Biomedical subjects

A Brahme

Publications and source records attributed to A Brahme.

At least 19 recordsLinked to original sources

PubMed2006

Development of dose delivery verification by PET imaging of photonuclear reactions following high energy photon therapy.

A method for dose delivery monitoring after high energy photon therapy has been investigated based on positron emission tomography (PET). The technique is based on the activation of body tissues by high energy bremsstrahlung beams, preferably with energies well above 20 MeV, resulting primarily in 11C and 15O but also 13N, all positron-emitting radionuclides produced by photoneutron reactions in the nuclei of 12C, 16O and 14N. A PMMA phantom and animal tissue, a frozen hind leg of a pig, were irradiated to 10 Gy and the induced positron activity distributions were measured off-line in a PET camera a couple of minutes after irradiation. The accelerator used was a Racetrack Microtron at the Karolinska University Hospital using 50 MV scanned photon beams. From photonuclear cross-section data integrated over the 50 MV photon fluence spectrum the predicted PET signal was calculated and compared with experimental measurements. Since measured PET images change with time post irradiation, as a result of the different decay times of the radionuclides, the signals from activated 12C, 16O and 14N within the irradiated volume could be separated from each other. Most information is obtained from the carbon and oxygen radionuclides which are the most abundant elements in soft tissue. The predicted and measured overall positron activities are almost equal (-3%) while the predicted activity originating from nitrogen is overestimated by almost a factor of two, possibly due to experimental noise. Based on the results obtained in this first feasibility study the great value of a combined radiotherapy-PET-CT unit is indicated in order to fully exploit the high activity signal from oxygen immediately after treatment and to avoid patient repositioning. With an RT-PET-CT unit a high signal could be collected even at a dose level of 2 Gy and the acquisition time for the PET could be reduced considerably. Real patient dose delivery verification by means of PET imaging seems to be applicable provided that biological transport processes such as capillary blood flow containing mobile 15O and 11C in the activated tissue volume can be accounted for.

Animals↗

PubMed2006

Influence of electrodes on the photon energy deposition in CVD-diamond dosimeters studied with the Monte Carlo code PENELOPE.

A new dosimeter, based on chemical vapour deposited (CVD) diamond as the active detector material, is being developed for dosimetry in radiotherapeutic beams. CVD-diamond is a very interesting material, since its atomic composition is close to that of human tissue and in principle it can be designed to introduce negligible perturbations to the radiation field and the dose distribution in the phantom due to its small size. However, non-tissue-equivalent structural components, such as electrodes, wires and encapsulation, need to be carefully selected as they may induce severe fluence perturbation and angular dependence, resulting in erroneous dose readings. By introducing metallic electrodes on the diamond crystals, interface phenomena between high- and low-atomic-number materials are created. Depending on the direction of the radiation field, an increased or decreased detector signal may be obtained. The small dimensions of the CVD-diamond layer and electrodes (around 100 microm and smaller) imply a higher sensitivity to the lack of charged-particle equilibrium and may cause severe interface phenomena. In the present study, we investigate the variation of energy deposition in the diamond detector for different photon-beam qualities, electrode materials and geometric configurations using the Monte Carlo code PENELOPE. The prototype detector was produced from a 50 microm thick CVD-diamond layer with 0.2 microm thick silver electrodes on both sides. The mean absorbed dose to the detector's active volume was modified in the presence of the electrodes by 1.7%, 2.1%, 1.5%, 0.6% and 0.9% for 1.25 MeV monoenergetic photons, a complete (i.e. shielded) (60)Co photon source spectrum and 6, 18 and 50 MV bremsstrahlung spectra, respectively. The shift in mean absorbed dose increases with increasing atomic number and thickness of the electrodes, and diminishes with increasing thickness of the diamond layer. From a dosimetric point of view, graphite would be an almost perfect electrode material. This study shows that, for the considered therapeutic beam qualities, the perturbation of the detector signal due to charge-collecting graphite electrodes of thicknesses between 0.1 and 700 microm is negligible within the calculation uncertainty of 0.2%.

Diamond↗

PubMed2006

Assessing the difference between planned and delivered intensity-modulated radiotherapy dose distributions based on radiobiological measures.

