Localization of deformable tumors from short-arc projections using Bayesian estimation.

PURPOSE: The authors present a stochastic framework for radiotherapy patient positioning directly utilizing radiographic projections. This framework is developed to be robust against anatomical nonrigid deformations and to cope with challenging imaging scenarios, involving only a few cone beam CT projections from short arcs. METHODS: Specifically, a Bayesian estimator (BE) is explicitly derived for the given scanning geometry. This estimator is compared to reference methods such as chamfer matching (CM) and the minimization of the median absolute error adapted as tools of robust image processing and statistics. In order to show the performance of the stochastic short-arc patient positioning method, a CIRS IMRT thorax phantom study is presented with movable markers and the utilization of an Elekta Synergy(®) XVI system. Furthermore, a clinical prostate CBCT scan of a Varian(®) On-Board Imager(®) system is utilized to investigate the robustness of the method for large variations of image quality (anterior-posterior vs lateral views). RESULTS: The results show that the BE shifts reduce the initial setup error of up to 3 cm down to 3 mm at maximum for an imaging arc as short as 10° while CM achieves residual errors of 7 mm at maximum only for arcs longer than 40°. Furthermore, the BE can compensate robustly for low image qualities using several low quality projections simultaneously. CONCLUSIONS: In conclusion, an estimation method for marker-based patient positioning for short imaging arcs is presented and shown to be robust and accurate for deformable anatomies.

Stochastic formulation of patient positioning using linac-mounted cone beam imaging with prior knowledge.

PURPOSE: In this work, a novel stochastic framework for patient positioning based on linac-mounted CB projections is introduced. Based on this formulation, the most probable shifts and rotations of the patient are estimated, incorporating interfractional deformations of patient anatomy and other uncertainties associated with patient setup. METHODS: The target position is assumed to be defined by and is stochastically determined from positions of various features such as anatomical landmarks or markers in CB projections, i.e., radiographs acquired with a CB-CT system. The patient positioning problem of finding the target location from CB projections is posed as an inverse problem with prior knowledge and is solved using a Bayesian maximum a posteriori (MAP) approach. The prior knowledge is three-fold and includes the accuracy of an initial patient setup (such as in-room laser and skin marks), the plasticity of the body (relative shifts between target and features), and the feature detection error in CB projections (which may vary depending on specific detection algorithm and feature type). For this purpose, MAP estimators are derived and a procedure of using them in clinical practice is outlined. Furthermore, a rule of thumb is theoretically derived, relating basic parameters of the prior knowledge (initial setup accuracy, plasticity of the body, and number of features) and the parameters of CB data acquisition (number of projections and accuracy of feature detection) to the expected estimation accuracy. RESULTS: MAP estimation can be applied to arbitrary features and detection algorithms. However, to experimentally demonstrate its applicability and to perform the validation of the algorithm, a water-equivalent, deformable phantom with features represented by six 1 mm chrome balls were utilized. These features were detected in the cone beam projections (XVI, Elekta Synergy) by a local threshold method for demonstration purposes only. The accuracy of estimation (strongly varying for different plasticity parameters of the body) agreed with the rule of thumb formula. Moreover, based on this rule of thumb formula, about 20 projections for 6 detectable features seem to be sufficient for a target estimation accuracy of 0.2 cm, even for relatively large feature detection errors with standard deviation of 0.5 cm and spatial displacements of the features with standard deviation of 0.5 cm. CONCLUSIONS: The authors have introduced a general MAP-based patient setup algorithm accounting for different sources of uncertainties, which are utilized as the prior knowledge in a transparent way. This new framework can be further utilized for different clinical sites, as well as theoretical developments in the field of patient positioning for radiotherapy.

Radiation-induced suppression of the Bmp2 signal transduction pathway in the pluripotent mesenchymal cell line C2C12: an in vitro model for prevention of heterotopic ossification by radiotherapy.

