Accelerated cascade melanoma therapy using enzyme-nanozyme-integrated dissolvable polymeric microneedles.

Dissolvable polymeric microneedles (DPMNs) have emerged as a powerful technology for the localized treatment of diseases, such as melanoma. Herein, we fabricated a DPMN patch containing a potent enzyme-nanozyme composite that transforms the upregulated glucose consumption of cancerous cells into lethal reactive oxygen species via a cascade reaction accelerated by endogenous chloride ions and external near-infrared (NIR) irradiation. This was accomplished by combining glucose oxidase (Gox) with a NIR-responsive chloroperoxidase-like copper sulfide (CuS) nanozyme. In contrast with subcutaneous injection, the microneedle system highly localizes the treatment, enhancing nanomedicine uptake by the tumor and reducing its systemic exposure to the kidneys and spleen. NIR irradiation further controls the potency and toxicity of the formulation by thermally disabling Gox. In a mouse melanoma model, this unique combination of photothermal, starvation, and chemodynamic therapies resulted in complete tumor eradication (99.2 ± 0.8 % reduction in tumor volume within 10 d) without producing signs of systemic toxicity. By comparison, other treatment combinations only resulted in a 42-76.5 % reduction in tumor growth. The microneedle patch design is therefore not only highly potent but also with regulated toxicity and improved safety.

Prostate volumetric-modulated arc therapy: dosimetry and radiobiological model variation between the single-arc and double-arc technique.

This study investigates the dosimetry and radiobiological model variation when a second photon arc was added to prostate volumetric-modulated arc therapy (VMAT) using the single-arc technique. Dosimetry and radiobiological model comparison between the single-arc and double-arc prostate VMAT plans were performed on five patients with prostate volumes ranging from 29-68.1 cm3. The prescription dose was 78 Gy/39 fractions and the photon beam energy was 6 MV. Dose-volume histogram, mean and maximum dose of targets (planning and clinical target volume) and normal tissues (rectum, bladder and femoral heads), dose-volume criteria in the treatment plan (D99% of PTV; D30%, D50%, V17Gy and V35Gy of rectum and bladder; D5% of femoral heads), and dose profiles along the vertical and horizontal axis crossing the isocenter were determined using the single-arc and double-arc VMAT technique. For comparison, the monitor unit based on the RapidArc delivery method, prostate tumor control probability (TCP), and rectal normal tissue complication probability (NTCP) based on the Lyman-Burman-Kutcher algorithm were calculated. It was found that though the double-arc technique required almost double the treatment time than the single-arc, the double-arc plan provided a better rectal and bladder dose-volume criteria by shifting the delivered dose in the patient from the anterior-posterior direction to the lateral. As the femoral head was less radiosensitive than the rectum and bladder, the double-arc technique resulted in a prostate VMAT plan with better prostate coverage and rectal dose-volume criteria compared to the single-arc. The prostate TCP of the double-arc plan was found slightly increased (0.16%) compared to the single-arc. Therefore, when the rectal dose-volume criteria are very difficult to achieve in a single-arc prostate VMAT plan, it is worthwhile to consider the double-arc technique.

Dosimetry of small bone joint calculated by the analytical anisotropic algorithm: a Monte Carlo evaluation using the EGSnrc.

This study compared a small bone joint dosimetry calculated by the anisotropic analytical algorithm (AAA) and Monte Carlo simulation using megavoltage (MV) photon beams. The performance of the AAA in the joint dose calculation was evaluated using Monte Carlo simulation, and dependences of joint dose on its width and beam angle were investigated. Small bone joint phantoms containing a vertical water layer (0.5-2 mm) sandwiched by two bones (2 × 2 × 2 cm3) were irradiated by the 6 and 15 MV photon beams with field size equal to 4 × 4 cm2. Depth doses along the central beam axis in a joint (cartilage) were calculated with and without a bolus (thickness = 1.5 cm) added on top of the phantoms. Different beam angles (0°-15°) were used with the isocenter set to the center of the bone joint for dose calculations using the AAA (Eclipse treatment planning system) and Monte Carlo simulation (the EGSnrc code). For dosimetry comparison and normalization, dose calculations were repeated in homogeneous water phantoms with the bone substituted by water. Comparing the calculated dosimetry between the AAA and Monte Carlo simulation, the AAA underestimated joint doses varying with its widths by about 6%-12% for 6 MV and 12%-23% for 15 MV without bolus, and by 7% for 6 MV and 13%-17% for 15 MV with bolus. Moreover, joint doses calculated by the AAA did not vary with the joint width and beam angle. From Monte Carlo results, there was a decrease in the calculated joint dose as the joint width increased, and a slight decrease as the beam angle increased. When bolus was added to the phantom, it was found that variations of joint dose with its width and beam angle became less significant for the 6 MV photon beams. In conclusion, dosimetry deviation in small bone joint calculated by the AAA and Monte Carlo simulation was studied using the 6 and 15 MV photon beam. The AAA could not predict variations of joint dose with its width and beam angle, which were predicted by the Monte Carlo simulations.

