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Dimos Baltas

dimos.baltas@klinikum-offenbach.de

Journal articles

2008
 
PMID 
D Baltas, G Lymperopoulou, N Zamboglou (2008)  On the use of HDR 60Co source with the MammoSite radiation therapy system.   Med Phys 35: 12. 5263-5268 Dec  
Abstract: This work summarizes Monte Carlo results in order to evaluate the potential of using HDR 60Co sources in accelerated partial breast irradiation (APBI) with the MammoSite applicator. Simulations have been performed using the MCNP5 Monte Carlo Code, in simple geometries comprised of two concentric spheres; the internal consisting of selected concentrations, C, of a radiographic contrast solution in water (Omnipaque 300) to simulate the MammoSite balloon and the external consisting of water to simulate surrounding tissue. The magnitude of the perturbation of delivered dose due to the radiographic contrast medium used in the MammoSite applicator is calculated. At the very close vicinity of the balloon surface, a dose build-up region is observed, which leads to a dose overestimation by the treatment planning system (TPS) which depends on Omnipaque 300 solution concentration (and is in order of 2.3%, 3.0%, and 4.5%, respectively, at 1 mm away from the balloon - water interface, for C=10%, 15%, and 20%). However, dose overestimation by the TPS is minimal for points lying at the prescription distance (d=1 cm) or beyond, for all simulated concentrations and radii of MammoSite balloon. An analytical estimation of the integral dose outside the CTV in the simple geometries simulated shows that dose to the breast for MammoSite applications is expected to be comparable using HDR 60Co and 192Ir sources, and higher than that for 169Yb. The higher enegies of 60Co sources result to approximately twice radiation protection requirements as compared to 169Ir sources. However, they allow for more accurate dosimetry calculation with currently used treatment planning algorithms for 60Co sources, compared to 169Ir.
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P Papagiannis, D Baltas, D Granero, J Pérez-Calatayud, J Gimeno, F Ballester, J L M Venselaar (2008)  Radiation transmission data for radionuclides and materials relevant to brachytherapy facility shielding.   Med Phys 35: 11. 4898-4906 Nov  
Abstract: To address the limited availability of radiation shielding data for brachytherapy as well as some disparity in existing data, Monte Carlo simulation was used to generate radiation transmission data for 60Co, 137CS, 198Au, 192Ir 169Yb, 170Tm, 131Cs, 125I, and 103pd photons through concrete, stainless steel, lead, as well as lead glass and baryte concrete. Results accounting for the oblique incidence of radiation to the barrier, spectral variation with barrier thickness, and broad beam conditions in a realistic geometry are compared to corresponding data in the literature in terms of the half value layer (HVL) and tenth value layer (TVL) indices. It is also shown that radiation shielding calculations using HVL or TVL values could overestimate or underestimate the barrier thickness required to achieve a certain reduction in radiation transmission. This questions the use of HVL or TVL indices instead of the actual transmission data. Therefore, a three-parameter model is fitted to results of this work to facilitate accurate and simple radiation shielding calculations.
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2007
 
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Christos Kolotas, Nikolaos Tselis, Manon Sommerlad, Sandra Röddiger, Thomas Schnabel, Dimos Baltas, Anna Kalogera-Fountzila, George Fountzilas, Nikolaos Zamboglou (2007)  Reirradiation for recurrent neck metastases of head-and-neck tumors using CT-guided interstitial 192Ir HDR brachytherapy.   Strahlenther Onkol 183: 2. 69-75 Feb  
Abstract: PURPOSE: To report the therapeutic results obtained with CT-guided interstitial high-dose-rate brachytherapy (HDR-BRT) as exclusive treatment for recurrent neck metastases of head-and-neck tumors. PATIENTS AND METHODS: Between 1995 and 1999, 49 patients with prior radiation therapy (RT) with or without surgery for primary head-and-neck tumors were treated for recurrent neck metastases located within previously irradiated volumes. All patients had fixed lymphadenopathy with a mean tumor volume of 96 cm(3) (range, 15-452 cm(3)). There were 38 males and eleven females with a mean age of 60 years (range, 28-79 years). All patients had previously received RT as primary or adjuvant treatment with a mean dose of 54 Gy (range, 45-80 Gy). 36 patients (73%) underwent surgery, and 26 (53%) received adjuvant or palliative chemotherapy. The accelerated hyperfractionated interstitial HDR-BRT (2 x 3.0 Gy/day) delivered 30 Gy in 37/49 (75%) and 36 Gy in 12/49 implants (25%). RESULTS: At a minimum 6-week follow-up, the response rate was 83% (41/49) with complete remission in 20% (10/49) and partial remission in 63% (31/49) of the implanted tumor sites. 8/49 patients (17%) did not respond to the treatment. After 19 months of median follow-up, the local control rate was 69% and a total of 15/49 patients (30%) experienced local disease progression. Of these, nine (18%) had locoregional progression and six (12%) progression within the treated volume. The median post-BRT survival was 14 months. The overall survival rate was 52% at 1 year, 31% at 2 years, and 6% at 3 years. CONCLUSION: In patients with recurrent cervical lymphadenopathy of head-and-neck tumors, exclusive interstitial HDR-BRT can provide palliation and tumor control.
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Christian Kirisits, Frank-André Siebert, Dimos Baltas, Marisol De Brabandere, Taran Paulsen Hellebust, Daniel Berger, Jack Venselaar (2007)  Accuracy of volume and DVH parameters determined with different brachytherapy treatment planning systems.   Radiother Oncol 84: 3. 290-297 Sep  
Abstract: PURPOSE: To determine the uncertainties in dose volume histogram (DVH) analysis used in modern brachytherapy treatment planning systems (TPSs). MATERIALS AND METHODS: A phantom with three different volumes was scanned with CT and MRI. An inter-observer analysis was based on contouring performed by 5 persons. The volume of a standard contour set was calculated using seven different TPSs. For five systems a typical brachytherapy dose distribution was used to compare DVH determination. RESULTS: The inter-observer variability (1SD) was 13% for a small cylindrical volume, 5% for a large cylinder and 3% for a conical shape. A standardized volume for a 4mm CT scan contoured on seven different TPS varied by 7%, 2%, and 5% (1SD). Use of smaller slice thickness reduced the variations. A treatment plan with the sources between the large cylindrical shape and the cone showed variations for D(2cc) of 1% and 5% (1SD), respectively. Deviations larger than 10% were observed for a smaller source to cylinder surface distance of 5mm. CONCLUSIONS: Modern TPSs minimize the volumetric and dosimetric calculation uncertainties. These are comparable to inter-observer contouring variations. However, differences in volume result from the methods of calculation in the first and last slice of a contoured structure. For this situation and in case of high dose gradients inside analyzed volumes, high uncertainties were observed. The use of DVH parameters in clinical practice should take into account the method of calculation and the possible uncertainties.
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Ioannis Tsougos, Eduard Schreibmann, Michael Lahanas, Kiki Theodorou, Constantin Kappas, Dimos Baltas (2007)  Geometrical pre-planning for conformal radiotherapy.   Acta Oncol 46: 7. 918-927  
Abstract: The optimum selection of beams and arcs in conformal techniques is of the outmost importance in modern radiotherapy. In this work we give a description of an analytic method to aid optimum selection, which is based on minimizing the intersection between beams and organs at risk (OAR) and on minimizing the intersection between the beam and the planning target volume (PTV). An arc-selection function that permits selection of irradiation arcs based on individual beam feasibility is introduce. The method simulates the treatment process by defining a computed beam feasibility, for every possible set of gantry-table angles, by taking into account accurately computer intersection volumes between the OAR and beams. The beams are shaped to conform the target using realistic parameters for the treatment process. The results are displayed on a virtual sphere centred at the isocenter with color-coded regions indicating beam feasibility. Arcs selections are performed by searching the map for successive gantry positions at a certain table angle, with feasibility values greater than a user-specified threshold. The accuracy of the method was confirmed by using geometrical regular shapes, as well as real clinical cases.
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P Papagiannis, P Karaiskos, E Georgiou, D Baltas, G Lymperopoulou, E Pantelis, L Sakelliou (2007)  On the use of high dose rate 192Ir and 169Yb sources with the MammoSite radiation therapy system.   Med Phys 34: 9. 3614-3619 Sep  
Abstract: Ample literature exists on the dose overestimation by commercially available treatment planning systems in MammoSite applications using high dose rate 192Ir sources for partial breast brachytherapy as monotherapy, due to their inability to predict the dose reduction caused by the radiographic contrast solution in the balloon catheter. In this work Monte Carlo simulation is used to verify the dose rate reduction in a balloon breast applicator which does not vary significantly with distance and it is 1.2% at the prescription distance for the reference simulated geometry of 10% diluted radiographic contrast media and 2.5 cm balloon radius. Based on these findings and the minimal hardening of the initially emitted photon spectrum for 192Ir, a simple analytical method is proposed and shown capable for correcting dosimetry planning in clinical applications. Simulations are also performed to assess the corresponding dose reduction in applications of balloon breast applicators using high dose rate 169Yb sources that have recently become available. Results yield a far more significant and distance dependent dose reduction for 169Yb (on the order of 20% at the prescription distance for the abovementioned reference simulation geometry). This dose reduction cannot be accounted for using simple analytical methods as for 192Ir due to the significant hardening of the initially emitted 169Yb photons within the diluted radiographic contrast media. Combined with results of previous works regarding the effect of altered scatter conditions (relative to treatment planning system assumptions) on breast treatment planning accuracy, which is more pronounced for 169Yb relative to 192Ir, these findings call for the amendment of dose treatment planning systems before using 169Yb high dose rate sources in balloon breast applicators.
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Nikolaos Tselis, Christos Kolotas, Gerhard Birn, Sandra Röddiger, Ineza Filipowicz, Marina Kontova, George Fountzilas, Panayiotis Selviaridis, Dimos Baltas, Reinhard Heyd, Georgios Anagnostopoulos, Nikolaos Zamboglou (2007)  CT-guided interstitial HDR brachytherapy for recurrent glioblastoma multiforme. Long-term results.   Strahlenther Onkol 183: 10. 563-570 Oct  
Abstract: BACKGROUND AND PURPOSE: Recurrences of glioblastoma multiforme (GBM) within previously irradiated volumes pose a serious therapeutic challenge. This retrospective study evaluates the long-term tumor control of recurrent GBM treated with interstitial high-dose-rate brachytherapy (HDR-BRT). PATIENTS AND METHODS: Between 1995 and 2003, 84 patients were treated for recurrent cerebral GBM located within previously irradiated volumes. All patients had received adjuvant external radiotherapy following primary surgery, with a focal dose up to 60 Gy. The median recurrent tumor volume was 51 cm(3) (3-207 cm(3)), and the HDR-BRT consisted of an afterloading (192)Ir implant which delivered a median dose of 40 Gy (30-50 Gy). Catheter implantation was implemented using interactive computed tomography (CT) guidance under local anesthesia and sedoanalgesia. RESULTS: After a median follow-up of 61 months, 5/84 patients (6%) were alive. The median post-BRT survival was 37 weeks, and the median overall survival 78 weeks. Moderate to severe complications occurred in 5/84 cases (6%). CONCLUSION: For patients with recurrences of GBM within previously irradiated volumes, CT-guided interstitial HDR-BRT is a feasible treatment option that can play an important role in providing palliation.
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2006
 
