Boron Neutron Capture Therapy for glioblastoma multiforme: advantage of prolonged infusion of BPA-f.

OBJECTIVES: To assess possible improved efficacy of Boron Neutron Capture Therapy (BNCT) for glioblastoma multiforme (GBM) using prolonged infusion and a correspondingly higher dose of l-boronophenylalanine, as the fructose complex (BPA-f). MATERIALS AND METHODS: The benefit of prolonged infusion was analyzed by comparing the results from a Phase II study using 6 h infusion of BPA-f with those obtained from a Phase I/II study using 2 h of infusion. Median survival time (MST) from diagnosis, patient baseline characteristics, salvage treatment and severe adverse events were considered in the comparison. RESULTS: MST increased significantly, from 12.8 (95% confidence interval or CI: 10.3-14.0) months with 2 h infusion to 17.7 (95% CI: 13.6-19.9) months with 6 h of infusion. The fraction of patients with WHO grade 3-4 adverse events was similar in the two studies at 13% and 14%, respectively. CONCLUSION: Prolonged infusion was found to be beneficial for the efficacy of BNCT and it is suggested that 6 h infusion of BPA-f should be used in future trials of BNCT for GBM. BNCT, which is a single-day treatment with mild side effects, should be assessed in a controlled trial, as an alternative to 30 daily fractions of conventional fractionated photon therapy over a period of 6 weeks.

An international dosimetry exchange for BNCT part II: computational dosimetry normalizations.

The meaningful sharing and combining of clinical results from different centers in the world performing boron neutron capture therapy (BNCT) requires improved precision in dose specification between programs. To this end absorbed dose normalizations were performed for the European clinical centers at the Joint Research Centre of the European Commission, Petten (The Netherlands), Nuclear Research Institute, Rez (Czech Republic), VTT, Espoo (Finland), and Studsvik, Nyköping (Sweden). Each European group prepared a treatment plan calculation that was bench-marked against Massachusetts Institute of Technology (MIT) dosimetry performed in a large, water-filled phantom to uniformly evaluate dose specifications with an estimated precision of +/-2%-3%. These normalizations were compared with those derived from an earlier exchange between Brookhaven National Laboratory (BNL) and MIT in the USA. Neglecting the uncertainties related to biological weighting factors, large variations between calculated and measured dose are apparent that depend upon the 10B uptake in tissue. Assuming a boron concentration of 15 microg g(-1) in normal tissue, differences in the evaluated maximum dose to brain for the same nominal specification of 10 Gy(w) at the different facilities range between 7.6 and 13.2 Gy(w) in the trials using boronophenylalanine (BPA) as the boron delivery compound and between 8.9 and 11.1 Gy(w) in the two boron sulfhydryl (BSH) studies. Most notably, the value for the same specified dose of 10 Gy(w) determined at the different participating centers using BPA is significantly higher than at BNL by 32% (MIT), 43% (VTT), 49% (JRC), and 74% (Studsvik). Conversion of dose specification is now possible between all active participants and should be incorporated into future multi-center patient analyses.

An investigation of boron neutron capture therapy for recurrent glioblastoma multiforme.

Objectives - To explore the use of boron neutron capture therapy (BNCT) for patients with glioblastoma multiforme (GBM), recurring after surgery and conventional radiotherapy (photon radiotherapy). Materials and Methods - Boron uptake in recurrent GBM was measured for four patients. Twelve patients were subsequently treated by BNCT with boronophenylalanine-fructose (900 mg/kg body weight), administered by intravenous infusion for 6 h. Results - Median survival time from initial diagnosis was 22.2 months. Comparison with other BNCT studies indicates a clinical advantage of the prolonged infusion. BNCT was well tolerated and quality of life remained stable until tumor progression for all 12 patients. No correlation was found between survival times and minimum tumor dose and number of radiation fields. Conclusions - Boron neutron capture therapy, with the prolonged procedure for infusion, is at least as effective as other radiation therapies for recurrent GBM and is delivered in one treatment session, with low radiation dose to the healthy brain. Survival from diagnosis compares favorably with that obtained with conventional radiotherapy plus concomitant and adjuvant temozolomide (TMZ) and survival from recurrence compares favorably with that obtained with TMZ at first relapse. The results of the present investigation are encouraging and should be confirmed in a randomized trial.

An international dosimetry exchange for boron neutron capture therapy. Part I: Absorbed dose measurements.

