Floyd H. Gilles

Sequence of Central Nervous System Myelination in Human Infancy. I. An Autopsy Study of Myelination

This study establishes the sequence of myelination in a population of autopsied infants from birth through the second postnatal year. Myelination was assessed in 62 precisely defined central nervous system (CNS) sites of 162 infants with diverse diseases who were autopsied from 1972 to 1984 at Childrens Hospital, Boston. The degree of myelination was graded on an ordinal scale of 0–4 using the inferior cerebellar peduncle as an internal standard. This grading system is a modification of that used for fetal myelination in the National Collaborative Perinatal Project (NCPP). The data are summarized by 1) median degree of myelination for each age group and site; and 2) Ayer estimates for the age at which at least 10, 50, and 90% of infants reach a particular myelin degree in each site. “Marker” sites in the cerebrum are provided for the pathologist to compare myelination between an individual infant brain and the brains from our autopsy population. These data should be useful in identifying diverse peri- and postnatal conditions affecting myelination in human infancy. They also provide guidelines for the assessment of CNS myelination by sophisticated imaging techniques in living infants.

Selective expression of adhesion molecules on human brain microvascular endothelial cells

Human microvascular endothelial cells were isolated from childrens brain and examined for their morphological characteristics and upregulation of cell adhesion molecules in response to TNF alpha. Our human brain microvascular endothelial cells (HBMEC) were positive for factor VIII-Rag, carbonic anhydrase IV, Ulex Europeus Agglutinin I, took up fluorescently labeled acetylated low density lipoprotein and expressed gamma glutamyl transpeptidase, demonstrating their brain endothelial cell characteristics. Upon treatment with TNF alpha. VCAM and ICAM but little ELAM was expressed on HBMEC, while VCAM, ICAM and ELAM were clearly evident on HUVEC. This selective expression of cell adhesion molecules was also demonstrated by in situ stimulation of brain tissues. In conclusion, microvascular endothelial cells from childrens brains display selective expression of cell adhesion molecules, which differ from macrovascular endothelial cells. This may have consequences for leukocyte trafficking into the central nervous system.

Revision of the world health organization classification of brain tumors for childhood brain tumors

A classification for childhood brain tumors based upon revision of nomenclature of all brain tumors published by the World health Organization (WHO) in 1979 is proposed. Applicability of the WHO classification scheme was tested in a combined study of the clinical and pathologic features of approximately 3300 brain tumors in children. It was found to be adequate for many of the neoplasms but unsuitable for a significant proportion, including a number of complex cerebral tumors for which there was no appropriate name. Nomenclature of poorly differentiated or densely cellular neuroepithelial tumors was simplified to reflect the current state of knowledge of neuroembryology and neuro‐oncology, although the Committee members recognized that such a proposal would likely perpetuate the longstanding and continuing controversy relative to the nature and origin of these neoplasms. Cancer 56: 1869‐1886, 1985.

αv-Integrin antagonist EMD 121974 induces apoptosis in brain tumor cells growing on vitronectin and tenascin

Orthotopic brain tumor growth is inhibited in athymic mice by the daily systemic administration of the αv‐integrin antagonist EMD 121974. This compound, a cyclic RGD‐penta‐peptide, is a potent inhibitor of angiogenesis, which induces apoptosis of growing endothelial cells through inhibition of their αv‐integrin interaction with the matrix proteins vitronectin and tenascin. Here we show that EMD 121974 also induces apoptosis in the αv‐integrin‐expressing tumor cell lines U87 MG and DAOY by detaching them from vitronectin and tenascin, matrix proteins known to be essential for brain tumor growth and invasion. These matrix proteins are shown to be produced by the brain tumor cells in vitro and in vivo. Furthermore, only tumor cells expressing αv‐integrins responded to the treatment with EMD 121974, after xenotransplantation into the forebrain of nude mice, supporting the importance of tumor cell‐matrix interactions in tumor cell survival in the brain. Thus, the αv‐antagonist EMD 121974 suppresses brain tumor growth through induction of apoptosis in both brain capillary and brain tumor cells by preventing their interaction with the matrix proteins vitronectin and tenascin. The dual action of this peptide explains its potent growth suppression of orthotopically transplanted brain tumors.

Ventriculomegaly, delayed myelination, white matter hypoplasia, and periventricular leukomalacia : How are they related?

Preterm infants, including some who have sustained intracranial hemorrhage, appear to be at increased risk of lateral ventricular enlargement. Although some occurrences might be due to an impairment of cerebrospinal fluid flow or absorption, many instances of ventriculomegaly without accompanying macrocephaly reflect diffuse white matter damage resulting in diminished (i.e., hypoplastic) white matter or an inadequate density of axons. Perinatally acquired widespread white matter damage is sometimes associated with the focal white matter necrosis. We hypothesize that in some infants both ventriculomegaly and delayed myelination are consequences of disturbances to myelinogenesis that result from an impairment of cells destined to become oligodendroglia or of disturbances to rapidly growing axons. The vulnerability of developing white matter in preterm newborns might, in part, reflect the diminished availability of growth/ survival factors, or a vulnerability to toxins or physiologic perturbations. Awareness that some ventriculomegaly reflects widely distributed white matter damage should prevent overtreatment of what might appear to be hydrocephalus, but is not due to impaired cerebrospinal fluid dynamics. Increased understanding of the phenomena leading to ventriculomegaly related to paucity of white matter should lead to successful efforts to prevent white matter damage in preterm newborns.

