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Biomedical subjects

E C Alvord

Publications and source records attributed to E C Alvord.

At least 19 recordsLinked to original sources
PubMed2002

Virtual brain tumours (gliomas) enhance the reality of medical imaging and highlight inadequacies of current therapy.

Gliomas are brain tumours that differ from most other cancers by their diffuse invasion of the surrounding normal tissue and their notorious recurrence following all forms of therapy. We have developed a mathematical model to quantify the spatio-temporal growth and invasion of gliomas in three dimensions throughout a virtual human brain. The model quantifies the extent of tumorous invasion of individual gliomas in three-dimensions to a degree beyond the limits of present medical imaging, including even microscopy, and makes clear why current therapies based on existing imaging techniques are inadequate and cannot be otherwise without other methods for detecting tumour cells in the brain. The model's estimate of the extent of tumourous invasion beyond that defined by standard medical imaging can be useful in more accurately planning therapy regimes as well as predicting sites of potential recurrence without waiting for reemergence on follow-up imaging.

Brain↗
PubMed2000

A quantitative model for differential motility of gliomas in grey and white matter.

We have extended a mathematical model of gliomas based on proliferation and diffusion rates to incorporate the effects of augmented cell motility in white matter as compared to grey matter. Using a detailed mapping of the white and grey matter in the brain developed for a MRI simulator, we have been able to simulate model tumours on an anatomically accurate brain domain. Our simulations show good agreement with clinically observed tumour geometries and suggest paths of submicroscopic tumour invasion not detectable on CT or MRI images. We expect this model to give insight into microscopic and submicroscopic invasion of the human brain by glioma cells. This method gives insight in microscopic and submicroscopic invasion of the human brain by glioma cells. Additionally, the model can be useful in defining expected pathways of invasion by glioma cells and thereby identify regions of the brain on which to focus treatments.

Brain Neoplasms↗
PubMed1997

Pleomorphic xanthoastrocytoma: DNA flow cytometry and outcome analysis of 12 patients.

BACKGROUND: Pleomorphic xanthoastrocytoma (PXA) is an astrocytic tumor occurring primarily in childhood and adolescence with some malignant histologic features but a relatively slow clinical course. However, some tumors progress more rapidly and can undergo malignant degeneration. The authors attempted to determine whether various histologic features or tumor cell proliferative indices might help identify lesions at risk for early progression and distinguish PXAs from malignant gliomas. METHODS: In a retrospective study of 12 patients with PXA, the tumor's histologic features and DNA flow cytometric parameters were compared with their clinical course. DNA flow cytometry values for the S- and G2-phase of the PXAs also were compared with control group samples of malignant and low grade astrocytomas. RESULTS: Of the 12 tumors at initial diagnosis, 5 were considered typical PXAs whereas 7 had some atypical features (4 with paucity of reticulin fibers, 1 with focal necrosis, and 2 with both atypical reticulin and focal necrosis). During the follow-up period (range, 3.75-11 years; mean, 6.8 years), 2 patients had recurrences; 1 atypical reticulin PXA progressed to glioblastoma after 6.5 years and the 1 tumor with focal necrosis recurred at 6 months and again at 2 years with typical histologic features. DNA flow cytometry parameters of the typical PXA group were similar to values for malignant astrocytoma and significantly higher than values for control specimens of low grade astrocytomas. There were no distinctive DNA flow cytometric features that could distinguish this last tumor from others with a more benign clinical course. CONCLUSIONS: Measurements of the S-phase and G2-phase obtained from DNA flow cytometry and atypical histologic features cannot reliably identify PXA patients at risk for early progression and overall are significantly higher than values obtained for low grade gliomas. Therefore, frequent (i.e., two to three times per year) postoperative clinical and radiologic examinations are necessary to judge the appropriateness of adjuvant therapy in patients with PXA. The paradox of slow growth but DNA flow cytometry consistent with aggressive malignant lesions may represent a cell-cycle arrest mechanism in these lesions that could be verified in subsequent studies.