An international collaboration was organized to undertake a dosimetry exchange to enable the future combination of clinical data from different centers conducting neutron capture therapy trials. As a first step (Part I) the dosimetry group from the Americas, represented by MIT, visited the clinical centers at Studsvik (Sweden), VTT Espoo (Finland), and the Nuclear Research Institute (NRI) at Rez (Czech Republic). A combined VTT/NRI group reciprocated with a visit to MIT. Each participant performed a series of dosimetry measurements under equivalent irradiation conditions using methods appropriate to their clinical protocols. This entailed in-air measurements and dose versus depth measurements in a large water phantom. Thermal neutron flux as well as fast neutron and photon absorbed dose rates were measured. Satisfactory agreement in determining absorbed dose within the experimental uncertainties was obtained between the different groups although the measurement uncertainties are large, ranging between 3% and 30% depending upon the dose component and the depth of measurement. To improve the precision in the specification of absorbed dose amongst the participants, the individually measured dose components were normalized to the results from a single method. Assuming a boron concentration of 15 microg g(-1) that is typical of concentrations realized clinically with the boron delivery compound boronophenylalanine-fructose, systematic discrepancies in the specification of the total biologically weighted dose of up to 10% were apparent between the different groups. The results from these measurements will be used in future to normalize treatment plan calculations between the different clinical dosimetry protocols as Part II of this study.

Reference dosimetry at the neutron capture therapy facility at Studsvik.

The purpose of this publication was to present and evaluate the methods for reference dosimetry in the epithermal neutron beam at the neutron capture therapy facility at Studsvik. Measurements were performed in a PMMA phantom and in air using ionization chambers and activation probes in order to calibrate the epithermal neutron beam. Appropriate beam-dependant calibration factors were determined using Monte Carlo methods for the detectors used in the present publication. Using the presented methodology, the photon, neutron and total absorbed dose to PMMA was determined with an estimated uncertainty of +/- 5.0%, +/- 25%, and +/- 5.5% (2 SD), respectively. The uncertainty of the determination of the photon absorbed dose was comparable to the case in conventional radiotherapy, while the uncertainty of the neutron absorbed dose is much higher using the present methods. The thermal neutron group fluence, i.e., the neutron fluence in the energy interval 0-0.414 eV, was determined with an estimated uncertainty of +/- 2.8% (2 SD), which is acceptable for dosimetry in epithermal neutron beams.

Boron neutron capture therapy for newly diagnosed glioblastoma multiforme: an assessment of clinical potential.

The purpose of this analysis was to assess the potential of BNCT, with L-boronophenylalanine (L-BPA), as first line radiotherapy for glioblastoma multiforme (GBM). The survival of patients with newly diagnosed GBM from a phase II BNCT study was compared with those from the two arms of a phase III study with conventional radiotherapy (RT) vs. RT plus concomitant and adjuvant medication with temozolomide (TMZ). A small subgroup, for which the methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) DNA-repair gene was known, was also considered. The results indicated that the use of BNCT with BPA should be explored in a stratified randomized phase II trial in which patients with the unmethylated MGMT DNA-repair gene are offered BNCT vs. RT plus TMZ.

Boron neutron capture therapy for newly diagnosed glioblastoma multiforme: an assessment of clinical potential.

The purpose of this study was to assess the potential of boron neutron capture therapy (BNCT), with a 6-h infusion of the boron carrier l-boronophenylalanine as a fructose preparation (BPA-f), as first-line radiotherapy for newly diagnosed glioblastoma multiforme (GBM). Patient survival data from a Phase II study using BNCT were compared with retrospective data from the two arms of a Phase III study using conventional radiotherapy (RT) in the reference arm and using RT plus concomitant and adjuvant medication with temozolomide (TMZ) in the experimental arm, and were also compared with small subgroups of these patients for whom the methylation status of the MGMT (O(6)-methylguanine-DNA methyltransferase) DNA repair gene was known. Differences in the baseline characteristics, salvage therapy after recurrence and levels of severe adverse events were also considered. The results indicate that BNCT offers a treatment that is at least as effective as conventional RT alone. For patients with an unmethylated MGMT DNA repair gene, a possible clinical advantage of BNCT over RT/TMZ was suggested. BNCT is a single-day treatment, which is of convenience to patients, with mild side effects, which would offer an initial 6 weeks of good-quality life during the time when patients would otherwise be undergoing daily treatments with RT and TMZ. It is suggested that the use of BNCT with a 6-h infusion of BPA-f should be explored in a stratified randomised Phase II trial in which patients with the unmethylated MGMT DNA repair gene are offered BNCT in the experimental arm and RT plus TMZ in the reference arm.

