Biomedical subjects

J A Coderre

Publications and source records attributed to J A Coderre.

At least 37 records · Page 2Linked to original sources

PubMed2000

Improved survival after boron neutron capture therapy of brain tumors by Cereport-mediated blood-brain barrier modulation to enhance delivery of boronophenylalanine.

OBJECTIVE: Cereport (Alkermes, Inc., Cambridge, MA), or, as it has been previously called, RMP-7 (receptor-mediated permeabilizer-7), is a bradykinin analog that has been shown to produce a transient, pharmacologically mediated opening of the blood-brain barrier. The purpose of the present study was to determine whether the efficacy of boron neutron capture therapy (BNCT) could be enhanced by means of intracarotid (i.c.) infusion of Cereport, in combination with intravenous (i.v.) injection or i.c. infusion of boronophenylalanine (BPA) in the F98 rat glioma model. METHODS: For biodistribution studies, Fischer rats bearing intracerebral implants of the F98 glioma received i.v. or i.c. injections of 300 or 500 mg/kg body weight (b.w.) of BPA with or without i.c. infusion of 1.5 microg/kg b.w. of Cereport. For therapy studies, BNCT was initiated 14 days after intracerebral implantation of 10(3) F98 cells. The i.v. or i.c. injection of BPA (500 mg/kg b.w.) was given with or without Cereport, and the animals were irradiated 2.5 hours later at the Brookhaven Medical Research Reactor with a collimated beam of thermal neutrons delivered to the head. RESULTS: At a BPA dose of 500 mg/kg b.w., tumor boron concentrations (mean +/- standard deviation) were 55.7 +/- 9.6 microg/g with Cereport versus 33.6 +/- 3.9 microg/g without Cereport at 2.5 hours after i.c. infusion of BPA, and concentrations were 29.4 +/- 9.9 microg/g with Cereport versus 15.4 +/- 3.5 microg/g without Cereport (P < 0.05) after i.v. injection of BPA. After i.c. administration of BPA and Cereport, the tumor-to-blood ratio was 5.4 +/- 0.6, and the tumor-to-brain ratio was 5.2 +/- 2.4. After BNCT with BPA at a dose of 500 mg/kg, the survival time was 50 +/- 16 days for i.c. administration of BPA with Cereport versus 40 +/- 6 days without Cereport (P = 0.05), 38 +/- 4 days for i.v. administration of BPA with Cereport versus 34 +/- 3 days without Cereport (P = 0.02), 28 +/- 5 days for irradiated controls, and 23 +/- 3 days for untreated controls. Compared with untreated controls, there was a 117% increase in lifespan in rats that received an i.c. infusion of Cereport and then BPA, and an 86% increase in lifespan in rats that received i.c. administration of BPA without Cereport. CONCLUSION: These studies have established that i.c. administration of Cereport can not only increase tumor uptake of BPA, but also enhance the efficacy of BNCT.

Animals↗

PubMed2000

A conducting plastic simulating brain tissue.

A new conducting plastic has been composed which accurately simulates the photon and neutron absorption properties of brain tissue. This tissue-equivalent (TE) plastic was formulated to match the hydrogen and nitrogen constituents recommended by ICRU Report #44 for brain tissue. Its development was initiated by the inability of muscle tissue-equivalent plastic to closely approximate brain tissue with respect to low-energy neutron interactions. This new plastic is particularly useful as an electrode in TE dosimetry devices for boron neutron capture therapy (BNCT), which utilizes low-energy neutrons for radiotherapy of the brain. Absorbed dose measurements in a clinical BNCT beam using a proportional counter constructed from this TE plastic show good agreement with Monte Carlo calculations.

Boron Neutron Capture Therapy↗

PubMed2000

Boron neutron capture therapy of the rat 9L gliosarcoma: evaluation of the effects of shark cartilage.

