Martti Kulvik

Non-linear model for the kinetics of 10B in blood after BPA?fructose complex infusion

A numerical model with a memory effect was created to describe the kinetics of 10B in blood after a single 4-dihydroxyborylphenylalanine-fructose complex (BPA-F) infusion in boron neutron capture therapy (BNCT). The model formulation was based on the averaged data from 10 glioma patients from the Brookhaven National Laboratory (BNL) BNCT-trials. These patients received a 2 h i.v. infusion of a BPA-fructose complex that delivered 290 mg BPA/kg body weight. The model was validated by fitting the original BNL patient data and new patient data from the Finnish BNCT-trials. The new 3-parameter non-linear model provided mean absolute differences between the measured and estimated 10B concentrations in blood that were less than 3.9% when used to simulate actual patient irradiations that comprised two irradiation fields separated by a break to reposition the patient. The flexibility of the model was successfully tested with two different infusion protocols. The patient data were modelled with a two-compartment model and a bi-exponential fit for comparison. The 3-parameter model is better than previously described models in predicting the time course of blood 10B concentration after cessation of intravenous infusion of BPA-fructose.

Uptake of 4-borono-2-[18F]fluoro-L-phenylalanine in sporadic and neurofibromatosis 2-related schwannoma and meningioma studied with PET.

PurposeMeningiomas and schwannomas associated with neurofibromatosis 2 (NF2) are difficult to control by microsurgery and stereotactic radiotherapy alone. Boron neutron capture therapy (BNCT) is a chemically targeted form of radiotherapy requiring increased concentration of boron-10 in tumour tissue. PET with the boron carrier 4-borono-2-[18F]fluoro-L-phenylalanine ([18F]FBPA) allows investigation of whether 4-borono-L-phenylalanine (BPA) concentrates in NF2 tumours, which would make BNCT feasible.MethodsWe studied dynamic uptake of [18F]FBPA in intracranial meningiomas (n=4) and schwannomas (n=6) of five sporadic and five NF2 patients. Tracer input function and cerebral blood volume were measured. [18F]FBPA uptake in tumour and brain was assessed with a three-compartmental model and graphical analysis. These, together with standardised uptake values (SUVs), were used to define tumour-to-brain [18F]FBPA tissue activity gradients.ResultsModel fits with three parameters K1 (transport), k2 (reverse transport) and k3 (intracellular metabolism) were found to best illustrate [18F]FBPA uptake kinetics. Maximum SUV was two- to fourfold higher in tumour as compared with normal brain and independent of NF2 status. The increased uptake was due to higher transport of [18F]FBPA in tumour. In multiple-time graphical analysis (MTGA, Gjedde-Patlak plot) the tumour-to-brain [18F]FBPA influx constant (Ki -MTGA) ratios varied between 1.8 and 5.4 in NF2-associated tumours while in sporadic tumours the ratio was 1–1.4.Conclusion[18F]FBPA PET offers a viable means to evaluate BPA uptake in meningiomas and schwannomas in NF2. Based on our results on tumour uptake of [18F]FBPA, some of these benign neoplasms may be amenable to BNCT.

Clinical implementation of 4-dihydroxyborylphenylalanine synthesised by an asymmetric pathway.

Boron neutron capture therapy (BNCT) is an experimental therapeutic modality combining a boron pharmaceutical with neutron irradiation. 4-Dihydroxyborylphenylalanine (L-BPA) synthesised via the asymmetric pathway by Malan and Morin [Synlett. 167-168 (1996)] was developed to be the boron containing pharmaceutical in the first series of Finnish BNCT clinical trials. The final product was >98.5% chemically pure L-BPA with L-phenylalanine and L-tyrosine as the residual impurities. The solubility of L-BPA was enhanced by complex formation with fructose (BPA-F). The pH and osmolarity of the BPA-F preparation is in the physiological range. Careful attention was given to the pharmaceutical quality of the BPA-F preparations. Prior to starting clinical trials the acute toxicity of L-BPA was studied in male albino Sprague-Dawley rats. In accordance with earlier studies no adverse effects were observed. After completion of the development work L-BPA solution was administered to brain tumour patients in conjunction with clinical studies for development and testing of BPA-based BNCT. No clinically significant adverse events attributable to the L-BPA i.v. infusions were observed. We conclude that our synthesis development, complementary preclinical and clinical observations justify the safe use of L-BPA up to clinical phase III studies with L-BPA produced by the asymmetric pathway, originally presented by Malan and Morin in 1996.