Neuropathological postmortem evaluation of BNCT for GBM.

BACKGROUND: Thirty patients with glioblastoma multiforme (GBM) were treated by boron neutron capture therapy (BNCT) at the Studsvik facility in Sweden, in a clinical trial exploring a procedure in which 900 mg p-boronophenylalanine (BPA) per kilo body weight was infused in 6 h. OBJECTIVE: The present study was designed to assess tumor efficacy and radiation damage to the brain for the seven patients in the Studsvik trial that were available for postmortem neuropathological examination. METHOD: Whole brain slices containing the initial tumor site and other regions showing pathological changes were chosen for microscopy and selected areas were studied by immunological methods. RESULTS: Local control of GBM was observed in all cases. Conclusive evidence for radiation induced brain damage was not found. CONCLUSION: Using a novel procedure for BPA infusion, BNCT achieves local control of GBM for minimum tumor doses as low as 15 wGy, allowing treatment with very low concomitant doses to surrounding healthy tissues.

Neuropeptidomics: expanding proteomics downwards.

Biological function is mainly carried out by a dynamic population of proteins and peptides which may be used as markers for disease diagnosis, prognosis and as a guide for effective treatment. The study of proteins is called proteomics and it is generally performed by two-dimensional gel electrophoresis and mass spectrometric methods. However, gel-based proteomics is methodologically restricted from the low mass region, which includes important endogenous peptides. The study of endogenous peptides, peptidomics, is complicated by protein fragments produced post-mortem during conventional sample handling. Nanoflow liquid chromatography and MS, together with improved methods for sample preparation, have been used to semi-quantitatively monitor endogenous peptides in brain tissue. When rapidly heat-denatured brain tissue was analysed, these methods enabled simultaneous detection of hundreds of peptides and the identification of several endogenous peptides not previously described in the literature. In an application of the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model for Parkinson's disease, the expression of the small protein PEP-19 was compared with controls. The levels were found to be significantly decreased in the striatum of MPTP-treated animals.

BNCT for recurrent intracranial meningeal tumours - case reports.

OBJECTIVES: The investigation was designed to explore the efficacy of boron neutron capture therapy (BNCT) as treatment for recurrent intracranial meningeal tumours. MATERIALS AND METHODS: Three patients with meningeal tumours, recurring after initial surgery, radiation therapy and several reoperations, were evaluated for treatment with BNCT by determination of the accumulation of boronophenylalanine fructose (BPA-F) in tumour and in surrounding tissue. Two of these patients were subsequently treated by BNCT. RESULTS: The present results indicate that BNCT could be effective in prolonging time to recurrence, and thus in extending survival time, for patients with recurrent intracranial meningeal tumours. CONCLUSIONS: BNCT is potentially an effective radiation treatment modality for malignant intracranial meningeal tumours, which could increase progression-free survival, thus reducing the need for additional surgical interventions. Indications for BNCT would be even larger if recurrent grade II meningiomas could be treated, as indicated by the results of the boron uptake study.

Effect of a chlorhexidine/thymol-containing varnish on prostaglandin E2 levels in gingival crevicular fluid.

The aim was to study the effect of a chlorhexidine/thymol-containing varnish (Cervitec) on the levels of prostaglandin E2 (PGE2) in gingival crevicular fluid (GCF). The material consisted of 25 adolescents and young adults with fixed orthodontic appliances exhibiting gingival inflammation. Four buccal sites, adjacent to bands and brackets, were selected on each patient and randomly treated with either a varnish containing chlorhexidine diacetate (1% w/w) and thymol (1% w/w) or a placebo varnish without active ingredients. After baseline registration, the varnishes were applied twice within 3 d. Follow-up examinations were performed after 3, 8 and 30 d. The gingival inflammation was assessed by bleeding on probing, volume of GCF with a Periotron 8000 and PGE2 level in GCF by using a radioimmuno assay. Compared with baseline, a statistically significant reduction in the volume of GCF was recorded at the chlorhexidine/thymol treated sites in contrast to the placebo. The mean PGE2 levels were significantly reduced after the test varnish treatment compared with baseline and differed significantly from placebo after 8 d. The findings suggest that treatments with the antibacterial varnish result in reduced gingival inflammation and may thus be beneficial for patients with fixed orthodontic appliances.