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G A Macheras, P J Papagelopoulos, K Kateros, A T Kostakos, D Baltas, T S Karachalios (2006)  Radiological evaluation of the metal-bone interface of a porous tantalum monoblock acetabular component.   J Bone Joint Surg Br 88: 3. 304-309 Mar  
Abstract: Between January 1998 and December 1998, 82 consecutive patients (86 hips) underwent total hip arthroplasty using a trabecular metal monoblock acetabular component. All patients had a clinical and radiological follow-up evaluation at six, 12 and 24 weeks, 12 months, and then annually thereafter. On the initial post-operative radiograph 25 hips had a gap between the outer surface of the component and the acetabular host bed which ranged from 1 to 5 mm. All patients were followed up clinically and radiologically for a mean of 7.3 years (7 to 7.5). The 25 hips with the 1 to 5 mm gaps were studied for component migration at two years using the Einzel-Bild-Roentgen-Analyse (EBRA) digital measurement method. At 24 weeks all the post-operative gaps were filled with bone and no acetabular component had migrated. The radiographic outcome of all 86 components showed no radiolucent lines and no evidence of lysis. No acetabular implant was revised. There were no dislocations or other complications. The bridging of the interface gaps (up to 5 mm) by the trabecular metal monoblock acetabular component indicates the strong osteoconductive, and possibly osteoinductive, properties of trabecular metal.
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Sandra J Roddiger, Christos Kolotas, Ineza Filipowicz, Ralf Kurek, Ralph Paul Kuner, Thomas Martin, Dimos Baltas, Bernd Rogge, Marina Kontova, Gerald Hoffmann, Bettina Pollow, Nikolaos Zamboglou (2006)  Neoadjuvant interstitial high-dose-rate (HDR) brachytherapy combined with systemic chemotherapy in patients with breast cancer.   Strahlenther Onkol 182: 1. 22-29 Jan  
Abstract: BACKGROUND AND PURPOSE: This is the first study investigating neoadjuvant interstitial high-dose-rate (HDR) brachytherapy combined with chemotherapy in patients with breast cancer. The goal was to evaluate the type of surgical treatment, histopathologic response, side effects, local control, and survival. PATIENTS AND METHODS: 53 patients, who could not be treated with breast-conserving surgery due to initial tumor size (36/53) or due to an unfavorable breast-tumor ratio (17/53), were analyzed retrospectively. All but one were in an intermediate/high-risk group (St. Gallen criteria). The patients received a neoadjuvant protocol consisting of systemic chemotherapy combined with fractionated HDR brachytherapy (2 x 5 Gy/day, total dose 30 Gy). In cases, where breast-conserving surgery was performed, patients received additional external-beam radiotherapy (EBRT, 1.8 Gy/day, total dose 50.4 Gy). In patients, who underwent mastectomy but showed an initial tumor size of T3/T4 and/or more than three infiltrated lymph nodes, EBRT was also performed. RESULTS: In 30/53 patients (56.6%) breast-conserving surgery could be performed. The overall histopathologic response rate was 96.2% with a complete remission in 28.3% of patients. 49/53 patients were evaluable for follow-up. After a median of 58 months (45-72 months), one patient showed a mild fibrosis of the breast tissue, three patients had mild to moderate lymphatic edema of the arm. 6/49 (12.2%) patients died of distant metastases, 4/49 (8.2%) were alive with disease, and 39/49 (79.6%) were free from disease. Local recurrence was observed in only one case (2%) 40 months after primary therapy. After mastectomy, this patient is currently free from disease. CONCLUSION: The combination of interstitial HDR brachytherapy and chemotherapy is a well-tolerated and effective neoadjuvant treatment in patients with breast cancer. Compared to EBRT, treatment time is short. Postoperative EBRT of the whole breast -- if necessary -- is still possible after neoadjuvant brachytherapy. Even though the number of patients does not permit definite conclusions, the results are promising regarding survival and the very low rate of local recurrences.
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P Papagiannis, E Pantelis, E Georgiou, P Karaiskos, A Angelopoulos, L Sakelliou, S Stiliaris, D Baltas, I Seimenis (2006)  Polymer gel dosimetry for the TG-43 dosimetric characterization of a new 125I interstitial brachytherapy seed.   Phys Med Biol 51: 8. 2101-2111 Apr  
Abstract: In this work, a polymer gel-magnetic resonance (MR) imaging method is employed for the dosimetric characterization of a new 125I low dose rate seed (IsoSeed model I25.S17). Two vials filled with PABIG gel were prepared in-house and one new seed as well as one commercially available 125I seed of similar dose rate and well-known dosimetric parameters (IsoSeed model I25.S06) were positioned in each vial. Both seeds in each vial were MR scanned simultaneously on days 11 and 26 after implantation. The data obtained from the known seed in each vial are used to calibrate the gel dose response which, for the prolonged irradiation duration necessitated by the investigated dose rates, depends on the overall irradiation time. Data for this study are presented according to the AAPM TG-43 dosimetric formalism. Polymer gel results concerning the new seed are compared to corresponding, published dosimetric results obtained, for the purpose of the new seed clinical implementation, by our group using the established methods of Monte Carlo (MC) simulation and thermo-luminescence dosimetry (TLD). Polymer gel dosimetry yields an average dose rate constant value of lambda = (0.921 +/- 0.031) cGy h(-1) U(-1) relative to (MC)lambda = (0.929 +/- 0.014) cGy h(-1) U(-1), (TLD)lambda = (0.951 +/- 0.044) cGy h(-1) U(-1) and the average value of Lambda = (0.940 +/- 0.051) cGy h(-1) U(-1) proposed for the clinical implementation of the new seed. Results for radial dose function, g(L)(r), and anisotropy function, F(r, theta), also agree with corresponding MC calculations within experimental uncertainties which are smaller for the polymer gel method compared to TLD. It is concluded that the proposed polymer gel-magnetic resonance imaging methodology could be used at least as a supplement to the established techniques for the dosimetric characterization of new low energy and low dose rate interstitial brachytherapy seeds.
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G Lymperopoulou, P Papagiannis, A Angelopoulos, P Karaiskos, E Georgiou, D Baltas (2006)  A dosimetric comparison of 169Yb and 192Ir for HDR brachytherapy of the breast, accounting for the effect of finite patient dimensions and tissue inhomogeneities.   Med Phys 33: 12. 4583-4589 Dec  
Abstract: Monte Carlo simulation dosimetry is used to compare 169Yb to 192Ir for breast high dose rate (HDR) brachytherapy applications using multiple catheter implants. Results for bare point sources show that while 169Yb delivers a greater dose rate per unit air kerma strength at the radial distance range of interest to brachytherapy in homogeneous water phantoms, it suffers a greater dose rate deficit in missing scatter conditions relative to 192Ir. As a result of these two opposing factors, in the scatter conditions defined by the presence of the lung and the finite patient dimensions in breast brachytherapy the dose distributions calculated in a patient equivalent mathematical phantom by Monte Carlo simulations for the same implant of either 169Yb or 1921r commercially available sources are found comparable. Dose volume histogram results support that 169Yb could be at least as effective as 192Ir delivering the same dose to the lung and slightly reduced dose to the breast skin. The current treatment planning systems' approach of employing dosimetry data precalculated in a homogeneous water phantom of given shape and dimensions, however, is shown to notably overestimate the delivered dose distribution for 169Yb. Especially at the skin and the lung, the treatment planning system dose overestimation is on the order of 15%-30%. These findings do not undermine the potential of 169Yb HDR sources for breast brachytherapy relative to the most commonly used 192Ir HDR sources. They imply, however, that there could be a need for the amendment of dose calculation algorithms employed in clinical treatment planning of particular brachytherapy applications, especially for intermediate photon energy sources such as 169Yb.
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G Lymperopoulou, P Papagiannis, L Sakelliou, E Georgiou, C J Hourdakis, D Baltas (2006)  Comparison of radiation shielding requirements for HDR brachytherapy using 169Yb and 192Ir sources.   Med Phys 33: 7. 2541-2547 Jul  
Abstract: 169Yb has received a renewed focus lately as an alternative to 192Ir sources for high dose rate (HDR) brachytherapy. Following the results of a recent work by our group which proved 169Yb to be a good candidate for HDR prostate brachytherapy, this work seeks to quantify the radiation shielding requirements for 169Yb HDR brachytherapy applications in comparison to the corresponding requirements for the current 192Ir HDR brachytherapy standard. Monte Carlo simulation (MC) is used to obtain 169Yb and 192Ir broad beam transmission data through lead and concrete. Results are fitted to an analytical equation which can be used to readily calculate the barrier thickness required to achieve a given dose rate reduction. Shielding requirements for a HDR brachytherapy treatment room facility are presented as a function of distance, occupancy, dose limit, and facility workload, using analytical calculations for both 169Yb and 192Ir HDR sources. The barrier thickness required for 169Yb is lower than that for 192Ir by a factor of 4-5 for lead and 1.5-2 for concrete. Regarding 169Yb HDR brachytherapy applications, the lead shielding requirements do not exceed 15 mm, even in highly conservative case scenarios. This allows for the construction of a lead door in most cases, thus avoiding the construction of a space consuming, specially designed maze. The effects of source structure, attenuation by the patient, and scatter conditions within an actual treatment room on the above-noted findings are also discussed using corresponding MC simulation results.
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2005
 
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G Lymperopoulou, P Papagiannis, L Sakelliou, P Karaiskos, P Sandilos, A Przykutta, D Baltas (2005)  Monte Carlo and thermoluminescence dosimetry of the new IsoSeed model I25.S17 125I interstitial brachytherapy seed.   Med Phys 32: 11. 3313-3317 Nov  
Abstract: Monte Carlo simulation and experimental thermoluminescence dosimetry were utilized for the dosimetric characterization of the new IsoSeed model I25.S17 125I interstitial brachytherapy seed. The new seed design is similar to that of the selectSeed and 6711 seeds, with the exception of its molybdenum marker. Full dosimetric data are presented following the recommendations in the Update of the AAPM Task Group 43 report (TG-43U1). A difference of 3.3% was found between Monte Carlo dose rate constant results calculated by air kerma strengths from simulations using a point detector and a detector resembling the solid angle subtended to the seed by the Wide Angle Free Air Chamber (WAFAC) in the primary standard calibration geometry. Following the TG-43U1 recommendations, an average value of lambdaMC = (0.929 +/- 0.014) cGy h(-1) U(-1) was adopted for the new seed. This value was then averaged with the measured value of lambdaEXP = (0.951 +/- 0.044) cGy h(-1) U(-1) to yield the proposed dose rate constant for the new seed that is equal to lambda = (0.940 +/- 0.051) cGy h(-1) U(-1). The Monte Carlo calculated radial dose function and two-dimensional (2-D) anisotropy function results for the new seed were found in agreement with experimental results to within statistical uncertainty of repeated measurements. Monte Carlo simulations were also performed for 125I seeds of similar geometry and dimensions for the purpose of comparison. The new seed presents dosimetric characteristics that are very similar to that of the selectSeed. In comparison to the most extensively studied Amersham 6711 seed, the new one presents similar dosimetric characteristics with a slightly reduced dose rate constant (1.5%).
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Evaggelos Pantelis, Panagiotis Papagiannis, Pantelis Karaiskos, Angelos Angelopoulos, Giorgos Anagnostopoulos, Dimos Baltas, Nikolaos Zamboglou, Loukas Sakelliou (2005)  The effect of finite patient dimensions and tissue inhomogeneities on dosimetry planning of 192Ir HDR breast brachytherapy: a Monte Carlo dose verification study.   Int J Radiat Oncol Biol Phys 61: 5. 1596-1602 Apr  
Abstract: PURPOSE: To evaluate the accuracy of clinical dosimetry planning using commercially available treatment planning systems in (192)Ir high-dose-rate (HDR) breast brachytherapy, with emphasis on skin dose, in view of potential uncertainties owing to the patient finite dimensions and the presence of the lung. METHODS AND MATERIALS: A patient-equivalent mathematical phantom was constructed on the basis of the patient computed tomography scan used in the clinical treatment planning procedure. The actual treatment plan delivered to the patient, involving an implant of six plastic catheters and 26 programmed source dwell positions, was simulated by means of the Monte Carlo method. Results are compared with corresponding dose calculations of a commercially available treatment planning system in the form of prescribed dose percentage isodose contours and cumulative dose-volume histograms. RESULTS: The comparison of Monte Carlo results and treatment planning system calculations revealed that all percentage isodose contours greater than 60% of the prescribed dose are not affected by the finite breast dimensions or the presence of the lung. Treatment planning system calculations overestimate dose in the lung as well as lower isodose contours at points lying both close to the breast or lung surface and relatively away from the implant. In particular, skin dose is overestimated by 5% in the central breast region and within 10% at all other points. CONCLUSIONS: Dose-volume histogram and all other relevant planning quality indices for the planning target volume calculated by the treatment planning system are credible. Skin and lung dose calculations by the treatment planning system can be thought of as a conservative approach in view of the reported dose overestimation.
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G Lymperopoulou, P Papagiannis, L Sakelliou, N Milickovic, S Giannouli, D Baltas (2005)  A dosimetric comparison of 169Yb versus 192Ir for HDR prostate brachytherapy.   Med Phys 32: 12. 3832-3842 Dec  
Abstract: For the purpose of evaluating the use of 169Yb for prostate High Dose Rate brachytherapy (HDR), a hypothetical 169Yb source is assumed with the exact same design of the new microSelectron source replacing the 192Ir active core by pure 169Yb metal. Monte Carlo simulation is employed for the full dosimetric characterization of both sources and results are compared following the AAPM TG-43 dosimetric formalism. Monte Carlo calculated dosimetry results are incorporated in a commercially available treatment planning system (SWIFT), which features an inverse treatment planning option based on a multiobjective dose optimization engine. The quality of prostate HDR brachytherapy using the real 192Ir and hypothetical 169Yb source is compared in a comprehensive analysis of different prostate implants in terms of the multiobjective dose optimization solutions as well as treatment quality indices such as Dose Volume Histograms (DVH) and the Conformal Index (COIN). Given that scattering overcompensates for absorption in intermediate photon energies and distances in the range of interest to prostate HDR brachytherapy, 169Yb proves at least equivalent to 192Ir irrespective of prostate volume. This has to be evaluated in view of the shielding requirements for the 169Yb energies that are minimal relative to that for 192Ir.
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2004
 
