Correlation between apparent diffusion coefficient value on diffusion-weighted MR imaging and Gleason score in prostate cancer.

OBJECTIVES: To investigate whether diffusion-weighted imaging (DWI) apparent diffusion coefficient (ADC) correlates with prostate cancer aggressiveness and further to compare the diagnostic performance of ADC and normalized ADC (nADC: normalized to non-tumor tissue). PATIENTS AND METHODS: Thirty pre-treatment patients (mean age, 69years; range: 59-78years) with prostate cancer underwent magnetic resonance imaging (MRI) examination, including DWI with three b values: 50, 400, and 800s/mm2. Both ADC and nADC were correlated with the Gleason score obtained through transrectal ultrasound-guided biopsy. RESULTS: The tumor minimum ADC (ADCmin: the lowest ADC value within tumor) had an inverse correlation with the Gleason score (r=-0.43, P<0.05), and it was lower in patients with Gleason score 3+4 than in those with Gleason score 3+3 (0.54±0.11×103mm2/s vs. 0.64±0.12×10-3mm2/s, P<0.05). Both the nADCmin and nADCmean correlated with the Gleason score (r=-0.52 and r=-0.55, P<0.01; respectively), and they were lower in patients with Gleason score 3+4 than those with Gleason score 3+3 (P<0.01; respectively). Receiver operating characteristic (ROC) analysis showed that the area under the ROC curve was 0.765, 0.818, or 0.833 for the ADCmin, nADCmin, or nADCmean; respectively, in differentiating between Gleason score 3+4 and 3+3 tumors. CONCLUSION: Tumor ADCmin, nADCmin, and nADCmean are useful markers to predict the aggressiveness of prostate cancer.

Performance of two commercial electron beam algorithms over regions close to the lung-mediastinum interface, against Monte Carlo simulation and point dosimetry in virtual and anthropomorphic phantoms.

Electron radiotherapy is applied to treat the chest wall close to the mediastinum. The performance of the GGPB and eMC algorithms implemented in the Varian Eclipse treatment planning system (TPS) was studied in this region for 9 and 16 MeV beams, against Monte Carlo (MC) simulations, point dosimetry in a water phantom and dose distributions calculated in virtual phantoms. For the 16 MeV beam, the accuracy of these algorithms was also compared over the lung-mediastinum interface region of an anthropomorphic phantom, against MC calculations and thermoluminescence dosimetry (TLD). In the phantom with a lung-equivalent slab the results were generally congruent, the eMC results for the 9 MeV beam slightly overestimating the lung dose, and the GGPB results for the 16 MeV beam underestimating the lung dose. Over the lung-mediastinum interface, for 9 and 16 MeV beams, the GGPB code underestimated the lung dose and overestimated the dose in water close to the lung, compared to the congruent eMC and MC results. In the anthropomorphic phantom, results of TLD measurements and MC and eMC calculations agreed, while the GGPB code underestimated the lung dose. Good agreement between TLD measurements and MC calculations attests to the accuracy of "full" MC simulations as a reference for benchmarking TPS codes. Application of the GGPB code in chest wall radiotherapy may result in significant underestimation of the lung dose and overestimation of dose to the mediastinum, affecting plan optimization over volumes close to the lung-mediastinum interface, such as the lung or heart.

Radiobiological evaluation of breast cancer radiotherapy accounting for the effects of patient positioning and breathing in dose delivery. A meta analysis.

