Mike Makrigiorgos

Experimental evaluation of the accuracy of skin dose calculation for a commercial treatment planning system

The present work uses the Eclipse treatment planning system (TPS) to investigate the accuracy of skin dose calculations. Micro‐MOSFETs (metal oxide semiconductor field effect transistors) were used to measure skin dose for a range of irradiation conditions (open fields, physical wedges, dynamic wedges, various source‐to‐surface distances) for 6‐MV and 10‐MV beams, and the results were compared with the calculated mean dose to a “skin” structure 2 mm thick for semi‐cylindrical phantoms (representative of a neck or breast). Agreement between the calculated and measured skin dose values was better than ±20% for 95% of all measured points (6‐MV and 10‐MV X‐ray spectra alike). For a fixed geometry, the TPS correctly calculated relative changes in dose, showing that minimization of skin dose in intensity‐modulated radiation therapy will be effective in Eclipse. PACS numbers: 87.53.Bn, 87.53.Dq, 87.66.Pm, 87.66.Xa

Radiation dose enhancement of gadolinium-based AGuIX nanoparticles on HeLa cells

UNLABELLED Radiation dose enhancement of high-Z nanoparticles is an active area of research in cancer therapeutics. When kV and MV energy photon beams interact with high-Z nanoparticles in a tumor, the release of secondary electrons can injure tumor cells, leading to a higher treatment efficacy than radiation alone. We present a study that characterizes the radiation dose enhancing effects of gadolinium-based AGuIX nanoparticles on HeLa cells. Our in vitro clonogenic survival assays showed an average dose enhancement of 1.54× for 220 kVp radiation and 1.15× for 6 MV radiation. The sensitivity enhancement ratio at 4 Gy (SER4Gy) was 1.54 for 220 kVp and 1.28 for 6 MV, indicating that these nanoparticles may be useful for clinical radiation therapy. FROM THE CLINICAL EDITOR This study characterized the radiation dose enhancing effects of gadolinium-based AGuIX nanoparticles on HeLa cells, showing clear effects at 220 kV as well as 6 MV, suggesting that after additional studies, these nanoparticles may be beneficial in human radiation therapy.

A stochastic model of cell survival for high‐Z nanoparticle radiotherapy

PURPOSE The authors present a stochastic framework for the assessment of cell survival in gold nanoparticle radiotherapy. METHODS The authors derive the equations for the effective macroscopic dose enhancement for a population of cells with nonideal distribution of gold nanoparticles (GNP), allowing different number of GNP per cell and different distances with respect to the cellular target. They use the mixed Poisson distribution formalism to model the impact of the aforementioned physical factors on the effective dose enhancement. RESULTS The authors show relatively large differences in the estimation of cell survival arising from using approximated formulae. They predict degeneration of the cell killing capacity due to different number of GNP per cell and different distances with respect to the cellular target. CONCLUSIONS The presented stochastic framework can be used in interpretation of experimental cell survival or tumor control probability studies.

The effect of flattening filter free delivery on endothelial dose enhancement with gold nanoparticles.

PURPOSE The aim of this study is to quantify and to compare the dose enhancement factor from gold nanoparticles (AuNP) to tumor endothelial cells for different concentrations of AuNP, and clinical MV beam configurations. METHODS Tumor endothelial cells are modeled as slabs measuring 10 × 10 × 2 μm. A spherical AuNP is simulated on the surface of the endothelial cell, within the blood vessel. 6 MV photon beams with and without the flattening filter are investigated for different field sizes, depths in material and beam modulation. The incident photon energy spectra for each configuration is generated using EGSnrc. The dose enhancement in the tumor endothelial cell is found using an analytical calculation. The endothelial dose enhancement factor is defined to be the ratio of the dose deposited with and without AuNPs. RESULTS It is found that clinical beam parameters may be chosen to maximize the effect of gold nanoparticles during radiotherapy. This effect is further amplified ~20% by the removal of the flattening filter. Modulation of the clinical beam with the multileaf collimator tends to decrease the proportion of low energy photons, therefore providing less enhancement than the corresponding open field. CONCLUSIONS The results of this work predict a dose enhancement to tumor blood vessel endothelial cells using conventional therapeutic (MV) x-rays and quantify the relative change in enhancement with treatment depth and field size.