A number of anti-angiogenic substances are now under evaluation, both experimentally and clinically, as potential agents for the treatment of cancer. It has recently been demonstrated that anti-angiogenic agents can increase the therapeutic potential of photon irradiation in a range of tumour models. In the present communication a preliminary assessment is made of the effects of shark cartilage on the response of the rat 9L gliosarcoma to boron neutron capture therapy (BNCT). Shark cartilage was administered orally as an aqueous suspension at a daily dose of approximately 2000 mg kg-1 body weight. The mean survival time of rats receiving no treatment was 20.7 +/- 0.5 days post intracranial tumour implantation. Administration of shark cartilage alone extended the survival time. Two of the rats treated with shark cartilage were healthy and fully active at the end of the evaluation period (43 days post implantation). At autopsy the brain tumours of these animals were a factor of approximately 4 smaller than controls. In a repeat study with shark cartilage alone the survival time was extended by approximately 30%. After boronophenylalanine-mediated BNCT, with or without shark cartilage, the survival time of rats that eventually became moribund was increased by a factor of approximately 2 relative to controls. In both treatment groups approximately 20% of rats were healthy at 1 year after BNCT. There was no evidence of residual tumour at post-mortem. It was concluded that shark cartilage, when given alone, significantly increased the survival time of tumour-bearing rats, presumably owing to an anti-angiogenic effect. However, the survival data suggested that boronophenylalanine-mediated BNCT did not appear to be enhanced by the administration of shark cartilage.

Angiogenesis Inhibitors↗

PubMed2000

Mechanisms of transport of p-borono-phenylalanine through the cell membrane in vitro.

The mechanisms of transport of p-(dihydroxyboryl)-phenylalanine (BPA) through the cell membrane were investigated in vitro, evaluating especially the systems responsible for the transport of neutral amino acids as potential carriers for BPA. Rat 9L gliosarcoma cells and Chinese hamster V79 cells were exposed to BPA under controlled conditions and in a defined medium that was free of amino acids. The time course of (10)B (delivered by BPA) uptake and efflux was measured under different conditions. To analyze the intracellular boron content, direct-current plasma atomic emission spectroscopy (DCP-AES) was used after separating the cells from extracellular boron in the cell medium using an oil filtration technique. The dependence of factors such as cell type, temperature, composition and concentration of amino acids and specific substrates for amino acid transport systems in the culture medium or in intracellular compartments on BPA uptake and efflux were studied. The results of this study support the hypothesis that BPA is transported by the L system and that transport can be further stimulated by amino acids preaccumulated in the cell by either the L or A amino acid transport system.

Animals↗

PubMed2000

Boron neutron capture therapy for malignant gliomas.

Boron neutron capture therapy (BNCT) represents a promising modality for a relatively selective radiation dose delivery to the tumour tissue. Boron-10 nuclei capture slow 'thermal' neutrons preferentially and, upon capture, promptly undergo 10B(n,alpha)7Li reaction. The ionization tracks of energetic and heavy lithium and helium ions resulting from this reaction are only about one cell diameter in length (approximately 14 microm). Because of their high linear energy transfer (LET) these ions have a high relative biological effectiveness (RBE) for controlling tumour growth. The key to effective BNCT of tumours, such as glioblastoma multiforme (GBM), is the preferential accumulation of boron-10 in the tumour, including the infiltrating GBM cells, as compared with that in the vital structures of the normal brain. Provided that a sufficiently high tumour boron-10 concentration (approximately 10(9) boron-10 atoms/cell) and an adequate thermal neutron fluence (approximately 10(12) neutrons/cm2) are achieved, it is the ratio of the boron-10 concentration in tumour cells to that in the normal brain cells that will largely determine the therapeutic gain of BNCT.