Comparison of dosimetric variation between prostate IMRT and VMAT due to patient's weight loss: Patient and phantom study.

AIM: This study compared the dosimetric impact between prostate IMRT and VMAT due to patient's weight loss. BACKGROUND: Dosimetric variation due to change of patient's body contour is difficult to predict in prostate IMRT and VMAT, since a large number of small and irregular segmental fields is used in the delivery. MATERIALS AND METHODS: Five patients with prostate volumes ranging from 32.0 to 86.5 cm(3) and a heterogeneous pelvis phantom were used for prostate IMRT and VMAT plans using the same set of dose-volume constraints. Doses in IMRT and VMAT plans were recalculated with the patient's and phantom's body contour reduced by 0.5-2 cm to mimic size reduction. Dose coverage/criteria of the PTV and CTV and critical organs (rectum, bladder and femoral heads) were compared between IMRT and VMAT. RESULTS: In IMRT plans, increases of the D99% for the PTV and CTV were equal to 4.0 ± 0.1% per cm of reduced depth, which were higher than those in VMAT plans (2.7 ± 0.24% per cm). Moreover, increases of the D30% of the rectum and bladder per reduced depth in IMRT plans (4.0 ± 0.2% per cm and 3.5 ± 0.5% per cm) were higher than those of VMAT (2.2 ± 0.2% per cm and 2.0 ± 0.6% per cm). This was also true for the increase of the D5% for the right femoral head in a patient or phantom with size reduction due to weight loss. CONCLUSIONS: VMAT would be preferred to IMRT in prostate radiotherapy, when a patient has potential to suffer from weight loss during the treatment.

Knowledge Distillation Meets Label Noise Learning: Ambiguity-Guided Mutual Label Refinery.

Knowledge distillation (KD), which aims at transferring the knowledge from a complex network (a teacher) to a simpler and smaller network (a student), has received considerable attention in recent years. Typically, most existing KD methods work on well-labeled data. Unfortunately, real-world data often inevitably involve noisy labels, thus leading to performance deterioration of these methods. In this article, we study a little-explored but important issue, i.e., KD with noisy labels. To this end, we propose a novel KD method, called ambiguity-guided mutual label refinery KD (AML-KD), to train the student model in the presence of noisy labels. Specifically, based on the pretrained teacher model, a two-stage label refinery framework is innovatively introduced to refine labels gradually. In the first stage, we perform label propagation (LP) with small-loss selection guided by the teacher model, improving the learning capability of the student model. In the second stage, we perform mutual LP between the teacher and student models in a mutual-benefit way. During the label refinery, an ambiguity-aware weight estimation (AWE) module is developed to address the problem of ambiguous samples, avoiding overfitting these samples. One distinct advantage of AML-KD is that it is capable of learning a high-accuracy and low-cost student model with label noise. The experimental results on synthetic and real-world noisy datasets show the effectiveness of our AML-KD against state-of-the-art KD methods and label noise learning (LNL) methods. Code is available at https://github.com/Runqing-forMost/ AML-KD.

Photoresponsive polymeric microneedles: An innovative way to monitor and treat diseases.

