Lawrence Recht

Practice parameter: Anticonvulsant prophylaxis in patients with newly diagnosed brain tumors Report of the Quality Standards Subcommittee of the American Academy of Neurology

The Quality Standards Subcommittee seeks to develop scientifically sound, clinically relevant practice parameters for the practice of neurology. Practice parameters are strategies for patient management that assist physicians in clinical decision making. A practice parameter is one or more specific recommendations based on analysis of evidence on a specific clinical problem. These might include diagnosis, symptoms, treatment, or procedure evaluation. American Academy of Neurology (AAN) members have requested the publication of a practice parameter on the use of prophylactic anticonvulsants in patients with primary and metastatic brain tumors. Physicians often administer anticonvulsant medication prophylactically to patients with brain tumors, despite the lack of definitive evidence that prophylactic anticonvulsant therapy is effective in preventing first seizures.1-4 If anticonvulsant medications were free of side effects, their prophylactic use might be attractive even without such evidence. However, discomfort, expense, and inconvenience result from drug treatment and periodic monitoring of serum drug concentrations. Typical anticonvulsant-induced side effects, including cognitive impairment, myelosuppression, liver dysfunction, and dermatologic reactions (ranging from minor rashes to life-threatening Stevens–Johnson syndrome), appear to occur more frequently in patients with brain tumors than in other patient groups,3,5-16 although direct comparison studies have not been published. A spectrum of side effects unique to patients with brain tumors must also be considered. Phenytoin, carbamazepine, and phenobarbital reduce the efficacy of corticosteroids,17-21 which are administered almost universally to brain tumor patients. In addition, the ability of these anticonvulsants to stimulate the cytochrome P450 enzyme system results in markedly accelerated metabolism of a wide spectrum of chemotherapeutic agents including nitrosoureas, paclitaxel, cyclophosphamide, topotecan, irinotecan, thiotepa, 9-aminocampothecin, adriamycin, and methotrexate.22-34 As a result, inadequate chemotherapeutic dosing of brain tumor patients has been identified recently as a widespread and critically important problem.35 Conversely, …

Central Nervous System Cancers

Primary and metastatic tumors of the central nervous system are a heterogeneous group of neoplasms with varied outcomes and management strategies. Recently, improved survival observed in 2 randomized clinical trials established combined chemotherapy and radiation as the new standard for treating patients with pure or mixed anaplastic oligodendroglioma harboring the 1p/19q codeletion. For metastatic disease, increasing evidence supports the efficacy of stereotactic radiosurgery in treating patients with multiple metastatic lesions but low overall tumor volume. These guidelines provide recommendations on the diagnosis and management of this group of diseases based on clinical evidence and panel consensus. This version includes expert advice on the management of low-grade infiltrative astrocytomas, oligodendrogliomas, anaplastic gliomas, glioblastomas, medulloblastomas, supratentorial primitive neuroectodermal tumors, and brain metastases. The full online version, available at NCCN. org, contains recommendations on additional subtypes.

Functional Network Analysis Reveals Extended Gliomagenesis Pathway Maps and Three Novel MYC-Interacting Genes in Human Gliomas

Gene expression profiling has proven useful in subclassification and outcome prognostication for human glial brain tumors. The analysis of biological significance of the hundreds or thousands of alterations in gene expression found in genomic profiling remains a major challenge. Moreover, it is increasingly evident that genes do not act as individual units but collaborate in overlapping networks, the deregulation of which is a hallmark of cancer. Thus, we have here applied refined network knowledge to the analysis of key functions and pathways associated with gliomagenesis in a set of 50 human gliomas of various histogenesis, using cDNA microarrays, inferential and descriptive statistics, and dynamic mapping of gene expression data into a functional annotation database. Highest-significance networks were assembled around the myc oncogene in gliomagenesis and around the integrin signaling pathway in the glioblastoma subtype, which is paradigmatic for its strong migratory and invasive behavior. Three novel MYC-interacting genes (UBE2C, EMP1, and FBXW7) with cancer-related functions were identified as network constituents differentially expressed in gliomas, as was CD151 as a new component of a network that mediates glioblastoma cell invasion. Complementary, unsupervised relevance network analysis showed a conserved self-organization of modules of interconnected genes with functions in cell cycle regulation in human gliomas. This approach has extended existing knowledge about the organizational pattern of gene expression in human gliomas and identified potential novel targets for future therapeutic development.

