Mitchell S. Berger

Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors

BACKGROUND The prediction of clinical behavior, response to therapy, and outcome of infiltrative glioma is challenging. On the basis of previous studies of tumor biology, we defined five glioma molecular groups with the use of three alterations: mutations in the TERT promoter, mutations in IDH, and codeletion of chromosome arms 1p and 19q (1p/19q codeletion). We tested the hypothesis that within groups based on these features, tumors would have similar clinical variables, acquired somatic alterations, and germline variants. METHODS We scored tumors as negative or positive for each of these markers in 1087 gliomas and compared acquired alterations and patient characteristics among the five primary molecular groups. Using 11,590 controls, we assessed associations between these groups and known glioma germline variants. RESULTS Among 615 grade II or III gliomas, 29% had all three alterations (i.e., were triple-positive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple-negative, and 10% had only TERT mutations; 5% had other combinations. Among 472 grade IV gliomas, less than 1% were triple-positive, 2% had TERT and IDH mutations, 7% had only IDH mutations, 17% were triple-negative, and 74% had only TERT mutations. The mean age at diagnosis was lowest (37 years) among patients who had gliomas with only IDH mutations and was highest (59 years) among patients who had gliomas with only TERT mutations. The molecular groups were independently associated with overall survival among patients with grade II or III gliomas but not among patients with grade IV gliomas. The molecular groups were associated with specific germline variants. CONCLUSIONS Gliomas were classified into five principal groups on the basis of three tumor markers. The groups had different ages at onset, overall survival, and associations with germline variants, which implies that they are characterized by distinct mechanisms of pathogenesis. (Funded by the National Institutes of Health and others.).

Cellular composition and cytoarchitecture of the adult human subventricular zone: A niche of neural stem cells

The lateral wall of the lateral ventricle in the human brain contains neural stem cells throughout adult life. We conducted a cytoarchitectural and ultrastructural study in complete postmortem brains (n = 7) and in postmortem (n = 42) and intraoperative tissue (n = 43) samples of the lateral walls of the human lateral ventricles. With varying thickness and cell densities, four layers were observed throughout the lateral ventricular wall: a monolayer of ependymal cells (Layer I), a hypocellular gap (Layer II), a ribbon of cells (Layer III) composed of astrocytes, and a transitional zone (Layer IV) into the brain parenchyma. Unlike rodents and nonhuman primates, adult human glial fibrillary acidic protein (GFAP)+ subventricular zone (SVZ) astrocytes are separated from the ependyma by the hypocellular gap. Some astrocytes as well as a few GFAP‐cells in Layer II in the SVZ of the anterior horn and the body of the lateral ventricle appear to proliferate based on proliferating cell nuclear antigen (PCNA) and Ki67 staining. However, compared to rodents, the adult human SVZ appears to be devoid of chain migration or large numbers of newly formed young neurons. It was only in the anterior SVZ that we found examples of elongated Tuj1+ cells with migratory morphology. We provide ultrastructural criteria to identify the different cells types in the human SVZ including three distinct types of astrocytes and a group of displaced ependymal cells between Layers II and III. Ultrastructural analysis of this layer revealed a remarkable network of astrocytic and ependymal processes. This work provides a basic description of the organization of the adult human SVZ. J. Comp. Neurol. 494:415–434, 2006.

Variants near TERT and TERC influencing telomere length are associated with high-grade glioma risk

Glioma, the most common central nervous system cancer in adults, has poor prognosis. Here we identify a new SNP associated with glioma risk, rs1920116 (near TERC), that reached genome-wide significance (Pcombined = 8.3 × 10−9) in a meta-analysis of genome-wide association studies (GWAS) of high-grade glioma and replication data (1,644 cases and 7,736 controls). This region has previously been associated with mean leukocyte telomere length (LTL). We therefore examined the relationship between LTL and both this new risk locus and other previously established risk loci for glioma using data from a recent GWAS of LTL (n = 37,684 individuals). Alleles associated with glioma risk near TERC and TERT were strongly associated with longer LTL (P = 5.5 × 10−20 and 4.4 × 10−19, respectively). In contrast, risk-associated alleles near RTEL1 were inconsistently associated with LTL, suggesting the presence of distinct causal alleles. No other risk loci for glioma were associated with LTL. The identification of risk alleles for glioma near TERC and TERT that also associate with telomere length implicates telomerase in gliomagenesis.

Preradiation Chemotherapy in Primary High-Risk Brainstem Tumors: Phase II Study CCG-9941 of the Children’s Cancer Group

PURPOSE This Childrens Cancer Group group-wide phase II trial evaluated the efficacy and toxicity of two chemotherapy arms administered before hyperfractionated external-beam radiotherapy (HFEBRT). PATIENTS AND METHODS Thirty-two patients with newly diagnosed brainstem gliomas were randomly assigned to regimen A and 31 to regimen B. Regimen A comprised three courses of carboplatin, etoposide, and vincristine; regimen B comprised cisplatin, etoposide, cyclophosphamide, and vincristine. Both arms included granulocyte colony-stimulating factor. Patients were evaluated by magnetic resonance imaging after induction chemotherapy and HFEBRT at a dose of 72 Gy. RESULTS Ten percent +/- 5% of regimen A patients objectively responded to chemotherapy. For combined induction and radiotherapy, 27% +/- 9% of patients improved. The neuroradiographic response rate for regimen B was 19% +/- 8% for chemotherapy and 23% +/- 9% after HFEBRT. Response rates were not statistically significant between regimens after induction or chemotherapy/HFEBRT. Event-free survival was 17% +/- 5% (estimate +/- SE) at 1 year and 6% +/- 3% at 2 years. Survival was significantly longer among patients who responded to chemotherapy (P <.05). Among patients who received regimen A induction, grades 3 and 4 leukopenia were observed in 50% to 65%, with one toxicity-related death. For regimen B, severe leukopenia occurred in 86% to 100%, with febrile neutropenia in 48% to 60% per course. CONCLUSION Neither chemotherapy regimen meaningfully improved response rate, event-free survival, or overall survival relative to previous series of patients with brainstem gliomas who received radiotherapy with or without chemotherapy.