Microneedles (MN) technology is an emerging technology for the transdermal delivery of therapeutics. When combined with photoresponsive (PR) materials, MNs can deliver therapeutics precisely and effectively with enhanced efficacy or synergistic effects. This review systematically summarizes the therapeutic applications of PRMNs in cancer therapy, wound healing, diabetes treatment, and diagnostics. Different PR approaches to activate and control the release of therapeutic agents from MNs are also discussed. Overall, PRMNs are a powerful tool for stimuli-responsive controlled-release therapeutic delivery to treat various diseases.

When Sparse Neural Network Meets Label Noise Learning: A Multistage Learning Framework.

Recent methods in network pruning have indicated that a dense neural network involves a sparse subnetwork (called a winning ticket), which can achieve similar test accuracy to its dense counterpart with much fewer network parameters. Generally, these methods search for the winning tickets on well-labeled data. Unfortunately, in many real-world applications, the training data are unavoidably contaminated with noisy labels, thereby leading to performance deterioration of these methods. To address the above-mentioned problem, we propose a novel two-stream sample selection network (TS 3 -Net), which consists of a sparse subnetwork and a dense subnetwork, to effectively identify the winning ticket with noisy labels. The training of TS 3 -Net contains an iterative procedure that switches between training both subnetworks and pruning the smallest magnitude weights of the sparse subnetwork. In particular, we develop a multistage learning framework including a warm-up stage, a semisupervised alternate learning stage, and a label refinement stage, to progressively train the two subnetworks. In this way, the classification capability of the sparse subnetwork can be gradually improved at a high sparsity level. Extensive experimental results on both synthetic and real-world noisy datasets (including MNIST, CIFAR-10, CIFAR-100, ANIMAL-10N, Clothing1M, and WebVision) demonstrate that our proposed method achieves state-of-the-art performance with very small memory consumption for label noise learning. Code is available at https://github.com/Runqing-forMost/TS3-Net/tree/master.

A Nanomedicine Structure-Activity Framework for Research, Development, and Regulation of Future Cancer Therapies.

Despite their clinical success in drug delivery applications, the potential of theranostic nanomedicines is hampered by mechanistic uncertainty and a lack of science-informed regulatory guidance. Both the therapeutic efficacy and the toxicity of nanoformulations are tightly controlled by the complex interplay of the nanoparticle's physicochemical properties and the individual patient/tumor biology; however, it can be difficult to correlate such information with observed outcomes. Additionally, as nanomedicine research attempts to gradually move away from large-scale animal testing, the need for computer-assisted solutions for evaluation will increase. Such models will depend on a clear understanding of structure-activity relationships. This review provides a comprehensive overview of the field of cancer nanomedicine and provides a knowledge framework and foundational interaction maps that can facilitate future research, assessments, and regulation. By forming three complementary maps profiling nanobio interactions and pathways at different levels of biological complexity, a clear picture of a nanoparticle's journey through the body and the therapeutic and adverse consequences of each potential interaction are presented.

Degradable multifunctional gold-liposomes as an all-in-one theranostic platform for image-guided radiotherapy.

To improve tumor destruction and minimize adverse effects to healthy tissues, image-guided radiation therapy (IGRT) has been developed to allow for the accurate delivery of radiation energy to tumor sites facilitated by real-time imaging. Nevertheless, the current IGRT platform still suffers from the limitation of poor tissue contrast, resulting in the incidental irradiation of healthy tissue. Gold nanoparticles (GNPs) have been identified as promising candidates to simultaneously improve both radiotherapy and imaging, thereby improving both the accuracy and safety of IGRT. However, despite much preclinical study, little clinical progress has been made due to uncertainty over GNP toxicity. Herein, we demonstrate the great potential of using GNP-coated liposomes, i.e., Lipogold, which combine the advantages of both large and small nanoparticles into one multifunctional formulation, as an ideal platform for IGRT. When irradiated with low doses (<2 Gy) of therapeutic X-rays, Lipogold induced a significant radiosensitization effect for PC-3 prostate cancer cells, which are moderately radiation-resistant. When imaged with computed tomography (CT), Lipogold was also found to possess consistent X-ray contrast of âˆ¼ 18-23 HU/mg across tube X-ray voltages (70-140 kVp), which could be boosted via the encapsulation of a small-molecule contrast agent containing iodine.