AIMS: Because of the highly conformal distributions that can be obtained with intensity-modulated radiotherapy (IMRT), any discrepancy between the intended and delivered distributions would probably affect the clinical outcome. Consequently, there is a need for a measure that would quantify those differences in terms of a change in the expected clinical outcome. MATERIALS AND METHODS: To evaluate such a measure, cancer of the cervix was used, where the bladder and rectum are proximal and partially overlapping with the internal target volume. A solid phantom simulating the pelvic anatomy was fabricated and a treatment plan was developed to deliver the prescribed dose to the phantom. The phantom was then irradiated with films positioned in several transverse planes. The racetrack microtron at 50 MV was used in the treatment planning and delivery processes. The dose distribution delivered was analysed based on the film measurements and compared against the treatment plan. The differences in the measurements were evaluated using both physical and biological criteria. Whereas the physical comparison of dose distributions can assess the geometric accuracy of delivery, it does not reflect the clinical effect of any measured dose discrepancies. RESULTS: It is shown how small inaccuracies in delivered dose can affect the treatment outcome in terms of complication-free tumour cure. CONCLUSIONS: With highly conformal IMRT, the accuracy of the patient set-up and treatment delivery are critical for the success of the treatment. A method is proposed to evaluate the precision of the delivered plan based on changes in complication and control rates as they relate to uncertainties in dose delivery.

Dose-Response Relationship, Radiation↗

PubMed2004

Influence of multiple scattering and energy loss straggling on the absorbed dose distributions of therapeutic light ion beams: I. Analytical pencil beam model.

The lateral and longitudinal distributions of absorbed dose of broad and narrow light ion beams in water are investigated. An analytical algorithm based on the generalized Fermi-Eyges theory is developed and used to calculate the effects of multiple scattering and range straggling on the dose distribution of light ion beams in water. A first-order Gaussian multiple scattering and energy loss straggling approach is generally sufficiently accurate for describing the lateral and longitudinal spread of the Bragg peak and the associated energy deposition distribution of therapeutic light ion beams at ranges of clinical interest. Nuclear reactions are not taken into account in this study. The analytical algorithm given in the present study allows an accurate description of the radial spread and the range straggling of light ions traversing matter. A verification of this approach by comparing with experimental data, Monte Carlo methods and other analytical techniques will be presented in a forthcoming paper.

Algorithms↗

PubMed2004

Biologically effective doses in radiotherapy of cervical carcinoma*.

Presented study evaluates biologically effective dose (BED) in patients receiving low-medium dose-rate (LDR/MDR) brachytherapy (BRT) plus external beam radiotherapy (XRT) based on tumor cell proliferation values in cancer of the cervix patients. This study includes 229 patients treated entirely by radiotherapy at the Centre Oncology in Krakow. Doses to Point A were estimated for total treatment for each brachytherapy insertion. BED3 were calculated for reference points in the rectum. The linear quadratic equation was used to calculate BED, which is proportional to log cell kill, and the normalized total dose (NTD), that is, equivalent to a 2 Gy fraction schedule. In BEDs 10 calculation overall treatment time for each patient. Tumor proliferation rate was based on Bromodeoxyuridine labeling index (BrdUrdLI) assessed on biopsy material before beginning the radiotherapy. Total BED at those points was summed for each patient. The medium overall treatment time was 90 days (range 30--210). The mean calculated total BED for point A for tumour and "early reactions" was equal to 104.0 Gy10 and 229.0 Gy3 for the rectum, equivalent to NTD=86.6 Gy and 137.4 Gy in 2 Gy fractions, respectively. Kaplan-Meier analysis revealed that age >50 years, higher than mean BRBEDs and totBEDs doses, gaps in treatments shorter than 40 days and disease free survival (DFS) was significant prognostic factor for overall survival. In the multivariate Cox anaysis age >50 years, BRBED10 >77 Gy and gaps ?40 days appeared to be significant for overall survival. None of the examined parameters was significant for tumor control. However, patientś age and shorter gaps in the treatment were predictive for DFS.

Carcinoma↗

PubMed2003

Low and high LET radiation-induced apoptosis in M059J and M059K cells.