Endotoxin leucoencephalopathy in the telencephalon of the newborn kitten

Prolonged exposure of the neonatal kitten to a lipopolysaccharide results in a telencephalic leucoencephalopathy characterized by astrogliosis and necrosis. The visceral organs of neonatal kittens and the telencephalon of mature cats are relatively resistent to the adverse effects of this lipopolysaccharide.

Perinatal telencephalic leucoencephalopathy.

The frequent, though generally unrecognized, occurrence of damage to telencephalic white matter during the perinatal period prompted the present characterization of the pathological changes as well as a consideration of associated clinical and necropsy findings. Symmetrical astrocytosis or acutely damaged glial cells found predominantly in regions undergoing myelination suggest that the latter is associated with enhanced vulnerability. Although a single aetiological factor could not be identified in the clinical and necropsy data of the infants in this study, it may well be that the changes in developing white matter are non-specific morphological responses to a variety of noxious stimuli. The available data indicate an increasing deficit in brain weight with increasing survival age and the speculation is tendered that infants may survive the neonatal period with varying degrees of permanent symmetrical deficit of telencephalic white matter.

A different approach to cysts of the posterior fossa

Posterior fossa cysts are frequently identified on MR studies. This paper takes a different approach to analyzing these cysts based on the pathology of the cyst wall and the embryology of the hindbrain, choroid plexus, and meninges. The type of cyst depends on the histologic components of the cyst wall. Frequent types of posterior fossa cysts are arachnoid, Blake’s pouch, and cysts associated with Dandy Walker malformation. All of these cysts may mimic the others in terms of position of the torcula, vermian abnormalities, and mass effect on the cerebellum and occipital bone. A clue to the nature of the cyst may be the position of the choroid plexus in the fourth ventricle; normal in arachnoid cyst, absent in Dandy Walker malformation, and displaced into the superior cyst wall in Blake’s pouch. When the cyst wall histology is not known, it is suggested to use a descriptive term such as “retrocerebellar cyst”.

The influence of central review on outcome associations in childhood malignant gliomas: results from the CCG-945 experience.

To examine the influence of the pathology review mechanism on the results of analyses of therapeutic efficacy and biological prognostic correlates for pediatric high-grade gliomas, we evaluated the effects of using single-expert review or consensus review, as alternatives to institutional classification, in determining outcome results of a large randomized trial. The study group was the randomized cohort of Childrens Cancer Group study 945, which compared efficacy of 2 chemotherapy regimens adjuvant to surgery and radiation. Trial eligibility required institutional histopathologic diagnosis of high-grade glioma. Sections of study tumors also were centrally reviewed, initially by a study review neuropathologist and subsequently by 5 neuropathologists, including the review pathologist. Reviews were independent, and reviewers were masked to clinical factors and outcomes, and consensus diagnoses of the panel were then established. Among 172 eligible patients, 42 tumors were classified as discordant on single-expert review and 51 on consensus review. Progression-free survival probabilities calculated for patients with tumors classified as high-grade gliomas by either single-expert or consensus review were inferior to those for the overall, institutionally diagnosed cohort. However, conclusions of the study regarding relative efficacy of treatment and clinical and molecular outcome correlates were unaffected by diagnosis method. Resection extent, proliferation index, and p53 expression were associated strongly with outcome, regardless of diagnosis method. However, comparisons between arms in which inclusion was determined by different review criteria for each arm caused spurious conclusions about efficacy differences between treatments. We conclude that the pathology review mechanism had little effect on within-trial comparisons of therapeutic effects or prognostic correlates in this randomized study, but strongly influenced survival distributions that were calculated for each treatment arm. These results support the implementation of expedited central review in therapeutic studies involving childhood malignant gliomas as a way to prospectively identify and exclude cases with discordant diagnoses and indicate the need for additional measures, such as molecular assessments, to increase the reproducibility of neuropathologic classification for these tumors.

Huntington's disease in children. Neuropathologic study of four cases.

The striking clinical disparity between the manifestations of Huntington’s chorea in children and those in adults is a challenge t o the physiologist and neuropathologist. The disease in children i s characterized by rigidity, dementia and seizures,’ whereas chorea and dementia are the expected hallmarks in adults.’ Neuropathologic studies of I0 cases in children are known to US.^-^ We are presently reporting the findings in four more cases in the hope that the additional information may give some clue as t o the reasons for the disparity and to suggest that further clinical studies include those of vestibular function.