Quantitative Analysis of the Loss of Distinction Between Gray and White Matter in Comatose Patients After Cardiac Arrest

Background and Purpose Anecdotal reports suggest that a loss of distinction between gray (GM) and white matter (WM) as adjudged by CT scan predicts poor outcome in comatose patients after cardiac arrest. To address this, we quantitatively assessed GM and WM intensities at various brain levels in comatose patients after cardiac arrest. Methods Patients for whom consultation was requested within 24 hours of a cardiac arrest were identified with the use of a computerized database that tracks neurological consultations at our institution. Twenty-five comatose patients were identified for whom complete medical records and CT scans were available for review. Twenty-five consecutive patients for whom a CT scan was interpreted as normal served as controls. Hounsfield units (HUs) were measured in small defined areas obtained from axial images at the levels of the basal ganglia, centrum semiovale, and high convexity area. Results At each level tested, lower GM intensity and higher WM intensity were noted in comatose patients compared with normal controls. The GM/WM ratio was significantly lower among comatose patients compared with controls (P <0.0001, rank sum test). There was essentially no overlap in GM/WM ratios between control and study patients. The difference was greatest at the basal ganglia level. We also observed a marginally significant difference in the GM/WM ratio at the basal ganglia level between those patients who died and those who survived cardiac arrest (P =0.035, 1-tailed t test). Using receiver operating characteristic curve analysis, we determined that a difference in GM/WM ratio of <1.18 at the basal ganglia level was 100% predictive of death. At the basal ganglia level, none of 12 patients below this threshold survived, whereas the survival rate was 46% among patients in whom the ratio was >1.18. The empirical risk of death was 21.67 for comatose patients with a value below threshold. Conclusions The ratio in HUs of GM to WM provides a reproducible measure of the distinction between gray and white matter. A lower GM/WM ratio is observed in comatose patients immediately after cardiac arrest. The basal ganglia level seems to be the most sensitive location on CT for measuring this relationship. Although a GM/WM ratio <1.18 at this level predicted death in this retrospective study, the difference in this study is not robust enough to recommend that management decisions be dictated by CT results. The results, however, do warrant consideration of a prospective study to determine the reliability of CT scanning in predicting outcome for comatose patients after cardiac arrest.

High-resolution genome-wide mapping of genetic alterations in human glial brain tumors.

High-resolution genome-wide mapping of exact boundaries of chromosomal alterations should facilitate the localization and identification of genes involved in gliomagenesis and may characterize genetic subgroups of glial brain tumors. We have done such mapping using cDNA microarray-based comparative genomic hybridization technology to profile copy number alterations across 42,000 mapped human cDNA clones, in a series of 54 gliomas of varying histogenesis and tumor grade. This gene-by-gene approach permitted the precise sizing of critical amplicons and deletions and the detection of multiple new genetic aberrations. It has also revealed recurrent patterns of occurrence of distinct chromosomal aberrations as well as their interrelationships and showed that gliomas can be clustered into distinct genetic subgroups. A subset of detected alterations was shown predominantly associated with either astrocytic or oligodendrocytic tumor phenotype. Finally, five novel minimally deleted regions were identified in a subset of tumors, containing putative candidate tumor suppressor genes (TOPORS, FANCG, RAD51, TP53BP1, and BIK) that could have a role in gliomagenesis.

Motexafin gadolinium combined with prompt whole brain radiotherapy prolongs time to neurologic progression in non-small-cell lung cancer patients with brain metastases: results of a phase III trial.

PURPOSE To determine the efficacy of motexafin gadolinium (MGd) in combination with whole brain radiotherapy (WBRT) for the treatment of brain metastases from non-small-cell lung cancer. METHODS AND MATERIALS In an international, randomized, Phase III study, patients with brain metastases from non-small-cell lung cancer were randomized to WBRT with or without MGd. The primary endpoint was the interval to neurologic progression, determined by a centralized Events Review Committee who was unaware of the treatment the patients had received. RESULTS Of 554 patients, 275 were randomized to WBRT and 279 to WBRT+MGd. Treatment with MGd was well tolerated, and 92% of the intended doses were administered. The most common MGd-related Grade 3+ adverse events included liver function abnormalities (5.5%), asthenia (4.0%), and hypertension (4%). MGd improved the interval to neurologic progression compared with WBRT alone (15 vs. 10 months; p = 0.12, hazard ratio [HR] = 0.78) and the interval to neurocognitive progression (p = 0.057, HR = 0.78). The WBRT patients required more salvage brain surgery or radiosurgery than did the WBRT+MGd patients (54 vs. 25 salvage procedures, p < 0.001). A statistically significant interaction between the geographic region and MGd treatment effect (which was in the prespecified analysis plan) and between treatment delay and MGd treatment effect was found. In North American patients, where treatment was more prompt, a statistically significant prolongation of the interval to neurologic progression, from 8.8 months for WBRT to 24.2 months for WBRT+MGd (p = 0.004, HR = 0.53), and the interval to neurocognitive progression (p = 0.06, HR = 0.73) were observed. CONCLUSION In the intent-to-treat analysis, MGd exhibited a favorable trend in neurologic outcomes. MGd significantly prolonged the interval to neurologic progression in non-small-cell lung cancer patients with brain metastases receiving prompt WBRT. The toxicity was acceptable.