Heterotopic ossification is a common complication after total hip replacement. Clinical studies showed the effectiveness of radiation for prevention of heterotopic ossification. The mechanism of radiotherapy responsible for the reduction of heterotopic ossification is unclear. The purpose of this study was to study an analogue model showing a time- and dose-dependent effect of radiation. Using cells of the defined embryonic mouse cell line C2C12, the influence of ionizing radiation on the Bmp-induced signal cascade leading to osteogenic differentiation was analyzed. Binding of iodinated Bmp2 to the receptors, Smad1 activation, and alkaline phosphatase (ALP) activity were determined in cells with or without irradiation. The cytotoxic effect of radiotherapy was evaluated using viability tests. Radiotherapy reduced formation of the Bmp2/Bmp receptor complex. This effect was dependent on dose. The phosphorylation (activation) of Smad1 decreased after irradiation in a time-dependent manner, whereas the level of total Smads was not influenced by radiotherapy. The ALP activity decreased after radiotherapy. A dose of 7 Gy delivered 6 h before or after incubation with Bmp resulted in about a 30% decrease in ALP activity. No signs of cytotoxic effects were observed within the time window studied using doses of 0 to 20 Gy. The time- and dose-dependent effect of radiotherapy for prevention of heterotopic ossification known from the results of clinical studies has an analogue in the C2C12 cell model. The primary mechanism of radiotherapy seems to be an influence on cellular responsiveness to the Bmp2-induced osteoblastic differentiation. The results suggest a down-regulation of the Bmp2/receptor complex.

Radiation-induced reduction of BMP-induced proteoglycan synthesis in an embryonal mesenchymal tissue equivalent using the chicken "limb bud" test.

PURPOSE: Heterotopic ossification (HO) is a common complication following total hip replacement. Clinical studies showed the effectiveness of irradiation for prevention of heterotopic ossification. The mechanism of radiotherapy responsible for the reduction of heterotopic ossification is unclear. The purpose of this study was to find a suitable cell system, which can reproduce in-vitro data resulting from clinical in-vivo studies. The establishment of such a cell model allows detailed analyses of the mechanism of radiotherapy. METHOD: The chicken limb bud test was used as an in-vitro model. The cells acquired by the limb bud test were irradiated with different doses (0 Gy, 3 Gy, 7 Gy, 10 Gy, 20 Gy). Irradiation was set either 1 hour before, or 1 or 3 days after BMP-2 incubation. The synthesis of proteoglycans (PGS) upon treatment with bone morphogenetic protein (BMP)-2 was measured in cells incubated with BMP-2 for 4 days followed by 35SO4(2-) labeling for 6 hours. Labeled proteoglycans were precipitated using Alcian blue and measured in a raytest radio-TLC analyzer. The incubation with BMP-2 was defined to correlate the in-vivo stimulus meaning the operation. RESULTS: The proteoglycan synthesis was significantly reduced by irradiation 1 hour before or 1 day after BMP-2 incubation, if the dosage was at least 7 Gy. Higher doses than 7 Gy did not lead to lower proteoglycan levels. There was only a trend for a reduction of proteoglycan synthesis by 3 Gy irradiation, but no significant difference compared to the non-irradiated control. An irradiation 3 days after BMP-2 incubation had no effect on proteoglycan. CONCLUSION: A dose and time dependent effect of radiation on BMP-2-induced proteoglycan synthesis was observed. Therefore the results of clinical in-vivo studies were reproduced exactly by the limb bud test. We established an in-vitro cell model to analyze the mechanism of the prevention of heterotopic ossification by radiotherapy on cellular or sub-cellular level.

p53 and Ki-67 as predictive markers for radiosensitivity in squamous cell carcinoma of the oral cavity? an immunohistochemical and clinicopathologic study.

PURPOSE: Previously published data relating the expression of p53 and Ki-67 to radiation response in head and neck cancer are conflicting. This may be due to differences in patient selection and treatment modalities. In this study of a homogenous population of patients with oral cavity cancer, Ki-67 and p53 indices were correlated with histopathologically assessed tumor regression after preoperative radiochemotherapy and longterm outcome. METHODS AND MATERIALS: Eighty-eight patients with squamous cell carcinoma of the oral cavity and treated between September 1985 and November 1995 by preoperative radiochemotherapy and definitive surgery were included in this analysis. By immunohistochemistry (IHC) the pre-irradiation expression of p53 and of Ki-67 were analyzed and correlated with the histopathologically proven tumor regression, overall survival and local control. RESULTS: The overall 2- and 5-year survival rates were 76.5% and 63%, the locoregional control rates were 84% and 79%, respectively. After preoperative radiochemotherapy 29 patients (33%) showed complete tumor regression (ypT(0) classification). Survival and local control rates were significantly higher for patients showing ypT(0) classification than ypT(1-4) classification (p < 0.01). This effect was independent of pretreatment tumor classification in multivariate analysis. Pre-irradiation p53 status and Ki-67 index had no influence on tumor regression and clinical outcome in these patients. CONCLUSION: Complete tumor regression after preoperative treatment is related to an improved outcome in combined modality treatment of oral cavity cancer. The presented study could not demonstrate an influence of p53 and Ki-67 status as detected by immunohistochemical staining on survival, local control, or tumor regression after radiochemotherapy.

