Erik Blomquist

Boron neutron capture therapy (BNCT) for glioblastoma multiforme: A phase II study evaluating a prolonged high-dose of boronophenylalanine (BPA)

BACKGROUND AND PURPOSE To evaluate the efficacy and safety of boron neutron capture therapy (BNCT) for glioblastoma multiforme (GBM) using a novel protocol for the boronophenylalanine-fructose (BPA-F) infusion. PATIENT AND METHODS This phase II study included 30 patients, 26-69 years old, with a good performance status of which 27 have undergone debulking surgery. BPA-F (900 mg BPA/kg body weight) was given i.v. over 6h. Neutron irradiation started 2h after the completion of the infusion. Follow-up reports were monitored by an independent clinical research institute. RESULTS The boron-blood concentration during irradiation was 15.2-33.7 microg/g. The average weighted absorbed dose to normal brain was 3.2-6.1 Gy (W). The minimum dose to the tumour volume ranged from 15.4 to 54.3 Gy (W). Seven patients suffered from seizures, 8 from skin/mucous problem, 5 patients were stricken by thromboembolism and 4 from abdominal disturbances in close relation to BNCT. Four patients displayed 9 episodes of grade 3-4 events (WHO). At the time for follow-up, minimum ten months, 23 out of the 29 evaluable patients were dead. The median time from BNCT treatment to tumour progression was 5.8 months and the median survival time after BNCT was 14.2 months. Following progression, 13 patients were given temozolomide, two patients were re-irradiated, and two were re-operated. Patients treated with temozolomide lived considerably longer (17.7 vs. 11.6 months). The quality of life analysis demonstrated a progressive deterioration after BNCT. CONCLUSION Although, the efficacy of BNCT in the present protocol seems to be comparable with conventional radiotherapy and the treatment time is shorter, the observed side effects and the requirement of complex infrastructure and higher resources emphasize the need of further phase I and II studies, especially directed to improve the accumulation of (10)B in tumour cells.

The influence of RBE variations in a clinical proton treatment plan for a hypopharynx cancer

Currently, most clinical range-modulated proton beams are assumed to have a fixed overall relative biological effectiveness (RBE) of 1.1. However, it is well known that the RBE increases with depth in the spread-out Bragg peak (SOBP) and becomes about 10% higher than mid-SOBP RBE at 2 mm from the distal edge (Paganetti 2003 Technol. Cancer Res. Treat. 2 413-26) and can reach values of 1.3-1.4 in vitro at the distal edge (Robertson et al 1975 Cancer 35 1664-77, Courdi et al 1994 Br. J. Radiol. 67 800-4). We present a fast method for applying a variable RBE correction with linear energy transfer (LET) dependent tissue-specific parameters based on the alpharef/betaref ratios suitable for implementation in a treatment planning system. The influence of applying this variable RBE correction on a clinical multiple beam proton dose plan is presented here. The treatment plan is evaluated by RBE weighted dose volume histograms (DVHs) and the calculation of tumour control probability (TCP) and normal tissue complication probability (NTCP) values. The variable RBE correction yields DVHs for the clinical target volumes (CTVs), a primary advanced hypopharynx cancer and subclinical disease in the lymph nodes, that are slightly higher than those achieved by multiplying the absorbed dose with RBE=1.1. Although, more importantly, the RBE weighted DVH for an organ at risk, the spinal cord is considerably increased for the variable RBE. As the spinal cord in this particular case is located 8 mm behind the planning target volume (PTV) and hence receives only low total doses, the NTCP values are zero in spite of the significant increase in the RBE weighted DVHs for the variable RBE. However, high NTCP values for the non-target normal tissue were obtained when applying the variable RBE correction. As RBE variations tend to be smaller for in vivo systems, this study-based on in vitro data since human tissue RBE values are scarce and have large uncertainties-can be interpreted as showing the upper limits of the possible effects of utilizing a variable RBE correction. In conclusion, the results obtained here still indicate a significant difference in introducing a variable RBE compared to applying a generic RBE of 1.1, suggesting it is worth considering such a correction in clinical proton therapy planning, especially when risk organs are located immediately behind the target volume.

