Faculty Bibliography

Classifying adult gliomas remains largely a histologic diagnosis based on morphology; however astrocytic, oligodendroglial and mixed lineage tumors can display overlapping histologic features. We used multiplexed exome sequencing (OncoPanel) on 108 primary or recurrent adult gliomas, comprising 65 oligodendrogliomas, 28 astrocytomas and 15 mixed oligoastrocytomas to identify lesions that could enhance lineage classification. Mutations in TP53 (20/28, 71%) and ATRX (15/28, 54%) were enriched in astrocytic tumors compared to oligodendroglial tumors of which 4/65 (6%) had mutations in TP53 and 2/65 (3%) had ATRX mutations. We found that oligoastrocytomas harbored mutations in TP53 (80%, 12/15) and ATRX (60%, 9/15) at frequencies similar to pure astrocytic tumors, suggesting that oligoastrocytomas and astrocytomas may represent a single genetic or biological entity. p53 protein expression correlated with mutation status and showed significant increases in astrocytomas and oligoastrocytomas compared to oligodendrogliomas, a finding that also may facilitate accurate classification. Furthermore our OncoPanel analysis revealed that 15% of IDH1/2 mutant gliomas would not be detected by traditional IDH1 (p.R132H) antibody testing, supporting the use of genomic technologies in providing clinically relevant data. In all, our results demonstrate that multiplexed exome sequencing can support evaluation and classification of adult low-grade gliomas with a single clinical test.

High angular resolution diffusion imaging (HARDI) demonstrates transient radial coherence of telencephalic white matter in the human fetus. Our objective was to define the neuroanatomic basis of this radial coherence through correlative HARDI- and postmortem tissue analyses. Applying immunomarkers to radial glial fibers (RGFs), axons, and blood vessels in 18 cases (19 gestational weeks to 3 postnatal years), we compared their developmental profiles to HARDI tractography in brains of comparable ages (n = 11). At midgestation, radial coherence corresponded with the presence of RGFs. At 30-31 weeks, the transition from HARDI-defined radial coherence to corticocortical coherence began simultaneously with the transformation of RGFs to astrocytes. By term, both radial coherence and RGFs had disappeared. White matter axons were radial, tangential, and oblique over the second half of gestation, whereas penetrating blood vessels were consistently radial. Thus, radial coherence in the fetal white matter likely reflects a composite of RGFs, penetrating blood vessels, and radial axons of which its transient expression most closely matches that of RGFs. This study provides baseline information for interpreting radial coherence in tractography studies of the preterm brain in the assessment of the encephalopathy of prematurity.

Glioblastoma is the most common and most fatal primary malignant brain tumor in adults. Despite progress in characterizing the genetic and molecular mechanisms of glioblastomas, advances in treatment that translate into substantial improvement in prognosis have yet to be realized. A role for cytomegalovirus in glioblastoma pathogenesis was proposed more than a decade ago and has generated considerable debate as a possible therapeutic target. Independent groups have had variable success in detecting cytomegalovirus infection in tumor cells; the overall consensus is that very low levels of viral proteins and nucleic acids can be observed. Although cytomegalovirus has not been found to be oncogenic in this context, a possible oncomodulatory role has been suggested. A recent clinical trial evaluating valganciclovir as an adjuvant therapy for the treatment of glioblastoma did not demonstrate a beneficial effect on tumor growth or overall survival, although retrospective analysis subsequently indicted a significant survival benefit. In light of the publicity of that report, patients and neuro-oncologists are requesting cytomegalovirus testing to justify antiviral treatment. Based on questions on the significance of cytomegalovirus infection in glioblastomas and the lack of a clear clinical benefit of valganciclovir, we reviewed this topic and conclude that, at this time, there is insufficient evidence to recommend routine testing and treatment.

BACKGROUND: The Safe Passage Study is a large, prospective, multidisciplinary study designed to (1) investigate the association between prenatal alcohol exposure, sudden infant death syndrome (SIDS), and stillbirth, and (2) determine the biological basis of the spectrum of phenotypic outcomes from exposure, as modified by environmental and genetic factors that increase the risk of stillbirth, SIDS, and in surviving children, fetal alcohol spectrum disorders. METHODS: The results provided are based on an interim assessment of 6004 women enrolled, out of the 12,000 projected, from the Northern Plains, US, and Cape Town, South Africa, areas known to be of high risk for maternal drinking during pregnancy. Research objectives, study design, and descriptive statistics, including consent, recruitment, and retention information, are provided. RESULTS: Overall visit compliance is 87%, and includes prenatal, delivery/newborn, and postnatal contacts through 1 year post-delivery. Pregnancy outcome ascertainment is 98% prior to medical chart review; less than 2% of women withdraw. Consent for the use of DNA and placental tissue exceed 94%, and consent to participate in the autopsy portion of the study is 71%. CONCLUSIONS: The Safe Passage Study is the first multi-site study of SIDS and stillbirth to integrate prospectively collected exposure information with multidisciplinary biological information in the same maternal and fetal/infant dyad using a common protocol. Essential components of the study design and its success are close ties to the community and rigorous systems and processes to ensure compliance with the study protocol and procedures.

Imaging three-dimensional cerebellar connectivity using diffusion tractography is challenging because of the ubiquitous features of crossing axonal pathways within a folium as well as intersecting pathways from neighboring folia. We applied high-angular resolution diffusion imaging (HARDI) tractography to intact postmortem adult brainstem and cerebellum to examine the 3-dimensional white matter and local gray matter pathways. The middle cerebellar peduncles conveyed fibers from the rostral pons to the lateral and caudal aspects of the cerebellar hemisphere, and from the caudal pons to medial and rostral parts of the cerebellar hemisphere. In the cerebellar cortex, tractography detected tangential coherence superficially in the cerebellar cortex and revealed fibers coursing parallel to the long axis of the folia. These fibers were consistent with the location and direction of parallel fibers in the molecular layer. Crossing with these parallel fibers were tangential fibers running perpendicular to the long axis of the folia, consistent with axons of the cortical interneurons - stellate cells and basket cells. These tangential fibers within the cerebellar cortex were distinct from the fibers linking the cerebellar cortex with the deep cerebellar nuclei and the brainstem. Our results show the potential for HARDI tractography to resolve axonal pathways from different neuronal elements within the cerebellar cortex, and improve our understanding of adult cerebellar neural circuitry and connectivity in both white and gray matter.