PURPOSE: To investigate and compare the ability of DNA-dependent protein kinase (DNA-PK)-deficient and -proficient cells to undergo apoptosis after exposure to low and high linear energy transfer (LET) radiation. MATERIALS AND METHODS: A human glioma cell line M059J lacking the catalytic subunit of DNA-PK (DNA-PKcs) and its DNA-PKcs-proficient counterpart, M059K, were exposed to 1 and 4 Gy of accelerated nitrogen ions (14N, 140 eV nm(-1), 8-12 Gy min(-1)) or 60Co gamma-rays (0.2 eV nm(-1), 0.7 Gy min(-1)). The induction of apoptosis was studied up to 144 h post-irradiation using two different methods: morphological characterization of apoptotic cells after fluorescent staining and cell size distribution analysis to detect apoptotic bodies. In parallel, protein expression of DNA-PKcs and poly(ADP-ribose) polymerase (PARP) as well as DNA-PK and caspase-3 activity were investigated. RESULTS: Low and high LET radiations (4 Gy) induced a time-dependent apoptotic response in both cell lines. Low LET radiation induced a significantly elevated apoptotic response in M059J as compared with M059K cells at 144 h post-irradiation. Following high LET radiation exposure, there was no difference between the cell lines at this time. PARP cleavage was detected in M059J cells following both low and high LET irradiation, while only high LET radiation induced PARP cleavage in M059K cells. These cleavages occurred in the absence of caspase-3 activation. CONCLUSIONS: M059J and M059K cells both display radiation-induced apoptosis, which occur independently of caspase-3 activation. The apoptotic course differs between the two cell lines and is dependent on the quality of radiation.

Apoptosis↗

PubMed2003

Repairable-conditionally repairable damage model based on dual Poisson processes.

The advent of intensity-modulated radiation therapy makes it increasingly important to model the response accurately when large volumes of normal tissues are irradiated by controlled graded dose distributions aimed at maximizing tumor cure and minimizing normal tissue toxicity. The cell survival model proposed here is very useful and flexible for accurate description of the response of healthy tissues as well as tumors in classical and truly radiobiologically optimized radiation therapy. The repairable-conditionally repairable (RCR) model distinguishes between two different types of damage, namely the potentially repairable, which may also be lethal, i.e. if unrepaired or misrepaired, and the conditionally repairable, which may be repaired or may lead to apoptosis if it has not been repaired correctly. When potentially repairable damage is being repaired, for example by nonhomologous end joining, conditionally repairable damage may require in addition a high-fidelity correction by homologous repair. The induction of both types of damage is assumed to be described by Poisson statistics. The resultant cell survival expression has the unique ability to fit most experimental data well at low doses (the initial hypersensitive range), intermediate doses (on the shoulder of the survival curve), and high doses (on the quasi-exponential region of the survival curve). The complete Poisson expression can be approximated well by a simple bi-exponential cell survival expression, S(D) = e(-aD) + bDe(-cD), where the first term describes the survival of undamaged cells and the last term represents survival after complete repair of sublethal damage. The bi-exponential expression makes it easy to derive D(0), D(q), n and alpha, beta values to facilitate comparison with classical cell survival models.

Cell Line↗

PubMed2002

Comparison of Monte Carlo calculated electron slowing-down spectra generated by 60Co gamma-rays, electrons, protons and light ions.

When analysing the factors affecting the relative biological effectiveness (RBE) of different radiation qualities, it is essential to consider particularly the low-energy slowing-down electrons (around 100 eV to 1 keV) since they have the potential of inflicting severe damage to the DNA. We present a modified and extended version of the Monte Carlo code PENELOPE that enables scoring of slowing-down spectra. mean local energy imparted spectra and average intra-track nearest-neighbour energy deposition distances of the secondary electrons generated by different radiation qualities, such as electrons, photons, protons and light ions in general. The resulting spectra show that the low-linear energy transfer (LET) beams, 60Co gamma-rays and electrons with initial energies of 0.1 MeV and higher, have as expected approximately the same electron slowing-down fluence per unit dose in the biologically important low-energy interval. Consistent with the general behaviour of the RBE of low-energy electrons, protons and light ions, the low-energy electron slowing-down fluence per unit dose is larger than for low-LET beams, and it increases with decreasing initial projectile energy.

