Clinical characteristics and outcomes of patients with haematologic malignancies and COVID-19 suggest that prolonged SARS-CoV-2 carriage is an important issue.

Specificities of COVID-19 disease course in patients with haematologic malignancies are still poorly studied. So, we aimed to compare patients with haematologic malignancies to patients without malignancies, matched by sex and age and hospitalised for COVID-19 at the same time and in the same centre. Among 25 patients with haematologic malignancies, we found that mortality (40% versus 4%, p < 0.01), number of days with RT-PCR positivity (21.2 ± 15.9 days [range, 3-57] versus 7.4 ± 5.6 days [range, 1-24], p < 0.01), maximal viral load (mean minimal Ct, 17.2 ± 5.2 [range, 10-30] versus 26.5 ± 5.1 [range, 15-33], p < 0.0001) and the delay between symptom onset and clinical worsening (mean time duration between symptom onset and first day of maximum requirement in inspired oxygen fraction, 14.3 ± 10.7 days versus 9.6 ± 3.7 days, p = 0.0485) were higher than in other patients. COVID-19 course in patients with haematologic malignancies has a delayed onset and is more severe with a higher mortality, and patients may be considered as super-spreaders. Clinicians and intensivists need to be trained to understand the specificity of COVID-19 courses in patients with haematological malignancies.

Respiratory gated beam delivery cannot facilitate margin reduction, unless combined with respiratory correlated image guidance.

PURPOSE/OBJECTIVE: In radiotherapy of targets moving with respiration, beam gating is offered as a means of reducing the target motion. The purpose of this study is to evaluate the safe magnitude of margin reduction for respiratory gated beam delivery. MATERIALS/METHODS: The study is based on data for 17 lung cancer patients in separate protocols at Rigshospitalet and Stanford Cancer Center. Respiratory curves for external optical markers and implanted fiducials were collected using equipment based on the RPM system (Varian Medical Systems). A total of 861 respiratory curves represented external measurements over 30 fraction treatment courses for 10 patients, and synchronous external/internal measurements in single sessions for seven patients. Variations in respiratory amplitude (simulated coaching) and external/internal phase shifts were simulated by perturbation with realistic values. Variations were described by medians and standard deviations (SDs) of position distributions of the markers. Gating windows (35% duty cycle) were retrospectively applied to the respiratory data for each session, mimicking the use of commercially available gating systems. Medians and SDs of gated data were compared to those of ungated data, to assess potential margin reductions. RESULTS: External respiratory data collected over entire treatment courses showed SDs from 1.6 to 8.1mm, the major part arising from baseline variations. The gated data had SDs from 1.5 to 7.7mm, with a mean reduction of 0.3mm (6%). Gated distributions were more skewed than ungated, and in a few cases a marginal miss of gated respiration would be found even if no margin reduction was applied. Regularization of breathing amplitude to simulate coaching did not alter these results significantly. Simulation of varying phase shifts between internal and external respiratory signals showed that the SDs of gated distributions were the same as for the ungated or smaller, but the median values were markedly shifted. The gated distributions could generally not be covered by margins derived from ungated data, if the phase shift was not accounted for. CONCLUSIONS: Margins can only be reduced for respiratory gated radiotherapy, if respiratory baseline shifts and variations in external/internal motion correlation are accounted for. Gated beam delivery alone cannot facilitate margin reduction. In the worst case, margins must be increased to accommodate inter-fraction variations in respiration.

Moving from IMRT QA measurements toward independent computer calculations using control charts.

BACKGROUND AND PURPOSE: In this study, we investigated IMRT QA using Statistical Process Control for the purpose of comparing the processes of patient-specific measurements and the corresponding independent computer calculations. MATERIALS AND METHODS: Point dose data from the treatment planning system (TPS), independent computer calculations, and physical measurements for prostate and head and neck cases were studied. Control charts were used to analyze the IMRT QA processes from several institutions in the academic and community setting. Control charts are a method to describe the performance of a process. The width of the control chart limits (or action limits) describes the process' ability to meet clinical specifications of +/-5%. In all, 24 process comparisons were made (12 measurement QA and 12 independent computer calculation QA). RESULTS: For head and neck IMRT QA, the average process ability for the measurement QA was +/-6.9% compared to +/-7.2% for the independent computer calculation QA. For prostate IMRT QA, the average process ability was 4.4% for both measurement QA and independent computer calculation QA. It was found that 11 of the 24 processes were in control. At none of the institutions were the processes of measurements and independent computer calculations both in control and performing within clinical specifications. CONCLUSION: There is room to improve the processes of IMRT QA measurements and independent computer calculations. In situations where the improvement of the processes is such that each is in control and well within clinical specifications, it may be appropriate to suspend patient-specific IMRT QA measurements for every patient in the place of independent computer calculations.