Measuring intellectual capital and sources of equity financing - value platform perspective within the Finnish biopharmaceutical industry

The aim of this study is to create a theoretically derived basis for measuring intellectual capital within the Finnish biopharmaceutical industry, and to relate these measures to ownership structures. Our empirical model employs survey data from small and medium-sized Finnish biopharmaceutical companies. The sources of equity financing are identified and the means of measuring Intellectual Capital (IC) in the value platform framework is created. Various sources of financing are related to the intellectual capital and other characteristic features of these companies. The biotechnology company owned by another firm is distinctive, corresponding to different strategic functions designated to the company by the owner firm. The largest investor group, venture capital companies, seem to prefer a well-balanced combination of intellectual capital. The other owner groups showed among themselves a rather similar pattern of investment preferences.

Projected growth effects of the biotechnology industry in Finland: the fourth pillar of the economy?

This study assesses the impact of the Finnish biotechnology industry on economic growth in Finland. The study employs official data from Statistics Finland and new survey data covering 84 Finnish biotechnology companies. An econometric forecast for the economy-wide growth impact of the biotechnology industry in Finland is presented. In the estimation procedure, this study employs the survey data both in forming growth anticipations within a new emerging industry and assessing inter-industrial growth effects. Applied Monte Carlo simulations predict that the contribution of the biotechnology industry to annual GDP growth in 2002–2006 will be in the range of 0.05–0.09 percentage points per annum with a probability of 90%. These results imply that it will take decades rather than years for the biotechnology industry to become a fourth pillar of the Finnish economy beside the forest industry, the metal products and machinery industry, and the electronics industry.

Compartmental and Non-Compartmental Methods in Studying the Kinetics of Boron-10 after Boronophenylalanine Fructose Complex (BPA-F)-Infusion in Dogs

One of the essential requirements for optimising BNC-treatment is to know the boron-10 concentration in tissues under irradiation. A model which describes the kinetics of boron-10 in the patient would be valuable. The primary aim of the present study was to create a model for the pharmacokinetics of boron-10 in dogs after 4-dihydroxy-borylphenylalanine fructose complex (BPA-F) infusion so that we could predict the boron-10 concentration in blood during the irradiation.1 In addition we wanted to clarify if it is possible to design a simple compartmental model which could be used in defining the kinetic behaviour of boron-10 in the blood circulation.

At the Threshold of Clinical Trials

The aim of the Finnish BNCT-project is to start BNC-treatments of malignant brain tumors. The first clinical trial is planned to start in early 1999 at the treatment facility of the 250kW FiR 1 TRIGA research reactor. Excellent patient treatment facilities have been built at the reactor which is located only 5 km from the Helsinki University Central Hospital making the treatment facility very easy to reach.

On-Line Boron-10 Determination from Blood Samples by ICP-MS

Accurate and fast boron analysis is essential in BNC-treatment of glioma patients. Standard boron analytical assay from biological samples are direct current plasma atomic emission spectrometry,1 inductively coupled plasma-atomic emission spectrometry,2 inductively coupled plasma-mass spectrometry3 or prompt gamma-ray analysis.4 Various standard and alternative techniques for boron analysis have been tested by the Finnish BNCT research group.5

Biodistribution of boron after intravenous 4-dihydroxyborylphenylalanine-fructose (BPA-F) infusion in meningioma and schwannoma patients: A feasibility study for boron neutron capture therapy

We studied the uptake of boron after 100 mg/kg BPA infusion in three meningioma and five schwannoma patients as a pre-BNCT feasibility study. With average tumour-to-whole blood boron concentrations of 2.5, we discuss why BNCT could, and probably should, be developed to treat severe forms of the studied tumours. However, analysing 72 tumour and 250 blood samples yielded another finding: the plasma-to-whole blood boron concentrations varied with time, suggesting that the assumed constant boron ratio of 1:1 between normal brain tissue and whole blood deserves re-assessment.

An economic model to assess the cost-benefit of BNCT

We have constructed a formal model on cost-benefit of new technology in health care, and apply it on boron neutron capture therapy (BNCT). We assume that the patient health benefit from getting cured in acute treatment is always higher than the patient utility resulting from any long term treatment or death. This assumption makes it possible to evaluate the monetary cost impacts of a new technology and relate these measures to the patient health benefit.