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Biomedical subjects

E Grusell

Publications and source records attributed to E Grusell.

At least 19 recordsLinked to original sources

Potential gains using high-energy protons for therapy of malignant tumours.

High-energy protons have physical properties that virtually always will result in geometrically better dose distributions than can be achieved using photons or electrons. The clinical gains in terms of the probability of higher tumour control and/or the reduced probability of normal tissue complications are, however, not completely known. Comparative model dose planning studies using real patients offer the possibility of estimating the potential gains using a new technique. Several recently completed model studies, including clinically relevant endpoints, indicate that protons may have advantages, even when compared with the conventional treatment that is likely to be introduced at the most advanced hospitals world-wide within the next decade. These advantages can be seen not only in well-demarcated targets close to risk organs, but also when irradiating extended irregular tissue volumes at risk of containing tumour cells.

Humans

Comparative treatment planning between proton and x-ray therapy in esophageal cancer.

PURPOSE: Conformal treatment planning with megavoltage x-rays and protons for five patients with esophageal cancer has been studied in an attempt to determine if there are advantages of using protons instead of x-rays. METHODS AND MATERIALS: For each of the five patients, two different proton plans, one x-ray plan, and one mixed plan with x-rays and protons were made. A three-dimensional treatment planning system, TMS, was used. The evaluation of the different plans was made by applying the tumor control probability (TCP) model proposed by Nahum and Webb and the normal tissue complication (NTCP) model proposed by Lyman on the dose distributions in terms of dose-volume histograms (DVHs). RESULTS: The comparison shows advantages of using protons instead of x-rays for all five patients. The dose-limiting organs at risk are the spinal cord, the lungs, and the heart, but the proton plans also spare the kidneys better than the x-ray plan does. At 5% NTCP in any risk organ, the calculated mean TCP value for the five patients is increased by an average of 20%-units (from 2 to 23%-units) with the best proton plan compared with x-rays only. However, if we assume maximally a 1% risk in the spinal cord and a total NTCP for the two lungs of 100%, the mean TCP value for the five patients is increased from 6 to 49% with the best proton plan compared with x-rays only. The corresponding figure for the mixed plan is 27%. These gains are relatively insensitive to variations within reasonable limits in the biological parameters. CONCLUSIONS: Protons appear to have clear therapeutic advantages over conventional external radiotherapy when treating esophageal carcinoma.

Aged

Fast 2D phantom dosimetry for scanning proton beams.

A quality control system especially designed for dosimetry in scanning proton beams has been designed and tested. The system consists of a scintillating screen (Gd2O2S:Tb), mounted at the beam-exit side of a phantom, and observed by a low noise CCD camera with a long integration time. The purpose of the instrument is to make a fast and accurate two-dimensional image of the dose distribution at the screen position in the phantom. The linearity of the signal with the dose, the noise in the signal, the influence of the ionization density on the signal, and the influence of the field size on the signal have been investigated. The spatial resolution is 1.3 mm (1 s.d.), which is sufficiently smaller than typical penumbras in dose distributions. The measured yield depends linearly on the dose and agrees within 5% with the calculations. In the images a signal to noise ration (signal/1 s.d.) of 10(2) has been found, which is in the same order of magnitude as expected from the calculations. At locations in the dose distribution possessing a strong contribution of high ionization densities (i.e., in the Bragg peak), we found some quenching of the light output, which can be described well by existing models if the beam characteristics are known. For clinically used beam characteristics such as a Spread Out Bragg peak, there is at most 8% deviation from the NACP ionization chamber measurements. The conclusion is that this instrument is a useful tool for quick and reliable quality control of proton beams. The long integration-time capabilities of the system make it worthwhile to investigate its applicability in scanning proton beams and other dynamic treatment modalities.

Brachytherapy

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.

Animals

Faraday cup dosimetry in a proton therapy beam without collimation.

A Faraday cup in a proton beam can give an accurate measurement of the number of protons collected by the cup. It is shown that the collection efficiency with a proper design can be close to unity. To be able to calibrate an ionization chamber from such a measurement, as is recommended in some dosimetry protocols, the energy spectrum of the proton beam must be accurately known. This is normally not the case when the lateral beam extension is defined by collimators. Therefore a method for relating an ionization chamber measurement in an uncollimated beam to the total number of protons in the beam has been developed and is described together with experimental results from calibrating an ionization chamber using this method in the therapeutic beam in Uppsala. This method is applicable to ionization chambers of any shape and the accuracy is estimated to be 1.6% (1 SD).