Nanoparticle-based brachytherapy spacers for delivery of localized combined chemoradiation therapy.

PURPOSE In radiation therapy (RT), brachytherapy-inert source spacers are commonly used in clinical practice to achieve high spatial accuracy. These implanted devices are critical technical components of precise radiation delivery but provide no direct therapeutic benefits. METHODS AND MATERIALS Here we have fabricated implantable nanoplatforms or chemoradiation therapy (INCeRT) spacers loaded with silica nanoparticles (SNPs) conjugated containing a drug, to act as a slow-release drug depot for simultaneous localized chemoradiation therapy. The spacers are made of poly(lactic-co-glycolic) acid (PLGA) as matrix and are physically identical in size to the commercially available brachytherapy spacers (5 mm × 0.8 mm). The silica nanoparticles, 250 nm in diameter, were conjugated with near infrared fluorophore Cy7.5 as a model drug, and the INCeRT spacers were characterized in terms of size, morphology, and composition using different instrumentation techniques. The spacers were further doped with an anticancer drug, docetaxel. We evaluated the in vivo stability, biocompatibility, and biodegradation of these spacers in live mouse tissues. RESULTS The electron microscopy studies showed that nanoparticles were distributed throughout the spacers. These INCeRT spacers remained stable and can be tracked by the use of optical fluorescence. In vivo optical imaging studies showed a slow diffusion of nanoparticles from the spacer to the adjacent tissue in contrast to the control Cy7.5-PLGA spacer, which showed rapid disintegration in a few days with a burst release of Cy7.5. The docetaxel spacers showed suppression of tumor growth in contrast to control mice over 16 days. CONCLUSIONS The imaging with the Cy7.5 spacer and therapeutic efficacy with docetaxel spacers supports the hypothesis that INCeRT spacers can be used for delivering the drugs in a slow, sustained manner in conjunction with brachytherapy, in contrast to the rapid clearance of the drugs when administered systemically. The results demonstrate that these spacers with tailored release profiles have potential in improving the combined therapeutic efficacy of chemoradiation therapy.

Potential for Information and Communication Technologies to Catalyze Global Collaborations in Radiation Oncology

In response to a world in which cancer is a growing global health challenge, leaders in cancer policy from the United States and 14 economically diverse countries recently concluded that successful campaigns to control cancers and improve current strategies will increasingly depend on concerted international collaborations (1). Highlighting urgency for such collaborations, the 2014 World Health Organization Cancer Report (2) describes the growing cancer burden as alarming and a major obstacle to human development and well-being, with a growing annual economic cost of approximately 1.16 trillion US

Carbon fiber couches and skin sparing

. The report also highlights major global cancer disparities, with more than 60% of 14 million new cases and 70% of 8.2 million deaths per year occurring in low- and middle-income countries (LMICs), some of which, sadly, are the least capable of dealing with cancer without some form of collaboration. These major disparities in cancer deaths are in part a reflection of poignant underlying disparities in radiation oncology services. For example, radiation therapy, which is needed in the treatment of more than 50% of cancer patients (3), is not available in 31 of Africa’s 54 countries (4), and 55 of 139 LMICs reportedly (5) have no radiation therapy services at present. Therefore, having cancer in many LMICs often leads to a painful and distressing death.

New potential for enhancing concomitant chemoradiotherapy with FDA approved concentrations of cisplatin via the photoelectric effect

