The management of imaging dose during imageâ guided radiotherapy: Report of the AAPM Task Group 75

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134823/1/mp5667.pd

Improving treatment dose accuracy in radiation therapy

The thesis aims to improve treatment dose accuracy in brachytherapy using a high dose rate (HDR) Ir-192 stepping source and in external beam therapy using intensity modulated radiation therapy (IMRT). For HDR brachytherapy, this has been achieved by investigating dose errors in the near field and the transit dose of the HDR brachytherapy stepping source. For IMRT, this study investigates the volume effect of detectors in the dosimetry of small fields, and the clinical implementation and dosimetric verification of a 6MV photon beam for IMRT. For the study of dose errors in the near field of an HDR brachytherapy stepping source, the dose rate at point P at 0.25 cm in water from the transverse bisector of a straight catheter was calculated with Monte Carlo code MCNP 4.A. The Monte Carlo (MC) results were used to compare with the results calculated with the Nucletron Brachytherapy Planning System (BPS) formalism. Using the MC calculated radial dose function and anisotropy function with the BPS formalism, 1% dose calculation accuracy can be achieved even in the near field with negligible extra demand on computation time. A video method was used to analyse the entrance, exit and the inter-dwell transit speed of the HDR stepping source for different path lengths and step sizes ranging from 2.5 mm to 995 mm. The transit speeds were found to be ranging from 54 to 467 mm/s. The results also show that the manufacturer has attempted to compensate for the effects of inter-dwell transit dose by reducing the actual dwell time of the source. A well-type chamber was used to determine the transit doses. Most of the measured dose differences between stationary and stationary plus inter-dwell source movement were within 2%. The small-field dosimetry study investigates the effect of detector size in the dosimetry of small fields and steep dose gradients with a particular emphasis on IMRT measurements. Due to the finite size of the detector, local discrepancies of more than 10 % are found between calculated cross profiles of intensity modulated beams and intensity modulated profiles measured with film. A method to correct for the spatial response of finite sized detectors and to obtain the "real" penumbra width of cross profiles from measurements is introduced. Output factor measurements are performed with different detectors and are presented as a function of detector size for a 1 x 1 cm2 field. The study on the clinical implementation and dosimetric verification of a 6 MV photon beam for IMRT provides a systematic guideline for effective clinical implementation of IMRT in radiotherapy centres. Despite the beam model not taking in account for the effects of transmission through round leaf ends, adjusting the leaf position to account for the effective widening of the leaf opening shows good dose agreement within the acceptable criterion of ±3% or 2 mm in our in-house dose verification process. The Radiological Physics Centre (RPC) IMRT phantom provides a valuable independent check by the RPC on IMRT commissioning, validation and QA process

Investigation of timepix radiation detector for autoradiography and microdosimetry in targeted alpha therapy