Synergistic Multimodal Cancer Therapy Using Glucose Oxidase@CuS Nanocomposites.

Multimodal nanotherapeutic cancer treatments are widely studied but are often limited by their costly and complex syntheses that are not easily scaled up. Herein, a simple formulation of glucose-oxidase-coated CuS nanoparticles was demonstrated to be highly effective for melanoma treatment, acting through a synergistic combination of glucose starvation, photothermal therapy, and synergistic advanced chemodynamic therapy enabled by near-infrared irradiation coupled with Fenton-like reactions that were enhanced by endogenous chloride.

Monte Carlo calculation of monitor unit for electron arc therapy.

PURPOSE: Monitor unit (MU) calculations for electron are therapy were carried out using Monte Carlo simulations and verified by measurements. Variations in the dwell factor (DF), source-to-surface distance (SSD), and treatment are angle (a) were studied. Moreover, the possibility of measuring the DF, which requires gantry rotation, using a solid water rectangular, instead of cylindrical, phantom was investigated. METHODS: A phase space file based on the 9 MeV electron beam with rectangular cutout (physical size = 2.6 x 21 cm2) attached to the block tray holder of a Varian 21 EX linear accelerator (linac) was generated using the EGSnrc-based Monte Carlo code and verified by measurement. The relative output factor (ROF), SSD offset, and DF, needed in the MU calculation, were determined using measurements and Monte Carlo simulations. An ionization chamber, a radiographic film, a solid water rectangular phantom, and a cylindrical phantom made of polystyrene were used in dosimetry measurements. RESULTS: Percentage deviations of ROF, SSD offset, and DF between measured and Monte Carlo results were 1.2%, 0.18%, and 1.5%, respectively. It was found that the DF decreased with an increase in a, and such a decrease in DF was more significant in the a range of 0 degrees-60 degrees than 60 degrees-120 degrees. Moreover, for a fixed a, the DF increased with an increase in SSD. Comparing the DF determined using the rectangular and cylindrical phantom through measurements and Monte Carlo simulations, it was found that the DF determined by the rectangular phantom agreed well with that by the cylindrical one within +/- 1.2%. It shows that a simple setup of a solid water rectangular phantom was sufficient to replace the cylindrical phantom using our specific cutout to determine the DF associated with the electron arc. CONCLUSIONS: By verifying using dosimetry measurements, Monte Carlo simulations proved to be an alternative way to perform MU calculations effectively for electron are therapy. Since Monte Carlo simulations can generate a precalculated database of ROF, SSD offset, and DF for the MU calculation, with a reduction in human effort and linac beam-on time, it is recommended that Monte Carlo simulations be partially or completely integrated into the commissioning of electron are therapy.

Technical note: calculation of normal tissue complication probability using Gaussian error function model.

PURPOSE: The Gaussian error function was first used and verified in normal tissue complication probability (NTCP) calculation to reduce the dose-volume histogram (DVH) database by replacing the dose-volume bin set with the error function parameters for the differential DVH (dDVH). METHODS: Seven-beam intensity modulated radiation therapy (IMRT) treatment planning was performed in three patients with small (40 cm3), medium (53 cm3), and large (87 cm3) prostate volume, selected from a group of 20 patients. Rectal dDVH varying with the interfraction prostate motion along the anterior-posterior direction was determined by the treatment planning system (TPS) and modeled by the Gaussian error function model for the three patients. Rectal NTCP was then calculated based on the routine dose-volume bin set of the rectum by the TPS and the error function model. The variations in the rectal NTCP with the prostate motion and volume were studied. RESULTS: For the ranges of prostate motion of 8-2, 4-8, and 4-3 mm along the anterior-posterior direction for the small, medium, and large prostate patient, the rectal NTCP was determined varying in the ranges of 4.6%-4.8%, 4.5%-4.7%, and 4.6%-4.7%, respectively. The deviation of the rectal NTCP calculated by the TPS and the Gaussian error function model was within +/- 0.1%. CONCLUSIONS: The Gaussian error function was successfully applied in the NTCP calculation by replacing the dose-volume bin set with the model parameters. This provides an option in the NTCP calculation using a reduced size of dose-volume database. Moreover, the rectal NTCP was found varying in about +/- 0.2% with the interfraction prostate motion along the anterior-posterior direction in the radiation treatment. The dependence of the variation in the rectal NTCP with the interfraction prostate motion on the prostate volume was found to be more significant in the patient with larger prostate.