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Thomas Martin, Sandra Röddiger, Ralf Kurek, Thomas Dannenberg, Oliver Eckart, Christos Kolotas, Reinhard Heyd, Bernd Rogge, Dimos Baltas, Ulf Tunn, Nikolaos Zamboglou (2004)  3D conformal HDR brachytherapy and external beam irradiation combined with temporary androgen deprivation in the treatment of localized prostate cancer.   Radiother Oncol 71: 1. 35-41 Apr  
Abstract: PURPOSE: To evaluate treatment outcome of 3D conformal high dose rate (HDR) brachytherapy and external beam irradiation (EBRT) combined with temporary androgen deprivation for patients with localized prostate cancer. PATIENTS AND METHODS: Between January 1997 and September 1999 we treated 102 patients with stage T1-3 N0 M0 prostate cancer. Stage T1-2 was found in 71, T3 in 31 patients. Median pretreatment PSA level was 15.3 ng/ml. After ultrasound-guided transrectal implantation of four afterloading needles, CT based 3D brachytherapy planning was performed. All patients received four HDR implants using a reference dose per implant of 5 or 7Gy. Time between each implant was 14 days. After brachytherapy EBRT followed up to 39.6 or 45.0 Gy. All patients received temporary androgen deprivation, starting 2-19 months before brachytherapy, ending 3 months after EBRT. RESULTS: Median follow-up was 2.6 years (range 2.0-4.1 years). Actuarial biochemical control rate was 87% at 2 years and 82% at 3 years. In 14 patients we noted biochemical failure, in five patients clinical failure. Overall survival was 90%, disease specific survival 98.0% at 3 years. Acute grade 3 toxicity occurred in 4%, late grade 3 toxicity in 5%. One patient developed a prostatourethral-rectal fistula as late grade 4 toxicity. The conformal quality of 300 HDR implants was analyzed using dose volume histograms. CONCLUSIONS: 3D conformal HDR brachytherapy and EBRT combined with temporary androgen deprivation is an effective treatment modality for prostate cancer with minimal associated toxicity and encouraging biochemical control rates after a median follow-up of 2.6 years.
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E Pantelis, P Papagiannis, G Anagnostopoulos, D Baltas, P Karaiskos, P Sandilos, L Sakelliou (2004)  Evaluation of a TG-43 compliant analytical dosimetry model in clinical 192Ir HDR brachytherapy treatment planning and assessment of the significance of source position and catheter reconstruction uncertainties.   Phys Med Biol 49: 1. 55-67 Jan  
Abstract: A simple, time efficient, analytical model incorporating heterogeneities and body dimensions around a point 192Ir source is generalized for accurate dosimetry around commercially available 192Ir brachytherapy sources. The generalized model was verified in dosimetry of a clinical 192Ir high dose rate prostate monotherapy application, involving 16 catheters and 83 source dwell positions, through comparison with corresponding treatment planning system data. The computational time efficiency and accuracy of the proposed model allowed the assessment of the impact that uncertainties in source dwell positions and catheter reconstruction may have on dose distributions, and how these could potentially affect the clinical outcome. Results revealed that a 0.1 cm catheter reconstruction uncertainty and a 0.15 cm source position uncertainty along the catheter lead to a dose uncertainty of less than 2% for doses lower than 200% of the prescribed dose, reaching up to 5% for points lying in close proximity to the catheters. These uncertainties were found to have no impact (less than 1%) on dose volume histogram results of both the planning target volume and the urethra. A catheter reconstruction uncertainty as high as 0.2 cm results in a dose uncertainty greater than 2%, reaching up to 9%, only for points inside the 150% contour. However, even in this case, the impact on dose volume histogram calculations is less than 3%.
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Eduard Schreibmann, Michael Lahanas, Lei Xing, Dimos Baltas (2004)  Multiobjective evolutionary optimization of the number of beams, their orientations and weights for intensity-modulated radiation therapy.   Phys Med Biol 49: 5. 747-770 Mar  
Abstract: We propose a hybrid multiobjective (MO) evolutionary optimization algorithm (MOEA) for intensity-modulated radiotherapy inverse planning and apply it to optimize the number of incident beams, their orientations and intensity profiles. The algorithm produces a set of efficient solutions, which represent different clinical trade-offs and contains information such as variety of dose distributions and dose-volume histograms. No importance factors are required and solutions can be obtained in regions not accessible by conventional weighted sum approaches. The application of the algorithm using a test case, a prostate and a head and neck tumour case is shown. The results are compared with MO inverse planning using a gradient-based optimization algorithm.
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Thomas Martin, Dimos Baltas, Ralf Kurek, Sandra Röddiger, Marina Kontova, Georgios Anagnostopoulos, Thomas Dannenberg, Thomas Buhleier, Georgies Skazikis, Ulf Tunn, Nikolaos Zamboglou (2004)  3-D conformal HDR brachytherapy as monotherapy for localized prostate cancer. A pilot study.   Strahlenther Onkol 180: 4. 225-232 Apr  
Abstract: PURPOSE: Pilot study to evaluate feasibility, acute toxicity and conformal quality of three-dimensional (3-D) conformal high-dose- rate (HDR) brachytherapy as monotherapy for localized prostate cancer using intraoperative real-time planning. PATIENTS AND METHODS: Between 05/2002 and 05/2003, 52 patients with prostate cancer, prostate-specific antigen (PSA) < or = 10 ng/ml, Gleason score < or = 7 and clinical stage < or = T2a were treated. Median PSA was 6.4 ng/ml and median Gleason score 5. 24/52 patients had stage T1c and 28/52 stage T2a. For transrectal ultrasound-(TRUS-)guided transperineal implantation of flexible plastic needles into the prostate, the real-time HDR planning system SWIFT((R)) was used. After implantation, CT-based 3-D postplanning was performed. All patients received one implant for four fractions of HDR brachytherapy in 48 h using a reference dose (D(ref)) of 9.5 Gy to a total dose of 38.0 Gy. Dose-volume histograms (DVHs) were analyzed to evaluate the conformal quality of each implant using D(90), D(10) urethra, and D(10) rectum. Acute toxicity was evaluated using the CTC (Common Toxicity Criteria) scales. RESULTS: Median D(90) was 106% of D(ref) (range: 93-115%), median D(10) urethra 159% of D(ref) (range: 127-192%), and median D(10) rectum 55% of D(ref) (range: 35-68%). Median follow-up is currently 8 months. In 2/52 patients acute grade 3 genitourinary toxicity was observed. No gastrointestinal toxicity > grade 1 occurred. CONCLUSION: 3-D conformal HDR brachytherapy as monotherapy using intraoperative real-time planning is a feasible and highly conformal treatment for localized prostate cancer associated with minimal acute toxicity. Longer follow-up is needed to evaluate late toxicity and biochemical control.
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PMID 
G Anagnostopoulos, D Baltas, E Pantelis, P Papagiannis, L Sakelliou (2004)  The effect of patient inhomogeneities in oesophageal 192Ir HDR brachytherapy: a Monte Carlo and analytical dosimetry study.   Phys Med Biol 49: 12. 2675-2685 Jun  
Abstract: The effect of patient inhomogeneities surrounding the oesophagus on the dosimetry planning of an upper thoracic oesophageal 192Ir HDR brachytherapy treatment is studied. The MCNPX Monte Carlo code is used for dosimetry in a patient-equivalent phantom geometry and results are compared in terms of isodose contours as well as dose volume histograms with corresponding calculations by a contemporary treatment planning system software featuring a full TG-43 dose calculation algorithm (PLATO BPS version 14.2.4). It is found that the presence of patient inhomogeneities does not alter the delivery of the planned dose distribution to the planning treatment volume. Regarding the organs at risk, the common practice of current treatment planning systems (TPSs) to consider the patient geometry as a homogeneous water medium leads to a dose overestimation of up to 13% to the spinal cord and an underestimation of up to 15% to the sternum bone. These findings which correspond to the dose region of about 5-10% of the prescribed dose could only be of significance when brachytherapy is used as a boost to external beam therapy. Additionally, an analytical dosimetry model, which is efficient in calculating dose in mathematical phantoms containing inhomogeneity shells of materials of radiobiological interest, is utilized for dosimetry in the patient-equivalent inhomogeneous phantom geometry. Analytical calculations in this work are in good agreement with corresponding Monte Carlo results within the bone inhomogeneities of spinal cord and sternum bone but, like treatment planning system calculations, the model fails to predict the dose distribution in the proximal lung surface as well as within the lungs just as the TPS does, due to its inherent limitation in treating lateral scatter and backscatter radiation.
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PMID 
G Lymperopoulou, E Pantelis, P Papagiannis, H Rozaki-Mavrouli, L Sakelliou, D Baltas, P Karaiskos (2004)  A monte carlo dosimetry study of vaginal 192Ir brachytherapy applications with a shielded cylindrical applicator set.   Med Phys 31: 11. 3080-3086 Nov  
Abstract: A durable recommendation for brachytherapy treatment planning systems to account for the effect of tissue, applicator and shielding material heterogeneities exists. As different proposed approaches have not been integrated in clinical treatment planning routine yet, currently utilized systems disregard or, most commonly, do not fully account for the aforementioned effects. Therefore, it is of interest to evaluate the efficacy of current treatment planning in clinical applications susceptible to errors due to heterogeneities. In this work the effect of the internal structure as well as the shielding used with a commercially available cylindrical shielded applicator set (Nucletron part # 084.320) for vaginal and rectum treatments is studied using three-dimensional Monte Carlo simulation for a clinical treatment plan involving seven source dwell positions of the classic microSelectron HDR 192Ir source. Results are compared to calculations of a treatment planning system (Plato BPS v.14.2.7), which assumes homogeneous water medium and applies a constant, multiplicative transmission factor only at points lying in the shadow of the shield. It is found that the internal structure of the applicator (which includes stainless steel, air and plastic materials) with no shield loaded does not affect the dose distribution relative to homogeneous water. In the unshielded side of the applicator with a 90 degrees, 180 degrees, or 270 degrees tungsten alloy shield loaded, an overestimation of treatment planning system calculations relative to Monte Carlo results was observed which is both shield and position dependent. While significant (up to 15%) at increased distances, which are not of major clinical importance, this overestimation does not affect dose prescription distances by more than 3%. The inverse effect of approx. 3% dose increase at dose prescription distances is observed for stainless steel shields. Regarding the shielded side of the applicator, it is shown that the default treatment planning system transmission factors for tungsten alloy result in a consistent dose over-estimation thus constituting a safe approach given the nature of associated clinical applications. Stainless steel is shown to be an ineffective shielding material with transmission factors reaching up to 0.68 at increased distances irrespective of shield geometry.
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2003
 