Adolescent↗
PubMed1997

Fatal head injuries in ground-level falls.

We analyzed 75 cases of fatal ground-level falls that were investigated by the King County Medical Examiner over a 48-month period, with autopsies performed on 87% of the deaths: 69% of the cases were men and 61% occurred in ages > or = 70 years; only 12% were aged < 50 years, with the youngest aged 28 years. Most of the falls occurred in or about the residence, and many individuals were known to have fallen onto hard surfaces. In 77% of cases there was significant pre-existing natural disease, mostly cardiovascular disease. Liver disease was more frequently a contributing factor in those aged < 50 years. Ethanol was present in 48% of those cases tested, more frequently present in men than in women. Basal skull fractures were present in 37% of cases, and acute subdural hematomas, the most common intracranial lesion, were present in 85%. We concluded that fatal ground-level falls were much more common in elderly persons, owing to a greater predisposition to falling, as well as intrinsic age-related changes, including a greater susceptibility to acute subdural hematoma.

Accidental Falls↗
PubMed1997

Resolution of CNS lesions following treatment of experimental allergic encephalomyelitis in macaques with monoclonal antibody to the CD18 leukocyte integrin.

Experimental allergic encephalomyelitis (EAE) in macaques is an acute inflammatory and demyelinating disease of the central nervous system (CNS) which has been studied extensively as a model of the human demyelinating disease multiple sclerosis (MS). The in vivo administration of monoclonal antibodies against CD18, the common beta-chain of a leukocyte integrin, at the onset of clinical disease, significantly prolonged the survival of nine of 11 macaques (82%) and in some cases completely reversed the clinical appearance of disease. Treatment with anti-CD18 mAbs dramatically reduced the extent of inflammation in brain lesions as determined by magnetic resonance imaging (MRI). These improvements confirm that anti-CD18 mAbs are powerful anti-inflammatory agents in vivo and suggest that such mAbs may provide effective treatment of both demyelinating and inflammatory CNS diseases in man.

Animals↗
PubMed1997

Neuropathology of the limbic system.

The history and development of the fanciful terminology concerning the structures of the limbic system are discussed. The diseases involving the limbic system are divided into three groups; (1) diseases in which the limbic system is more or less selectively involved, such as limbic encephalitis, herpes simplex encephalitis, cerebral confusions by the falx and tentorium, and internal herniations through the falx and tentorium; (2) diseases in which the limbic system is predominantly involved, such as arhinencephalia, holoprosencephaly, cyst of cavum septi pellucidi, Pick's disease, Alzheimer's disease, hippocampal sclerosis, and vascular diseases of the hippocampal formation; and (3) diseases in which the limbic system is randomly involved, such as various types of neoplasms and vascular and inflammatory lesions. The relationship between destructive lesions of the hippocampus and memory also is emphasized.

Alzheimer Disease↗
PubMed1997

The interaction of growth rates and diffusion coefficients in a three-dimensional mathematical model of gliomas.

This paper is a natural three-dimensional extension of a simple two-dimensional mathematical model of glioma growth and diffusion. The model was originally constructed to simulate a case of recurrent anaplastic astrocytoma treated with chemotherapy, and then modified to allow estimation of the effects of the extent of surgical resection and of variations in growth and diffusion to cover the whole range of glioma behavior. Growth is considered to be constant and exponential (analogous to continuously compounding interest) and is expressed as a decimal fraction per day; the diffusion coefficient is expressed as cm2 per day. Model predictions suggest that diffusion, practically ignored until the present, is a more important component of glioma growth than the growth rate. Even with very early diagnosis, only those tumors with a low diffusion coefficient and a rapid growth rate benefit from a wide resection. Surgical resections generally fail, just as dropping fire-fighters into the burned out center of a forest fire fails, the action being on the periphery as the tumor cells or fires spread out from the center.

Astrocytoma↗
PubMed1997

Human mucopolysaccharidosis IIID: clinical, biochemical, morphological and immunohistochemical characteristics.