Biophysical Phenomena

Dose calculations in proton beams: range straggling corrections and energy scaling.

Three-dimensional dose planning systems employing accurate proton transport algorithms are essential for calculating absorbed dose distributions in proton therapy. In this paper, a pencil beam algorithm for the transport of protons in materials of interest for radiation therapy is developed. The Fermi-Eyges multiple-scattering theory is used to derive transport equations for calculating proton fluence and absorbed dose distributions. The multiple-scattering theory of Molière is used to predict mean square scattering angles and to develop an expression for calculating the root mean square (RMS) radial spread of a proton pencil beam, as a function of depth, in an arbitrary scattering material. A correction factor is suggested to account for the decrease in the radial spread at the end of the range due to range straggling. The effects of neglecting large-angle scattering events and the possibility of incorporating such events into the pencil beam algorithm are discussed. An energy scaling technique for determining the water-equivalent surface energy at a given depth in a heterogeneous scattering medium is developed. The water-equivalent energy, giving the same Molière scattering parameter B in water, is determined and the 1/e angle in water is scaled to the appropriate width in the scattering material. By using stored analytically or Monte Carlo calculated pencil beam distributions in water, the large-angle single-scattering events may be incorporated by approximating the scattering in an arbitrary material by the scattering in water for protons of the appropriate water-equivalent surface energy.

Algorithms

Ionization chamber dosimetry of proton beams using cylindrical and plane parallel chambers. Nw versus Nk ion chamber calibrations.

Determinations of the absorbed dose in a 170 MeV proton beam have been performed using seven ionization chambers of different types: five cylindrical (two FWT IC-18 and three NE-2571, of which one was modified to have the central electrode made of graphite) and two plane parallel (NACP-02 and Roos FK-6). The ionization was converted into absorbed dose in the proton beam according to the generalization of the formalism provided by the IAEA Code of Practice (TRS 277), which enables the use of the same equations for all kinds of beam used in radiotherapy. The absorbed dose obtained with the two IC-18 chambers, a chamber type commonly used as a reference in proton beams, was up to 1.5% lower than that obtained with the Farmer NE-2571 chamber, which was used as the reference in this work when calibration factors in terms of NK were used. To investigate this difference, experimental ND factors for six chambers (the two IC-18 chambers, the NACP-02, the FK-6 and two of the NE-2571 chambers) were determined in a high-energy electron beam. The procedure commonly recommended for plane parallel ion chambers was used for all the chambers, using the same reference chamber, a Farmer NE-2571. In the 170 MeV proton beam all the ND factors yielded consistent absorbed dose determinations within the estimated experimental uncertainties. This finding calls into question the value of the product kattkm for the IC-18 chamber given by the IAEA Code of Practice used in this comparison, and points at possible chamber to chamber variations that theoretical kattkm factors cannot predict. The investigations enabled the determination of the Pwall(60Co) factor of the Roos FK-6 plane parallel chamber, yielding 1.003 +/- 0.5%, and a correction for the effect of the aluminium central electrode of NE-2571 chambers in proton beams, equal to 1.003 +/- 0.4%. Two of the chambers (the plane parallel FK-6 and the modified cylindrical NE-2571) were provided with calibration factors in terms of absorbed dose to water, Nw, at the quality of 60Co by the Primary Standard Dosimetry Laboratory in Germany (PTB). Using the Nw formalism excellent agreement was found with the determination based on the experimental ND, giving support to the implementation of the NW procedure in therapeutic proton beams.

Humans

Patient positioning for fractionated precision radiation treatment of targets in the head using fiducial markers.

When irradiating targets in the brain, an accurately localised dose is often needed. One crucial moment to achieve this is the positioning of the patient. We have developed a positioning method where the patient is immobilised with a bite block and a head mould, and where the position of the target is determined by X-ray imaging of fiducial markers that are placed in the patient's skull. A method for computing the transformation needed to move the target from the observed to the prescribed position and orientation is described. This method uses the information from two orthogonal X-ray images and takes measurement errors and data from three or more markers into account. Results from using the method clinically in proton beam therapy are given.

Algorithms

Dose enhancement in fast neutron tumour therapy due to neutron captures in 10B.