Cobalt Radioisotopes↗

PubMed2002

RBE of 50 MV scanned bremsstrahlung beams determined using clonogenic assay.

PURPOSE: In order to compare the biological effectiveness of a 50 MV scanned bremsstrahlung beam to (60)Co and 6 MV photons, the survival of Chinese hamster cells (V79-379A), human normal fibroblasts cells (GSH(+/+)) and human small cell lung cancer cells (U-1690) were analysed. MATERIALS AND METHODS: Cells were irradiated in vitro under aerobic conditions in a plastic phantom. Dose to the cells was determined using ferrous sulphate and ionization chamber dosimetry. A number of cell survival models were fitted to the experimental data, including the standard LQ model with and without the induced repair. In particular, a new model treating damage and repair separately was used in combination with a new technique for accurate RBE determination. RESULTS: The measured RBE for the three cell lines were 0.988 (0.984-0.992), 0.999 (0.996-1.002) and 1.013 (1.009-1.016) for V79-379A, GSH(+/+) and U-1690 respectively and thus 50 MV scanned beams did not differ more than a fraction of a per cent from conventional therapy beams. CONCLUSIONS: The present study gives RBE consistent with previously calculated RBEs based on photonuclear reaction cross-sections of high-energy photons.

Animals↗

PubMed2002

Radiation response of hypoxic and generally heterogeneous tissues.

PURPOSE: Biologically based treatment optimisation can be based on the local mean values of the number of clonogenic cells and the cellular radiation response taken over macroscopic tissue voxels. Steep oxygen gradients in tumours may often lead to microscopic distributions of radiation resistance at the cellular level, far beyond the geometrical resolution of current diagnostic and radiotherapeutic methods. The present work focuses on quantifying the radiobiological effect of such microscopic distributions through tissue-oxygenation modelling and on calculating the corresponding radiation response on both micro- and macroscopic scales. MATERIALS AND METHODS: A simple model of tissue vasculature was developed with microvascular density and heterogeneity as its main parameters. New analytical expressions are presented for calculating the effective radiation response of tissues with generally heterogeneous radiation resistance and clonogen density. RESULTS: The oxygen distributions derived for different parameter sets agree very well with clinically measured oxygen distributions for both tumours and normal tissues. In addition to the vascular density, vascular heterogeneity is an important factor while estimating the hypoxic fraction in tissue. It is shown that both the local and global dose-response relation for tissues with heterogeneous radiation resistance can be accurately calculated from the effective initial clonogen number N(0,eff) and the effective radiation resistance D(0,eff). New equations are derived for calculating these quantities, for instance, from measured oxygen distributions. CONCLUSIONS: With the new methods presented here, existing techniques to measure the micro- and macroscopic oxygen distribution either using standard tumour-type or patient-specific oxygenation data can be used for biologically based treatment plan optimisation.

Cell Survival↗

PubMed2002

Relative biological effectiveness of boron ions on human melanoma cells.

PURPOSE: To compare the difference in relative biological effectiveness (RBE) between (10)B ions and a (60)Co gamma-ray beam for human melanoma cells using in vitro cell survival based on a clonogenic assay. MATERIALS AND METHODS: Cells were irradiated in vitro under aerobic conditions with (60)Co and (10)B ions with different linear energy transfer (LET) (40, 80 and 160 eV nm(-1)). The dose to the cells was determined using ferrous sulphate dosimetry and an ionisation chamber. The standard linear-quadratic model and the newly proposed repairable conditionally repairable damage (RCR) model were used to calculate the RBE. RESULTS: The RBE at 10% cell survival for 40, 80 and 160 eV nm(-1) boron ions compared with (60)Co were 1.98 (1.83-2.22), 2.85 (2.64-3.11) and 3.37 (3.17-3.58), respectively, of almost independence of the model used in the calculation. CONCLUSIONS: Different cell survival models may generate different RBE, especially at low doses and high cell survival levels.

Apoptosis↗

PubMed2001

Individualizing cancer treatment: biological optimization models in treatment planning and delivery.