Process control analysis of IMRT QA: implications for clinical trials.

The purpose of this study is two-fold: first is to investigate the process of IMRT QA using control charts and second is to compare control chart limits to limits calculated using the standard deviation (sigma). Head and neck and prostate IMRT QA cases from seven institutions in both academic and community settings are considered. The percent difference between the point dose measurement in phantom and the corresponding result from the treatment planning system (TPS) is used for analysis. The average of the percent difference calculations defines the accuracy of the process and is called the process target. This represents the degree to which the process meets the clinical goal of 0% difference between the measurements and TPS. IMRT QA process ability defines the ability of the process to meet clinical specifications (e.g. 5% difference between the measurement and TPS). The process ability is defined in two ways: (1) the half-width of the control chart limits, and (2) the half-width of +/-3sigma limits. Process performance is characterized as being in one of four possible states that describes the stability of the process and its ability to meet clinical specifications. For the head and neck cases, the average process target across institutions was 0.3% (range: -1.5% to 2.9%). The average process ability using control chart limits was 7.2% (range: 5.3% to 9.8%) compared to 6.7% (range: 5.3% to 8.2%) using standard deviation limits. For the prostate cases, the average process target across the institutions was 0.2% (range: -1.8% to 1.4%). The average process ability using control chart limits was 4.4% (range: 1.3% to 9.4%) compared to 5.3% (range: 2.3% to 9.8%) using standard deviation limits. Using the standard deviation to characterize IMRT QA process performance resulted in processes being preferentially placed in one of the four states. This is in contrast to using control charts for process characterization where the IMRT QA processes were spread over three of the four states with none of the processes in the ideal state. Control charts may be used for IMRT QA in clinical trials to categorize process performance, minimize protocol variation and guide process improvements. For the duration of an institution's participation in a protocol, updated control charts can be periodically sent to the protocol QA center to document continued process performance to protocol specifications.

Design and evaluation of a variable aperture collimator for conformal radiotherapy of small animals using a microCT scanner.

Treatment of small animals with radiation has in general been limited to planar fields shaped with lead blocks, complicating spatial localization of dose and treatment of deep-seated targets. In order to advance laboratory radiotherapy toward what is accomplished in the clinic, we have constructed a variable aperture collimator for use in shaping the beam of microCT scanner. This unit can image small animal subjects at high resolution, and is capable of delivering therapeutic doses in reasonable exposure times. The proposed collimator consists of two stages, each containing six trapezoidal brass blocks that move along a frame in a manner similar to a camera iris producing a hexagonal aperture of variable size. The two stages are offset by 30 degrees and adjusted for the divergence of the x-ray beam so as to produce a dodecagonal profile at isocenter. Slotted rotating driving plates are used to apply force to pins in the collimator blocks and effect collimator motion. This device has been investigated through both simulation and measurement. The collimator aperture size varied from 0 to 8.5 cm as the driving plate angle increased from 0 to 41 degrees. The torque required to adjust the collimator varied from 0.5 to 5 N x m, increasing with increasing driving plate angle. The transmission profiles produced by the scanner at isocenter exhibited a penumbra of approximately 10% of the collimator aperture width. Misalignment between the collimator assembly and the x-ray source could be identified on the transmission images and corrected by adjustment of the collimator location. This variable aperture collimator technology is therefore a feasible and flexible solution for adjustable shaping of radiation beams for use in small animal radiotherapy as well as other applications in which beam shaping is desired.

Investigation of linac-based image-guided hypofractionated prostate radiotherapy.