High energy neutrons, applied in fast neutron tumour therapy, lose energy when passing through tissue and are at the end of their trajectories captured in nitrogen, hydrogen or other normally occurring elements. If the tissue contains 10B, which has a very high cross section for capture of thermal neutrons, then disintegration products of this process, helium and lithium ions, give a dose enhancement which, if the boron is targeted to tumour cells, may be beneficial. The dose enhancement was in the present study calculated as a function of the 10B concentration in the cells and as a function of different thermal neutron fluencies. If the tumour cells contained 10 or 100 microns 10B/g the average dose enhancement was about 20 or 200 mGy respectively. This was obtained with the thermal neutron fluency 2.0 x 10(10) n/cm2. The relative biological effectiveness of the neutron capture process is unknown but assuming the factor 2, these doses correspond to 0.04 or 0.4 CGE (cobolt-60 gray equivalent) respectively, which could directly be compared to the 2-3 Gy of low-LET radiation that is daily applied in conventional radiotherapy. However, if thermal or epithermal neutron fields are directly applied to the patients a hundred times higher thermal neutron fluency can be used. This gives, in the cases with 10 or 100 micrograms 10B/g, about a hundred times higher average doses so that 2-20 Gy, corresponding to about 4-40 CGE, can be given to the patients. Thus, a successful targeting with high amounts of 10B in the tumour cells gives a significant dose enhancement when applied in fast neutron therapy but it is then more reasonable to treat the patient directly with thermal or epithermal neutrons since the average dose enhancement in the latter case is about a hundred times higher and curable doses might be obtained by the tumour specific capture processes alone.

Boron Neutron Capture Therapy

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)

Animals

Cellular differentiation: a theory based on simulation with computer graphics.

Rules are outlined in order to construct graphically a computer model that deals with cell growth, multiplication and differentiation. The process starts with a multicoloured stem cell and the end product will be differentiated cells represented by different colours. Various biological processes and neoplastic transformation can also be simulated. Based on the idea that the model corresponds to real events, predictions are made about the possible results of future experiments.

Animals

A facility for biomedical experiments with thermal neutrons.

The Studsvik thermal-neutron facility was originally designed for neutron capture radiography (NCR) at high thermal-neutron fluence and low fast-neutron contamination. It has now been modified to permit irradiation of living cells and animals without the need for stopping and restarting the R2-0 reactor. Previous calculations of the thermal-neutron intensity at the NCR position were performed using the two-dimensional diffusion theory code DIXY. In this report the Monte Carlo program MCNP 3B is used to calculate the neutron fluence at the radiography position, and neutron and photon fluences at the positions of the cell specimens. The normalized neutron fluences from the calculations agree well with measured values and show that the contamination with high-energy neutrons is low. The agreement between measured and calculated photon doses was reasonable. The thermal-neutron fluence rate is (2.3 +/- 0.1) x 10(9) cm-2 s-1 at 100 kW at the NCR position and (0.96 +/- 0.03 x 10(9) cm-2 s-1 at 100 kW at the front plate of the loading tube. The photon dose is about (1.6 +/- 0.2) x 10(-12) Gy per neutron. Survival curves of V79 cells grown as monolayers and irradiated in the thermal neutron beam, with and without boron, are presented.

Animals

Quantitative neutron capture radiography for boron in biological specimens.

Track-etch detectors made of cellulose nitrate (LR 115, Kodak Pathé) and polycarbonate (CR 39, Pershore Mouldings Ltd) were compared regarding sensitivity and background when used as detectors for boron determination in biological samples. Measurements were made on two kinds of sample, cryosectioned biological tissue, and liquid samples deposited directly on the detector surface as microdroplets. The CR 39 films were pretreated or washed before irradiation. When cryosectioned tissue was used, measurements were made with and without the inclusion of Mylar foils between the samples and the detectors. Foil thicknesses used were 2 microns in the case of LR 115 and 2, 4, and 6 microns in the case of CR 39. All samples were irradiated with a thermal-neutron fluence of 5 x 10(12) neutrons cm-2 at the thermal-neutron facility in Studsvik, Sweden. The use of a Mylar foil generally suppressed the background tracks relative to the tracks from the 10B disintegration. No difference in resolution between CR 39 and LR 115 was observed. Pretreatment of the CR 39 resulted in an improved sensitivity of detection but the detector became saturated at 0.25 parts per million of 10B. The background was found to be lower in the pretreated detector.

Blood

Accumulation of 10B in the central degenerative areas of human glioma and colon carcinoma spheroids after sulfhydryl boron hydride administration.

