Nancy S. Peress

Boron Neutron Capture Therapy for Glioblastoma Multiforme: Interim Results from the Phase I/II Dose-Escalation Studies

OBJECTIVE: The primary objective of these Phase I/II dose-escalation studies is to evaluate the safety of boronophenylalanine (BPA)-fructose-mediated boron neutron capture therapy (BNCT) for patients with glioblastoma multiforme (GBM). A secondary purpose is to assess the palliation of GBM by BNCT, if possible. METHODS: Thirty-eight patients with GBM have been treated. Subtotal or gross total resection of GBM was performed for 38 patients (median age, 56 yr) before BNCT. BPA-fructose (250 or 290 mg BPA/kg body weight) was infused intravenously, in 2 hours, approximately 3 to 5 weeks after surgery. Neutron irradiation was begun between 34 and 82 minutes after the end of the BPA infusion and lasted 38 to 65 minutes. RESULTS: Toxicity related to BPA-fructose was not observed. The maximal radiation dose to normal brain varied from 8.9 to 14.8 Gy-Eq. The volume-weighted average radiation dose to normal brain tissues ranged from 1.9 to 6.0 Gy-Eq. No BNCT-related Grade 3 or 4 toxicity was observed, although milder toxicities were seen. Twenty-five of 37 assessable patients are dead, all as a result of progressive GBM. No radiation-induced damage to normal brain tissue was observed in postmortem examinations of seven brains. The minimal tumor volume doses ranged from 18 to 55 Gy-Eq. The median time to tumor progression and the median survival time from diagnosis (from Kaplan-Meier curves) were 31.6 weeks and 13.0 months, respectively. CONCLUSION: The BNCT procedure used has been safe for all patients treated to date. Our limited clinical evaluation suggests that the palliation offered by a single session of BNCT is comparable to that provided by fractionated photon therapy. Additional studies with further escalation of radiation doses are in progress.

Biodistribution of boronophenylalanine in patients with glioblastoma multiforme: boron concentration correlates with tumor cellularity.

Boron-10 (10B) concentrations were measured in 107 surgical samples from 15 patients with glioblastoma multiforme who were infused with 95 atom% 10B-enriched p-boronophenylalanine (BPA) intravenously for 2 h just prior to surgery at doses ranging from 98 to 290 mg BPA/kg body weight. The blood 10B concentration reached a maximum at the end of the infusion (ranging from 9.3 to 26.0 microg 10B/g) and was proportional to the amount of BPA infused. The boron concentrations in excised tumor samples ranged from 2.7 to 41.3 microg 10B/g over the range of administered BPA doses and varied considerably among multiple samples from individual patients and among patients at the same BPA dose. A morphometric index of the density of viable-appearing tumor cells in histological sections obtained from samples adjacent to, and macroscopically similar to, the tumor samples used for boron analysis correlated linearly with the boron concentrations. From that correlation it is estimated that 10B concentrations in glioblastoma tumor cells were over four times greater than concurrent blood 10B concentrations. Thus, in the dose range of 98 to 290 mg BPA/kg, the accumulation of boron in tumor cells is a linear function of BPA dose and the variations observed in boron concentrations of tumor specimens obtained surgically are largely due to differences in the proportion of nontumor tissue (i.e. necrotic tissue, normal brain) present in the samples submitted for boron analysis. The tumor:blood 10B concentration ratio derived from this analysis provides a rationale for estimating the fraction of the radiation dose to viable tumor cells resulting from the boron neutron capture reaction based on measured boron concentrations in the blood at the time of BNCT without the need for analysis of tumor samples from individual patients.

Brain damage after intermittent partial cord occlusion in the chronically instrumented fetal lamb

The relationship between intermittent partial occlusion of the umbilical circulation and fetal acid base status, brain function, and neuropathologic outcome was assessed in nine control and nine experimental singleton fetal lambs to determine if transient episodes of partial cord occlusion play a role in antenatal brain damage in this species. Intermittent partial occlusion of the umbilical circulation for 1 minute of every 3 minutes for 2 hours was associated with a 89% incidence of histologically confirmed damage confined to the cerebral white matter. This occurred without systemic evidence of progressive acidosis, but both fetal heart rate patterns and electrocortical activity were altered. We conclude that in the late gestation fetal lamb, umbilical cord compromise plays a causal role in a specific type of antenatal central nervous system injury.

Identification of FcγRI, II and III on normal human brain ramified microglia and on microglia in senile plaques in Alzheimer's disease

Abstract Using monoclonal antibodies to the three known human leukocyte IgG receptors, FcγR, we examined the expression of FcγR in normal brains and in Alzheimers disease. We found FcγRI, II and III immunoreactivity in senile plaques and on ramified microglia throughout the cortex and white matter of normal and Alzheimers disease brains. FcγRI expression was independently confirmed by a murine isotype binding study. These findings suggest that intrinsic FcγR may play an important role in normal and disordered immune-related processes in the brain. The support the idea that microglia are brain macrophages.