A hypofractionation treatment protocol for prostate cancer was initiated in our department in December 2003. The treatment regimen consists of a total dose of 36.25 Gy delivered at 7.25 Gy per fraction over 10 days. We discuss the rationale for such a prostate hypofractionation protocol and the need for frequent prostate imaging during treatment. The CyberKnife (Accuray Inc., Sunnyvale, CA), a linear accelerator mounted on a robotic arm, is currently being used as the radiation delivery device for this protocol, due to its incorporation of near real-time kV imaging of the prostate via 3 gold fiducial seeds. Recently introduced conventional linac kV imaging with intensity modulated planning and delivery may add a new option for these hypofractionated treatments. The purpose of this work is to investigate the use of intensity modulated radiotherapy (IMRT) and the Varian Trilogy Accelerator with on-board kV imaging (Varian Medical Systems Inc., Palo Alto, CA) for treatment of our hypofractionated prostate patients. The dose-volume histograms and dose statistics of 2 patients previously treated on the CyberKnife were compared to 7-field IMRT plans. A process of acquiring images to observe intrafraction prostate motion was achieved in an average time of about 1 minute and 40 seconds, and IMRT beam delivery takes about 40 seconds per field. A complete 7-field IMRT plan can therefore be imaged and delivered in 10 to 17 minutes. The Varian Trilogy Accelerator with on-board imaging and IMRT is well suited for image-guided hypofractionated prostate treatments. During this study, we have also uncovered opportunities for improvement of the on-board imaging hardware/software implementation that would further enhance performance in this regard.

Statistical process control for radiotherapy quality assurance.

Every quality assurance process uncovers random and systematic errors. These errors typically consist of many small random errors and a very few number of large errors that dominate the result. Quality assurance practices in radiotherapy do not adequately differentiate between these two sources of error. The ability to separate these types of errors would allow the dominant source(s) of error to be efficiently detected and addressed. In this work, statistical process control is applied to quality assurance in radiotherapy for the purpose of setting action thresholds that differentiate between random and systematic errors. The theoretical development and implementation of process behavior charts are described. We report on a pilot project is which these techniques are applied to daily output and flatness/symmetry quality assurance for a 10 MV photon beam in our department. This clinical case was followed over 52 days. As part of our investigation, we found that action thresholds set using process behavior charts were able to identify systematic changes in our daily quality assurance process. This is in contrast to action thresholds set using the standard deviation, which did not identify the same systematic changes in the process. The process behavior thresholds calculated from a subset of the data detected a 2% change in the process whereas with a standard deviation calculation, no change was detected. Medical physicists must make decisions on quality assurance data as it is acquired. Process behavior charts help decide when to take action and when to acquire more data before making a change in the process.

Optical detection of tumors in vivo by visible light tissue oximetry.

Endoscopy is a standard procedure for identifying tumors in patients suspected of having gastrointestinal (G.I.) cancer. The early detection of G.I. neoplasms during endoscopy is currently made by a subjective visual inspection that relies to a high degree on the experience of the examiner. This process can be difficult and unreliable, as tumor lesions may be visually indistinguishable from benign inflammatory conditions and the surrounding mucosa. In this study, we evaluated the ability of local ischemia detection using visible light spectroscopy (VLS) to differentiate neoplastic from normal tissue based on capillary tissue oxygenation during endoscopy. Real-time data were collected (i) from human subjects (N = 34) monitored at various sites during endoscopy (enteric mucosa, malignant, and abnormal tissue such as polyps) and (ii) murine animal subjects with human tumor xenografts. Tissue oximetry in human subjects during endoscopy revealed a tissue oxygenation (StO2%, mean +/- SD) of 46 +/- 22% in tumors, which was significantly lower than for normal mucosal oxygenation (72 +/- 4%; P < or = 0.0001). No difference in tissue oxygenation was observed between normal and non-tumor abnormal tissues (P = N.S.). Similarly, VLS tissue oximetry for murine tumors revealed a mean local tumor oxygenation of 45% in LNCaP, 50% in M21, and 24% in SCCVII tumors, all significantly lower than normal muscle tissue (74%, P < 0.001). These results were further substantiated by positive controls, where a rapid real-time drop in tumor oxygenation was measured during local ischemia induced by clamping or epinephrine. We conclude that VLS tissue oximetry can distinguish neoplastic tissue from normal tissue with a high specificity (though a low sensitivity), potentially aiding the endoscopic detection of gastrointestinal tumors.

Usability study of the EduMod eLearning Program for contouring nodal stations of the head and neck.