Mucopolysaccharidosis IIID (MPS IIID) is one of the rarest of the MPS-III syndromes. To date, the clinical manifestations of 10 patients have been reported, the deficient N-acetylglucosamine 6-sulfatase (G6S) enzyme has been purified, and the G6S gene has been cloned, sequenced and localized. However, morphological manifestations of this condition have not been reported and the pathogenesis of the severe neurological deficits remains an enigma. In this paper we describe and correlate the clinical, biochemical and pathological observations for 2 cases of MPS IIID. We used monoclonal antibodies against heparan sulfate (HS) and GM2-ganglioside, thin layer chromatography, mass spectrometry, and morphological techniques to demonstrate the nature and the distribution of the uncatabolized substrates. The majority of the cells in various tissues showed morphological changes expected with lysosomal storage of HS. The central nervous system (CNS) was most severely affected because of the secondary storage of GM2 and GM3 gangliosides in addition to the primary accumulation of HS. The extent as well as the distribution of the diverse storage materials varied within and among different neurons as observed in MPS-III A, B, and C syndromes. This study supports the hypothesis that the neurological dysfunction and neurodegeneration common to the Sanfilippo syndromes is, in part, due to the secondary metabolic perturbations induced by HS accumulation.

Adolescent↗
PubMed1997

Neuropathology: art and science.

So many examples of computer-designed (rather than human-designed) displays occurred at a recent meeting of the American Association of Neuropathologists that we were stimulated to develop simple guides to help improve presentation. Various color combinations provide examples of the best (and worst) contrast between the message and the medium (background).

Art↗
PubMed1996

A mathematical model of glioma growth: the effect of extent of surgical resection.

We have developed a mathematical model based on proliferation and infiltration of neoplastic cells that allows predictions to be made concerning the life expectancies following various extents of surgical resection of gliomas of all grades of malignancy. The key model parameters are the growth rate and the diffusion rate. These rates were initially derived from analysis of a case of recurrent anaplastic astrocytoma treated by chemotherapies. Numerical simulations allow us to estimate what would have happened to that patient if various extents of surgical resection, rather than chemotherapies, had been used. In each case, the shell of the infiltrating tumour that remains after 'gross total removal' or even a maximal excision continues to grow and regenerates the tumour mass remarkably rapidly. By developing a model that allows the growth and diffusion rates to define the distribution of cells at the time of diagnosis, and then varying these rates by about 50%, we created a hypothetical tumour patient population whose survival times show good agreement with the results recently reported by Kreth for treatments of glioblastomas. Tenfold decreases in the rates of growth and diffusion mimic the results reported by many other investigators with more slowly growing gliomas. Thus, the model quantitatively supports the ideas that (i) gliomas infiltrate so diffusely that they cannot be cured by resection alone, surgical or radiological, no matter how extensive that may be; (ii) the more extensive the resection, regardless of the degree of malignancy of the glioma, the greater the life expectancy; and (iii) measurements of the two rates, growth and diffusion, may be able to predict survival rates better than the current histological estimates of the type and grade of gliomas.

Cell Division↗
PubMed1996

Global cerebral dysplasia due to dysplasia and hyperplasia of periventricular germinal cells.

Complete obliteration of the cerebral ventricular cavities has not been previously described as an entity among central nervous system malformations. Markedly disorganized maldevelopment of the deep cerebral nuclei and moderately disorganized maldevelopment of the cerebral cortex were observed in the brains of two cases, a 3-year-old female and a male newborn infant. One showed complete and the other partial obliteration of the lateral and third ventricles. Both showed severe maldevelopment of the basal ganglia, which were represented by a large central mass consisting of randomly distributed multiple nodules of gray matter without any discernible differentiation into lenticulostriate nuclei, thalamus, or hypothalamus. Minor malformations involved the cerebral cortex, cerebellum, and mesencephalon to varying degrees. Each of the above two cases was thought to be unique and different until the brain of a fetus of 155 days' gestation was studied. This fetal brain showed exuberant and disorganized periventricular proliferation and migration of germinal matrix cells, with obliteration of the lateral and third ventricles. It was concluded that hyperplasia and disorganized migration of the periventricular germinal matrix early in gestation of whatever cause itself can result in severe maldevelopment of the deep cerebral nuclei and obliteration of the ventricular cavities.