Boron Neutron Capture Therapy↗

PubMed2000

Treatment of isografted 9L rat brain tumors with beta-5-o-carboranyl-2'-deoxyuridine neutron capture therapy.

beta-5-o-Carboranyl-2'-deoxyuridine (D-CDU) is a nontoxic pyrimidine nucleoside analogue designed for boron neutron capture therapy of brain tumors. In vitro studies indicated that D-CDU accumulates to levels 92- and 117-fold higher than the extracellular concentration in rat 9L and human U-251 glioma cells, respectively, and persists for several hours at levels 5-fold higher than the extracellular concentration. Furthermore, D-CDU was not toxic to rats injected i.p. with up to 150 mg/kg. On the basis of these studies, D-CDU was evaluated as a neutron capture therapy agent using rats bearing stereotactically implanted intracranial 9L tumors at single i.p. doses of 30 mg/kg and 150 mg/kg of D-CDU (20% 10B enriched), given 2 h before irradiation with thermal neutrons. Boron concentrations in tumors 2 h after dosing were 2.3 +/- 1.6 and 7.4 +/- 1.3 micrograms boron/g tissue (mean +/- SD), corresponding to tumor/brain ratios of 11.5 +/- 3.6 and 6.8 +/- 2.0 micrograms boron/g tissue for the low and high doses, respectively. All untreated animals died within 28 days, whereas half survived at days 32, 55, and 38 for groups receiving neutrons only, 30 mg/kg D-CDU, and 150 mg/kg D-CDU, respectively. Odds ratios of all treatment groups differed significantly from the untreated group (P < 0.002; logrank test). The median survival time for the 30 mg/kg-treated group but not for the 150 mg/kg-treated group was significantly longer than for rats treated with neutrons only (P = 0.036), which may correlate with the decreased tumor selectivity for D-CDU observed at the higher dose. Additional pharmacodynamic studies are warranted to determine optimal dosing strategies for D-CDU.

Animals↗

PubMed1999

Effect of dose and infusion time on the delivery of p-boronophenylalanine for neutron capture therapy.

Clinical trials of boron neutron capture therapy (BNCT) for glioblastoma multiforme are currently in progress using p-boronophenylalanine (BPA) as the 10B delivery agent. Enhancement of tumor boron uptake and/or the tumor-to-blood (T:B) boron concentration ratio would have the potential of significantly improving the therapeutic gain of BNCT. The effects of total dose, infusion time, and route of administration of BPA on tumor and blood boron concentrations were studied in rats bearing the 9L gliosarcoma. Increasing the total dose of BPA from 250 to 1000 mg/kg, administered intravenously over a 2-h infusion period, resulted in an increase in tumor boron concentration from approximately 30 to approximately 70 microg 10B/g, with a constant T:B boron concentration ratio of about 3.7:1. Similarly, extension of the infusion time from 2 to 6 h, at a constant dose-rate of 125 mg BPA/kg/h, resulted in an increase in tumor boron concentration from approximately 30 to approximately 80 microg 10B/g, while, again, maintaining a constant T:B ratio of about 3.7:1. In contrast, intracarotid infusion of BPA for 1 h at a dose rate of 125 mg BPA/kg resulted in an increase in the tumor boron concentration from approximately 26 to approximately 38 microg 10B/g with a corresponding increase in the T:B ratio from 3.5:1 to 5.0:1. The effects of these results on the therapeutic gain potentially achievable with BNCT are discussed.

Animals↗

PubMed1999

Fission converter and metal-oxide-semiconductor field effect transistor study of thermal neutron flux distribution in an epithermal neutron therapy beam.

The depth distribution of the thermal neutron flux is a major factor in boron neutron capture therapy (BNCT) in determining the efficiency of cell sterilization. In this paper the fission detector method is developed and applied to measure the in-phantom thermal neutron flux depth distribution. Advantages of the fission detector include small size, direct measurement of thermal neutron flux in a mixed radiation field of BNCT beam, self-calibration, and the possibility of on-line measurement. The measurements were performed at epithermal a BNCT facility. The experimental results were compared with the thermal neutron flux calculated by the Monte Carlo method and found to be in good agreement.

Biophysical Phenomena↗

PubMed1999

Autosomal dominant hypoparathyroidism associated with short stature and premature osteoarthritis.