The Timepix detector developed by CERN is a novel and sophisticated particle detector. It consists of a semiconductor layer divided into an array of pixels. This array of pixels is bumpbonded to an electronics integrated layer (i.e. the readout chip). Timepix can be used for a wide range of measurements of electromagnetic radiation and particles and their applications in different fields such as space physics, nuclear physics, radiotherapy physics, imaging and radiation protection. The Timepix detector used in this work was purchased from Amsterdam Scientific Instruments, the Netherlands, in order to investigate its use for microdosimetry purposes, in particular in targeted alpha therapy. The device has the following properties: 256 x 256 pixels of 55 x 55 μm2 area each, the chip is effective for positive or negative charge and can be used to detect electrons, X-rays, neutrons and heavy charge particles. It can work as an energy spectrometer, has good spatial resolution and reason1ble detection efficiency. The device can operate in three common modes: Timepix mode, Medipix mode, and Time-Over-Threshold (TOT) mode. Targeted alpha therapy (TAT) is a novel type of radionuclide therapy in which an alpha emitting radioisotope is attached to a cancer cell seeking vector (so called radioimmunoconjugate (RIC)). Once attached to a cancer cell, it causes localized damage due to traversal and energy deposition high LET a-particles. There is, however, a lack of data related to a-particle distribution in TAT. These data are required to more accurately estimate the absorbed dose on a cellular level. As a result, this work aims to develop a microdosimetry technique, using Timepix detector that will estimate, or better yet determine the absorbed dose deposited by a-particles in cells as well as will measure the biodistribution of the radioisotope in a tumour. Initially, extensive Timepix characterization and testing has been done to evaluate the detector's response, including linearity, reproducibility, and sensitivity to low doses of radiations (μGy-mGy dose region) and energy dependence. 1-125 seeds and superficial X-rays (below 70 kVp), produced by the Gulmay superficial X-ray unit, were used. The measured Timepix pixel value was correlated with the known dose (based on the irradiation time used and TLD-100 measurements) and a pixel-value-to- dose calibration curve was obtained. It was confinned that Timepix value increased linearly with the dose delivered. The dose calibration curves using the superficial X-ray beams showed that the pixel value, however, depended on the energy of the X-ray beam. The application of Timepix to measure radioisotope biodistribution (i.e. autoradiography) was investigated. Mice with Lewis lung (LL2) tumours were treated with about 18 kBq oP27Thlabelled DAB4 murine monoclonal antibody that bounds to necrotic tumour cells. The rationale is to develop a-particle-mediated bystander kill of nearby viable tumour cells. To generate more necrotic tumour cells for 227Th-DAB4 binding, some mice also received chemotherapy before being injected with Th-227-DAB4. Finally, 5 mm tumour sections were cut from treated mice for autoradiography with Timepix. Each tumour section was mounted onto a slide with front face uncovered to allow emission of a-particles from the tumour section. Simple steel collimator (I cm radius, 2 cm length) was manufactured in-house and positioned around the tumour section. The slide was placed 2 cm away from the Timepix detector. Bias voltage of 7 V was applied, and a-particle filter was selected for acquisition. Detector cover was removed, exposing the Si layer, to allow the emitted a-particles ( - 6 Me V) to reach the detector. Image acquisition took -14 h. Good resolution autoradiographs of radiolabelled tumour sections were acquired, showing a-particle, electron and X-ray tracks. Timepix measurements also showed an increased Th-227-DAB4 uptake following chemotherapy due to increase in necrotic tissue volume. Timepix was also used to measure the uptake of Cr-51 by A549 cells (lung carcinoma cell line) for different pH levels and the dependence of uptake on pH was investigated. Timepix was observed to be sensitive to detect small changes in the activity/uptake of radioactive sources depending on the environmental condition and the number of cells. The last part of this thesis deals with the development of a transmitted a-particle microdosimetry technique. First, A549 cells were grown in vitro using standard protocols and were irradiated using a 6 MY photon beam with different doses varying between 2-8 Gy and Ra-226 source was used for a-particle irradiation to evaluate A549 radiation sensitivity using clonogenic assay and MTT assay. The cell line was found radiosensitive, with 050 of~ 2 Gy for X-ray irradiation. For transmitted dosimetry, A549 cells were either unirradiated (control) or irradiated for ~2, 1, 2 or 3 hours with a-particles emitted from a Ra-223 source positioned below a monolayer of A549 cells. The HTS Transwell" 96 well system (Corning, USA), consisting of 2 compartments, was used to develop a method for tracking a-particles through a cell mono layer. This system comprises of two compartments, with liquid Ra-223 evaporated in the lower compartment to avoid a-particle self-absorption inside the liquid. The measured activity of 5 kBq was unifonnly distributed, as confirmed by Timepix detector. The second compartment consists of a flat bottom polycarbonate membrane (I 0 μm thick) where cells are plated. It is sufficiently thin to allow a-particles to penetrate through and hit the cells. Fifteen thousand A549 cells were seeded in the upper compartment that was then inserted into the lower compartment containing the evaporated Ra-223. The transwell system was positioned under the Timepix detector. Transmitted a-particles were detected for 1;2, I, 2 or 3 hour irradiation times. Additionally, DNA double strand breaks (DSBs) in the form of y-H2AX foci, were examined by fluorescence microscopy. The number of transmitted a-particles was correlated with the observed DNA DSBs and the delivered radiation dose was estimated. Additionally, the dose deposited was calculated using Monte Carlo code SRIM. Approximately 20% of a-particles were transmitted and detected by Timepix. The frequency and number of y-H2AX foci increased significantly following a-particle irradiation as compared to unirradiated controls. The RBE equivalent dose delivered to A549 cells was estimated to be approximately 0.66 Gy, 1.32 Gy, 2.53 Gy and 3. 96 Gy after Y2, I, 2 and 3 h irradiation, respectively, considering a relative biological effectiveness of a-particles of 5.5. In summary, the Timepix detector can be used effectively for autoradiography in TAT, providing high resolution images and excellent spatial resolution of detected a-particles, as well as a transmitted a-particle microdosimetry detector. If cross-calibrated using biological dosimetry, this method will give a good indication of the biological effects of a-particles without the need for repeated biological dosimetry which is costly, time consuming and not readily available.Thesis (Ph.D.) (Research by Publication) -- University of Adelaide, School of Physical Sciences, 2017