Lewy bodies in tyrosine hydroxylase-synthesizing neurons of the human cerebral cortex

A population of neurons situated in the human cerebral neocortex contains mRNA coding for tyrosine hydroxylase, the key enzyme for catecholamine biosynthesis. Phosphorylated neurofilament-containing cytoplasmic inclusions occur in these neurons in diffuse Lewy body disease, indicating a tendency for selective involvement that is shared with subcortical catecholamine-containing neurons. These findings are relevant to the pathophysiology of several neurologic and psychiatric illnesses in which the monoamine-containing neurons of the neocortex may participate.

Glial transforming growth factor (TGF)-β isotypes in multiple sclerosis: differential glial expression of TGF-β1, 2 and 3 isotypes in multiple sclerosis

Abstract We studied glial transforming growth factor (TGF)-β isotype expression in 14 cases of multiple sclerosis. Acute active lesions exhibited selective TGF-β2 immunoreactivity of lesion encircling ramified microglia. In contrast, astrocytes within chronic active white matter lesions expressed all three isotypes. Chronic active lesions which extended into cortex exhibited selective cortical astrocyte TGF-β2 expression. This isotype was also selectively expressed by astrocytes in apparently normal white matter. A similar pattern of glial TGF-β expression was seen in the pathological control, progressive multifocal leukoencephalopathy. The results suggest that TGF-β cytokines are locally expressed in demyelination and that the β2 isotype may be uniquely regulated.

Neuropathology in the chronic fetal lamb preparation: structure-function correlates under different environmental conditions.

In this study we examined the relationship between fetal metabolism, cardiovascular function, brain function, and eventual neuropathological outcome in the last third of gestation in the chronic fetal lamb preparation under a variety of environmental conditions. We concluded that the progressive hypoxia and metabolic acidosis secondary to acute placental insufficiency result in cerebral damage and functional deficit. Growth retardation and its attendant chronic hypoxemia, secondary to chronic placental insufficiency, do not have these results. However, intermittent interference with the umbilical circulation is associated with both functional and structural evidence of cerebral damage without systemic metabolic abnormality. The experimental, physiologic, and clinical implications of these observations are discussed.

The Neuromuscular Pathology of the Eosinophilia-Myalgia Syndrome

The Eosinophilia-Myalgia Syndrome (EMS) is a recently recognized disorder in patients ingesting pharmacologic doses of L-tryptophan. We studied the lesions of skeletal muscle, peripheral nerve and skin in 12 cases of EMS. Perimyositis was severe in four, moderate in two, mild in three and absent in three cases. The lesions contained many eosinophils, T-helper cells, mast cells and activated macrophages. Type 2 myofiber atrophy was present in five cases and in one, this was the only pathologic finding. Severe epineurial inflammation was seen in the three sural nerve biopsies. Indirect evidence for peripheral neurologic involvement in three other cases consisted of inflammation surrounding intramuscular nerve twigs (two cases) and neurogenic atrophy (one case). Phlebitis accompanied the connective tissue inflammation in five cases and endarteritis in one. Fasciitis was present in three of four skin biopsies and dermal fibrosis in one.

The immunopathophysiological effects of chronic serum sickness on rat choroid plexus, ciliary process and renal glomeruli.

The immunopathological findings and their effects upon the vascular permeability of the ciliary process, choroid plexus and renal glomeruli to intravenously injected 123I-bovine serum albumin (BSA) have been studied in 26 rats who survived a prolonged period of bovine serum albuminemia following the experimental chronic serum sickness model of Fennell and Pardo (8). Rat IgG and C3 and BSA were demonstrated in the experimental rats by direct immunofluorescence in glomeruli, ciliary process and choroid plexus of 85, 38 and 39 percent of animals respectively. Age and sex matched control tissues were negative. Statistically significant differences in the 123I-BSA content of urine, eye and brain were observed between the experimental and control groups. This experimental model offers an approach to the understanding of ocular and central nervous system involvement in clinical situations characterized by circulating immune complexes as well as an experimental tool with which to explore further the physiological consequences of immune deposits within the choroid plexus and ciliary body.

The Choroid Plexus in Passive Serum Sickness

Immunofluorescent microscopy of the choroid plexus revealed the presence of rabbit IgG and either rat or mouse C3 in a high percentage of young male Wistar rats and CF1 mice who had received intravenous injections of preformed BSA-rabbit anti BSA complexes over a 3 day period. Electron dense deposits were observed in the basement membrane region of the choroid plexus in these animals. These findings were comparable to those noted in their renal glomeruli. This is the first description of involvement of the choroid plexus in passive immune complex disease. This experimental model is rapidly inducible and should be of value in future pathophysiological studies of this important structure.