Rejoining of DNA double-strand breaks induced by accelerated nitrogen ions

Rejoining of radiation-induced DNA double-strand breaks (dsb) was measured in cultured cells with pulsed-field gel electrophoresis after radiation doses in the range of 5-30 Gy. Human glioma, U-343MG and Chinese hamster, V79, cells were irradiated with either accelerated nitrogen ions of high linear energy transfer, LET approximately 125 keV/ microns, or photons from 60Co. The induction frequencies of dsb were similar for the two radiation qualities with a relative biological effectiveness, RBE, of 0.90 and 0.89 for the human and hamster cell lines respectively. The biphasic rejoining kinetics differed significantly between the two radiation qualities when studied in the human glioma cells. The difference was seen within the first hour after irradiation and after 6 h there were considerable differences in both the total amount of unrejoined dsb and the fraction of dsb rejoined during the slow phase. When rejoining was analysed 20-22 h after irradiation, the nitrogen ions gave 2.5-2.9 times more residual dsb than the gamma photons. The results for the hamster V79 cells were, up to 2h after irradiation, similar, but the difference between the two radiation qualities was less accentuated. In summary, similar initial yields of dsb after exposure of cells to high or low LET resulted in both radiation quality and cell type-dependent differences when the rejoining of these breaks were compared.

Stereotactic Irradiation of Skull Base Meningiomas with High Energy Protons

Summary Nineteen patients with inextirpable skull base meningioma with involvement of neurovascular structures were given irradiation with a 180 MeV proton beam at the The Svedberg Laboratory, Uppsala, Sweden. The patients were treated seated in a fixed position with a stereotactic approach. Titanium-markers to the outer table served for identification and verification of the target positioning for dose planning and irradiation. The patients were given a total dose of 24 Gy in four consecutive daily 6 Gy fractions. All patients have been followed for at least 36 months. So far no meningiomas have progressed after treatment. Two patients have developed corticosteroid responsive oedema in the target area 6 moths after treatment. Late, but not serious, symptoms of side effects have been observed in one patient.

Relative biological effectiveness of intermediate energy protons. Comparisons with 60Co gamma-radiation using two cell lines

Range modulated proton beams are used for radiotherapy of malignant tumours at several accelerator laboratories with the aim of introducing proton therapy as a clinical hospital-based therapy modality. Due to the finite range and the sharpness of the dose gradients, the dose to well defined target volumes can be raised without excessive irradiation of non-target tissue. The prescribed proton doses are determined in part on the basis of the relative biological effectiveness (RBE) of the particular radiation quality. In this study, RBE values were determined for a proton beam with a maximal range of 33 mm, which corresponds to an energy of approximately 67 MeV. The range modulated depth-dose distribution, with a 20 mm extended Bragg peak, was mainly designed for high precision treatment of small targets such as uveal melanomas. The tested cell lines, LS-174T and V79-379A, were chosen because of their suitability for clonogenic assays. The cells were irradiated with single doses in the range 2-10 Gy at different depths in the extended peak region of the range modulated proton beam. RBE values were determined by comparing the doses needed to obtain the same reduction in colony formation (0.5, 0.1 and 0.01) as with the reference 60Co gamma source. The mean RBE value was 1.22 with a standard deviation of 0.08. The variations depended on both cell type and on the survival levels considered.(ABSTRACT TRUNCATED AT 250 WORDS)

Potential significance of 11C-methionine PET as a marker for the radiosensitivity of low-grade gliomas

Abstract. The role for radiotherapy in patients with low-grade gliomas remains controversial. Two large prospective studies have failed to demonstrate a radiotherapeutic dose-response effect, and EORTC trial 22845 found no difference in survival between patients receiving adjuvant radiotherapy and those who received radiotherapy at tumour progression. The aim of this retrospective study was to analyse the patterns of carbon-11 methionine (MET) uptake on positron emission tomography (PET) in tumours treated with immediate radiotherapy and in those treated with delayed radiotherapy at the time of tumour progression. The 21 adult patients studied had histologically confirmed low-grade gliomas and had undergone a pre-treatment PET scan and a follow-up PET scan at the time of progression. Eleven of the patients had undergone initial radiotherapy a median of 5 weeks after the surgical procedure. The median time to progression was 3.5 years for this group, compared with 1.6 years for the group with delayed radiotherapy (P=0.06). At the time of progression, non-irradiated tumours had a significantly higher MET uptake (P=0.02) and a larger uptake volume (P=0.008) compared with baseline, whereas irradiated tumours showed no statistically significant change. We observed a correlation between high pre-treatment uptake of MET and reduction in MET uptake in response to radiotherapy (P=0.008). All irradiated tumours recurred within the radiation field. In conclusion, our results demonstrate signs of a residual radiation effect at the time of tumour progression in low-grade gliomas with high pre-treatment uptake of MET. Pre-treatment methionine uptake may be a marker for the radiosensitivity of low-grade gliomas.