Dosimetry of oblique tangential photon beams calculated by superposition/convolution algorithms: a Monte Carlo evaluation.

Although there are many works on evaluating dose calculations of the anisotropic analytical algorithm (AAA) using various homogeneous and heterogeneous phantoms, related work concerning dosimetry due to tangential photon beam is lacking. In this study, dosimetry predicted by the AAA and collapsed cone convolution (CCC) algorithm was evaluated using the tangential photon beam and phantom geometry. The photon beams of 6 and 15 MV with field sizes of 4 × 4 (or 7 × 7), 10 × 10 and 20 × 20 cm², produced by a Varian 21 EX linear accelerator, were used to test performances of the AAA and CCC using Monte Carlo (MC) simulation (EGSnrc-based code) as a benchmark. Horizontal dose profiles at different depths, phantom skin profiles (i.e., vertical dose profiles at a distance of 2 mm from the phantom lateral surface), gamma dose distributions, and dose-volume histograms (DVHs) of skin slab were determined. For dose profiles at different depths, the CCC agreed better with doses in the air-phantom region, while both the AAA and CCC agreed well with doses in the penumbra region, when compared to the MC. Gamma evaluations between the AAA/CCC and MC showed that deviations of 2D dose distribution occurred in both beam edges in the phantom and air-phantom interface. Moreover, the gamma dose deviation is less significant in the air-phantom interface than the penumbra. DVHs of skin slab showed that both the AAA and CCC underestimated the width of the dose drop-off region for both the 6 and 15 MV photon beams. When the gantry angle was 0°, it was found that both the AAA and CCC overestimated doses in the phantom skin profiles compared to the MC, with various photon beam energies and field sizes. The mean dose differences with doses normalized to the prescription point for the AAA and CCC were respectively: 7.6% ± 2.6% and 2.1% ± 1.3% for a 10 × 10 cm2 field, 6 MV; 16.3%± 2.1% and 6.7% ± 2.1% for a 20 × 20 cm2 field, 6 MV; 5.5% ± 1.2% and 1.7% ± 1.4% for a 10 × 10 cm2, 15 MV; 18.0% ± 1.3% and 8.3% ± 1.8% for a 20 × 20 cm², 15 MV. However, underestimations of doses in the phantom skin profile were found with small fields of 4 × 4 and 7 × 7 cm² for the 6 and 15 MV photon beams, respectively, when the gantry was turned 5° anticlockwise. As surface dose with tangential photon beam geometry is important in some radiation treatment sites such as breast, chest wall and sarcoma, it is found that neither of the treatment planning system algorithms can predict the dose well at depths shallower than 2 mm. The dosimetry data and beam and phantom geometry in this study provide a better knowledge of a dose calculation algorithm in tangential-like irradiation.

Dosimetric and radiobiological comparison of prostate VMAT plans optimized using the photon and progressive resolution algorithm.