DOI   
PMID 
Christos Kolotas, Sandra Röddiger, Gerd Strassmann, Thomas Martin, Nikolaos Tselis, Daniel M Aebersold, Dimos Baltas, Nikolaos Zamboglou (2003)  Palliative interstitial HDR brachytherapy for recurrent rectal cancer. Implantation techniques and results.   Strahlenther Onkol 179: 7. 458-463 Jul  
Abstract: PURPOSE: To report the methods and clinical results of CT-based interstitial high-dose-rate (HDR) brachytherapy procedures for the palliative treatment of recurrent rectal cancer. PATIENTS AND METHODS: A total of 44 brachytherapy implants were performed in 38 patients. CT-guided catheter implants were performed in 34 patients under local anesthesia and sedation, and four patients were implanted intraoperatively. Of 40 CT-guided implants, 20 were done using metallic needles introduced via the sacrum and 20 were transperineal implants of plastic tubes in the presacral region. Postimplant CT scans were used for three-dimensional (3-D) conformal brachytherapy planning. Patients implanted with metallic needles were given a single fraction of 10-15 Gy using HDR (192)Ir, and those who received transperineal implants of plastic catheters were given fractionated brachytherapy, 5 Gy twice daily to a total dose of 30-40 Gy. The median tumor volume was 225 cm(3) with a range of 41-2,103 cm(3). RESULTS: After a median follow-up of 23.4 months, a total of 13/38 patients were alive. The median postbrachytherapy survival was 15 months with 18 of the 25 deaths due to distant metastases. Tumor response was as follows: 6/38 partial remission, 28/38 stable disease, and 4/38 local progression. A planning target volume (PTV) coverage > 85% was achieved in 42/44 implants. The treatment was well tolerated, and no acute complications were observed. One patient developed a fistula after 8 months. Pain relief was recorded in 34 patients (89.5%), and the median duration of this palliative effect was 5 months with a range of 1-13 months. CONCLUSIONS: Interstitial HDR brachytherapy is a valuable tool for the delivery of high doses and achieves effective palliation in recurrent rectal carcinoma.
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PMID 
G Anagnostopoulos, D Baltas, P Karaiskos, E Pantelis, P Papagiannis, L Sakelliou (2003)  An analytical dosimetry model as a step towards accounting for inhomogeneities and bounded geometries in 192Ir brachytherapy treatment planning.   Phys Med Biol 48: 11. 1625-1647 Jun  
Abstract: A simple analytical dose rate calculation model based on primary and scatter separation that treats 192Ir as a monoenergetic source by use of appropriate attenuation and mass energy absorption coefficients is documented for accurate dosimetry in water. This model is then generalized and tested for use in any homogeneous tissue material of radiobiological interest using scatter to primary ratios calculated in water with a material density scaling to account for the difference in the scattering properties of these materials and water. The potential of the analytical model for predicting the effect of the interference of an inhomogeneity is then evaluated by comparison with corresponding Monte Carlo calculations. It is found that regardless of the inhomogeneity dimensions and position relative to the source, the model is capable of increased accuracy (better than 2%) in calculating the primary dose rate at any point not only for low-Z tissue materials but also for high-Z shielding materials where a severe hardening of the primary photons occurs. Overall, for low-Z tissue inhomogeneities the proposed model succeeds in correcting dosimetry results towards the right direction compared to commercial treatment planning systems that currently ignore the effect of phantom dimensions and inhomogeneity interference. Regarding high-Z shielding materials the proposed model accurately predicts the dose reduction just beyond the inhomogeneity (for example it predicts a dose reduction of 47% just behind a tungsten alloy cylinder of 1 cm diameter and 2 mm thickness placed at 1.4 cm away from an 192Ir source, in agreement with corresponding results in the literature) but does not account for the increasing contribution of the laterally scattered photons with increasing distance from the bounded inhomogeneity.
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PMID 
M Lahanas, D Baltas, N Zamboglou (2003)  A hybrid evolutionary algorithm for multi-objective anatomy-based dose optimization in high-dose-rate brachytherapy.   Phys Med Biol 48: 3. 399-415 Feb  
Abstract: Multiple objectives must be considered in anatomy-based dose optimization for high-dose-rate brachytherapy and a large number of parameters must be optimized to satisfy often competing objectives. For objectives expressed solely in terms of dose variances, deterministic gradient-based algorithms can be applied and a weighted sum approach is able to produce a representative set of non-dominated solutions. As the number of objectives increases, or non-convex objectives are used, local minima can be present and deterministic or stochastic algorithms such as simulated annealing either cannot be used or are not efficient. In this case we employ a modified hybrid version of the multi-objective optimization algorithm NSGA-II. This, in combination with the deterministic optimization algorithm, produces a representative sample of the Pareto set. This algorithm can be used with any kind of objectives, including non-convex, and does not require artificial importance factors. A representation of the trade-off surface can be obtained with more than 1000 non-dominated solutions in 2-5 min. An analysis of the solutions provides information on the possibilities available using these objectives. Simple decision making tools allow the selection of a solution that provides a best fit for the clinical goals. We show an example with a prostate implant and compare results obtained by variance and dose-volume histogram (DVH) based objectives.
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PMID 
Eduard Schreibmann, Michael Lahanas, Rosa Uricchio, Kiki Theodorou, Constantin Kappas, Dimos Baltas (2003)  A geometry based optimization algorithm for conformal external beam radiotherapy.   Phys Med Biol 48: 12. 1825-1841 Jun  
Abstract: A geometric solution of the problem of optimal orientation of beams in conformal external radiotherapy is presented. The method uses geometric derived quantities which consider the intersection volume between organs at risk (OAR) and the beam shape. In comparison to previous geometric methods a true 3D volume computation is used which takes into account beam divergence, concave shapes, as well as treatment settings such as individual beam shaping by blocks or multi-leaf collimators. For standard dosimetric cost functions used by dose optimization algorithms a corresponding set of geometric objective functions is proposed. We compare the correlations between geometric and dosimetric cost functions for two clinical cases, a prostate and a head tumour case. A correlation is observed for the prostate case, whereas for the head case it is less pronounced due to the larger part of overlapping volumes between the beams which cannot be considered by the used objectives. In comparison to not-optimized beam directions the dose distribution is significantly better for the beam directions found by the optimization of a geometric multi-objective cost function. An optimal dose distribution can easily be achieved using the geometric model. This is shown by comparing for the two cases the dose-volume histograms (DVH) of manually optimized plans by experienced planners and the DVHs of the geometrically found optimal solutions. In comparison to the manually optimized plans the solutions found by the geometric method significantly reduce the average dose in the OARs and NT, while maintaining the same PTV coverage. The optimization requires only a few seconds and could be used to improve the performance of inverse planning algorithms in radiotherapy for the determination of the optimal direction of beams.
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PMID 
M Lahanas, D Baltas, S Giannouli (2003)  Global convergence analysis of fast multiobjective gradient-based dose optimization algorithms for high-dose-rate brachytherapy.   Phys Med Biol 48: 5. 599-617 Mar  
Abstract: We consider the problem of the global convergence of gradient-based optimization algorithms for interstitial high-dose-rate (HDR) brachytherapy dose optimization using variance-based objectives. Possible local minima could lead to only sub-optimal solutions. We perform a configuration space analysis using a representative set of the entire non-dominated solution space. A set of three prostate implants is used in this study. We compare the results obtained by conjugate gradient algorithms, two variable metric algorithms and fast-simulated annealing. For the variable metric algorithm BFGS from numerical recipes, large fluctuations are observed. The limited memory L-BFGS algorithm and the conjugate gradient algorithm FRPR are globally convergent. Local minima or degenerate states are not observed. We study the possibility of obtaining a representative set of non-dominated solutions using optimal solution rearrangement and a warm start mechanism. For the surface and volume dose variance and their derivatives, a method is proposed which significantly reduces the number of required operations. The optimization time, ignoring a preprocessing step, is independent of the number of sampling points in the planning target volume. Multiobjective dose optimization in HDR brachytherapy using L-BFGS and a new modified computation method for the objectives and derivatives has been accelerated, depending on the number of sampling points, by a factor in the range 10-100.
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PMID 
P Karaiskos, A Angelopoulos, E Pantelis, P Papagiannis, L Sakelliou, E Kouwenhoven, D Baltas (2003)  Monte Carlo dosimetry of a new 192Ir pulsed dose rate brachytherapy source.   Med Phys 30: 1. 9-16 Jan  
Abstract: A new microSelectron pulsed dose rate source has been designed, containing two active pellets instead of one inactive and one active pellet contained in the old design, to facilitate the incorporation of higher activity up to 74 GBq (2 Ci). In this work, Monte Carlo simulation is used to derive full dosimetric data following the AAPM TG-43 formalism, as well as the dose rate per unit air kerma strength data in Cartesian, "away and along" coordinates for both source designs. The calculated dose rate constant of the new PDR source design was found equal to lambda=(1.121 +/- 0.006) cGy h(-1) U(-1) compared to lambda = (1.124 +/- 0.006) cGy h(-1) U(-1) for the old design. Radial dose functions of the two sources calculated using the point source approximated geometry factors were found in close agreement (within 1%) except for radial distances under 2 mm. At polar angles close to the longitudinal source axis at the sources' distal end, the new design presents increased anisotropy (up to 10%) compared to the old one due to its longer active core. At polar angles close to the longitudinal source axis at the sources' drive wire end however, the old design presents increased anisotropy (up to 18%) due to attenuation of emitted photons through the inactive Ir pellet. These differences, also present in "away and along" dose rate results, necessitate the replacement of treatment planning input data for the new microSelectron pulsed dose rate source.
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PMID 
P Kipouros, P Papagiannis, L Sakelliou, P Karaiskos, P Sandilos, P Baras, I Seimenis, M Kozicki, G Anagnostopoulos, D Baltas (2003)  3D dose verification in 192Ir HDR prostate monotherapy using polymer gels and MRI.   Med Phys 30: 8. 2031-2039 Aug  
Abstract: VIPAR polymer gels and 3D MRI techniques were evaluated for their ability to provide experimental verification of 3D dose distributions in a simulation of a 192Ir prostate monotherapy clinical application. A real clinical treatment plan was utilized, generated by post-irradiation, CT based calculations derived from Plato BPS and Swift treatment planning systems. The simulated treatment plan involved the use of 10 catheters and 39 source positions within a glass vessel of appropriate dimensions, homogeneously filled with the VIPAR gel. 3D high resolution MR scanning of the gel produced T2 relaxation time maps, from which 3D dose distributions were derived via an appropriate calibration procedure. Results were compared to corresponding dose distributions obtained from the Plato and Swift treatment planning systems. Quantitative comparison, on a point by point basis, was based on user adopted acceptance criteria of 5% dose-difference and 3 mm distance-to-agreement. Significant deviations between experimental and calculated dose distributions were found for doses lower than 50% due to the reduced dose resolution of the method in the low dose, low dose gradient region. Measurement errors were observed at 1.0-1.5 mm around each catheter due to MR imaging susceptibility artifacts. For most remaining points the acceptance criteria were fulfilled. Systematic offsets of the order of 1-2 mm, observed between measured and corresponding calculated isocontours at specific segments, are attributed to the 1 mm uncertainty in catheter reconstruction and 1 mm uncertainty in the alignment of the MR and CT imaging planes.
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PMID 
M Lahanas, D Baltas (2003)  Are dose calculations during dose optimization in brachytherapy necessary?   Med Phys 30: 9. 2368-2375 Sep  
Abstract: We consider the problem of anatomy based dose optimization in brachytherapy. A calculation method for some objective functions and their derivatives is proposed which significantly reduces the number of required operations. The optimization in some cases, ignoring a preprocessing step, is independent of the number of sampling points. The idea is that some of the objectives and their derivatives used for dose optimization do not require the explicit calculation of dose values. Dose optimization with the new modified computation method for the objectives and derivatives is, depending on the number of sampling points, up to 100 times faster than the conventional method with dose calculation.
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PMID 
G Anagnostopoulos, D Baltas, A Geretschlaeger, T Martin, P Papagiannis, N Tselis, N Zamboglou (2003)  In vivo thermoluminescence dosimetry dose verification of transperineal 192Ir high-dose-rate brachytherapy using CT-based planning for the treatment of prostate cancer.   Int J Radiat Oncol Biol Phys 57: 4. 1183-1191 Nov  
Abstract: PURPOSE: To evaluate the potential of in vivo thermoluminescence dosimetry to estimate the accuracy of dose delivery in conformal high-dose-rate brachytherapy of prostate cancer. METHODS AND MATERIALS: A total of 50 LiF, TLD-100 cylindrical rods were calibrated in the dose range of interest and used as a batch for all fractions. Fourteen dosimeters for every treatment fraction were loaded in a plastic 4F catheter that was fixed in either one of the 6F needles implanted for treatment purposes or in an extra needle implanted after consulting with the patient. The 6F needles were placed either close to the urethra or in the vicinity of the median posterior wall of the prostate. Initial results are presented for 18 treatment fractions in 5 patients and compared to corresponding data calculated using the commercial treatment planning system used for the planning of the treatments based on CT images acquired postimplantation. RESULTS: The maximum observed mean difference between planned and delivered dose within a single treatment fraction was 8.57% +/- 2.61% (root mean square [RMS] errors from 4.03% to 9.73%). Corresponding values obtained after averaging results over all fractions of a patient were 6.88% +/- 4.93% (RMS errors from 4.82% to 7.32%). Experimental results of each fraction corresponding to the same patient point were found to agree within experimental uncertainties. CONCLUSIONS: Experimental results indicate that the proposed method is feasible for dose verification purposes and suggest that dose delivery in transperineal high-dose-rate brachytherapy after CT-based planning can be of acceptable accuracy.
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PMID 
Michael Lahanas, Eduard Schreibmann, Dimos Baltas (2003)  Multiobjective inverse planning for intensity modulated radiotherapy with constraint-free gradient-based optimization algorithms.   Phys Med Biol 48: 17. 2843-2871 Sep  
Abstract: We consider the behaviour of the limited memory L-BFGS algorithm as a representative constraint-free gradient-based algorithm which is used for multiobjective (MO) dose optimization for intensity modulated radiotherapy (IMRT). Using a parameter transformation, the positivity constraint problem of negative beam fluences is entirely eliminated: a feature which to date has not been fully understood by all investigators. We analyse the global convergence properties of L-BFGS by searching for the existence and the influence of possible local minima. With a fast simulated annealing (FSA) algorithm we examine whether the L-BFGS solutions are globally Pareto optimal. The three examples used in our analysis are a brain tumour, a prostate tumour and a test case with a C-shaped PTV. In 1% of the optimizations global convergence is violated. A simple mechanism practically eliminates the influence of this failure and the obtained solutions are globally optimal. A single-objective dose optimization requires less than 4 s for 5400 parameters and 40000 sampling points. The elimination of the problem of negative beam fluences and the high computational speed permit constraint-free gradient-based optimization algorithms to be used for MO dose optimization. In this situation, a representative spectrum of possible solutions is obtained which contains information such as the trade-off between the objectives and range of dose values. Using simple decision making tools the best of all the possible solutions can be chosen. We perform an MO dose optimization for the three examples and compare the spectra of solutions, firstly using recommended critical dose values for the organs at risk and secondly, setting these dose values to zero.
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2002
 