Sulfhydryl boron hydride (BSH) (10B enriched) is presently used for boron neutron capture therapy of malignant gliomas. BSH must be close to the target cells to be effective in the inactivation of cell proliferation because of the short range of the reaction products (5-9 microns). Clinical experience indicates that BSH is taken up in gliomas but it is not known to which structures it binds at the cellular level. In vitro tests on monolayer cultured cells have indicated that BSH does not bind, or only shows very weak binding, to single isolated cells. It is possible that BSH accumulates in tumor regions due to the special conditions in poorly vascularized tumor tissue, such as low pO2, low extracellular pH, metabolic gradients, and degenerative changes. To test this we incubated three types of multicellular tumor spheroids with BSH for different times and analyzed both penetration and binding. The spatial distribution of 10B in sections of the spheroids was analyzed by neutron capture autoradiography. We found extensive accumulation of 10B in the central regions of both glioma and colon carcinoma spheroids. The accumulation closely followed the pattern of the degenerative changes which were characterized by massive necrosis in the central regions of the colon carcinoma spheroids and by a continuously increasing frequency of pyknotic nuclei as a function of depth in the glioma spheroids. The accumulation of 10B in the prostatic carcinoma spheroids was much lower. The penetration assay, based on freeze-drying and vapor fixation, showed that BSH penetrated easily since 10B equilibrated within 5-15 min in the studied spheroids. Thus, the low accumulation in the prostatic carcinoma spheroids was not due to penetration difficulties. The results of the present study on cellular spheroids and the results from previous studies on transplanted tumors support the observation that BSH penetrates easily into the degenerative tumor areas and that 10B, for some tumor types, might accumulate in these regions as a result of the BSH administration.

Autoradiography

Backscatter radiation at tissue-titanium interfaces. Analyses of biological effects from 60Co and protons.

It has been claimed that implanted metals can cause backscatter radiation in radiation therapy with a dose enhancement at the bone-metal and tissue-metal interfaces on the beam entrance side. Theoretical calculations and experimental measurements with ionization chambers have indicated that such effects might be significant. Titanium implants are increasingly used in oral and maxillo-facial surgery for reconstruction purposes. A more detailed knowledge of backscatter-induced effects is therefore desired when head and neck cancers in patients with implants are treated with radiotherapy. We have made comparisons of cell survival after irradiation of two types of cultured cells grown directly on titanium metal and on plastic control supports. The cell cultures were irradiated with either 60Co photons or range modulated protons. No significant differences in the colony-forming capacity were found between the irradiated cells grown on titanium and those grown on plastic control supports. This was the case for both radiation types and the results were also observed to be dose-independent. The only observed phenomena were that the two cell-lines differed in radiosensitivity and that protons gave higher biological effects than gamma radiation. The results show that there were no significant changes in cell survival at the interface between the tissue equivalent medium and titanium support indicating that a dose increase induced by backscatter radiation, which possibly could demolish the osseointegration or induce osteoradionecrosis, are minimal when high energy photons or range modulated protons are applied.

Animals

The narrow proton beam therapy unit at the the Svedberg Laboratory in Uppsala.

The synchrocyclotron at the The Svedberg Laboratory (TSL) in Uppsala is now reconstructed and can presently operate with fixed frequency and proton energies up to 100 MeV. A first treatment room with a narrow proton beam unit for therapy of eye tumours is now in operation. Therapy of eye melanomas started in April, 1989 and during 1989 and 1990, 19 patients were treated with 72 MeV protons. The narrow beam unit provides a fixed horizontal beam and the patient is treated in a seated position. The present paper describes mainly the technical aspects of the unit which so far has been used only for eye melanomas. In the future, modifications of the unit will allow therapy of intracranial targets when higher proton energies are available. In its final form, the proton therapy facility at TSL will harbour a second treatment unit. Here a rotating gantry for 200 MeV protons will provide a broad beam, which will enable treatment of tumours located anywhere in the body.

Eye Neoplasms

The possible use of a spallation neutron source for neutron capture therapy with epithermal neutrons.

Spallation is induced in a heavy material by 72-MeV protons. The resulting neutrons can be characterized by an evaporation spectrum with a peak energy of less than 2 MeV. The neutrons are moderated in two steps: first in iron and then in carbon. Results from neutron fluence measurements in a perspex phantom placed close to the moderator are presented. Monte Carlo calculations of neutron fluence in a water phantom are also presented under some chosen configurations of spallation source and moderator. The calculations and measurements are in good agreement and show that, for proton currents of less than 0.5 mA, useful thermal-neutron fluences are attainable in the depth of the brain. However, the dose contribution from the unavoidable gamma background component has not been included in the present investigation.

Boron