This study compared the dosimetric and radiobiological parameters of prostate volumetric modulated arc therapy (VMAT) plans using different prescriptions optimized by the photon optimization (PO) and progressive resolution optimization (PRO) algorithm. A total of 20 prostate patients were selected retrospectively and divided into 2 groups of VMAT plans using prescriptions of 60 Gy/20 fx and 79 Gy/38 fx. Inverse treatment planning optimized by the PO and PRO algorithm based on the dual-arc technique was carried out by the Eclipse treatment planning system. The maximum dose, minimum dose, mean dose, dose-volume points, and dose-volume indices of the targets and organs at risk (OAR) were calculated from the plans. In addition, radiobiological parameters such as tumor control probability (TCP), normal tissue complication probability (NTCP), and equivalent uniform dose (EUD) of the targets and OAR were determined based on their dose-volume histograms (DVHs). A paired Student's t-test was carried out to compare the difference between mean dose-volume points, radiobiological parameters, and dose-volume indices. Two-tailed p < 0.05 was defined as having statistical difference. For prostate VMAT plans optimized by the PO algorithm, equal or slightly larger mean dose and TCP of the PTV (1% for 60 Gy/20 fx and 0.2% for 78 Gy/39 fx) were found by comparing to the PRO. These were followed by finding the slightly larger conformity index (CI; 0.927 vs 0.895 and 0.910 vs 0.904), larger or equal homogeneity index (HI; 0.054 vs 0.052 and 0.058 vs 0.058), and smaller gradient index (GI; 1.366 vs 2.288 and 1.585 vs 1.742) of the PTV using plans optimized by the PO vs PRO using prescriptions of 60 Gy/20 fx and 78 Gy/39 fx. For the OAR, we found that the mean doses, NTCPs, and EUDs of the rectum, bladder, and femur were slightly larger for plans optimized by the PO algorithm compared to the PRO, though both optimization algorithms satisfied all the dose-volume criteria and objectives in the inverse planning. Both the PO and PRO algorithm can generate prostate VMAT plans fulfilling the required dose-volume criteria. It is concluded that plans optimized by the PO algorithm can produce prostate plan with very similar quality compared to PRO.

The effect of interfraction prostate motion on IMRT plans: a dose-volume histogram analysis using a Gaussian error function model.

The Gaussian error function model, containing pairs of error and complementary error functions, was used to carry out cumulative dose-volume histogram (cDVH) analysis on prostate intensity modulated radiation therapy (IMRT) plans with interfraction prostate motion. Cumulative DVHs for clinical target volumes (CTVs) shifted in the anterior-posterior directions based on a 7-beam IMRT plan were calculated and modeled using the Pinnacle3 treatment planning system and a Gaussian error function, respectively. As the parameters in the error function model, namely, a, b and c were related to the shape of the cDVH curve, evaluation of cDVHs corresponding to the prostate motion based on the model parameters becomes possible as demonstrated in this study. It was found that deviations of the cDVH for the CTV were significant, when the CTV-planning target volume (PTV) margin was underestimated in the anterior-posterior directions, particularly in the posterior direction for a patient with relatively small prostate volume (39 cm3). Analysis of the cDVH for the CTV shifting in the anterior-posterior directions using the error function model showed that parameters a1,2, which were related to the maximum relative volume of the cDVH, changed symmetrically when the prostate was shifted in the anterior and posterior directions. This change was more significant for the larger prostate. For parameters b related to the slope of the cDVH, b1,2 changed symmetrically from the isocenter, when the CTV was within the PTV. This was different from parameters c (c1,2 are related to the maximum dose of the cDVH), which did not vary significantly with the prostate motion in the anterior-posterior directions and prostate volume. Using the patient data, this analysis validates the error function model, and further verified the clinical application of this mathematical model on treatment plan evaluations.

Technical note: dose-volume histogram analysis in radiotherapy using the Gaussian error function.

A mathematical model based on the Gaussian error and complementary error functions was proposed to describe the cumulative dose-volume histogram (cDVH) for a region of interest in a radiotherapy plan. Parameters in the model (a, b, c) are related to different characteristics of the shape of a cDVH curve such as the maximum relative volume, slope and position of a curve drop off, respectively. A prostate phantom model containing a prostate, the seminal vesicle, bladder and rectum with cylindrical organ geometries was used to demonstrate the effect of interfraction prostate motion on the cDVH based on this error function model. The prostate phantom model was planned using a five-beam intensity modulated radiotherapy (IMRT), and a four-field box (4FB), technique with the clinical target volume (CTV) shifted in different directions from the center. In the case of the CTV moving out of the planning target volume (PTV), that is, the margin between the CTV and PTV is underestimated, parameter c (related to position of curve drop off) in the 4FB plan and parameters b (related to the slope of curve) and c in the IMRT plan vary significantly with CTV displacement. This shows that variation of the cDVH is present in the 4FB plan and such variation is more serious in the IMRT plan. These variations of cDVHs for 4FB and IMRT are due to the different dose gradients at the CTV edges in the anterior and posterior directions for the 4FB and IMRT plan. It is believed that a mathematical representation of the dose-volume relationship provides another viewpoint from which to illustrate problems with radiotherapy delivery such as internal organ motion that affect the dose distribution in a treatment plan.

