development of a primary CNS lymphoma. The mechanism of involvement of these locations by malignant B lymphocytes is unknown, but it might involve molecular targeting of lymphoma cells generated at cryptic systemic sites. The diagnosis of primary CNS lymphoma has been facilitated by advances in imaging techniques and the discovery of molecular markers. Methotrexate-based regimens, even when radiation is deferred, prolong overall survival to over 5 years, but relapses eventually occur in most cases. Better tools for earlier diagnosis and monitoring of treatment response will emerge from molecular studies of therapeutic targets.

Glioblastoma multiforme: overview of current treatment and future perspectives.

Glioblastoma multiforme is the most common primary malignant tumor of the central nervous system. Despite new insights into glioblastoma pathophysiology, the prognosis for patients diagnosed with this highly aggressive tumor remains bleak. Current treatment regimens combine surgical resection and chemoradiotherapy, providing an increase in median overall survival from 12.1 to 14.6 months. Ongoing preclinical and clinical studies evaluating the efficacy of novel therapies provide hope for increasing survival benefit. This article reviews the advancements in glioblastoma treatment in newly diagnosed and recurrent glioblastoma, including novel therapies such as antiangiogenic agents, mammalian target of rapamycin inhibitors, poly(ADP-ribose) polymerase-1 inhibitors, and immunotherapies.

Intravascular lymphoma: magnetic resonance imaging correlates of disease dynamics within the central nervous system

Background: Intravascular lymphoma (IVL) is a rare non-Hodgkin’s lymphoma with relative predilection for the central nervous system. In the absence of extraneural manifestations, the disease is not recognised until autopsy in the majority of cases underlining the need for new clinical markers. Methods: This is a retrospective series of five patients with IVL seen at a single institution over three years. An advanced magnetic resonance imaging (MRI) protocol was performed at various time points prior to diagnosis and during treatment. Results: MRI revealed multiple lesions scattered throughout the cerebral hemispheres; the brainstem, cerebellum, and spinal cord were less frequently involved. On initial presentation, hyperintense lesions were seen on diffusion weighted images suggestive of ischaemia in three of four patients in whom the images were obtained at that time point. In four patients lesions were also identifiable as hyperintense areas on fluid attenuated inversion recovery (FLAIR) sequences. Initial contrast enhancement was encountered in three cases. Diffusion weighted imaging lesions either vanished or followed the typical pattern of an ischaemic small vessel stroke with evolution of abnormal FLAIR signal followed by enhancement with gadolinium in the subacute stage and tissue loss in the chronic stage. Diffusion weighted imaging and FLAIR abnormalities proved to be partially reversible, correlating with the response to chemotherapy. Conclusion: We provide the first detailed description of the dynamic pattern of diffusion weighted MRI in IVL. These patterns in combination with systemic findings may facilitate early diagnosis and serve as a new tool to monitor treatment response.

Treatment-related myelodysplasia/AML in a patient with a history of breast cancer and an oligodendroglioma treated with temozolomide: Case study and review of the literature

The emergence of temozolomide as an effective alkylating agent with little acute toxicity or cumulative myelosuppression has led to protracted courses of chemotherapy for many patients with gliomas. Secondary, or treatment-related, myelodysplasia (t-MDS) and acute myelogenous leukemia (t-AML) are life-threatening complications of alkylating chemotherapy and have been reported in patients with primary brain tumors. We describe a case of temozolomide-related t-MDS/AML and discuss the clinical features of this condition. Administration of an alkylating agent in patient populations with long median survivals must be undertaken with an understanding of the potential for this treatment complication.

Proton magnetic resonance spectroscopic imaging can predict length of survival in patients with supratentorial gliomas.

OBJECTIVEWe compared the ability of proton magnetic resonance spectroscopic imaging (1H-MRSI) measures with that of standard clinicopathological measures to predict length of survival in patients with supratentorial gliomas. METHODSWe developed two sets of leave-one-out logistic regression models based on either 1) intratumoral 1H-MRSI features, including maximum values of a) choline and b) lactate-lipid, c) number of 1H-MRSI voxels with low N-acetyl group values, and d) number of 1H-MRSI voxels with high lactate-lipid values, all (a–d) of which were normalized to creatine in normal-appearing brain, or 2) standard clinicopathological features, including a) tumor histopathological grade, b) patient age, c) performance of surgical debulking, and d) tumor diagnosis (i.e., oligodendroglioma, astrocytoma). We assessed the accuracy of these two models in predicting patient survival for 6, 12, 24, and 48 months by performing receiver operating characteristic curve analysis. Cox proportional hazards analysis was performed to assess the extent to which patient survival could be explained by the above predictors. We then performed a series of leave-one-out linear multiple regression analyses to determine how well patient survival could be predicted in a continuous fashion. RESULTSThe results of using the models based on 1H-MRSI and clinicopathological features were equally good, accounting for 81 and 64% of the variability (r2) in patients’ actual survival durations. All features except number of 1H-MRSI voxels with lactate-lipid/creatine values of at least 1 were significant predictors of survival in the 1H-MRSI model. Two features (tumor grade and debulking) were found to be significant predictors in the clinicopathological model. Survival as a continuous variable was predicted accurately on the basis of the 1H-MRSI data (r = 0.77, P < 0.001; median prediction error, 1.7 mo). CONCLUSIONOur results suggest that appropriate analysis of 1H-MRSI data can predict survival in patients with supratentorial gliomas at least as accurately as data derived from more invasive clinicopathological features.