PURPOSE: A major strategy for improving radiation oncology education and competence evaluation is to develop eLearning programs that reproduce the real work environment. A valuable measure of the quality of an eLearning program is "usability," which is a multidimensional endpoint defined from the end user's perspective. The gold standard for measuring usability is the Software Usability Measurement Inventory (SUMI). The purpose of this study is to use the SUMI to measure usability of an eLearning course that uses innovative software to teach and test contouring of nodal stations of the head and neck. METHODS AND MATERIALS: This is a prospective institutional review board-approved study in which all participants gave written informed consent. The study population was radiation oncology residents from 8 different programs across the United States. The subjects had to pass all sections of the same 2 eLearning modules and then complete the SUMI usability evaluation instrument. We reached the accrual goal of 25 participants. Usability results for the EduMod eLearning course, "Nodal Stations of the Head and Neck," were compared with a large database of scores of other major software programs. Results were evaluated in 5 domains: Affect, Helpfulness, Control, Learnability, and Global Usability. RESULTS: In all 5 domains, usability scores for the study modules were higher than the database mean and statistically superior in 4 domains. CONCLUSIONS: This is the first study to evaluate usability of an eLearning program related to radiation oncology. Usability of 2 representative modules related to contouring nodal stations of the head and neck was highly favorable, with scores that were superior to the industry standard in multiple domains. These results support the continued development of this type of eLearning program for teaching and testing radiation oncology technical skills.

Dosimetry and radiobiologic model comparison of IMRT and 3D conformal radiotherapy in treatment of carcinoma of the prostate.

INTRODUCTION: Intensity-modulated radiotherapy (IMRT) has introduced novel dosimetry that often features increased dose heterogeneity to target and normal structures. This raises questions of the biologic effects of IMRT compared to conventional treatment. We compared dosimetry and radiobiologic model predictions of tumor control probability (TCP) and normal tissue complication probability (NTCP) for prostate cancer patients planned for IMRT as opposed to standardized three-dimensional conformal radiotherapy (3DCRT). METHODS AND MATERIALS: Segmented multileaf collimator IMRT treatment plans for 32 prostate cancer patients were compared to 3DCRT plans for the same patients. Twenty-two received local-field irradiation (LFI), and 10 received extended-field irradiation (EFI) that included pelvic lymph nodes. For LFI, IMRT was planned for delivery of 2 Gy minimum dose to the prostate (> or =99% volume coverage) for 35 fractions. The 3DCRT plans, characterized by more homogenous dose to the target, were designed according to a different protocol to deliver 2 Gy to the center of the prostate for 37 fractions. Mean total dose from 35 fractions of IMRT was equal to mean total dose from 37 fractions of 3DCRT. For EFI, both IMRT and 3DCRT were planned for 2 Gy per fraction to a total dose of 50 Gy to prostate and pelvic lymph nodes, followed by 2 Gy per fraction to 20 Gy to the prostate alone. Treatment dose for EFI-IMRT was defined as minimum dose to the target, whereas for EFI-3DCRT, it was defined as dose to the center of the prostate. TCP was calculated for the prostate in the linear-quadratic model for two choices of alpha/beta. NTCP was calculated with the Lyman model for organs at risk, using Kutcher-Burman dose-volume histogram reduction with Emami parameters. RESULTS AND CONCLUSIONS: Dose to the prostate, expressed as mean +/- standard deviation, was 74.7 +/- 1.1 Gy for IMRT vs. 74.6 +/- 0.3 Gy for 3D for the LFI plans, and 74.8 +/- 0.6 Gy for IMRT vs. 71.5 +/- 0.6 Gy for 3D for the EFI plans. For the studied protocols, TCP was greater for IMRT than for 3D across the full range of target sensitivity, for both localized- and extended-field irradiation. For LFI, this was due to the smaller number of fractions (35 vs. 37) used for IMRT, and for EFI, this was due to the greater mean dose for IMRT, compared to 3D. For all organs, mean NTCP tended to be lower for IMRT than for 3D, although NTCP values were very small for both 3D and IMRT. Differences were statistically significant for rectum (LFI and EFI), bladder (EFI), and bowel (EFI). For both LFI and EFI, the calculated NTCPs qualitatively agreed with early published clinical data comparing genitourinary and gastrointestinal complications of IMRT and 3D. Present calculations support the hypothesis that accurately delivered IMRT for prostate cancer can limit dose to normal tissue by reducing treatment margins relative to conventional 3D planning, to allow a reduction in complication rate spanning several sensitive structures while maintaining or increasing tumor control probability.