In breast cancer radiotherapy, significant discrepancies in dose delivery can contribute to underdosage of the tumor or overdosage of normal tissue, which is potentially related to a reduction of local tumor control and an increase of side effects. To study the impact of these factors in breast cancer radiotherapy, a meta analysis of the clinical data reported by Mavroidis et al. (2002) in Acta Oncol (41:471-85), showing the patient setup and breathing uncertainties characterizing three different irradiation techniques, were employed. The uncertainties in dose delivery are simulated based on fifteen breast cancer patients (5 mastectomized, 5 resected with negative node involvement (R-) and 5 resected with positive node involvement (R1)), who were treated by three different irradiation techniques, respectively. The positioning and breathing effects were taken into consideration in the determination of the real dose distributions delivered to the CTV and lung in each patient. The combined frequency distributions of the positioning and breathing distributions were obtained by convolution. For each patient the effectiveness of the dose distribution applied is calculated by the Poisson and relative seriality models and a set of parameters that describe the dose-response relations of the target and lung. The three representative radiation techniques are compared based on radiobiological measures by using the complication-free tumor control probability, P(+) and the biologically effective uniform dose, (BEUD)concepts. For the Mastectomy case, the average P(+) values of the planned and delivered dose distributions are 93.8% for a (BEUD)(CTV) of 51.8 Gy and 85.0% for a (BEUD)(CTV) of 50.3 Gy, respectively. The respective total control probabilities, P(B) values are 94.8% and 92.5%, whereas the corresponding total complication probabilities, P(1) values are 0.9% and 7.4%. For the R- case, the average P(+) values are 89.4% for a (BEUD)(CTV) of 48.9 Gy and 88.6% for a (BEUD)(CTV) of 49.2 Gy and 85.5% for a (BEUD)(CTV) of 49.1 Gy, respectively. The respective PB values are 90.2% and 90.1%, whereas the corresponding P(+) values are 4.1% and 4.6%. The combined effects of positioning uncertainties and breathing can introduce a significant deviation between the planned and delivered dose distributions in lung in breast cancer radiotherapy. The positioning and breathing uncertainties do not affect much the dose distribution to the CTV. The simulated delivered dose distributions show larger lung complication probabilities than the treatment plans. This means that in clinical practice the true expected complications are underestimated. Radiation pneumonitis of Grade 1-2 is more frequent and any radiotherapy optimization should use this as a more clinically relevant endpoint.

A TL-based anthropomorphic benchmark for verifying 3-D dose distributions from external electron beams calculated by radiotherapy treatment planning systems.

Initial results are reported of a Polish-Finnish project to verify electron dose distributions calculated by treatment planning systems (TPSs), CadPlan v.6.3.2 and Theraplan v.3.5, which use different electron beam dose distribution algorithms. Treatment of gross tumour volumes representing lung and parotid cancer was simulated in an Alderson anthropomorphic phantom with thermoluminescent detectors (TLDs) (Li(2)B(4)O(7):Mn,Si) placed at selected measurement points inside its volume. The observed discrepancy between relative values of dose calculated and measured by TLDs at each of the measurement points and those calculated by the different TPSs at the same points is discussed.

Clinical validation of the LKB model and parameter sets for predicting radiation-induced pneumonitis from breast cancer radiotherapy.

The choice of the appropriate model and parameter set in determining the relation between the incidence of radiation pneumonitis and dose distribution in the lung is of great importance, especially in the case of breast radiotherapy where the observed incidence is fairly low. From our previous study based on 150 breast cancer patients, where the fits of dose-volume models to clinical data were estimated (Tsougos et al 2005 Evaluation of dose-response models and parameters predicting radiation induced pneumonitis using clinical data from breast cancer radiotherapy Phys. Med. Biol. 50 3535-54), one could get the impression that the relative seriality is significantly better than the LKB NTCP model. However, the estimation of the different NTCP models was based on their goodness-of-fit on clinical data, using various sets of published parameters from other groups, and this fact may provisionally justify the results. Hence, we sought to investigate further the LKB model, by applying different published parameter sets for the very same group of patients, in order to be able to compare the results. It was shown that, depending on the parameter set applied, the LKB model is able to predict the incidence of radiation pneumonitis with acceptable accuracy, especially when implemented on a sub-group of patients (120) receiving [see text]|EUD higher than 8 Gy. In conclusion, the goodness-of-fit of a certain radiobiological model on a given clinical case is closely related to the selection of the proper scoring criteria and parameter set as well as to the compatibility of the clinical case from which the data were derived.