PMID 
Evaggelos Pantelis, Dimos Baltas, Konstantinos Dardoufas, Pantelis Karaiskos, Panagiotis Papagiannis, Heleni Rosaki-Mavrouli, Loukas Sakelliou (2002)  On the dosimetric accuracy of a Sievert integration model in the proximity of 192Ir HDR sources.   Int J Radiat Oncol Biol Phys 53: 4. 1071-1084 Jul  
Abstract: PURPOSE: To investigate the efficacy of a Sievert integration model in dosimetry close to 192Ir high-dose-rate brachytherapy sources and validate its accuracy and potential to resolve dosimetric differences between these sources in the cm and mm distance ranges relevant to interstitial and intravascular brachytherapy applications, respectively. METHODS AND MATERIALS: The dosimetric quantities of the generalized Task Group 43 formalism, as well as dose rate profiles in polar and Cartesian coordinates, are calculated, and results are compared to corresponding Monte Carlo data in the literature. RESULTS: Sievert calculations were found in excellent agreement with corresponding Monte Carlo published results. Dose rate polar angle profiles in the cm distance range depended significantly on corresponding anisotropy function data, whereas in the mm distance range, dose rate polar angle profiles are governed by the corresponding geometry function profiles, because anisotropy proved insignificant. Radial dose functions of the sources were found comparable. A simple equation for the calculation of the dose rate constant of the sources within clinically acceptable accuracy is provided. CONCLUSIONS: The particular Sievert model proved capable of resolving dosimetric differences of the sources and provides results within clinical accuracy. Therefore, it constitutes a useful tool for dosimetry in clinical practice and especially in intravascular applications, where there is currently a lack of available dosimetric data.
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PMID 
G Anagnostopoulos, D Baltas, P Karaiskos, P Sandilos, P Papagiannis, L Sakelliou (2002)  Thermoluminescent dosimetry of the selectseed 125I interstitial brachytherapy seed.   Med Phys 29: 5. 709-716 May  
Abstract: This work presents experimental dosimetry results for the new selectSeed 125I prostate seed design for use with the seedSelectron afterloading device, in accordance with the AAPM advisory that all new low energy interstitial brachytherapy seeds should undergo one Monte Carlo (MC) and at least one experimental dosimetry characterization. TLD dosimetry was performed using 120 cylindrical LiF TLD type-100 rods calibrated using a 6 MV photon beam. They were irradiated in solid water phantoms for the experimental determination of the seed dose rate constant, radial dose functions and anisotropy functions. MC simulations were performed for the determination of the TLDs relative energy response that was found position independent and equal to 1.40+/-0.03, and for the calculation of the ratio of dose in liquid water to dose in solid water that was found to be well described by Dliquidwater/Dsolidwater= 1.013*r+0.030 presenting only a minor dependence on polar angle. The selectSeed dose rate constant in liquid water was found equal to 0.938+/-0.065 cGy h(-1) U(-1), which agrees within experimental uncertainties with corresponding MC results of lambdaselect Seed=0.954+/-0.005 cGy h(-1) U(-1). The experimental radial dose and anisotropy function results were also found in good agreement with corresponding MC calculations.
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PMID 
N Milickovic, M Lahanas, M Papagiannopoulo, N Zamboglou, D Baltas (2002)  Multiobjective anatomy-based dose optimization for HDR-brachytherapy with constraint free deterministic algorithms.   Phys Med Biol 47: 13. 2263-2280 Jul  
Abstract: In high dose rate (HDR) brachytherapy, conventional dose optimization algorithms consider multiple objectives in the form of an aggregate function that transforms the multiobjective problem into a single-objective problem. As a result, there is a loss of information on the available alternative possible solutions. This method assumes that the treatment planner exactly understands the correlation between competing objectives and knows the physical constraints. This knowledge is provided by the Pareto trade-off set obtained by single-objective optimization algorithms with a repeated optimization with different importance vectors. A mapping technique avoids non-feasible solutions with negative dwell weights and allows the use of constraint free gradient-based deterministic algorithms. We compare various such algorithms and methods which could improve their performance. This finally allows us to generate a large number of solutions in a few minutes. We use objectives expressed in terms of dose variances obtained from a few hundred sampling points in the planning target volume (PTV) and in organs at risk (OAR). We compare two- to four-dimensional Pareto fronts obtained with the deterministic algorithms and with a fast-simulated annealing algorithm. For PTV-based objectives, due to the convex objective functions, the obtained solutions are global optimal. If OARs are included, then the solutions found are also global optimal, although local minima may be present as suggested.
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PMID 
K Karouzakis, M Lahanas, N Milickovic, S Giannouli, D Baltas, N Zamboglou (2002)  Brachytherapy dose-volume histogram computations using optimized stratified sampling methods.   Med Phys 29: 3. 424-432 Mar  
Abstract: A stratified sampling method for the efficient repeated computation of dose-volume histograms (DVHs) in brachytherapy is presented as used for anatomy based brachytherapy optimization methods. The aim of the method is to reduce the number of sampling points required for the calculation of DVHs for the body and the PTV. From the DVHs are derived the quantities such as Conformity Index COIN and COIN integrals. This is achieved by using partial uniform distributed sampling points with a density in each region obtained from a survey of the gradients or the variance of the dose distribution in these regions. The shape of the sampling regions is adapted to the patient anatomy and the shape and size of the implant. For the application of this method a single preprocessing step is necessary which requires only a few seconds. Ten clinical implants were used to study the appropriate number of sampling points, given a required accuracy for quantities such as cumulative DVHs, COIN indices and COIN integrals. We found that DVHs of very large tissue volumes surrounding the PTV, and also COIN distributions, can be obtained using a factor of 5-10 times smaller the number of sampling points in comparison with uniform distributed points.
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PMID 
P Papagiannis, A Angelopoulos, E Pantelis, L Sakelliou, D Baltas, P Karaiskos, P Sandilos, L Vlachos (2002)  Dosimetry comparison of 192Ir sources.   Med Phys 29: 10. 2239-2246 Oct  
Abstract: 192Ir sources besides being widely utilized in the field of conventional brachytherapy also find use in contemporary peripheral and coronal intravascular applications. In this study, the same Monte Carlo simulation code and input data were used to investigate differences between the dose rate distributions of the most commonly used 192Ir sources in the cm and mm distance range. Findings are discussed in view of differences in source and encapsulation dimensions as well as structural details. Results are presented in the AAPM TG-43 formalism, as generalized by AAPM TG-60, for five 192Ir HDR source designs as well as an LDR seed and an LDR wire source. Dose rate constants of the sources at r0 = 1 cm and r0 = 2 mm were found proportional to the corresponding geometry factors along the transverse source bisectors and an equation of the form lambda r0(cGyh(-1) U(-1)) = 1.12 x G(r0,90 degrees) provides results within clinical accuracy (less than 2%) for any 192Ir source. Radial dose functions do not depend significantly on source and encapsulation geometry and agree within 2% with that of a point 192Ir source. Anisotropy is of importance for accurate dosimetry at the cm distance range but it does not affect dose rate in the mm distance range significantly. At such short radial distances the source geometry factor defines the shape of isodose lines. Dose uniformity at given distances from the sources is strongly dependent on source dimensions as indicated by dose rate profiles in polar and Cartesian coordinates.
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PMID 
Panagiotis Kipouros, Georgios Anagnostopoulos, Angelos Angelopoulos, Dimos Baltas, Panagiotis Baras, Anargiros Drolapas, Pantelis Karaiskos, Evangelos Pantelis, Panagiotis Papagiannis, Loukas Sakelliou, Ioannis Seimenis (2002)  Dosimetric calculations and VIPAR polymer gel dosimetry close to the microSelectron HDR.   Z Med Phys 12: 4. 252-259  
Abstract: In the present study, different dosimetric methods were investigated for their ability to predict the energy dose in the vicinity of the microSelectron HDR 192Ir brachytherapy source. The results of a time-efficient Sievert integral model of proven accuracy in the cm distance range from all 192Ir sources were benchmarked against accurate Monte Carlo derived dosimetric data in the close vicinity of the source. This comparison revealed that the Sievert model is capable of accurate dosimetry even in the mm distance range from the source. The dose rate distributions were compared with results obtained from different versions (v. 13.7 and 14.2.2) of the Plato BPS commercial treatment planning system, for an application following the Paris trial intravascular irradiation protocol. The results of brachytherapy planning system calculations were found reliable at radial distances of clinical relevance. Noticeable errors existed only in the extreme case of dose calculations at 2 mm from the source axis using Plato v. 13.7. Experimental dosimetric data for the intravascular application, as obtained through the VIPAR polymer gel-MRI method, were also evaluated for dose verification purposes. This method allowed with reasonable accuracy the verification of absolute dose distributions for peripheral vessel applications using 192Ir sources.
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PMID 
E Andreopoulou, D Andreopoulos, K Adamidis, A Fountzila-Kalogera, G Fountzilas, M A Dimopoulos, G Aravantinos, N Zamboglou, D Baltas, N Pavlidis (2002)  Tumor volumetry as predictive and prognostic factor in the management of ovarian cancer.   Anticancer Res 22: 3. 1903-1908 May/Jun  
Abstract: BACKGROUND: The usefulness of tumor volumetry in ovarian epithelial cancer has never been intensively investigated. The aim of the present study was to determine the value of quantitative analysis of tumor volume as a predictive method for response to treatment and as a prognostic method for disease outcome. MATERIALS AND METHODS: Seventy-five women with advanced ovarian cancer who presented with measurable disease on CT scan prior to chemotherapy were retrospectively studied. The patients were treated with platinum-based chemotherapy. The median follow-up was 113.36 weeks. An independent radiologist identified and delineated tumor contours in each slice of sequential CT scans before and after therapy. Volumetry was measured with a three-dimensional approach by utilizing a digitizer and a specific algorithm on a software computed program. RESULTS: Data were analyzed according to initial and to residual tumor volumes. Patients with low initial volume of <52 cm3 exhibited higher responses (p<0.01), while patients with medium (52-165 cm3) or high (>165 CM3) initial tumor volume had a shorter time to progression (p<0.01). Patients without or with low residual volume of <35 cm3 were found to have a longer time to progression (p<0.05) and longer survival (p<0.01 and p<0.05). In addition, serum CA 125 levels followed precisely tumor volumetry for both initial and residual disease. CONCLUSION: Tumor volumetry in advanced ovarian cancer was found to have predictive value for response to platinum-based chemotherapy. Initial tumor volume has prognostic significance only for the time to progression, whereas residual tumor volume has for both time to progression and survival.
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PMID 
P Baras, I Seimenis, P Kipouros, P Papagiannis, A Angelopoulos, L Sakelliou, E Pappas, D Baltas, P Karaiskos, P Sandilos, L Vlachos (2002)  Polymer gel dosimetry using a three-dimensional MRI acquisition technique.   Med Phys 29: 11. 2506-2516 Nov  
Abstract: In this work, three-dimensional (3-D) MRI techniques are employed in N-Vinylpyrrolidone-Argon-(VIPAR-) based polymer gel dosimetry. VIPAR gels were irradiated using a Nucletron microSelection 192Ir HDR brachytherapy remote afterloading system with single source dwell position and intravascular brachytherapy irradiation protocols. A single VIPAR gel and a single irradiation are adequate to obtain the full calibration curve needed. The 3-D dose distributions obtained with the 3-D MRI method were found to be in good agreement with the corresponding Monte Carlo calculations, for brachytherapy and intravascular irradiations. The method allows the reconstruction of isodose contours over any plane, with increased spatial resolution and accuracy following a single MR acquisition. VIPAR gel measurements using a 3-D MRI readout technique can be of particular use in the experimental dosimetry of brachytherapy sources, as well as for dose verification purposes when complex irradiation regimes and three-dimensional dose gradients are investigated.
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2001
 