Familial hypoparathyroidism is an unusual and genetically heterogeneous group of disorders that may be isolated or may be associated with congenital or acquired abnormalities in other organs or glands. We have evaluated a family with a novel syndrome of autosomal dominant hypoparathyroidism, short stature, and premature osteoarthritis. A 74-yr-old female (generation I) presented with hypoparathyroidism, a movement disorder secondary to ectopic calcification of the cerebellum and basal ganglia, and a history of knee and hip replacements for osteoarthritis. Two members of generation II and one member of generation III were also documented with hypoparathyroidism, short stature, and premature osteoarthritis evident as early as 11 yr. Because of the known association between autosomal dominant hypoparathyroidism and activating mutations of the calcium-sensing receptor (CaR) gene, further studies were performed. Sequencing of PCR-amplified genomic DNA revealed a leucine to valine substitution at position 616 in the first transmembrane domain of the CaR, which cosegregated with the disorder. However, this amino acid sequence change did not affect the total accumulation of inositol phosphates as a function of extracellular calcium concentrations in transfected HEK-293 cells. In conclusion, a sequence alteration in the coding region of the CaR gene was identified, but is not conclusively involved in the etiology of this novel syndrome. The cosegregation of hypoparathyroidism, short stature, and osteoarthritis in this kindred does suggest a genetic abnormality involving a common molecular mechanism in parathyroid, bone, and cartilage.

Adolescent↗

PubMed1999

The effects of boron neutron capture irradiation on oral mucosa: evaluation using a rat tongue model.

The ventral surface of the tongue of male Fisher 344 rats was used to evaluate the response of oral mucosa to boron neutron capture irradiation. Three hours after i.p. injection of 700 mg/kg of the boron delivery agent p-boronophenylalanine (BPA), the boron concentrations in blood and tongue mucosal epithelium were approximately 21 and 23 microgram (10)B/g, respectively. The doses required to produce a 50% incidence of ulceration with X rays, the Brookhaven Medical Research Reactor thermal neutron beam alone, or the thermal neutron beam in the presence of BPA were 13.4 +/- 0.2, 4. 2 +/- 0.1, and 3.0 +/- 0.1 Gy, respectively. Ulceration of the tongue was evident by 6 to 7 days after irradiation, irrespective of the irradiation modality; healing was related to dose and was relatively rapid (</=19 days). Compared to 100 kVp X rays, the relative biological effectiveness factors were 3.2 for the thermal neutron beam and 4.9 for the products of the boron neutron capture reaction, (10)B(n,alpha)(7)Li. Oral mucosa is highly sensitive to BPA-mediated BNC irradiation and could be a dose-limiting normal tissue in BNCT of brain tumors, or if BPA-based BNCT is applied to the treatment of head and neck tumors.

Animals↗

PubMed1999

The radiation biology of boron neutron capture therapy.

Boron neutron capture therapy (BNCT) is a targeted radiation therapy that significantly increases the therapeutic ratio relative to conventional radiotherapeutic modalities. BNCT is a binary approach: A boron-10 (10B)-labeled compound is administered that delivers high concentrations of 10B to the target tumor relative to surrounding normal tissues. This is followed by irradiation with thermal neutrons or epithermal neutrons which become thermalized at depth in tissues. The short range (5-9 microm) of the alpha and 7Li particles released from the 10B(n,alpha)7Li neutron capture reaction make the microdistribution of 10B of critical importance in therapy. The radiation field in tissues during BNCT consists of a mixture of components with differing LET characteristics. Studies have been carried out in both normal and neoplastic tissues to characterize the relative biological effectiveness of each radiation component. The distribution patterns and radiobiological characteristics of the two 10B delivery agents in current clinical use, the amino acid p-boronophenylalanine (BPA) and the sulfhydryl borane (BSH), have been evaluated in a range of normal tissues and tumor types. Considered overall, BSH-mediated BNCT elicits proportionately less damage to normal tissue than does BNCT mediated with BPA. However, BPA exhibits superior in vivo tumor targeting and has proven much more effective in the treatment of brain tumors in rats. In terms of fractionation effects, boron neutron capture irradiation modalities are comparable with other high-LET radiation modalities such as fast-neutron therapy. There was no appreciable advantage in increasing the number of daily fractions of thermal neutrons beyond two with regard to sparing of normal tissue in the rat spinal cord model. The experimental studies described in this review constitute the radiobiological basis for the new BNCT clinical trials for glioblastoma at Brookhaven National Laboratory, at the Massachusetts Institute of Technology, and at the High Flux Reactor, Petten, The Netherlands. The radiobiology of experimental and clinical BNCT is discussed in detail.