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.

Photon scatter in intensity modulating filters evaluated by first Compton scatter and Monte Carlo calculations and experiments in broad beams.

High-atomic-number materials may be used as intensity modulating filters for inverse radiation treatment planning with photon beams. Such filters, when placed in a bremsstrahlung beam, attenuate the primary fluence, but also produce scattered photons that will reach the patient. To account for such effects in the optimization of photon beam intensities a semiempirical method based on narrow and broad beam transmission measurements was used to quantify the number of scattered photons produced in these filters. The method was verified by performing analytical calculations based on first scatter and a Monte Carlo simulation in 6 and 18 MV photon beams. The resultant experimental transmission ratios agree with calculations by these methods within 2 per cent under the experimental conditions investigated. The semiempirical method can thus be used as a basis for preliminary decision-making to select the proper material for intensity modulating filters and can provide a fast method to perform independent quality checks of the calculation accuracy of dose planning systems. Change in beam penetration is of less concern when treatments of target volumes at smaller depths are of interest. A 10 g cm(-2) thick filter made of low-melting-point alloy produces a change in percentage depth dose of less than 2 per cent for depths larger than 10 cm independent of field size. Similarly the scatter correction modifies the dose distribution by less than 5-10 per cent in most cases.

Optimization of the dose level for a given treatment plan to maximize the complication-free tumor cure.

During the past decade, tumor and normal tissue reactions after radiotherapy have been increasingly quantified in radiobiological terms. For this purpose, response models describing the dependence of tumor and normal tissue reactions on the irradiated volume, heterogeneity of the delivered dose distribution and cell sensitivity variations can be taken into account. The probability of achieving a good treatment outcome can be increased by using an objective function such as P+, the probability of complication-free tumor control. A new procedure is presented, which quantifies P+ from the dose delivery on 2D surfaces and 3D volumes and helps the user of any treatment planning system (TPS) to select the best beam orientations, the best beam modalities and the most suitable beam energies. The final step of selecting the prescribed dose level is made by a renormalization of the entire dose plan until the value of P+ is maximized. The index P+ makes use of clinically established dose-response parameters, for tumors and normal tissues of interest, in order to improve its clinical relevance. The results, using P+, are compared against the assessments of experienced medical physicists and radiation oncologists for two clinical cases. It is observed that when the absorbed dose level for a given treatment plan is increased, the treatment outcome first improves rapidly. As the dose approaches the tolerance of normal tissues the complication-free cure begins to drop. The optimal dose level is often just below this point and it depends on the geometry of each patient and target volume. Furthermore, a more conformal dose delivery to the target results in a higher control rate for the same complication level. This effect can be quantified by the increased value of the P+ parameter.

Optimal electron and combined electron and photon therapy in the phase space of complication-free cure.

The possibility of using intensity-modulated high-energy electrons beams alone or in combination with photon beams to treat tumours located at depths from 5 cm to 25 cm has been investigated. A radiobiologically based optimization algorithm using the probability of complication-free tumour control has been used to calculate the optimal dose distributions. Two different target volumes have been used; one advanced cervical cancer with locally involved lymph nodes and one astrocytoma in the upper brain hemisphere. Treatments with only electron beams and also combinations between electron and photon beams have been investigated. The dependence of the expected treatment outcome on the beam energy and directions was investigated, and to some extent on the number of beam portals. It is shown that the beam direction intervals resulting in a high expected treatment outcome increase with increasing electron energy and also with some electron-photon combinations. For an eccentrically placed, not too deeply situated tumour surrounded by sensitive normal tissue it is shown that the expected treatment outcome can be improved by using electron beams in combination with photon beams compared with using two photon beams, and using two electron beams results in almost as high an expected treatment outcome. The possibility of improving the dose conformity from electron beams by adding photon fields parallel or orthogonal to the electron beams is demonstrated.

Dose accuracy check of the 3D electron beam algorithm in a treatment planning system.