An investigation of a video-based patient repositioning technique.

PURPOSE: We have investigated a video-based patient repositioning technique designed to use skin features for radiotherapy repositioning. We investigated the feasibility of the clinical application of this system by quantitative evaluation of performance characteristics of the methodology. METHODS AND MATERIALS: Multiple regions of interest (ROI) were specified in the field of view of video cameras. We used a normalized correlation pattern-matching algorithm to compute the translations of each ROI pattern in a target image. These translations were compared against trial translations using a quadratic cost function for an optimization process in which the patient rotation and translational parameters were calculated. RESULTS: A hierarchical search technique achieved high-speed (compute correlation for 128 x 128 ROI in 512 x 512 target image within 0.005 s) and subpixel spatial accuracy (as high as 0.2 pixel). By treating the observed translations as movements of points on the surfaces of a hypothetical cube, we were able to estimate accurately the actual translations and rotations of the test phantoms used in our experiments to less than 1 mm and 0.2 degrees with a standard deviation of 0.3 mm and 0.5 degrees respectively. For human volunteer cases, we estimated the translations and rotations to have an accuracy of 2 mm and 1.2 degrees. CONCLUSION: A personal computer-based video system is suitable for routine patient setup of fractionated conformal radiotherapy. It is expected to achieve high-precision repositioning of the skin surface with high efficiency.

Quality assurance of magnetic resonance spectroscopic imaging-derived metabolic data.

PURPOSE: Spatially resolved metabolite maps, as measured by magnetic resonance spectroscopic imaging (MRSI) methods, are being increasingly used to acquire metabolic information to guide therapy, with metabolite ratio maps perhaps providing the most diagnostic information. We present a quality assurance procedure for MRSI-derived metabolic data acquired ultimately for guiding conformal radiotherapy. METHODS AND MATERIALS: An MRSI phantom filled with brain-mimicking solutions was custom-built with an insert holding eight vials containing calibration solutions of precisely varying metabolite concentrations that emulated increasing grade/density of brain tumor. Phantom metabolite ratios calculated from fully relaxed 1D, 2D, and 3D MRS data for each vial were compared with calibrated metabolite ratios acquired at 9.4 T. Additionally, 3D ratio maps were "discretized" to eight pseudoabnormality levels on a slice-by-slice basis and the accuracy of this procedure was verified. RESULTS: Regression analysis revealed expected linear relationships between experimental and calibration metabolite ratios with intercepts close to zero for the three acquisition modes. 1D MRS data agreed most with theoretical considerations (regression coefficient, b = 0.969; intercept 0.008). The 2D (b = 1.049; intercept -0.199) and 3D (correlation coefficient r(2) = 0.9978-0.7336 for five slices) MRSI indicated reduced MRS data quality in regions of degraded B(0) and B(1) homogeneity. Pseudoabnormality levels were found to be consistent with expectations within regions of adequate B(0) homogeneity. CONCLUSIONS: This simple phantom-based approach to generate baseline calibration curves for all MRS acquisition modes may be useful to identify temporal deviations from acceptable data quality in a routine clinical environment or for testing new MRS and MRSI acquisition software.

Enhanced effectiveness of radiochemotherapy with tirapazamine by local application of electric pulses to tumors.