Three-dimensional magnetic resonance spectroscopic imaging of histologically confirmed brain tumors

The goal of this study was to determine whether presurgical metabolite levels measured by 3D MR Spectroscopic Imaging (MRSI) can accurately detect viable cancer within human brain tumor masses. A total of 31 patients (33 exams, 39 pathology correlations) with brain tumors were studied prior to surgical biopsy and/or resection. The 3D MRSI was obtained with a spatial resolution of 0.2 to 1 cc throughout the majority of the mass and adjacent brain tissue using PRESS-CSI localization. Levels of choline, creatine and NAA were estimated from the locations of the resected tissue and normalized to normal appearing brain tissue. The data were correlated with subsequent histologic analysis of the biopsy tissue samples. Although there were large variations in the metabolite ratios, all regions of confirmed cancer demonstrated significant choline levels and a mean choline/NAA ratio of 5.84 + 2.58 with the lowest value being 1.3. This lowest value is greater than 4 standard deviations above the mean (0.52 +/- 0.13) found in 8 normal volunteers. The choline signal intensities in confirmed cancers were significantly elevated compared to normal appearing brain tissue with a mean ratio of 1.71 +/- 0.69. Spectra with no significant metabolite levels were observed in the non-enhancing necrotic core of the tumor masses. The results of this study indicate that 3D MRSI of brain tumors can detect abnormal metabolite levels in regions of viable cancer and grades and can differentiate cancer from necrosis and/or normal brain tissue.

Evolution of DNA repair defects during malignant progression of low-grade gliomas after temozolomide treatment

Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT–mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment-naïve LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ-treated hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated MGMT may undergo positive selection during TMZ treatment in the context of MMR deficiency.

Primary central nervous system tumors: advances in knowledge and treatment.

The ability to diagnose, monitor, and treat CNS tumors has been improved by new imaging techniques such as positron emission tomography (PET) scanning and functional MR imaging, stereotactic surgery, delivery of radiotherapy with brachytherapy and radiosurgery, and novel methods for delivering chemotherapy. These innovations combined with the new information about tumor pathogenesis and behavior revealed by molecular research give hope that more specific treatments for malignant CNS tumors will be developed in the future.

Neuroepithelial Cysts of the Posterior Fossa: Pathogenesis and Report of Two Cases

We present two cases of simple neuroepithelial cyst--one at the cerebellopontine angle and the other in the pontine brain stem--in which a basement membrane was detected. The pathogenesis of these cysts, their diagnosis using computed tomography-metrizamide cisternography and nuclear magnetic resonance imaging, and their surgical treatment by fenestration and drainage are discussed.

Phase II study of pre-irradiation chemotherapy for childhood intracranial ependymoma. Children's Cancer Group protocol 9942: A report from the Children's Oncology Group†

Standard therapy for childhood intracranial ependymoma is maximal tumor resection followed by involved‐field irradiation. Although not used routinely, chemotherapy has produced objective responses in ependymoma, both at recurrence and in infants. Because the presence of residual tumor following surgery is consistently associated with inferior outcome, the potential impact of pre‐irradiation chemotherapy was investigated.

Correction of congenital hydrocephalus in utero I. The model: Intracisternal kaolin produces hydrocephalus in fetal lambs and rhesus monkeys*

In the fetus with congenital hydrocephalus, obstruction to the flow of cerebrospinal fluid (CSF) results in ventricular dilation and neurologic impairment. Decompression of the obstructed ventricles before birth may ameliorate the damage and allow normal development to proceed. Although appealing, this pathophysiologic rationale has not been adequately tested because a satisfactory fetal model has not been available. We have developed a model of obstructive hydrocephalus in the fetal lamb and rhesus monkey by injecting kaolin into the cisterna magna through the posterior atlanto-occipital membrane early in the last trimester. Preliminary studies injecting silicone oil were unsuccessful. The development of fetal ventriculomegaly was followed using prenatal ultrasonography. Massive hydrocephalus developed in six sheep, three liveborn at term and three stillborn after premature vaginal delivery, and in 2 fetal rhesus monkeys. All treated animals had external signs of hydrocephalus with marked cranial enlargement. Neuropathologic examinations demonstrated fibrosis of the leptomeninges and subarachnoid spaces around the fourth ventricle. Dilation of the lateral and third ventricles resulted, with attenuation of the cerebral white matter. On histologic examination, the grey matter was relatively well preserved, while the white matter was severely attenuated. This model mimics the clinical and pathologic picture seen in human infants and should allow us to study the pathophysiology of congenital obstructive hydrocephalus and the efficacy and feasibility of its correction in utero.