The accuracy of the recently implemented three-dimensional electron beam dose calculating algorithm in CADPLAN version 2.62 manufactured by Varian Dosetek was investigated. The algorithm uses a generalized Gaussian pencil beam model and the dose distributions are calculated as the sum of three weighted Gaussians. To use the calculating program in an optimum way, one needs to know the dose calculation accuracy of the algorithm as well as its limitations. This investigation includes comparisons of measured relative dose distributions with calculated dose distributions and also comparisons of measured and calculated monitor units. The geometries tested were quadratic fields, irregularly shaped fields, oblique fields, irregularly shaped phantom surfaces and internal heterogeneities and were most often irradiated with 8 and 20 MeV electrons. The results indicate that the algorithm is well suited for clinical three-dimensional dose planning. Some deviations occurred but they were most often within the limits of international criteria of acceptability.

Optimization of 3D conformal electron beam therapy in inhomogeneous media by concomitant fluence and energy modulation.

The possibilities of using simultaneous fluence and energy modulation techniques in electron beam therapy to shape the dose distribution and almost eliminate the influences of tissue inhomogeneities have been investigated. By using a radiobiologically based optimization algorithm the radiobiological properties of the tissues can be taken into account when trying to find the best possible dose delivery. First water phantoms with differently shaped surfaces were used to study the effect of surface irregularities. We also studied water phantoms with internal inhomogeneities consisting of air or cortical bone. It was possible to improve substantially the dose distribution by fluence modulation in these cases. In addition to the fluence modulation the most suitable single electron energy in each case was also determined. Finally, the simultaneous use of several preselected electron beam energies was also tested, each with an individually optimized fluence profile. One to six electron energies were used, resulting in a slow improvement in complication-free cure with increasing number of beam energies. To apply these techniques to a more clinically relevant situation a post-operative breast cancer patient was studied. For simplicity this patient was treated with only one anterior beam portal to clearly illustrate the effect of inhomogeneities like bone and lung on the dose distribution. It is shown that by using fluence modulation the influence of dose inhomogeneities can be significantly reduced. When two or more electron beam energies with individually optimized fluence profiles are used the dose conformality to the internal target volume is further increased, particularly for targets with complex shapes.

Quantification of mean energy and photon contamination for accurate dosimetry of high-energy electron beams.

The scientific background of the standard procedure for determination of the mean electron energy at the phantom surface (E0) from the half-value depth (R50) has been studied. The influence of energy, angular spread and range straggling on the shape of the depth dose distribution and the R50 and Rp ranges is described using the simple Gaussian range straggling model. The relation between the R50 and Rp ranges is derived in terms of the variance of the range straggling distribution. By describing the mean energy imparted by the electrons both as a surface integral over the incident energy fluence and as a volume integral over the associated absorbed dose distribution, the relation between E0 and different range concepts, such as R50 and the maximum dose and the surface dose related mean energy deposition ranges, Rm and R0, is analysed. In particular the influence of multiple electron scatter and phantom generated bremsstrahlung on R50 is derived. A simple analytical expression is derived for the ratio of the incident electron energy to the half-value depth. Also, an analytical expression is derived for the maximum energy deposition in monoenergetic plane-parallel electron beams in water for energies between 2 and 50 MeV. Simple linear relations describing the relative absorbed dose and mass ionization at the depth of the practical range deposited by the bremsstrahlung photons generated in the phantom are derived as a function of the incident electron energy. With these relations and a measurement of the extrapolated photon background at Rp, the treatment head generated bremsstrahlung distribution can be determined. The identification of this photon contamination allows an accurate calculation of the absorbed dose in electron beams with a high bremsstrahlung contamination by accounting for the difference in stopping power ratios between a clean electron beam and the photon contamination. The absorbed dose determined using ionization chambers in heavily photon contaminated (10%) electron beams may be too low--by as much as 1.5%--without correction.