PTEN in Neural Precursor Cells: Regulation of Migration, Apoptosis, and Proliferation

PTEN is a lipid phosphatase, and PTEN mutations are associated with gliomas, macrocephaly, and mental deficiencies. We have used PTEN +/- mice to assess PTENs role in subventricular zone (SVZ) precursor cells. For cultured SVZ neurosphere cells, haploinsufficiency for PTEN increases phosphorylation of Akt and forkhead transcription factor and slightly enhances proliferation. Based on a filter penetration assay, PTEN +/- cells are substantially more migratory and invasive than +/+ cells. The +/- cells also are more resistant to H(2)O(2)-induced apoptosis. Analysis of PTEN +/- and +/+ mice by BrdU labeling reveals no difference in the rate of cell proliferation in the SVZ. Exit of BrdU-labeled cells from the SVZ and radial migration to the outer layers of the olfactory bulb are more rapid for +/- cells. These observations indicate that PTEN regulates SVZ precursor cell function and is particularly important for migration and apoptosis in response to oxidative stress.

Tumor Necrosis Factor-α–Induced Protein 3 As a Putative Regulator of Nuclear Factor-κB–Mediated Resistance to O6-Alkylating Agents in Human Glioblastomas

Purpose Pre-existing and acquired drug resistance are major obstacles to the successful treatment of glioblastomas. Methods We used an integrated resistance model and genomics tools to globally explore molecular factors and cellular pathways mediating resistance to O6-alkylating agents in glioblastoma cells. Results We identified a transcriptomic signature that predicts a common in vitro and in vivo resistance phenotype to these agents, a proportion of which is imprinted recurrently by gene dosage changes in the resistant glioblastoma genome. This signature was highly enriched for genes with functions in cell death, compromise, and survival. Modularity was a predominant organizational principle of the signature, with functions being carried out by groups of interacting molecules in overlapping networks. A highly significant network was built around nuclear factor-κB (NF-κB), which included the persistent alterations of various NF-κB pathway elements. Tumor necrosis factor-α–induced protein 3 (TNFAIP3) was...

Murine Embryonic Stem Cell-Derived Pyramidal Neurons Integrate into the Cerebral Cortex and Appropriately Project Axons to Subcortical Targets

Although embryonic stem (ES) cells have been induced to differentiate into diverse neuronal cell types, the production of cortical projection neurons with the correct morphology and axonal connectivity has not been demonstrated. Here, we show that in vitro patterning is critical for generating neural precursor cells (ES-NPCs) competent to form cortical pyramidal neurons. During the first week of neural induction, these ES-NPCs begin to express genes that are specific for forebrain progenitors; an additional week of differentiation produces mature neurons with many features of cortical pyramidal neurons. After transplantation into the murine cerebral cortex, these specified ES-NPCs manifest the correct dendritic and axonal connectivity for their areal location. ES-NPCs transplanted into the deep layers of the motor cortex differentiate into layer 5 pyramidal neurons and extend axons to distant subcortical targets such as the pons and as far caudal as the pyramidal decussation and descending spinal tract and, importantly, do not extend axons to inappropriate targets such as the superior colliculus (SC). ES-NPCs transplanted into the visual cortex extend axons to the dorsal aspect of the SC and pons but avoid ventral SC and the pyramidal tract, whereas cells transplanted deep into the somatosensory cortex project axons to the ventral SC, avoiding the dorsal SC. Thus, these data establish that ES-derived cortical projection neurons can integrate into anatomically relevant circuits.

EGFRvIII expression and PTEN loss synergistically induce chromosomal instability and glial tumors

Glioblastomas often show activation of epidermal growth factor receptor (EGFR) and loss of PTEN (phosphatase and tensin homolog deleted on chromosome 10) tumor suppressor, but it is not known if these two genetic lesions act together to transform cells. To answer this question, we infected PTEN-/- neural precursor cells with a retrovirus encoding EGFRvIII, which is a constitutively activated receptor. EGFRvIII PTEN-/- cells formed highly mitotic tumors with nuclear pleomorphism, necrotic areas, and glioblastoma markers. The transformed cells showed increased cell proliferation, centrosome amplification, colony formation in soft agar, self-renewal, expression of the stem cell marker CD133, and resistance to oxidative stress and ionizing radiation. The RAS/mitogen-activated protein kinase (ERK) and phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathways were activated, and checkpoint kinase 1 (Chk1), the DNA damage regulator, was phosphorylated at S280 by Akt, suppressing Chk1 phosphorylation at S345 in response to ionizing irradiation. The PTEN-/- cells showed low levels of DNA damage in the absence of irradiation, which was increased by EGFRvIII expression. Finally, secondary changes occurred during tumor growth in mice. Cells from these tumors showed decreased tumor latencies and additional chromosomal aberrations. Most of these tumor lines showed translocations of mouse chromosome 15. Intracranial injections of one of these lines led to invasive, glial fibrillary acidic protein-positive, nestin-positive tumors. These results provide a molecular basis for the occurrence of these two genetic lesions in brain tumors and point to a role in induction of genomic instability.