Animals↗

PubMed1998

Clinical reporting to primary care physicians leads to increased use and understanding of bone densitometry and affects the management of osteoporosis. A randomized trial.

BACKGROUND: A major barrier to wider use of bone densitometry has been a lack of reports that are comprehensible to primary care physicians. OBJECTIVE: To compare the effect of short technical reports and longer clinical reports on use, understanding, and acceptance of bone densitometry by primary care physicians and on management of osteoporosis. DESIGN: Randomized trial. SETTING: Osteoporosis center of a community teaching hospital. SUBJECTS: 57 primary care physicians ordering bone mineral density tests with dual x-ray absorptiometry. INTERVENTION: Physicians were randomly assigned to receive short technical reports or long clinical reports written by endocrinologists with access to clinical information. MEASUREMENTS: Physicians were interviewed by telephone after receiving at least two reports. RESULTS: Before being interviewed, physicians receiving short reports ordered a mean +/- SD of 0.72 +/- 0.71 tests per month; those receiving long reports ordered 1.30 +/- 1.21 tests per month (P = 0.002). At the first interview, 30% of physicians receiving short reports and 86% of those receiving long reports understood the bone mineral density definition of osteoporosis (P < 0.001). Receiving long reports led to more modifications in the pharmacologic treatment of osteoporosis by gynecologists (19% of patients whose reports were short and 61% of patients whose reports were long; P = 0.021) and less confusion about reports by all physicians (36% of physicians receiving short reports and 1% of those receiving long reports; P = 0.003). CONCLUSIONS: Clinical reporting of bone densitometry to primary care physicians increased use and understanding of bone densitometry, changed management of osteoporosis, and was well accepted. It may help achieve appropriate use of bone densitometry and may allow convenient dissemination of information on osteoporosis.

Absorptiometry, Photon↗

PubMed1998

Boron neutron-capture therapy (BNCT) for glioblastoma multiforme (GBM) using the epithermal neutron beam at the Brookhaven National Laboratory.

OBJECTIVE: Boron neutron-capture therapy (BNCT) is a binary form of radiation therapy based on the nuclear reactions that occur when boron (10B) is exposed to thermal neutrons. Preclinical studies have demonstrated the therapeutic efficacy of p-boronophenylalanine (BPA)-based BNCT. The objectives of the Phase I/II trial were to study the feasibility and safety of single-fraction BNCT in patients with GBM. MATERIALS AND METHODS: The trial design required (a) a BPA biodistribution study performed at the time of craniotomy; and (b) BNCT within approximately 4 weeks of the biodistribution study. From September 1994 to July 1995, 10 patients were treated. For biodistribution, patients received a 2-hour intravenous (i.v.) infusion of BPA-fructose complex (BPA-F). Blood samples, taken during and after infusion, and multiple tissue samples collected during surgical debulking were analyzed for 10B concentration. For BNCT, all patients received a dose of 250 mg BPA/kg administered by a 2-hour i.v. infusion of BPA-F, followed by neutron beam irradiation at the Brookhaven Medical Research Reactor (BMRR). The average blood 10B concentrations measured before and during treatment were used to calculate the time of reactor irradiation that would deliver the prescribed dose. RESULTS: 10B concentrations in specimens of scalp and tumor were higher than in blood by factors of approximately 1.5 and approximately 3.5, respectively. The 10B concentration in the normal brain was < or = that in the blood; however, for purposes of estimating radiation doses to normal brain endothelium, it was always assumed to be equal to blood. BNCT doses are expressed as gray-equivalent (Gy-Eq), which is the sum of the various physical dose components multiplied to appropriate biologic effectiveness factors. The dose to a 1-cm3 volume where the thermal flux reached a maximum was 10.6 +/- 0.3 Gy-Eq in 9 patients and 13.8 Gy-Eq in 1 patient. The minimum dose in tumor ranged from 20 to 32.3 Gy-Eq. The minimum dose in the target volume (tumor plus 2 cm margin) ranged from 7.8 to 16.2 Gy-Eq. Dose to scalp ranged from 10 to 16 Gy-Eq. All patients experienced in-field alopecia. No CNS toxicity attributed to BNCT was observed. The median time to local disease progression following BNCT was 6 months (range 2.7 to 9.0). The median time to local disease progression was longer in patients who received a higher tumor dose. The median survival time from diagnosis was 13.5 months. CONCLUSION: It is feasible to safely deliver a single fraction of BPA-based BNCT. At the dose prescribed, the patients did not experience any morbidity. To further evaluate the therapeutic efficacy of BNCT, a dose-escalation study delivering a minimum target volume dose of 17 Gy-Eq is in progress.