The role of phantom and treatment head generated bremsstrahlung in high-energy electron beam dosimetry.

An analytical expression has been derived for the phantom generated bremsstrahlung photons in plane-parallel monoenergetic electron beams normally incident on material of any atomic number (Be, H2O, Al, Cu and U). The expression is suitable for the energy range from 1 to 50 MeV and it is solely based on known scattering power and radiative and collision stopping power data for the material at the incident electron energy. The depth dose distribution due to the bremsstrahlung generated by the electrons in the phantom is derived by convolving the bremsstrahlung energy fluence produced in the phantom with a simple analytical energy deposition kernel. The kernel accounts for both electrons and photons set in motion by the bremsstrahlung photons. The energy loss by the primary electrons, the build-up of the electron fluence and the generation, attenuation and absorption of bremsstrahlung photons are all taken into account in the analytical formula. The longitudinal energy deposition kernel is derived analytically and it is consistent with both the classical biexponential relation describing the photon depth dose distribution and the exponential attenuation of the primary photons. For comparison Monte Carlo calculated energy deposition distributions using ITS3 code were used. Good agreement was found between the results with the analytical expression and the Monte Carlo calculation. For tissue equivalent materials, the maximum total energy deposition differs by less than 0.2% from Monte Carlo calculated dose distributions. The result can be used to estimate the depth dependence of phantom generated bremsstrahlung in different materials in therapeutic electron beams and the bremsstrahlung production in different electron absorbers such as scattering foils, transmission monitors and photon and electron collimators. By subtracting the phantom generated bremsstrahlung from the total bremsstrahlung background the photon contamination generated in the treatment head can be determined to allow accurate dosimetry of heavily photon contaminated electron beams.

Optimization of conformal electron beam therapy using energy- and fluence-modulated beams.

Fluence modulation of multiple electron beams of various energies has been used to optimize the delivered dose distribution during electron beam radiation therapy. By maximizing the probability of achieving tumor control without causing severe complications electron beam fluence profiles have been optimized for superficial target volumes. It is possible to use several equiportal fluence-modulated electron beams to modify the energy deposition with depth in a controlled manner making it possible to use the technique as an alternative to bolus. The technique was tested in two representative phantom geometries and in three clinical patient geometries using a set of five and two different energies. The local maxima in dose for the plans with five energies were typically lower than with the conventional or advanced bolus techniques. The principles for how the technique could be carried out in the future with a fourth generation radiotherapy accelerator are also indicated.

An improved energy-range relationship for high-energy electron beams based on multiple accurate experimental and Monte Carlo data sets.

A theoretically based analytical energy-range relationship has been developed and calibrated against well established experimental and Monte Carlo calculated energy-range data. Only published experimental data with a clear statement of accuracy and method of evaluation have been used. Besides published experimental range data for different uniform media, new accurate experimental data on the practical range of high-energy electron beams in water for the energy range 10-50 MeV from accurately calibrated racetrack microtrons have been used. Largely due to the simultaneous pooling of accurate experimental and Monte Carlo data for different materials, the fit has resulted in an increased accuracy of the resultant energy-range relationship, particularly at high energies. Up to date Monte Carlo data from the latest versions of the codes ITS3 and EGS4 for absorbers of atomic numbers between four and 92 (Be, C, H2O, PMMA, Al, Cu, Ag, Pb and U) and incident electron energies between 1 and 100 MeV have been used as a complement where experimental data are sparse or missing. The standard deviation of the experimental data relative to the new relation is slightly larger than that of the Monte Carlo data. This is partly due to the fact that theoretically based stopping and scattering cross-sections are used both to account for the material dependence of the analytical energy-range formula and to calculate ranges with the Monte Carlo programs. For water the deviation from the traditional energy-range relation of ICRU Report 35 is only 0.5% at 20 MeV but as high as -2.2% at 50 MeV. An improved method for divergence and ionization correction in high-energy electron beams has also been developed to enable use of a wider range of experimental results.