Tumor hypoxia is associated with resistance to radiotherapy and anticancer chemotherapy. However, it can be exploited to therapeutic advantage by concomitantly using hypoxic cytotoxins, such as tirapazamine (TPZ). Tumor electroporation offers the means to further increase tumor hypoxia by temporarily reducing tumor blood flow and therefore increase the cytotoxicity of TPZ. The primary objective of this work was to determine whether electric pulses combined with TPZ and radiotherapy (electroradiochemotherapy) was more efficacious than radiochemotherapy (TPZ + radiation). In these studies using the SCCVII tumor model in C3H mice, electroradiochemotherapy produced up to sixfold more tumor growth delay (TGD) than TPZ + radiation. In these studies, (1) large tumors (280 +/- 15 mm3) responded better to electroradiochemotherapy than small tumors (110 +/- 10 mm3), (2) TGD correlated linearly with tumor volume at the time of electroradiochemotherapy, (3) electric pulses induced a rapid but reversible reduction in O2 saturation, and (4) the electric field was highest near the periphery of the tumor in a 3D computer model. The findings suggested that electroradiochemotherapy gained its therapeutic advantage over TPZ + radiation by enhancing the cytotoxic action of TPZ through reduced tumor oxygenation. The greater antitumor effect achieved in large tumors may be related to tumor morphology and the electric-field distribution. These results suggest that electro-pulsation of large solid tumors may be of benefit to patients treated with radiation in combination with agents that kill hypoxic cells.

A three-source model for the calculation of head scatter factors.

Accurate determination of the head scatter factor Sc is an important issue, especially for intensity modulated radiation therapy, where the segmented fields are often very irregular and much less than the collimator jaw settings. In this work, we report an Sc calculation algorithm for symmetric, asymmetric, and irregular open fields shaped by the tertiary collimator (a multileaf collimator or blocks) at different source-to-chamber distance. The algorithm was based on a three-source model, in which the photon radiation to the point of calculation was treated as if it originated from three effective sources: one source for the primary photons from the target and two extra-focal photon sources for the scattered photons from the primary collimator and the flattening filter, respectively. The field mapping method proposed by Kim et al. [Phys. Med. Biol. 43, 1593-1604 (1998)] was extended to two extra-focal source planes and the scatter contributions were integrated over the projected areas (determined by the detector's eye view) in the three source planes considering the source intensity distributions. The algorithm was implemented using Microsoft Visual C/C++ in the MS Windows environment. The only input data required were head scatter factors for symmetric square fields, which are normally acquired during machine commissioning. A large number of different fields were used to evaluate the algorithm and the results were compared with measurements. We found that most of the calculated Sc's agreed with the measured values to within 0.4%. The algorithm can also be easily applied to deal with irregular fields shaped by a multileaf collimator that replaces the upper or lower collimator jaws.

Inverse planning for functional image-guided intensity-modulated radiation therapy.

Radiation therapy is an image-guided process whose success critically depends on the imaging modality used for treatment planning and the level of integration of the available imaging information. In this work, we establish a dose optimization framework for incorporating metabolic information from functional imaging modalities into the intensity-modulated radiation therapy (IMRT) inverse planning process and to demonstrate the technical feasibility of planning deliberately non-uniform dose distributions in accordance with functional imaging data. For this purpose, a metabolic map from functional images is discretized into a number of abnormality levels (ALs) and then fused with CT images. To escalate dose to the metabolically abnormal regions, we assume, for a given spatial point, a linear relation between the AL and the prescribed dose. But the formalism developed here is independent of the assumption and any other relation between AL and prescription is applicable. For a given AL and prescription relation, it is only necessary to prescribe the dose to the lowest AL in the target and the desired doses to other regions with higher AL values are scaled accordingly. To accomplish differential sparing of a sensitive structure when its functional importance (FI) distribution is known, we individualize the tolerance doses of the voxels within the structure according to their Fl levels. An iterative inverse planning algorithm in voxel domain is used to optimize the system with in homogeneous dose prescription. To model intra-structural trade-off, a mechanism is introduced through the use of voxel-dependent weighting factors, in addition to the conventional structure specific weighting factors which model the inter-structural trade-off. The system is used to plan a phantom case with a few hypothetical functional distributions and a brain tumour treatment with incorporation of magnetic resonance spectroscopic imaging data. The results indicated that it is technically feasible to produce deliberately non-uniform dose distributions according to the functional imaging requirements. Integration of functional imaging information into radiation therapy dose optimization allows for consideration of patient-specific biologic information and provides a significant opportunity to truly individualize radiation treatment. This should enhance our capability to safely and intelligently escalate dose and lays the technical foundation for future clinical studies of the efficacy of functional imaging-guided IMRT.

Concurrent transient activation of Wnt/ß-catenin pathway prevents radiation damage to salivary glands.