Brain↗
PubMed1995

Experimental allergic encephalomyelitis in non-human primates: MRI and MRS may predict the type of brain damage.

Volume-localized proton spectroscopy and T2-weighted MRI were performed on 23 monkeys with experimental allergic encephalomyelitis (EAE). The purpose of this study was to determine the relationships between temporal changes in lesion activity (measured on T2-weighted MRI), MRS [N-acetyl aspartate (NAA), creatine (CR), choline (CHO)], and the histologic definition of disease determined post-mortem. Animals were scanned in the same areas of the brain once a week before and after sensitization to myelin basic protein (BP). Histologic lesion types were predicted by a combination of preceding MRI and MRS measurements. Acutely fatal EAE lesions were large and monophasic as visualized by MRI, and increased CHO (p < 0.02, n = 16) and CHO/CR ratio (p < 0.001, n = 16) were detected by MRS at disease onset. Chronic EAE lesions were preceded by multiple inflammatory attacks as visualized by MRI and consistently low levels of NAA (p < 0.02, n = 13) and NAA/CR (p < 0.01, n = 13) which occurred after the initial attack. MRI negative brain regions (from animals that were sensitized to BP) were associated with low CHO/CR (p < 0.1, n = 5). The temporal correlation of MRI lesion activity and absolute MRS proton metabolites shows promise for predicting the subsequent duration and histologic type of lesions in EAE in non-human primates.

Animals↗
PubMed1995

A mathematical model of glioma growth: the effect of chemotherapy on spatio-temporal growth.

During the past two decades computerized tomography (CT) and magnetic resonance imaging (MRI) have permitted the detection of tumours at much earlier stages in their development than was previously possible. In spite of this earlier diagnosis the effects of earlier and more extensive treatments have been difficult to document. This failure has led to an increasing awareness of the importance of infiltration of glioma cells into surrounding grossly normal brain tissue such that recurrence still occurs. In this paper a simple mathematical model for the proliferation and infiltration of such tumours is introduced, based in part on quantitative image analysis of histological sections of a human brain glioma and especially on cross-sectional area/volume measurements of serial CT images while the patient was undergoing chemotherapy. The model parameters were estimated using optimization techniques to give the best fit of the simulated tumour area to the CT scan data. Numerical solution of the model on a two-dimensional domain, which took into account the geometry of the brain and its natural barriers to diffusion, was used to determine the effect of chemotherapy on the spatio-temporal growth of the tumour.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Experimental allergic encephalomyelitis in non-human primates: diffusion imaging of acute and chronic brain lesions.

Diffusion imaging and T2-weighted magnetic resonance imaging were performed on 16 monkeys with experimental allergic encephalomyelitis (EAE), a model of the human demyelinating disease MS. The purpose of this study was to determine whether local changes in diffusion image intensity could be correlated with the formation of acute and chronic demyelinating lesions. Diffusion image analysis was restricted to the internal capsule of the brain because of its anatomic orientation of fiber pathways. Acute inflammatory EAE lesions were large and monophasic, as visualized by T2-weighted MRI, and were accompanied by a decrease in the diffusion MR image signal with the diffusion-sensitizing gradient in all three orthogonal directions (n = 27 brain regions, P < 0.005). Chronic demyelinating lesions were preceded by multiple inflammatory attacks, as visualized by MRI, and by a decrease in diffusion MR image signal with the diffusion-sensitizing gradient in the two orthogonal directions perpendicular to the fibers of the internal capsule (n = 18 brain regions, P < 0.005). However, for the chronic group, there was no significant change in the diffusion MR image signal with diffusion-sensitizing gradient parallel to the fibers of the internal capsule at the terminal scan, suggesting little change in the water diffusion within the nerve fibers. These results suggest that diffusion imaging holds promise for measuring subtle changes in water diffusion due to different types of brain damage.

Acute Disease↗