Optical Contrast Agents to Visualize Molecular Expression in Breast Cancer

Breast cancer is the second leading cause of death of women in the United States. Improvements in screening technology have increased the breast cancer incidence rate, as smaller lesions are being detected. Due to the small size of lesions, patients can choose to receive breast conservation therapy (BCT) rather than a modified radical mastectomy. Even though the breast retains cosmesis after BCT, there is an increased risk of the patient having residual microscopic disease, known as positive margins. Patients with positive margins receive increased radiation and have an increased chance of second surgery. Pathology with hematoxylin and eosin (H&E) remains the gold standard for diagnosing margin status in patients. Intraoperative pathology has been shown to reduce the rate of positive margins in BCT. However, a minority of surgery centers have intraoperative pathology centers, limiting the number of patients that receive this standard of care. The expression profiles of surface receptors such as ErbB2 (HER2-positive) and epidermal growth factor receptor (EGFR) provide information about the aggressiveness of a particular tumor. Recent research has shown that there was elevated EGFR expression in patients with a local recurrence even though the biopsies were assessed to be disease free using standard H&E. If the physicians had known the molecular expression of these biopsies, a different treatment regimen or excision of more tissue might have prevented the recurrence. This thesis investigates targeted molecular contrast agents that enhance the visualization of molecular markers such as glucose transporters (GLUTs) and growth factor receptors in tissue specimens. First, application of 2-NBDG, a fluorescent deoxy-glucose, enhances signal in cancerous tissue with a 20-minute incubation. Then, antibody functionalized silica-gold nanoshells enhance the visualization of ErbB2 overexpression in specimens with a 5-minute incubation. To image these contrast agents in cancerous tissue, a portable, inexpensive device was developed as a tool to help physicians visualize expression of surface markers. The system visualizes absorbance from nanoshell aggregates and fluorescence in the visible and near-infrared light spectrum. This study represents the first step in the development of an intraoperative optical imaging device to enhance the visualization of molecular markers overexpressed in cancerous cells

Diagnostic Significance of Exosomal miRNAs in the Plasma of Breast Cancer Patients

Poster Session AbstractsBackground and Aims: Emerging evidence that microRNAs (miRNAs) play an important role in cancer development has opened up new opportunities for cancer diagnosis. Recent studies demonstrated that released exosomes which contain a subset of both cellular mRNA and miRNA could be a useful source of biomarkers for cancer detection. Here, we aim to develop a novel biomarker for breast cancer diagnosis using exosomal miRNAs in plasma. Methods: We have developed a rapid and novel isolation protocol to enrich tumor-associated exosomes from plasma samples by capturing tumor specific surface markers containing exosomes. After enrichment, we performed miRNA profiling on four sample sets; (1) Ep-CAM marker enriched plasma exosomes of breast cancer patients; (2) breast tumors of the same patients; (3) adjacent non-cancerous tissues of the same patients; (4) Ep-CAM marker enriched plasma exosomes of normal control subjects. Profiling is performed using PCR-based array with human microRNA panels that contain more than 700 miRNAs. Results: Our profiling data showed that 15 miRNAs are concordantly up-regulated and 13 miRNAs are concordantly down-regulated in both plasma exosomes and corresponding tumors. These account for 25% (up-regulation) and 15% (down-regulation) of all miRNAs detectable in plasma exosomes. Our findings demonstrate that miRNA profile in EpCAM-enriched plasma exosomes from breast cancer patients exhibit certain similar pattern to that in the corresponding tumors. Based on our profiling results, plasma signatures that differentiated breast cancer from control are generated and some of the well-known breast cancer related miRNAs such as miR-10b, miR-21, miR-155 and miR-145 are included in our panel list. The putative miRNA biomarkers are validated on plasma samples from an independent cohort from more than 100 cancer patients. Further validation of the selected markers is likely to offer an accurate, noninvasive and specific diagnostic assay for breast cancer. Conclusions: These results suggest that exosomal miRNAs in plasma may be a novel biomarker for breast cancer diagnosis.link_to_OA_fulltex