PURPOSE: Many head and neck cancer survivors treated with radiotherapy suffer from permanent impairment of their salivary gland function, for which few effective prevention or treatment options are available. This study explored the potential of transient activation of Wnt/ß-catenin signaling in preventing radiation damage to salivary glands in a preclinical model. METHODS AND MATERIALS: Wnt reporter transgenic mice were exposed to 15 Gy single-dose radiation in the head and neck area to evaluate the effects of radiation on Wnt activity in salivary glands. Transient Wnt1 overexpression in basal epithelia was induced in inducible Wnt1 transgenic mice before together with, after, or without local radiation, and then saliva flow rate, histology, apoptosis, proliferation, stem cell activity, and mRNA expression were evaluated. RESULTS: Radiation damage did not significantly affect activity of Wnt/ß-catenin pathway as physical damage did. Transient expression of Wnt1 in basal epithelia significantly activated the Wnt/ß-catenin pathway in submandibular glands of male mice but not in those of females. Concurrent transient activation of the Wnt pathway prevented chronic salivary gland dysfunction following radiation by suppressing apoptosis and preserving functional salivary stem/progenitor cells. In contrast, Wnt activation 3 days before or after irradiation did not show significant beneficial effects, mainly due to failure to inhibit acute apoptosis after radiation. Excessive Wnt activation before radiation failed to inhibit apoptosis, likely due to extensive induction of mitosis and up-regulation of proapoptosis gene PUMA while that after radiation might miss the critical treatment window. CONCLUSION: These results suggest that concurrent transient activation of the Wnt/ß-catenin pathway could prevent radiation-induced salivary gland dysfunction.

Calculation and prediction of the effect of respiratory motion on whole breast radiation therapy dose distributions.

The standard treatment technique used for whole-breast irradiation can result in undesirable dose distributions in the treatment site, leading to skin reaction/fibrosis and pulmonary and cardiac toxicities. Hence, the technique has evolved from conventional wedged technique (CWT) to segment intensity-modulated radiation therapy (SIMRT) and beamlet IMRT (IMRT). However, these newer techniques feature more highly modulated dose distributions that may be affected by respiration. The purpose of this work was to conduct a simple study of the clinical impact of respiratory motion on breast radiotherapy dose distributions for the three treatment planning techniques. The ultimate goal was to determine which patients would benefit most from the use of motion management. Eight patients with early-stage breast cancer underwent a free-breathing (FB) computed tomography (CT) simulation, with medial and lateral markers placed on the skin. Two additional CT scans were obtained at the end of inspiration (EI) and the end of expiration (EE). The FB-CT scan was used to develop treatment plans using each technique. Each plan was then applied to EI and EE-CT scans. Compared with the FB CT scan, the medial markers moved up to 1.8 cm in the anterior-superior direction at the end of inspiration (EI-scan), and on average 8 mm. The CWT and SIMRT techniques were not "sensitive" to respiratory motion, because the % clinical target volume (CTV) receiving 95% of the prescription dose (V(95%)) remained constant for both techniques. For patients that had large respiratory motion indicated by marker movement >0.6 cm, differences in coverage of the CTV at the V100% between FB and EI for beamlet IMRT plans were on the order of >10% and up to 18%. A linear model was developed to relate the dosimetric coverage difference introduced by respiration with the motion information. With this model, the dosimetric coverage difference introduced by respiratory motion could be evaluated during patient CT simulation. An appropriate treatment method can be chosen after the simulation.

Partial differential equations-based segmentation for radiotherapy treatment planning.

The purpose of this study is to develop automatic algorithms for the segmentation phase of radiotherapy treatment planning. We develop new image processing techniques that are based on solving a partial diferential equation for the evolution of the curve that identifies the segmented organ. The velocity function is based on the piecewise Mumford-Shah functional. Our method incorporates information about the target organ into classical segmentation algorithms. This information, which is given in terms of a three- dimensional wireframe representation of the organ, serves as an initial guess for the segmentation algorithm. We check the performance of the new algorithm on eight data sets of three diferent organs: rectum, bladder, and kidney. The results of the automatic segmentation were compared with a manual seg- mentation of each data set by radiation oncology faculty and residents. The quality of the automatic segmentation was measured with the k-statistics", and with a count of over- and undersegmented frames, and was shown in most cases to be very close to the manual segmentation of the same data. A typical segmentation of an organ with sixty slices takes less than ten seconds on a Pentium IV laptop.