Dear Editor, Over the last few years, medical LINAC manufacturers have started to offer couch tops or inserts designed for image-guided radiation therapy (IGRT). These couch tops have a homogeneous construction, with a carbon fiber shell and no metal components. Although the use of these couches may offer some advantages in image quality, it can have a potentially serious impact on skin sparing.(1) The characteristics of new carbon fiber couches have been reported in this journal previously,(2,3) but the reports focus on couch transmission. We think the readers of the Journal of Applied Clinical Medical Physics may find our measurements of skin sparing for some modern couches useful when deciding on new couches. This data will supplement that of Higgins et al. who reported on a Sinmed BV couch.(1) We used a thin-window parallel plate ion chamber (Capintec PS-033) in solid water to measure the TPR in the build-up region for 6 MV and 10 MV beams (10 by 10 cm field) with three different IGRT couches [IGRT insert for Exact couch (Varian), IGRT couch (Varian), Robotic Couch (BrainLAB)], with the regular tennis-racket insert (Varian), and also with no couch in the beam. The results are shown in Fig. 1. All data is normalized at 10 cm depth to 0.775cGy/MU and 0.842cGy/MU for 6 MV and 10 MV beams, respectively. It can be seen in Fig. 1 that the use of carbon fiber couches reduces skin sparing significantly, and in one case eliminates it completely. Although the loss of skin sparing is less important for multifield treatments, it might become an issue for AP-PA or PA treatments that can comprise a significant fraction of treatments. For example, the use of a carbon fiber couch may increase the skin dose for a PA spine treatment from around 40% of prescription dose to 90–100% of the prescription dose, depending on the couch used. The skin dose for AP-PA treatments may also increase to more than 90% of the

Single-Tube, Highly Parallel Mutation Enrichment in Cancer Gene Panels by Use of Temperature-Tolerant COLD-PCR

We predict, for the first time, that by using United States Food and Drug Administration approved concentrations of cisplatin, major radiosensitization may be achieved via photoelectric mechanism during concomitant chemoradiotherapy (CCRT). Our analytical calculations estimate that radiotherapy (RT) dose to cancer cells may be enhanced via this mechanism by over 100% during CCRT. The results proffer new potential for significantly enhancing CCRT via an emerging clinical scenario, where the cisplatin is released in-situ from RT biomaterials loaded with cisplatin nanoparticles.

TU-C-BRB-11: In Vitro Dose Enhancement from Gold Nanoparticles under Different Clinical MV Photon Beam Configurations

BACKGROUND Multiplexed detection of low-level mutations presents a technical challenge for many technologies, including cancer gene panels used for targeted-resequencing. Analysis of mutations below approximately 2%-5% abundance in tumors with heterogeneity, samples with stromal contamination, or biofluids is problematic owing to increased noise from sequencing errors. Technologies that reduce noise via deep sequencing unavoidably reduce throughput and increase cost. Here we provide proof of principle that coamplification at lower denaturation temperature (COLD)-PCR technology enables multiplex low-level mutation detection in cancer gene panels while retaining throughput. METHODS We have developed a multiplex temperature-tolerant COLD-PCR (fast-TT-COLD-PCR) approach that uses cancer gene panels developed for massively parallel sequencing. After multiplex preamplification from genomic DNA, we attach tails to all amplicons and perform fast-TT-COLD-PCR. This approach gradually increases denaturation temperatures in a step-wise fashion, such that all possible denaturation temperatures are encompassed. By introducing modified nucleotides, fast-COLD-PCR is adapted to enrich for melting temperature (Tm)-increasing mutations over all amplicons, in a single tube. Therefore, in separate reactions, both Tm-decreasing and Tm-increasing mutations are enriched. RESULTS Using custom-made and commercial gene panels containing 8, 50, 190, or 16 000 amplicons, we demonstrate that fast-TT-COLD-PCR enriches mutations on all examined targets simultaneously. Incorporation of deoxyinosine triphosphate (dITP)/2,6-diaminopurine triphosphate (dDTP) in place of deoxyguanosine triphosphate (dGTP)/deoxyadenosine triphosphate (dATP) enables enrichment of Tm-increasing mutations. Serial dilution experiments demonstrate a limit of detection of approximately 0.01%-0.1% mutation abundance by use of Ion-Torrent and 0.1%-0.3% by use of Sanger sequencing. CONCLUSIONS Fast-TT-COLD-PCR improves the limit of detection of cancer gene panels by enabling mutation enrichment in multiplex, single-tube reactions. This novel adaptation of COLD-PCR converts subclonal mutations to clonal, thereby facilitating detection and subsequent mutation sequencing.