Lucian Wielopolski

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.

Carbon cycling in soil

As yet, nobody knows what effects climate change will have on soil carbon reserves, or how those changes will affect the global carbon cycle. Soils are the primary terrestrial repository for carbon, so minor changes in the balance between belowground carbon storage and release could have major impacts on greenhouse gases. Soil fauna, roots, fungi, and microbes interact with mineral and organic matter to process soil carbon. Studies have been hampered by the difficulty of observing processes beneath the earths surface, but advances in science and technology are improving our ability to understand belowground ecosystems.

Evaluation of different soil carbon determination methods.

Determining soil carbon (C) with high precision is an essential requisite for the success of the terrestrial C sequestration program. The informed choice of management practices for different terrestrial ecosystems rests upon accurately measuring the potential for C sequestration. Numerous methods are available for assessing soil C. Chemical analysis of field-collected samples using a dry combustion method is regarded as the standard method. However, conventional sampling of soil and their subsequent chemical analysis is expensive and time consuming. Furthermore, these methods are not sufficiently sensitive to identify small changes over time in response to alterations in management practices or changes in land use. Presently, several different in situ analytic methods are being developed purportedly offering increased accuracy, precision and cost-effectiveness over traditional ex situ methods. We consider that, at this stage, a comparative discussion of different soil C determination methods will improve the understanding needed to develop a standard protocol.

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.

Feasibility of noninvasive analysis of lead in the human tibia by soft x-ray fluorescence.

A postmortem study was conducted to assess the feasibility of measuring bone lead concentrations noninvasively in vivo. Characteristic L x rays were induced with an external source of 125I in the superficial tibial cortex of the intact legs of six adults who had no history of occupational exposure to lead. Tibial lead concentrations in the same bones subsequently determined by flameless atomic absorption spectroscopy varied from 15 to 35 micrograms Pb/g wet weight. The upper limit for the modern normal range of lead in the bone is about 25 mg Pb/g wet tissue. The linear correlation coefficient (r) between the measurements made with x-ray fluorescence and lead concentration by absorption spectroscopy was 0.90. Radiation doses of 10 mGy (1 rad) to 1 cm2 of skin, with associated doses to the marrow of adjacent bone of about 0.6 mGy (60 mrad), yielded net lead fluorescence signals ranging from one to seven times the standard deviation of background.

Imaging tree root systems in situ

The study of root growth and development in soil has been intellectually and technically challenging. In response to concern about increasing levels of atmospheric carbon dioxide (CO 2 ), resulting from increase in global energy use, the cycling of carbon has become the object of many intensive investigations.. Terrestrial ecosystems are a huge, natural biological scrubber for CO 2 currently sequestering, directly from the atmosphere, about 22% of annual anthropogenic carbon emissions. It is assumed that a significant fraction of this carbon uptake goes into roots. Presently, there are no means by which root morphology, distribution, and mass can be measured without serious sampling artifacts that alter these properties. This is because the current methods are destructive and labor intensive. A non-invasive, imaging procedure for examining roots in situ would be a powerful tool quantifying subsurface storage, as well as for documenting changes in root structure. Preliminary results using a high frequency, 1.5 Ghz, impulse Ground Penetrating Radar (GPR) for non-destructive imaging of tree root systems in situ are presented. Two 3D reconstructed images taking advantage of the polarization effect are used to assess root morphology and dimensions. The constraints, limitations, and potential solutions for using GPR for tree root systems imaging and analysis are discussed.

Feasibility Study for the in Vivo Measurement of Lead in Bone Using L-X-Ray Fluorescence

Lead deposits in bone were detected by x-ray fluorescence using x-rays from either a 125 I or a 109Cd source. Measurements were taken from tibia in intact human legs, post-mortem. On the basis of preliminary measurements, it was concluded that an exposure of one rad is adequate for determination of lead in bone. Both the advantages and the disadvantages of L-x-rays, used in the technique developed for this study, are compared with those of K-x-rays.

Samarium-145: a new brachytherapy source

A new radiation source has been produced for brachytherapy, with radiation energies slightly above those of 125I, and a T1/2 of 340 d. This source, 145Sm, is produced by neutron irradiation of 144Sm (96.5% enriched). Decay is by electron capture with 140 K x-rays per 100 disintegrations in the energy region between 38-45 keV, plus 13 gamma-rays at 61 keV. These sources are encapsulated in Ti tubes, approximately 0.8 mm X 4.5 mm, and have been developed for temporary implantation in brain and ocular tumours. The 38-61 keV photons should make such sources easy to shield, while providing a dose distribution from source arrays somewhat more homogeneous than that from 125I. In addition, the 340 d half life of 145Sm permits its use for times significantly longer than that of 60 d 125I. While the 145Sm sources have been designed primarily for implantation in a brain tumour, they should be useful for almost any conventional brachytherapy application.

Application of the library least-squares analysis to whole-body counter spectra derived from an array of detectors.

The library least-squares method was applied to the analysis of gamma-ray spectra obtained from an array of 54 NaI(T1) detectors in a whole-body counter. The analysis of spectra which were obtained over a period of 8 yr demonstrates the applicability of the method despite inherent variations encountered in large counting systems. The elements of interest analyzed were total-body K, Ca, Na, Cl, and P. Least-squares fits obtained with library standards derived from distributed sources were better than those obtained from library standards derived from localized sources.

The effects of boron on the electron paramagnetic resonance spectra of alanine irradiated with thermal neutrons

The effects of boric acid admixture on the intensity and line structure of EPR spectra of free radicals produced in alanine by thermal neutrons are presented. The EPR signal enhancement, up to a factor of 40 depending on the boron concentration, is related to additional energy deposition in alanine crystals by the disintegration products resulting from the capture of a thermal neutron by boron, 10B(n,alpha)7Li. The changes in the shape of the EPR spectra observed by changing the microwave power are due to the differences in the microwave power saturation of the free radicals produced by a low-LET radiation and those produced by the high-LET components of the radiation after the neutron capture reaction.