Dose-volume and radiobiological dependence on the calculation grid size in prostate VMAT planning.

This study evaluated the effects of dose-volume and radiobiological dependence on the calculation grid size in prostate volumetric-modulated arc therapy (VMAT) planning. Ten patients with prostate cancer were selected for this retrospective treatment planning study. Prostate VMAT plans were created for the patients using the 6 MV photon beam produced by a Varian TrueBEAM linac with the calculation grid size equal to 1, 2, 2.5, 3, 4, and 5 mm. Dose-volume histograms (DVHs) of targets and organs at risk were generated for different grid sizes. We calculated the radiobiological parameters of the tumor control probability (TCP) of clinical target volume (CTV) and planning target volume (PTV), and the normal tissue complication probability (NTCP) of organs at risk (rectal wall, rectum, bladder wall, bladder, left femur, and right femur). The homogeneity, conformity, and gradient indexes of CTV and PTV were calculated for different grid sizes. The TCP of PTV was found decreasing with a rate of 0.06%/mm when the calculation grid size increased from 1 to 5 mm. On the other hand, both NTCPs of rectal wall and rectum were found decreasing with rates of 0.03%/mm and 0.05%/mm, respectively, with an increase of grid size. The homogeneity index of PTV increased with a rate of 0.57/mm of the calculation grid size, whereas the conformity index of PTV decreased with a rate of 0.0075/mm. The gradient index of PTV was found increasing with a rate equal to 0.05/mm. In prostate VMAT planning, variations of dose-volume and radiobiological parameters with calculation grid size on PTV, rectal wall, and rectum were more significant than those of CTV and other organs at risk such as bladder wall, bladder, and femurs. Results in this study are important in the treatment planning quality assurance when the calculation grid size is varied to compromise a shorter dose computing time.

The use of spatial dose gradients and probability density function to evaluate the effect of internal organ motion for prostate IMRT treatment planning.

The aim of this study is to investigate the effects of internal organ motion on IMRT treatment planning of prostate patients using a spatial dose gradient and probability density function. Spatial dose distributions were generated from a Pinnacle3 planning system using a co-planar, five-field intensity modulated radiation therapy (IMRT) technique. Five plans were created for each patient using equally spaced beams but shifting the angular displacement of the beam by 15 degree increments. Dose profiles taken through the isocentre in anterior-posterior (A-P), right-left (R-L) and superior-inferior (S-I) directions for IMRT plans were analysed by exporting RTOG file data from Pinnacle. The convolution of the 'static' dose distribution D0(x, y, z) and probability density function (PDF), denoted as P(x, y, z), was used to analyse the combined effect of repositioning error and internal organ motion. Organ motion leads to an enlarged beam penumbra. The amount of percentage mean dose deviation (PMDD) depends on the dose gradient and organ motion probability density function. Organ motion dose sensitivity was defined by the rate of change in PMDD with standard deviation of motion PDF and was found to increase with the maximum dose gradient in anterior, posterior, left and right directions. Due to common inferior and superior field borders of the field segments, the sharpest dose gradient will occur in the inferior or both superior and inferior penumbrae. Thus, prostate motion in the S-I direction produces the highest dose difference. The PMDD is within 2.5% when standard deviation is less than 5 mm, but the PMDD is over 2.5% in the inferior direction when standard deviation is higher than 5 mm in the inferior direction. Verification of prostate organ motion in the inferior directions is essential. The margin of the planning target volume (PTV) significantly impacts on the confidence of tumour control probability (TCP) and level of normal tissue complication probability (NTCP). Smaller margins help to reduce the dose to normal tissues, but may compromise the dose coverage of the PTV. Lower rectal NTCP can be achieved by either a smaller margin or a steeper dose gradient between PTV and rectum. With the same DVH control points, the rectum has lower complication in the seven-beam technique used in this study because of the steeper dose gradient between the target volume and rectum. The relationship between dose gradient and rectal complication can be used to evaluate IMRT treatment planning. The dose gradient analysis is a powerful tool to improve IMRT treatment plans and can be used for QA checking of treatment plans for prostate patients.