PURPOSE: During the last 30 years radiation therapy has developed from classical rectangular beams via conformation therapy with largely uniform dose delivery, but irregular field shapes, to fully intensity modulated dose delivery where the total dose distribution in the tumor can be fully controlled in three dimensions. This last step has been developed during the last 15-20 years and has opened up the possibilities for truly optimized radiation therapy. METHODS AND MATERIALS: Today it is not only possible to produce almost any desired dose distribution in the tumor volume. It is also possible to deliver the dose distribution, which has the highest probability to cure the patient without inducing severe complications in normal tissues. To fully exploit the advantages of intensity-modulated radiation therapy, quality of life or radiobiologic objectives have to be used, preferably combined with predictive assay of radiation sensitivity. RESULTS: This article will briefly discuss the biologic objective functions and the associated advantages in the treatment outcome using new approaches such as consideration of stochastic variations in sensitivity and optimization of the angle of incidence and fractionation schedule with intensity-modulated beams. Finally, different possibilities for realizing general three-dimensional intensity-modulated dose delivery will be discussed. CONCLUSIONS: Once accurate genetically and/or cell survival based predictive assays become available, radiation therapy will become an exact science allowing truly individual optimization considering also the panorama of side-effects that the patient is willing to accept.

Cell Survival↗

PubMed2001

Generalization of the normalized dose-response gradient to non-uniform dose delivery.

A generalization of the standard dose-response gradient to arbitrarily heterogeneous dose distributions has been developed. The generalized dose-response gradient is the scalar product of the vector representing the dose distribution and the gradient of the dose-response relation with respect to that dose vector. It is shown that, for a tumor, the individual gamma-values for each portion of the tumor divided by the corresponding local tumor control probability should be added to get the total value for the heterogeneously irradiated tumor. This corresponds to summing up the contributions of all tumor volumes so that the total value of the gradient is related to the logarithm of the total tumor clonogen number. General expressions are also derived for the change in the dose-response relation as a function of a change in the delivered dose distribution.

Dose Fractionation, Radiation↗

PubMed2001

Biologically optimized radiation therapy.

Advanced treatment optimization is possible using quantitative radiobiological dose response models. Although all present models are necessarily linked to a certain degree of uncertainty, this will only have a small influence on the relative shape of the resultant optimal dose distribution. However the exact dose level should perferably be determined clinically by dose escalation with the optimized dose plan as a control arm. It is shown that a large part of the biological effect of high linear energy transfer radiation is due to the spectrum of low-energy delta-electrons that can generate dense clusters of complex DNA damage. Such electrons are efficiently generated by low-energy photons or densely ionizing ion beams and to a considerably smaller degree by high-energy electrons, photons and protons. A new analytical expression is developed for the effective radiation resistance of heterogeneous tumors, making it possible to approximate the response of such tumors by the effective clonogen number N0,eff and the effective D0 value D0,eff. It is shown that a relatively small number of resistant tumor cells may well be sufficient to dominate the response of hypoxic or otherwise heterogeneous tumors. Finally, several examples are given of intensity-modulated dose distributions generated by multiple radiation modalities, the total effect of which is biologically optimized.

Cell Survival↗

PubMed2001

Cellular effects of high-intensity focused continuous wave ultrasound alone and in combination with X-rays.

PURPOSE: To investigate the cellular effects of 1.1 MHz high-intensity focused continuous wave (CW) ultrasound alone and in combination with X-rays. MATERIALS AND METHODS: V79 cells were exposed to ultrasound of different intensities for 30s (non-hyperthermic conditions). In the combined treatments, cells were exposed to ultrasound (63 W/cm2) either before or after 2 Gy X-irradiation. Cellular effects studied were clonogenic survival, DNA strand breaks (pulsed-field gel electrophoresis, DNA precipitation assay) and membrane integrity (morphological analysis). RESULTS: With increasing ultrasound intensity, cell survival decreased in a dose-dependent manner as the induction of DNA strand breaks, the fraction of cells with lost membrane integrity and cell lysis increased. In the treatments with combined exposures, the regimen with X-rays before ultrasound had a nearly additive effect on cell kill, whereas the reverse regimen with ultrasound exposure before X-irradiation resulted in a synergistic effect (p<0.012). CONCLUSIONS: High-intensity focused CW ultrasound induces an intensity-dependent reduction in clonogenic survival in V79 cells, which seems to depend on both DNA and membrane damage. Combined exposures of ultrasound and X-rays resulted in a synergistic reduction in cell survival when cells were exposed to ultrasound before X-rays but not for the reverse regimen. Thus, a larger fraction of the repairable sublethal cell damage induced by an initial ultrasound exposure was rendered non-repairable by a subsequent X-ray exposure than if the reverse treatment order was used.