PMID 
P Papagiannis, E Pappas, P Kipouros, A Angelopoulos, L Sakelliou, P Baras, P Karaiskos, I Seimenis, P Sandilos, D Baltas (2001)  Dosimetry close to an 192Ir HDR source using N-vinylpyrrolidone based polymer gels and magnetic resonance imaging.   Med Phys 28: 7. 1416-1426 Jul  
Abstract: In this work, the utilization of polymer gel-MRI dosimetry for measurements at distances relevant to clinical brachytherapy and intravascular applications [i.e., in the mm range, where steep three-dimensional (3-D) dose gradients exist] is investigated using N-vinylpyrrolidone-based gels. Transverse axis radial dose distributions, dose distributions parallel to the source axis, and 2-D dose distributions around the commonly used microSelectron 192Ir HDR source are measured for single source dwell position irradiations. Experimental results are found in good agreement with verified Monte Carlo calculations, even for distances less than 3 mm from the source. The effect of various MRI parameters, such as slice thickness, slice mispositioning, and in-plane resolution, on the accuracy of the method is also investigated. Possible limitations of the method are discussed, and its' overall potential in brachytherapy dosimetry is evaluated. Experimental 2-D dose distributions for an intravascular application following the Paris irradiation protocol are compared to corresponding commercial treatment planning system calculations. Results suggest that polymer gel-MRI dosimetry is capable of experimentally verifying dose distributions in relevant clinical intravascular applications.
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DOI   
PMID 
N Milickovic, D Baltas, S Giannouli, M Lahanas, N Zamboglou (2001)  A new algorithm for autoreconstruction of catheters in computed tomography-based brachytherapy treatment planning.   IEEE Trans Biomed Eng 48: 3. 372-383 Mar  
Abstract: This paper describes innovative software for automatic reconstruction, which we term autoreconstruction, of plastic and metallic brachytherapy catheters using computed tomography (CT) data. No such automatic facility has previously existed in any treatment planning software. The patient data consists of a set of post-implantation CT images with the catheters in situ in their final positions. This new software solves those difficulties which arise when the catheters are intersecting or when loop techniques are used. With the software algorithms, catheter reconstruction time is significantly reduced and accuracy is also improved when compared with that achieved using the classical manual method of CT-slice-by-CT-slice reconstruction.
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PMID 
C Cotrutz, M Lahanas, C Kappas, D Baltas (2001)  A multiobjective gradient-based dose optimization algorithm for external beam conformal radiotherapy.   Phys Med Biol 46: 8. 2161-2175 Aug  
Abstract: A multiobjective gradient-based algorithm has been developed for the purpose of dose distribution optimization in external beam conformal radiotherapy. This algorithm is based on the concept of gathering the values of all objectives into a single value. The weighting factors of the composite objective values are varied in different steps, allowing the reconstruction of the trade-off surfaces (three or more objectives) or curves (two objectives) which define the boundary between the feasible and non-feasible domain regions. The analysis of these curves allows the decision-maker to select the solution that best fits the clinical goals. In contrast to all the other algorithms, our method provides not a single solution but a sample of solutions representing all possible clinical importance factors (weights) for the objectives used. The application of this algorithm to two test cases shows that a correct selection for the importance factors to multiply the individual objectives in the global objective value is not trivial and that the location and shape of the boundary region between the feasible and non-feasible solution regions are case dependent. Provided that the individual objective functions are analytically differentiable and that the number of objectives is the range of two to three, the computation times are acceptable for clinical use. Furthermore, the optimization for a unique combination of importance factors within the aggregate objective function is performed in less than 1 min.
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PMID 
P Karaiskos, P Papagiannis, A Angelopoulos, L Sakelliou, D Baltas, P Sandilos, L Vlachos (2001)  Dosimetry of 192Ir wires for LDR interstitial brachytherapy following the AAPM TG-43 dosimetric formalism.   Med Phys 28: 2. 156-166 Feb  
Abstract: Implementation of the AAPM Task Group 43 dosimetric formalism for 192Ir wires used as interstitial sources in low dose-rate (LDR) brachytherapy applications is investigated. Geometry factors, dose-rate constant values, radial dose functions, and anisotropy functions, utilized in this formalism, were calculated for various lengths of all commercially available wire source designs by means of a well-established Monte Carlo simulation code and an improved modification of the Sievert integral method. Results are presented in the form of look up tables that allow interpolation for dose-rate calculations around all practically used wire lengths, with accuracy acceptable for clinical applications.
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PMID 
A C Dhanantwari, S Stergiopoulos, N Zamboglou, D Baltas, H G Vogt, G Karangelis (2001)  Correcting organ motion artifacts in x-ray CT systems based on tracking of motion phase by the spatial overlap correlator. II. Experimental study.   Med Phys 28: 8. 1577-1596 Aug  
Abstract: This paper presents the experimental part of an investigation on tracking and eliminating organ motion artifacts in x-ray CT cardiac applications with emphasis on imaging coronary calcification. The system methodology consists of a software implementation of the spatial overlap correlator (SSOC) concept in x-ray CT scanners to track the net amplitude and phase of organ motion during the CT data acquisition process. A coherent sinogram synthesis (CSS) method is then used to identify the repeated phases of a periodic organ motion from the information provided by the SSOC process and hence synthesize a new sinogram with no motion effects. Since the SSOC scheme is capable of tracking cardiac motion, it identifies also the projection points associated with minimum amplitude cardiac motion effects. These points are used to identify a 180 degrees plus the fan angle sinogram for image reconstruction. This leads to a retrospective gating (RG) scheme that is based on the output of the SSOC process. Performance comparison of the proposed methodology with the retrospective ECG gating using real data sets with phantoms and human patients provides a performance assessment of the merits of the proposed methods. Real results demonstrate that the new methodology eliminates the requirement for ECG gating. Moreover, the CSS and the new RG methods do not require breath holding and they can be implemented in x-ray CT scanners to image coronary calcification and the heart's ventricles.
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PMID 
D Baltas, P Karaiskos, P Papagiannis, L Sakelliou, E Loeffler, N Zamboglou (2001)  Beta versus gamma dosimetry close to Ir-192 brachytherapy sources.   Med Phys 28: 9. 1875-1882 Sep  
Abstract: The relative importance of the dose rate component owing to the beta spectrum emitted by 192Ir brachytherapy sources at the short radial distances of interest in intravascular and endobronchial applications is investigated. Separate dosimetric calculations, using Monte Carlo simulations, were performed for the gamma and beta dose rate components of an 192Ir ideal point source as well as real 192Ir source designs used in clinical practice including wire and seed sources and both Nucletron and Varian, old and new, high dose rate (HDR) source designs. A significant dose rate enhancement due to the beta spectrum emitted by 192Ir, greater than 50% for radial distances r<2 mm, was observed for an ideal point source. For real source designs, however, the magnitude of this enhancement was found to depend strongly on the sources' geometric as well as compositional details of the active core and encapsulation. A detectable effect was found for the majority of the investigated sources at radial distances less than 1 mm, but overall findings suggest that the contribution of beta particles is not significant in 192Ir clinical intravascular applications that are currently carried out. However, since treatment of vessels with smaller diameters, in the future, may lead to the development of 192Ir sources and catheters of reduced diameters, the potential effect of the beta spectrum in terms of dose enhancement to tissues in close proximity to 192Ir sources should not be ignored.
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PMID 
P Karaiskos, P Papagiannis, L Sakelliou, G Anagnostopoulos, D Baltas (2001)  Monte Carlo dosimetry of the selectSeed 125I interstitial brachytherapy seed.   Med Phys 28: 8. 1753-1760 Aug  
Abstract: This work provides full dosimetric data for the new selectSeed 125I prostate seed source to be distributed by Nucletron B.V. The AAPM TG-43 dosimetric formalism and the new 1999 NIST air kerma strength calibration standard have been followed. Air kerma strength, dose rate constant, radial dose functions, anisotropy functions, and anisotropy factors were calculated using Monte Carlo simulation. Corresponding calculations were also performed for the commercially available 6711 seed source, which is of similar design, for reasons of comparison. The calculated dose rate constant of the selectSeed was 0.954+/-0.005 cGy h(-1) U(-1) compared to 0.953+/-0.005 cGy h(-1) U(-1) for the 6711 source design. The latter value for the 6711 source suggests that the correction factor proposed by NIST for conversion of dose rate constants to the new 1999 NIST calibration standard may be overestimated by 2-3%. Radial dose functions of the two sources were found in good agreement for radial distances up to 4 cm, the selectSeed being less penetrating at greater radial distances (approximately 4% at 10 cm). The selectSeed source presents similar anisotropy characteristics with the 6711 source design. For both source designs, a distance and polar angle dependent discontinuity of anisotropy function values was observed owing to the dose contribution of radioactivity distributed on the ends of the cylindrical source cores. Variation of dosimetric parameters with possible variation in radioactive silver halide coating thickness of the silver source core of the new source was also investigated.
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2000
 