Stimulation of fibroblast migration by epidermal growth factor

Epidermal growth factor has been found to stimulate the migration of human foreskin fibroblasts grown at low serum concentration. This effect may be caused by a direct activation of the cytoskeletal elements or indirectly via an increased production of migration facilitating matrix proteins. We speculate on the possible implications of the present finding in the invasive properties of growth factor releasing transformed cells and in the direction of migration of cells in embryonal development.

Ageing of human glial cells in culture: increase in the fraction of non-dividers as demonstrated by a minicloning technique.

A minicloning technique was used to analyse quantitatively the fraction of cells incapable of division in mass populations of human glial cells at various passage levels. The percentage of non-dividers rose from 18 to 73% between passages 11 and 40 at which further subcultivation of the mass culture became impossible. The non-dividers were predominantly arrested in G1; only a minor fraction of G2 arrested cells was established. Although not conclusive, the data suggest that commitment to irreversible loss of division potential increases as a function of the number of completed cell cycles which a glial cell has completed.

Characterization of novel and complex genomic aberrations in glioblastoma using a 32K BAC array.

Glioblastomas (GBs) are malignant CNS tumors often associated with devastating symptoms. Patients with GB have a very poor prognosis, and despite treatment, most of them die within 12 months from diagnosis. Several pathways, such as the RAS, tumor protein 53 (TP53), and phosphoinositide kinase 3 (PIK3) pathways, as well as the cell cycle control pathway, have been identified to be disrupted in this tumor. However, emerging data suggest that these aberrations represent only a fraction of the genetic changes involved in gliomagenesis. In this study, we have applied a 32K clone-based genomic array, covering 99% of the current assembly of the human genome, to the detailed genetic profiling of a set of 78 GBs. Complex patterns of aberrations, including high and narrow copy number amplicons, as well as a number of homozygously deleted loci, were identified. Amplicons that varied both in number (three on average) and in size (1.4 Mb on average) were frequently detected (81% of the samples). The loci encompassed not only previously reported oncogenes (EGFR, PDGFRA, MDM2, and CDK4) but also numerous novel oncogenes as GRB10, MKLN1, PPARGC1A, HGF, NAV3, CNTN1, SYT1, and ADAMTSL3. BNC2, PTPLAD2, and PTPRE, on the other hand, represent novel candidate tumor suppressor genes encompassed within homozygously deleted loci. Many of these genes are already linked to several forms of cancer; others represent new candidate genes that may serve as prognostic markers or even as therapeutic targets in the future. The large individual variation observed between the samples demonstrates the underlying complexity of the disease and strengthens the demand for an individualized therapy based on the genetic profile of the patient.

Irregular variations in radiation sensitivity when the linear energy transfer is increased

Seven cell lines were analyzed for clonogenic survival after irradiation with photons (60Co) or accelerated helium or nitrogen ions. The cell lines showed different sensitivity to photon radiation and most of the differences decreased after irradiation with helium ions with a linear energy transfer (LET) of about 40 keV/microns. However, all cell types had individual LET sensitization patterns and the mean relative biological effectiveness (RBE) at 10% survival ranged from 1.46 +/- 0.12 to 2.41 +/- 0.26 for the helium ions. This difference was significant and the differences increased further when higher survival levels were considered. There was only a weak tendency towards a relation between photon and helium ion sensitivity when the linear component of the survival curves, the alpha-values, were compared, and no relation at all for other parameters. It was not possible to predict the response to an increased LET from the photon responses obtained. Three of the cell lines were also irradiated with nitrogen ions with an LET of 125 keV/microns. These cells were, as expected, sensitized further and the average RBE at 10% survival was 3.67 +/- 0.67. However, one cell line was more resistant than the others in this case. Furthermore, the quadratic component of the survival curves, the beta values, were higher after irradiation with nitrogen than with helium ions. Thus, several irregular and unexpected results were seen when the LET was increased.