Intensity modulated radiation therapy with irregular multileaf collimated field: a dosimetric study on the penumbra region with different leaf stepping patterns.

Using a Varian 21 EX linear accelerator with a multileaf collimator (MLC) of 120 leaves, the penumbra regions of beam profiles within an irregular multileaf collimated fields were studied. MLC fields with different leaf stepping angles from 21.8 degrees to 68.2 degrees were used. Beam profiles in different directions: (1) along the cross-line and in-line axis, (2) along the leaf stepping edges of the field, and (3) parallel to the stepping edges but in the middle of the field, were measured and calculated using Kodak XV radiographic film and Pinnacle3 treatment planning system version 7.4f. These beam profiles were measured and calculated at source to axis distance= 100 cm with 5 cm of solid water slab on top. On the one hand, for both cross-line and in-line beam profiles, the penumbra widths of 20%-80% did not vary with the leaf stepping angles and were about 0.4 cm. On the other hand, the penumbra widths of 10%-90% of the above two profiles varied with the stepping angles and had maximum widths of about 1.9 cm (cross-line) and 1.65 cm (in-line) for stepping angles of 38.7 degrees and 51.3 degrees , respectively. For profiles crossing the "rippled" stepping edges of the field, the penumbra widths (10%-90%) at the regions between two opposite leaves (i.e., profile end at the Y1/Y2 jaw position) decreased with the stepping angles. At the penumbra regions between two leaf edges with the tongue-and-groove structure of the same bank (i.e., profile end at the X1/X2 jaw position), the penumbra widths increased with the stepping angles. When the penumbra widths were measured between two opposite leaf edges and at corners between two leaves, the widths first decreased with the stepping angles and then increased beyond the minimum width point at stepping angle of 45 degrees. The penumbra width (10%-90%) measured at the leaf edge was larger than that at the corner. For the beam profiles calculated using Pinnacle3, it is found that the results agreed well with the measurements along the cross-line and in-line axis, while there was a deviation for the profiles along the leaf stepping edge of the field compared to the film measurements. The measured results in this study can help us to understand the dosimetric effect of the leaf stepping (due to finite leaf width), tongue-and-groove and rounded leaf end structure in the penumbra region of an irregular MLC field. A more dedicated penumbra model can be developed for the treatment planning system.

IMRT: improvement in treatment planning efficiency using NTCP calculation independent of the dose-volume-histogram.

The normal tissue complication probability (NTCP) is a predictor of radiobiological effect for organs at risk (OAR). The calculation of the NTCP is based on the dose-volume-histogram (DVH) which is generated by the treatment planning system after calculation of the 3D dose distribution. Including the NTCP in the objective function for intensity modulated radiation therapy (IMRT) plan optimization would make the planning more effective in reducing the postradiation effects. However, doing so would lengthen the total planning time. The purpose of this work is to establish a method for NTCP determination, independent of a DVH calculation, as a quality assurance check and also as a mean of improving the treatment planning efficiency. In the study, the CTs of ten randomly selected prostate patients were used. IMRT optimization was performed with a PINNACLE3 V 6.2b planning system, using planning target volume (PTV) with margins in the range of 2 to 10 mm. The DVH control points of the PTV and OAR were adapted from the prescriptions of Radiation Therapy Oncology Group protocol P-0126 for an escalated prescribed dose of 82 Gy. This paper presents a new model for the determination of the rectal NTCP (R(NTCP)). The method uses a special function, named GVN (from Gy, Volume, NTCP), which describes the R(NTCP) if 1 cm3 of the volume of intersection of the PTV and rectum (R(int)) is irradiated uniformly by a dose of 1 Gy. The function was "geometrically" normalized using a prostate-prostate ratio (PPR) of the patients' prostates. A correction of the R(NTCP) for different prescribed doses, ranging from 70 to 82 Gy, was employed in our model. The argument of the normalized function is the R(int), and parameters are the prescribed dose, prostate volume, PTV margin, and PPR. The R(NTCPs) of another group of patients were calculated by the new method and the resulting difference was < +/- 5% in comparison to the NTCP calculated by the PINNACLE3 software where Kutcher's dose-response model for NTCP calculation is adopted.