PMID 
G Strassmann, S Walter, C Kolotas, R Heyd, D Baltas, D Debertshäuser, H Nier, C Tonus, G Sakas, N Zamboglou (2000)  Reconstruction and navigation system for intraoperative brachytherapy using the flab technique for colorectal tumor bed irradiation.   Int J Radiat Oncol Biol Phys 47: 5. 1323-1329 Jul  
Abstract: PURPOSE: To present the development of a new navigation and reconstruction system based on an electromagnetic free-hand tracker and on CT imaging for treatment planning of intraoperative high-dose-rate brachytherapy (IORT-HDRB) in the sacral region. Our aim is to improve accuracy and to enable individualized treatment planning and dose documentation to be performed for IORT-HDRB using a flab technique. METHODS AND MATERIALS: The material consists of an electromagnetic 3D tracker system, a PC workstation with Microsoft Windows NT 4.0 operating system, and a recognition program for continuous speech. In addition, we designed an external reference system constructed of titanium and Perspex, which is positioned in the pelvis, and a special digitizer pen for reconstruction of the flab geometry. The flab design incorporates a series of silicon 10-mm-diameter spherical pellets. Measurements were made with a pelvic phantom in order to study the accuracy of the system. The reconstruction results are stored and can be exported via network or floppy to our different treatment planning systems. RESULTS: Our results for the reconstruction of a flab with six catheters and a total of 100 spherical pellets give mean errors in the range (2.5 +/- 0.6) mm to (3.5 +/- 0.8) mm depending on the positions of the pelvic phantom and transmitter relative to the operation table. These errors are calculated by comparing the reconstruction results of our system with those using a CT-based reconstruction of the flab geometry. For the accuracy of the navigation system for the pelvic phantom, we obtained mean errors in the range (2.2 +/- 0.7) mm to (3. 1 +/- 1.0) mm. CONCLUSIONS: The new system we have developed enables navigation and reconstruction within the surgical environment with a clinically acceptable level of accuracy. It offers the possibility of individualized treatment planning and effective documentation of the 3D dose distribution in IORT-HDRB using a flab technique.
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PMID 
G Strassmann, C Kolotas, R Heyd, S Walter, D Baltas, T Martin, H Vogt, G Ioannidis, G Sakas, N Zamboglou (2000)  Navigation system for interstitial brachytherapy.   Radiother Oncol 56: 1. 49-57 Jul  
Abstract: PURPOSE: To develop a computed tomography (CT) based electromagnetic navigation system for interstitial brachytherapy. This is especially designed for situations when needles have to be positioned adjacent to or within critical anatomical structures. In such instances interactive 3D visualisation of the needle positions is essential. METHODS AND MATERIALS: The material consisted of a Polhemus electromagnetic 3D digitizer, a Pentium 200 MHz laptop and a voice recognition for continuous speech. In addition, we developed an external reference system constructed of Perspex which could be positioned above the tumour region and attached to the patient using a non-invasive fixation method. A specially designed needle holder and patient bed were also developed. Measurements were made on a series of phantoms in order to study the efficacy and accuracy of the navigation system. RESULTS: The mean navigation accuracy of positioning the 20.0 cm length metallic needles within the phantoms was in the range 2.0-4.1 mm with a maximum of 5.4 mm. This is an improvement on the accuracy of a CT-guided technique which was in the range 6.1-11.3 mm with a maximum of 19.4 mm. The mean reconstruction accuracy of the implant geometry was 3.2 mm within a non-ferromagnetic environment. We found that although the needles were metallic this did not have a significant influence. We also found for our experimental setups that the CT table and operation table non-ferromagnetic parts had no significant influence on the navigation accuracy. CONCLUSIONS: This navigation system will be a very useful clinical tool for interstitial brachytherapy applications, particularly when critical structures have to be avoided. It also should provide a significant improvement on our existing technique.
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PMID 
M Lahanas, D Baltas, S Giannouli, N Milickovic, N Zamboglou (2000)  Generation of uniformly distributed dose points for anatomy-based three-dimensional dose optimization methods in brachytherapy.   Med Phys 27: 5. 1034-1046 May  
Abstract: We have studied the accuracy of statistical parameters of dose distributions in brachytherapy using actual clinical implants. These include the mean, minimum and maximum dose values and the variance of the dose distribution inside the PTV (planning target volume), and on the surface of the PTV. These properties have been studied as a function of the number of uniformly distributed sampling points. These parameters, or the variants of these parameters, are used directly or indirectly in optimization procedures or for a description of the dose distribution. The accurate determination of these parameters depends on the sampling point distribution from which they have been obtained. Some optimization methods ignore catheters and critical structures surrounded by the PTV or alternatively consider as surface dose points only those on the contour lines of the PTV. D(min) and D(max) are extreme dose values which are either on the PTV surface or within the PTV. They must be avoided for specification and optimization purposes in brachytherapy. Using D(mean) and the variance of D which we have shown to be stable parameters, achieves a more reliable description of the dose distribution on the PTV surface and within the PTV volume than does D(min) and D(max). Generation of dose points on the real surface of the PTV is obligatory and the consideration of catheter volumes results in a realistic description of anatomical dose distributions.
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PMID 
T Martin, S Hey-Koch, G Strassmann, C Kolotas, D Baltas, B Rogge, S Röddiger, H G Vogt, R Heyd, T Dannenberg, R Kurek, U Tunn, N Zamboglou (2000)  3D interstitial HDR brachytherapy combined with 3D external beam radiotherapy and androgen deprivation for prostate cancer. Preliminary results.   Strahlenther Onkol 176: 8. 361-367 Aug  
Abstract: BACKGROUND: Evaluation of feasibility, tolerance and efficiency for a new 3D interstitial HDR brachytherapy technique combined with 3D external beam radiotherapy and androgen deprivation for prostate cancer. PATIENTS AND METHODS: Between January 1997 and August 1998 we treated 35 patients with stage cT1-3 N0 M0 prostate cancer. Thirty-two patients with a follow-up of 12 to 28 months (median: 18 months) were evaluated. After ultrasound-guided transrectal implantation of 4 non-parallel needles, CT based 3D brachytherapy treatment planning ("Offenbach system") was performed. All patients received 4 fractions brachytherapy using a fractional dose of 5 or 7 Gy. Time between each fraction was 14 days. After brachytherapy 3D external irradiation followed up to 39.6 or 45.0 Gy. All patients received androgen deprivation, starting 2 to 19 months before brachytherapy, ending 3 months after 3D external radiotherapy. RESULTS: Posttreatment PSA levels dropped to < 1.5 ng/ml in 29/32 patients (91%). In 25 patients PSA levels were < 0.5 ng/ml, in 4 patients 0.5 to 1.5 ng/ml. In 2 patients we noted biochemical relapse. Transrectal implantation was very well tolerated. Grade 3 acute urinary toxicity occurred in 1 patient. We noted no Grade 2 or higher acute gastrointestinal toxicity. One patient developed a Grade 3 late urinary toxicity. No patient showed late gastrointestinal side effects. All 140 dose-volume histograms for 3D HDR brachytherapy were analyzed. CONCLUSIONS: The new 3D HDR brachytherapy technique, combined with 3D external irradiation and androgen deprivation, is a feasible, so far well-tolerated and effective treatment in the short-time follow-up of median 18 months.
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PMID 
N Milickovic, S Giannouli, D Baltas, M Lahanas, C Kolotas, N Zamboglou, N Uzunoglu (2000)  Catheter autoreconstruction in computed tomography based brachytherapy treatment planning.   Med Phys 27: 5. 1047-1057 May  
Abstract: The aim of this study is to develop an automatic reconstruction of brachytherapy catheters using CT (computed tomography) data. Previously no such automatic facility has existed in any treatment planning software. To achieve this facility we have developed tools for the automatic reconstruction (which we term autoreconstruction) of plastic and metallic catheters. These algorithms overcome a number of difficulties which arise when a large number of catheters are present. These include situations with intersecting catheters and with loop techniques. The time required for the catheter reconstruction process using our autoreconstruction method is significantly reduced. The accuracy of our autoreconstruction is at least as high as the classical manual slice-by-slice method.
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PMID 
S Giannouli, D Baltas, N Milickovic, M Lahanas, C Kolotas, N Zamboglou, N Uzunoglu (2000)  Autoactivation of source dwell positions for HDR brachytherapy treatment planning.   Med Phys 27: 11. 2517-2520 Nov  
Abstract: The most accurate classical dose optimization algorithms in HDR brachytherapy strongly depend on an appropriate selection of source dwell positions which fulfill user-defined geometrical boundary conditions which are relative to patient anatomy. Most anatomical situations, such as for prostate and head and neck tumors, are complex and can require geometries with 5-15 catheters with 48 possible dwell positions per catheter depending on the tumor volume. The manual selection of dwell positions using visual checks by trial and error is very time consuming. This can only be improved by the use of a technique which automatically recognizes and selects the optimum dwell positions for each catheter. We have developed an algorithm, termed an autoactivation algorithm, which improves implant planning by providing a facility for the necessary automatic recognition of HDR source dwell positions.
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PMID 
T Kemmerer, M Lahanas, D Baltas, N Zamboglou (2000)  Dose-volume histograms computation comparisons using conventional methods and optimized fast Fourier transforms algorithms for brachytherapy.   Med Phys 27: 10. 2343-2356 Oct  
Abstract: In anatomy based optimization procedures for large volume implants the calculation of dose-volume histograms (DVH) accounts for the major part of the time involved and can be as long as a few hours. This time is proportional to the number of seeds or source dwell positions required for the implant. A procedure for the calculation of brachytherapy seed dose distribution calculation employing fast Fourier transforms (FFT) and the convolution theorem has been described by others and was supposed to significantly improve the speed of the dose distribution computation. Using new significantly improved FFT algorithms and various other optimization techniques we have compared the calculated differential and integral DVHs in high dose rate (HDR) brachytherapy with a single stepping source using actual clinical implants. This is so that we could assess the efficiency and accuracy of the FFT method with that of conventional methods. Our results showed that the FFT based method of calculating DVHs in brachytherapy is comparable in speed with conventional dose calculation methods, but only for implants with more than 287 sources. It is therefore of limited practical use even for large implants. This result is in direct opposition to the claim by other authors.
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PMID 
M Lahanas, T Kemmerer, N Milickovic, K Karouzakis, D Baltas, N Zamboglou (2000)  Optimized bounding boxes for three-dimensional treatment planning in brachytherapy.   Med Phys 27: 10. 2333-2342 Oct  
Abstract: It is sometimes necessary to determine the optimal value for a direction dependent quantity. Using a search technique based on Powell's quadratic convergent method such an optimal direction can be approximated. The necessary geometric transformations in n-dimensional space are introduced. As an example we consider the approximation of the minimum bounding box of a set of three-dimensional points. Minimum bounding boxes can significantly improve accuracy and efficiency of the calculations in modern brachytherapy treatment planning of the volumes of objects or the dose distribution inside an object. A covariance matrix based approximation method for the minimum bounding box is compared with the results of the search method. The benefits of the use of optimal oriented bounding boxes in brachytherapy treatment planning systems are demonstrated and discussed.
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1999
 
PMID 
M Lahanas, D Baltas, N Zamboglou (1999)  Anatomy-based three-dimensional dose optimization in brachytherapy using multiobjective genetic algorithms.   Med Phys 26: 9. 1904-1918 Sep  
Abstract: In conventional dose optimization algorithms, in brachytherapy, multiple objectives are expressed in terms of an aggregating function which combines individual objective values into a single utility value, making the problem single objective, prior to optimization. A multiobjective genetic algorithm (MOGA) was developed for dose optimization based on an a posteriori approach, leaving the decision-making process to a planner and offering a representative trade-off surface of the various objectives. The MOGA provides a flexible search engine which provides the maximum of information for a decision maker. Tests performed with various treatment plans in brachytherapy have shown that MOGA gives solutions which are superior to those of traditional dose optimization algorithms. Objectives were proposed in terms of the COIN distribution and differential volume histograms, taking into account patient anatomy in the optimization process.
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PMID 
D Baltas, K Geramani, G T Ioannidis, K Hierholz, B Rogge, C Kolotas, K Müller-Sievers, N Milickovic, B Kober, N Zamboglou (1999)  Comparison of calibration procedures for 192Ir high-dose-rate brachytherapy sources.   Int J Radiat Oncol Biol Phys 43: 3. 653-661 Feb  
Abstract: PURPOSE: To compare the efficacy of different calibration procedures for 192Ir high-dose-rate (HDR) brachytherapy sources and to determine their suitability in clinical practice. In addition the manufacturer's calibration is compared with our experimental measurements so that the accuracy of the source strength on the manufacturer certificate which is supplied with each new 192Ir source can be accessed. METHODS AND MATERIALS: We compared three types of calibration system: well-type chambers (HDR-1000 and SDS), cylindrical phantom, and plate phantom. The total number of measurements we obtained was 365. The number of sources used for the calibration procedure comparison was 20 and the number used for comparison with the manufacturer's calibration was 46. This study was made during the period 1989-1997. Also, Physikalisch-Technische Bundesanstalt (PTB) calibrated one of our sources using their PTB protocol so that the results could be compared with our own. RESULTS: The sensitivity of each system on scattering from the room walls was studied. It was found that different minimum lateral distances from the walls were required for the different systems tested: 15 cm and 25 cm for the well-type chambers, 75 cm for the cylindrical phantom, and 13 cm for the plate phantom. The minimum thickness required to reach phantom scattering saturation for the plate phantom setup is 24 cm. The influence of the applicator material used in the calibration setup was found to be 1.7% for the stainless steel dosimetry applicator compared to the plastic 5F applicator. The accuracy of source positioning within the applicator can lead to dosimetric errors of +/-1.2% for the radial distance of 8.0 cm used with both solid phantoms. The change in the response for both well-type chambers was only 0.1% for changes in the source position within +/-7.5 mm around the response peak. Good agreement was found between all dosimetry systems included in our study. Taking the HDR-1000 well-type chamber results as a reference, we observed percentage root mean square (RMS) values of 0.11% for the SDS well-type chamber, 0.44% for the cylindrical, and 0.60% for the plate phantom setup. A comparison of our results using the cylindrical phantom with those of the manufacturer showed a percentage RMS value of 3.3% with a percentage fractional error range of -13.0% to +6.0%. The comparison of our calibration results with those of PTB gave deviations less than 0.4% for all systems. CONCLUSIONS: Our results have shown that with careful use of all calibration system protocols an accurate determination of source strength can be obtained. However, the manufacturer's calibration is not accurate enough on its own, and it should be mandatory for clinics to always measure the source strength of newly delivered 192Ir brachytherapy sources. The influence of the applicator material, metal or plastic, should always be taken into account.
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PMID 
C Kolotas, D Baltas, N Zamboglou (1999)  CT-Based interstitial HDR brachytherapy.   Strahlenther Onkol 175: 9. 419-427 Sep  
Abstract: PURPOSE: Development, application and evaluation of a CT-guided implantation technique and a fully CT-based treatment planning procedure for brachytherapy. METHODS AND MATERIALS: A brachytherapy procedure based on CT-guided implantation technique and CT-based treatment planning has been developed and clinical evaluated. For this purpose a software system (PROMETHEUS) for the 3D reconstruction of brachytherapy catheters and patient anatomy using only CT scans has been developed. An interface for the Nucletron PLATO BPS treatment planning system for optimization and calculation of dose distribution has been devised. The planning target volume(s) are defined as sets of points using contouring tools and are used for optimization of the 3D dose distribution. Dose-volume histogram based analysis of the dose distribution (COIN analysis) enables a clinically realistic evaluation of the brachytherapy application to be made. The CT-guided implantation of catheters and the CT-based treatment planning procedure has been performed for interstitial brachytherapy and for different tumor sites in 197 patients between 1996 and 1997. RESULTS: The accuracy of the CT reconstruction was tested using first a quality assurance phantom and second, a simulated interstitial implant of 12 needles. These were compared with the results of reconstruction using radiographs. Both methods gave comparable results with regard to accuracy, but the CT based reconstruction was faster. Clinical feasibility was proved in pre-irradiated recurrences of brain tumors, in pretreated recurrences or metastatic disease, and in breast carcinomas. The tumor volumes treated were in the range 5.1 to 2,741 cm3. Analysis of implant quality showed a slightly significant lower COIN value for the bone implants, but no differences with respect to the planning target volume. CONCLUSIONS: The Offenbach system, incorporating the PROMETHEUS software for interstitial HDR brachytherapy has proved to be extremely valuable in routine clinical practice for many tumor sites. Our CT-guided implantation technique together with a fully CT-based planning system has enabled conformal brachytherapy treatment to become routine.
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PMID 
T Martin, C Kolotas, T Dannenberg, G Strassmann, H G Vogt, R Heyd, B Rogge, D Baltas, R Kurek, U Tunn, N Zamboglou (1999)  New interstitial HDR brachytherapy technique for prostate cancer: CT based 3D planning after transrectal implantation.   Radiother Oncol 52: 3. 257-260 Sep  
Abstract: We have developed a new interstitial HDR brachytherapy technique for the treatment of prostate cancer using CT based 3D planning after transrectal implantation of four non-parallel needles. CT based needle reconstruction, target definition, evaluation and documentation, including DVHs and 3D imaging, is a feasible, safe and well tolerated treatment concept.
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PMID 
C Kolotas, G Birn, D Baltas, B Rogge, P Ulrich, N Zamboglou (1999)  CT guided interstitial high dose rate brachytherapy for recurrent malignant gliomas.   Br J Radiol 72: 860. 805-808 Aug  
Abstract: This paper describes the technique and preliminary results of high dose rate (HDR) interstitial brachytherapy for recurrent grade III and grade IV gliomas. Although in the initial treatment of malignant gliomas brachytherapy has been shown to give better results than external beam therapy, this has previously always been with low dose rate (LDR) brachytherapy. Stereotactic frames are used for interstitial LDR brachytherapy but a CT image-guided technique does not require such a frame. The survival rates for our initial 53 patients do not significantly differ from LDR results. However, using HDR there are several advantages, including a much shorter treatment time with HDR than LDR and better patient comfort. HDR also allows better individualized optimization of the treatment than LDR.
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PMID 
C Kolotas, C Tonus, D Baltas, M Cernea, H G Vogt, T Martin, G Strassmann, N Zamboglou (1999)  Clinical relevance of tumor ploidy and micronucleus formation for oral cavity cancer.   Tumori 85: 4. 253-258 Jul/Aug  
Abstract: AIMS AND BACKGROUND: To study the clinical relevance of tumor ploidy and micronucleus formation as prognostic factors. METHODS AND STUDY DESIGN: Twenty-eight patients with squamous cell carcinoma of the oral cavity were treated with primary radiochemotherapy consisting of irradiation up to 70 Gy in combination with cisplatin. Cell cycle distribution, micronucleus formation and ploidy were evaluated by flow cytometry of biopsies taken before treatment and after irradiation to 10 Gy (5x2 Gy). Sexteen out of 28 patients relapsed after a minimum follow-up period of two years. RESULTS: Flow cytometry of the recurrence biopsy showed hyperpentaploid (5c exceeding) cells in 13/16 (81%) of the relapsed patients. In 7 patients the hyperploid clone was not present in the flow cytometry of the primary tumors. Ploidy could retrospectively be determined also by image cytometry in archival tumor material of the pretreatment specimens. Patients with a level below 100 5c cells per 10,000 cell nuclei were shown to have a significantly better prognosis than patients with more than 100 hyperpentaploid tumor cells. The micronucleus formation was 2-5 times higher in tumors showing a good response to treatment than in carcinomas relapsing within two years. CONCLUSIONS: The 5c-exceeding ratio measured by image cytometry and micronucleus formation proved to be good prognostic parameters for the clinical outcome of patients with locally advanced head and neck carcinomas.
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1998
 