Transcranial sonography: integration into target volume definition for glioblastoma multiforme.

PURPOSE: Recent studies indicate that transcranial sonography (TCS) reliably displays the extension of malignant brain tumors. The effect of integrating TCS into radiotherapy planning for glioblastoma multiforme (GBM) was investigated herein. METHODS AND MATERIALS: Thirteen patients subtotally resected for GBM underwent TCS during radiotherapy planning and were conventionally treated (54 to 60 Gy). Gross tumor volumes (GTVs) and stereotactic boost planning target volumes (PTVs, 3-mm margin) were created, based on contrast enhancement on computed tomography (CT) only (PTV(CT)) or the combined CT and TCS information (PTV(CT+TCS)). Noncoplonar conformal treatment plans for both PTVs were compared. Tumor progression patterns and preoperative magnetic resonance imaging (MRI) were related to both PTVs. RESULTS: A sufficient temporal bone window for TCS was present in 11 of 13 patients. GTVs as defined by TCS were considerably larger than the respective CT volumes: Of the composite GTV(CT+TCS) (median volume 42 ml), 23%, 13%, and 66% (medians) were covered by the overlap of both methods, CT only and TCS only, respectively. Median sizes of PTV(CT) and PTV(CT+TCS) were 34 and 74 ml, respectively. Addition of TCS to CT information led to a median increase of the volume irradiated within the 80% isodose by 32 ml (median factor 1.51). PTV(CT+TCS) volume was at median 24% of a "conventional" MRI(T2)-based PTV. Of eight progressions analyzed, three and six occurred inside the 80% isodose of the plans for PTV(CT) and for PTV(CT+TCS), respectively. CONCLUSION: Addition of TCS tumor volume to the contrast-enhancing CT volume in postoperative radiotherapy planning for GBM increases the treated volume by a median factor of 1.5. Since a high frequency of marginal recurrences is reported from dose-escalation trials of this disease, TCS may complement established methods in PTV definition.

Influence of patient positioning on dose-volume histogram and normal tissue complication probability for small bowel and bladder in patients receiving pelvic irradiation: a prospective study using a 3D planning system and a radiobiological model.

PURPOSE: A prospective study was undertaken to evaluate the influence of patient positioning (prone position using a belly board vs. supine position) on the dose-volume histograms (DVHs) of organs of risk, and to analyze its possible clinical relevance using radiobiological models. METHODS AND MATERIALS: From November 1996 to August 1997 a computed tomography (CT) scan was done in the prone position using a belly board and in supine position in 20 consecutive patients receiving postoperative pelvic irradiation because of rectal cancer. Using a three-dimensional (3D) planning system (Helax, TMS) the DVH for small bowel, bladder, a standard planning target volume (PTV) of postoperative irradiation of rectal cancer, the intersection of volume of PTV and small bowel (PTV intersection V(SB), respectively, of PTV and bladder (PTV intersection V(B)) were defined in each axial CT slice. The normal tissue complication probability (NTCP) was determined by the radiobiological model of Lyman and Kutcher using the tolerance data of Emami. For evaluation of late toxicity alpha/beta ratio was 2.5; for evaluation of acute toxicity, it was 10. Total dose was 50.4 Gy (1.8 Gy/fraction) (ICRU 50). RESULTS: Using the prone position compared to the supine position, the median volume of PTV intersection V(B) was reduced by 18.5 cm3 (62%). Median dose (related to the reference dose) to the bladder was 44.5% (22.4 Gy) in prone and 66.05% (33.3 Gy) in supine position (p<0.001). Median V(B) within the 90% (45.4 Gy), 80% (40.3 Gy), 60% (30.2 Gy), and 40% (20.2 Gy) isodose was significantly lower in the prone position when compared to the supine position. Using the radiobiological models, however, there was no difference of NTCP between prone position or supine position. In the prone position, median volume of PTV intersection V(SB) was reduced by 32.5 cm3 (54%). The median dose to small bowel was 30.85% (15.4 Gy) in the prone position and 47.35% (23.9Gy) in the supine position (p<0.001). Significant differences between prone and supine position were found for median V(SB) within the 90% (45.4 Gy), 80% (40.3 Gy), 60% (30.2 Gy), and 40% (20.2 Gy) isodose. According to the method of Lyman, median NTCP of small bowel was significant lower in prone than in supine position. CONCLUSION: The prone position with a standard belly board should be the standard positioning technique for patients receiving adjuvant postoperative radiation therapy following surgery of rectal cancer. Both irradiated volume and total dose to the organs of risk can be reduced significantly. As a consequence of this, radiation induced toxicity will be minimized.