Aged↗

PubMed1998

Effects of human lymphocyte-conditioned medium on MG-63 human osteosarcoma cell function.

Lymphocytes are implicated in the pathogenesis of bone disease in chronic inflammation, osteoporosis, transplantation and osteopetrosis. The effects of lymphocytes and lymphocyte-conditioned medium on bone-resorbing activity and osteoclast function have been well studied, but there are few studies of the effects of LCM on bone formation and osteoblast function. The effects of LCM on the function of the MG-63 human osteosarcoma cell line were studied, which, when stimulated with 1,25-(OH)2D3, demonstrates many of the properties of the mature human osteoblast. Lymphocytes contain oestrogen receptors and the model was also used to test the hypothesis that the effects of oestrogen on bone cells may be mediated indirectly via lymphokines. Lymphokines were measured by ELISA in human lymphocyte conditioned medium (LCM) collected following incubation of mixed lymphocytes with or without stimulation for 72 h. Unstimulated LCM increased proliferation of MG-63 cells and this increase was not affected by neutralization of interleukin 1 (IL-1), IL-3, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor (TNF), lymphotoxin alpha, or interferon gamma (IFN-gamma). Phytohaemagglutinin-stimulated LCM decreased proliferation of MG-63 cells, as well as induced expression of IL-6 mRNA, increased alkaline phosphatase production, and inhibited osteocalcin production. The decrease in proliferation was abolished by neutralization of IFN-gamma but was unaffected by neutralization of IL-1, IL-2, IL-3, IL-4, IL-6, GM-CSF, TNF, or lymphotoxin alpha. Neutralization of IFN-gamma in stimulated LCM also partially inhibited the increase in alkaline phosphatase production but had no effects on the decrease in osteocalcin production. Although oestrogen inhibited lymphocyte proliferation, the effects of LCM collected from lymphocytes in the presence of oestrogen on MG-63 cell proliferation and function was no different than the effects of LCM collected in the absence of oestrogen. LCM has multiple effects on MG-63 cell function and gene expression. Lymphocyte stimulation during the preparation of LCM further modulates these effects. Although partially mediated by IFN-gamma, the effects of LCM on these cells cannot be completely explained by individual component lymphokines. This may have implications for understanding the pathophysiology of bone loss in inflammatory disorders as well as possible feedback loops of locally generated cytokines in bone.

Culture Media, Conditioned↗

PubMed1998

Boron neutron capture therapy: re-irradiation response of the rat spinal cord.

PURPOSE: To evaluate the retreatment response of the CNS to BNC irradiation using a rat spinal cord model. MATERIALS AND METHODS: Fischer 344 rats were irradiated with single doses of 6 MeV X-rays which were 22, 40 or 80% of a total effect (TE). An additional group of rats was irradiated with a single exposure of thermal neutrons in the presence of the neutron capture agent boronophenylalanine (BPA) to a dose that represented 82% of the TE. After an interval of 26 weeks, animals were re-irradiated using various single doses of thermal neutrons in combination with BPA. RESULTS: The re-irradiation ED50 doses represented 77, 80 or 50% of the TE after an initial X-ray dose of 22, 40 or 80% of the TE, respectively. The re-irradiation ED50 dose was 55% of the TE after an initial BNC irradiation dose representing 82% of the TE. CONCLUSION: The level of the initial radiation damage had a direct bearing on the re-irradiation response. Recovery following initial treatment with BNC irradiation was similar to that after initial irradiation with X-rays.