PMID 
D Baltas, C Kolotas, K Geramani, R F Mould, G Ioannidis, M Kekchidi, N Zamboglou (1998)  A conformal index (COIN) to evaluate implant quality and dose specification in brachytherapy.   Int J Radiat Oncol Biol Phys 40: 2. 515-524 Jan  
Abstract: PURPOSE: To propose a new index (COIN) that can be easily understood and computed to assess high dose rate (HDR) brachytherapy interstitial implant quality and dose specification and is an improvement on existing indexes. METHODS AND MATERIALS: The COIN index is based on an extension of dose-volume histograms and employs an analogous concept to that of cost-benefit analysis, which has already been applied to quality-of-life assessments for two alternative treatment protocols. The COIN index calculation methodology is shown for two cases: with and without critical structures. An analysis is given of dose distributions for two planning treatment volumes (PTV) of simple geometrical shape, applying both the rules of the Paris system and that of the "Offenbach" system. 40 patients who have received interstitial implants form the clinical material. With current HDR brachytherapy technology both for dose delivery, using remote afterloaders, and for three-dimensional (3D) treatment planning, it is now possible to relatively easily plan conformal brachytherapy treatments that would have been impossible with manual afterloading techniques and two-dimensional (2D) treatment planning. RESULTS: Examples of the use of the COIN index are presented for experimental and clinical data. CONCLUSIONS: The results show that COIN is a useful and practical index to improve the quality of treatment of interstitial brachytherapy implants. Further work will be undertaken with a larger population of implanted cancer patients and a subdivision of the results by treatment site.
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PMID 
D Baltas, S Giannouli, A Garbi, F Diakonos, K Geramani, G T Ioannidis, A Tsalpatouros, N Uzunoglu, C Kolotas, N Zamboglou (1998)  Application of the Monte Carlo integration (MCI) method for calculation of the anisotropy of 192Ir brachytherapy sources.   Phys Med Biol 43: 6. 1783-1801 Jun  
Abstract: Source anisotropy is a very important factor in the brachytherapy quality assurance of high-dose rate (HDR) 192Ir afterloading stepping sources. If anisotropy is not taken into account then doses received by a brachytherapy patient in certain directions can be in error by a clinically significant amount. Experimental measurements of anisotropy are very labour intensive. We have shown that within acceptable limits of accuracy, Monte Carlo integration (MCI) of a modified Sievert integral (3D generalization) can provide the necessary data within a much shorter time scale than can experiments. Hence MCI can be used for routine quality assurance schedules whenever a new design of HDR or PDR 192Ir is used for brachytherapy afterloading. Our MCI calculation results are compared with published experimental data and Monte Carlo simulation data for microSelectron and VariSource 192Ir sources. We have shown not only that MCI offers advantages over alternative numerical integration methods, but also that treating filtration coefficients as radial distance-dependent functions improves Sievert integral accuracy at low energies. This paper also provides anisotropy data for three new 192Ir sources, one for the microSelectron-HDR and two for the microSelectron-PDR, for which data are currently not available. The information we have obtained in this study can be incorporated into clinical practice.
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1997
 
PMID 
A Tsalpatouros, D Baltas, C Kolotas, R van der Laarse, D Koutsouris, N K Uzunoglu, N Zamboglou (1997)  CT-based software for 3-D localization and reconstruction in stepping source brachytherapy.   IEEE Trans Inf Technol Biomed 1: 4. 229-242 Dec  
Abstract: This paper describes innovative software for catheter localization and three-dimensional (3-D) reconstruction in stepping source brachytherapy applications. Patient information is a set of computed tomography (CT) slices scanned during the implantation of brachytherapy catheters. Catheter geometry and patient anatomy are exported for use with dose calculation software modules. The errors produced by the system are also encouragingly low. Time saving was achieved, in terms of other traditional reconstruction techniques. Various automated procedures, 3-D graphics and a user-friendly GUI, have contributed to providing a powerful, comprehensive software tool, directly useable in the clinical practice.
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PMID 
K Müller-Sievers, D Baltas, B Kober (1997)  A quality assurance program of simulators in radiation therapy. 2. Extent and results of long-term quality assurance test on a therapy simulator   Strahlenther Onkol 173: 12. 693-699 Dec  
Abstract: BACKGROUND: Since 1990 we follow a quality assurance program with periodical tests of functional performance values of a 16-year-old simulator. MATERIAL AND METHOD: For this purpose we adopted and modified German standards for quality assurance on linear accelerators and international standards elaborated for simulators (International Electrotechnical Commission). The tests are subdivided into daily visual checks (light field indication, optical distance indicator, isocentre-indicating devices, indication of gantry and collimator angles) and monthly and annually tests of relevant simulator parameters. Some important examples demonstrate the small variation of parameters over 6 years: position of the light field centre when rotating the collimator, diameter of the isocentre circle when rotating the gantry, accuracy of the isocentre indication device, and coincidence of light field and simulated radiation field. RESULTS: As an important result we can state, that by these rigid periodic tests it was possible to detect and compensate deteriorations of simulators quality rapidly. CONCLUSIONS: Technical improvements and specific calling-in of maintenance personnel whenever felt appropriate provided performance characteristics of our old simulator which are required by international recommendations as a basis for modern radiotherapy.
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1996
 
PMID 
H Krieger, D Baltas, P Kneschaurek (1996)  A proposal for dosage and volume specification and documentation in HDR brachytherapy   Strahlenther Onkol 172: 10. 527-542 Oct  
Abstract: BACKGROUND: Modern computer-aided brachytherapy techniques and the various clinical and radiobiological methods require a review and standardization of dose specification and documentation in brachytherapy. METHOD: The methods and the extent of the dose specification and documentation have been analysed on the base of known international and national procedure. A new modified report has been prepared for the standardized dose specification for HDR-brachytherapy techniques. RESULT: Brachytherapy treatments are supposed to be documented in 3 different levels (I to III), the extent of which depending on the treated volume, the therapeutic aim and the equipment available. CONCLUSION: The extent of documentation and dose specification proposed in this paper requires the close cooperation of radio-oncologists and medical physicists. It seems to be advantageous to use prepared sheets or computer prints in order to minimize the time and efforts for a sufficient documentation.
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1993
 
PMID 
D Baltas, K Müller-Sievers, B Kober (1993)  A quality assurance program for simulators in radiotherapy. 1: The universal phantom for quality control of therapy simulators and teletherapy equipment   Strahlenther Onkol 169: 5. 296-303 May  
Abstract: A new phantom is described which shall be utilized to check geometric parameters of simulators and therapy units. Because of its mechanical assembly technique construction it is possible to use any part of the system fixed on a base plate which has to be adjusted only once. The application of the different parts of the phantom will be illustrated by some check examples on simulators and linacs. An intercomparison of quality control data referring to therapy simulators in various centres of South Germany has been started whereby the usability and reliability of the phantom also will be tested. The preliminary results give objective reasons for its suitability to study generally the performance tolerances of simulators with regard to quality assurance in radiotherapy.
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1989
 
PMID 
D Baltas, D Fehrentz, I Turesson (1989)  Analysis of late effects data using dose-response models: application to human skin telangiectasia data.   Radiother Oncol 16: 1. 41-53 Sep  
Abstract: The clinical data for skin telangiectasia from previous prospective studies at the Radiotherapy Department in Gothenborg are reanalyzed using two dose-response models - the general formulations of the well known linear-quadratic (LQ) and NSD isoeffect models. Assuming that essentially no repopulation appears in the vessel endothelium for overall treatment times up to 68 days, the alpha/beta-value of 2.75 Gy is obtained for the LQ-model. The time factor is found not to be significant by the NSD-model for the treatment times used (less than or equal to 68 days) at the 95% level of confidence. The estimated value of the exponent of the number of fractions, A, is 0.321. The obtained values of the alpha/beta-ratio and of A show high sensitivity of the vessel endothelium to changes in the dose per fraction. Our results show that within the interval of the number of fractions used, 10-35 fractions, the NSD-model gives predictions comparable to those of the LQ-model. For number of fractions smaller than 5, a high discrepancy occurs between the two models, the NSD-model predicting higher values of the isoeffective total dose. The maximal deviation between the models appears for N = 1; 25% and 27% at the 5 and 50% level of effect, respectively. For large N and especially at low effect probabilities the NSD-model again predicts higher isoeffective doses: the dose predicted by the NSD-model for a regimen with 40 fractions and for 5% probability of telangiectasia is 7.5%, higher than that predicted by the LQ-model. Based on the estimated dose-response curves, considering the telangiectasia as the decisive late tissue effect, the requirement for the combined uncertainty in the dose delivery is estimated between 3 and 4.5%.
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