Animals↗

PubMed2001

Biologically effective uniform dose (D) for specification, report and comparison of dose response relations and treatment plans.

Developments in radiation therapy planning have improved the information about the three-dimensional dose distribution in the patient. Isodose graphs, dose volume histograms and most recently radiobiological models can be used to evaluate the dose distribution delivered to the irradiated organs and volumes of interest. The concept of a biologically effective uniform dose (D) assumes that any two dose distributions are equivalent if they cause the same probability for tumour control or normal tissue complication. In the present paper the D concept both for tumours and normal tissues is presented, making use of the fact that probabilities averaged over both dose distribution and organ radiosensitivity are more relevant to the clinical outcome than the expected number of surviving clonogens or functional subunits. D can be calculated in complex target volumes or organs at risk either from the 3D dose matrix or from the corresponding dose volume histograms of the dose plan. The value of the D concept is demonstrated by applying it to two treatment plans of a cervix cancer. Comparison is made of the D concept with the effective dose (Deff ) and equivalent uniform dose (EUD) that have been suggested in the past. The value of the concept for complex targets and fractionation schedules is also pointed out.

Dose Fractionation, Radiation↗

PubMed2001

Photon scatter kernels for intensity modulating radiation therapy filters.

The most important beam property while optimizing photon therapy is the ability to modulate the intensity of the beam. The use of photon absorbers for intensity modulation of beam profiles requires special attention to be paid to the alteration of beam properties due to scatter and spectral changes, in addition to the desired intensity modulation. In this study the influence of photon scatter in high-density filters irradiated with very narrow photon pencil beams was investigated. A simple analytical relation is developed to quantify the contribution by scattered photons. A scatter kernel was derived by convolving the first Compton scatter distribution with an approximate expression for the second-order scattered photons. The calculations were validated experimentally with film dosimetry and also by using Monte Carlo simulations. Results show that the difference in photon scatter estimation by different methods is relatively small when higher order scattering is accounted for. At 6 MV x-rays the agreement is slightly better than that for 18 MV x-rays results. The simple relation presented in this paper can be used to account for the scattered photon contribution in filter optimization codes to deliver biologically or physically optimized intensity modulated treatments.

Models, Statistical↗

PubMed2000

Development of radiation therapy optimization.

The principal radiobiological problems in the treatment of advanced tumors and the solution of many of them by radiobiologically optimized intensity-modulated radiation therapy are presented. Considerable improvements of the treatment outcome using radiobiologically optimized intensity-modulated treatments are achieved by: (a) increasing the tumor dose and dose per fraction; (b) keeping constant or even reducing slightly the dose and dose per fraction to organs at risk, (c) reducing the overall treatment time and the number of treatment fractions. The merits of the new radiation modalities and advanced intensity-modulated treatment techniques are compared in terms of equipment costs per patient cured. It is predicted that the new development of radiobiologically optimized intensity-modulated radiation therapy will rapidly become an important clinical tool, increasing the efficiency of the collaboration between radiation physicists, radiation biologists and radiation oncologists. Not only does it allow the optimal treatment of every patient, but it also promotes an efficient feedback of treatment outcome and complication data to improve the accuracy of known dose response relations to further augment future treatment results. Equipment costs may go up during a transition period until efficient interfaces between new diagnostic equipment, treatment-planning systems and intensity-modulated treatment units are fully developed. From then onwards the cost of high quality biologically optimized intensity-modulated treatments will decrease and so will the treatment time and personnel requirements, at the same time as the treatment quality is greatly improved particularly for more advanced tumors.

Dose Fractionation, Radiation↗