Animals↗

PubMed1998

Biodistribution of p-boronophenylalanine in patients with glioblastoma multiforme for use in boron neutron capture therapy.

OBJECTIVE: The success of boron neutron capture therapy depends on the safety and specificity of the boron delivery agent. As a preface to clinical boron neutron capture therapy of glioblastoma multiforme, a biodistribution study of intravenous p-boronophenylalanine (BPA) in patients undergoing craniotomy for resection of glioblastoma was performed. METHODS: Varying doses of intravenously administered BPA-fructose (130-250 mg BPA per kilogram of body weight) were given to patients 2 to 3 hours prior to the start of craniotomy for either suspected or known glioblastoma multiforme. Blood samples were collected over a 48-hour period for boron assay. At surgery, multiple samples of tumor, brain, and scalp were obtained for boron and histological analysis. RESULTS: Seventeen patients were studied; all but one had glioblastoma multiforme. No adverse effects from the BPA infusions were noted. The boron concentration in the blood reached a maximum at the end of the BPA infusion and was proportional to the administered dose of BPA. Normal brain concentrations of boron generally were equal to or less than that in blood. Tumor-blood boron ratios were highly variable: 1.6 +/- 0.8 (mean +/- standard deviation; n = 187; range, 0.3-3.5). The observed heterogeneity of BPA uptake in glioblastoma samples appears to correlate with the degree of cellularity observed on histological examination. CONCLUSION: Intravenous BPA administration up to a dose of 250 mg/kg is safe and well tolerated. BPA uptake in surgical samples of glioblastoma tissue is variable and may depend on the fraction of viable tumor cells in the individual sample. Further clinical studies using BPA as a boron delivery agent for boron neutron capture therapy of glioblastoma multiforme appear warranted.

Boron Compounds↗

PubMed1998

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.

Boron↗

PubMed1997

Boron neutron capture therapy for glioblastoma multiforme using p-boronophenylalanine and epithermal neutrons: trial design and early clinical results.

A Phase I/II clinical trial of boron neutron capture therapy (BNCT) for glioblastoma multiforme is underway using the amino acid analog p-boronophenylalanine (BPA) and the epithermal neutron beam at the Brook-haven Medical Research Reactor. Biodistribution studies were carried out in 18 patients at the time of craniotomy using an i.v. infusion of BPA, solubilized as a fructose complex (BPA-F). There were no toxic effects related to the BPA-F administration at doses of 130, 170, 210, or 250 mg BPA/kg body weight. The tumor/ blood, brain/blood and scalp/blood boron concentration ratios were approximately 3.5:1, 1:1 and 1.5:1, respectively. Ten patients have received BNCT following 2-hr infusions of 250 mg BPA/kg body weight. The average boron concentration in the blood during the irradiation was 13.0 +/- 1.5 micrograms 10B/g. The prescribed maximum dose to normal brain (1 cm3 volume) was 10.5 photon-equivalent Gy (Gy-Eq). Estimated maximum and minimum doses (mean +/- sd, n = 10) to the tumor volume were 52.6 +/- 4.9 Gy-Eq (range: 64.4-47.6) and 25.2 +/- 4.2 Gy-Eq (range: 32.3-20.0), respectively). The estimated minimum dose to the target volume (tumor +2 cm margin) was 12.3 +/- 2.7 Gy-Eq (range: 16.2-7.8). There were no adverse effects on normal brain. The scalp showed mild erythema, followed by epilation in the 8 cm diameter field. Four patients developed recurrent tumor, apparently in the lower dose (deeper) regions of the target volume, at post-BNCT intervals of 7,5,3.5 and 3 months, respectively. The remaining patients have had less than 4 months of post-BNCT follow-up. BNCT, at this starting dose level, appears safe. Plans are underway to begin the dose escalation phase of this protocol.

Adult↗