Comparison of performance standards for radiation beam uniformity characteristics of a linear accelerator.

The recent international standards published by the International Electrotechnical Commission (IEC) on the performance of medical electron accelerators describe suggested test procedures for the performance of radiotherapy accelerators. The recommendations of the Nordic Association of Clinical Physics for testing of the radiation beam characteristics include test conditions, methods and suggested tolerances that are different from those of the IEC. In this work the two publications were compared for acceptance testing of a Philips SL25 linear accelerator. It is important to gain experience on the practical use of these standards.

Testing of autonomic cardiovascular regulation--methodological considerations.

The different analyses of the results on autonomic nervous function tests were evaluated in 43 male and 32 female diabetic patients and in 24 male and 24 female control subjects, aged 47-67 years, all without any known heart disease. The Valsalva ratio of the first effort did not differ from the mean Valsalva ratio of three efforts. During deep breathing, heart rate variation and max/min R-R interval ratio determined from the first three breathing cycles did not differ from the respective variables calculated from six consecutive breathing cycles. Diastolic blood pressure response to isometric handgrip was greater during the third minute than during the first and the first two minutes. In conclusion, the tests for the evaluation of autonomic nervous function can be simplified without losing their diagnostic value.

Quantitative radioisotope measurement of duodenogastric reflux in patients with ulcer or gastrectomized for ulcer.

In this work the duodenogastric reflux was quantified as the amount of radioactivity entering the stomach after an i.v. administration of 99mTc-HIDA in ulcer patients and in patients who had undergone BI gastrectomy. The results were compared with visual evidence of gastric activity in the gamma camera images and biochemical determination of gastric bile reflux. The method is useful in quantifying the reflux if the activity is above the background activity. It allows the determination of an upper limit for the reflux when the reflux is evident visually. Only two or three images are needed for the quantitation. No correlation was found between biochemical measurement of fasting bile reflux in the stomach and radioisotopic quantification.

Estimation of parameters affecting the uptake of 99mTc-methylenediphosphonate in rat femur with model simulation.

The uptake of 99mTc-methylenediphosphonate (MDP) in different parts of rat femur was simulated using a local three-space model for tracer transfer. The model consisted of bone blood, bone ECF-space and space for tracer deposition. The measured 99mTc-MDP concentration in the systemic blood and the local bone blood flow measured by 131I-macroaggregated albumin microspheres were used as input parameters. The measured blood flow values were 6.3, 3.1 and 15.3 ml/100 g/min for proximal, middle and distal femur, respectively. The model parameters that gave the best fit to measured 99mTc-MDP uptake curves in computer simulation showed that bone blood flow, volume of ECF-space, permeability surface area product and accretion constant from ECF-space to space for tracer deposition were highest in distal and lowest in middle femur. The values corresponded to peak extraction fractions of 0.38, 0.62, and 0.31 for proximal, middle and distal femur, respectively. We conclude that the simulation gives acceptable model parameters, and indicates applicability of a similar model into clinical quantitative bone scintigraphy.

Exercise capacity in subjects with high oxygen affinity.

Exercise capacity and hemodynamic parameters were measured in ten patients with a previously unpublished variant of hemoglobin (Hb-Linköping) and in ten age- and sex-matched controls. Bicycle ergometer test was almost maximal and the indices of working capacity and cardiac tolerance were similar in patients and controls. The hemoglobin dissociation curve was shifted to the left at rest and after exercise the shift to right was half of the corresponding shift in controls. Lactate accumulation during exercise was similar in patients and controls, also the elimination rate seems identical, but requires further studies. Hydrogen ion production in the patients during exercise was more marked than in the controls. If this is a sign of altered energy metabolism remains to be ascertained in future studies. In acute short-term exercise the patients with abnormally high hemoglobin oxygen affinity seem to have similar tolerance and cardiovascular load. Aberrant metabolism and adaptation to relative hypoxia in spite of erythrocytosis may have long-term effects that require long-term follow-up of these patients.