Name: construction of a preclinical multimodality phantom using tissue-mimicking materials for quality assurance in tumor size measurement
Uploaded: 2013-07-29T12:00:00
Description: Watch this Scientific Journal Video about Construction of a Preclinical Multimodality Phantom Using Tissue-mimicking Materials for Quality Assurance in Tumor Size Measurement at JoVE.com

The authors are thankful to Dr. Madsen at the University of Wisconsin-Madison and Cristel Baiu at Gammex Inc. for providing advice on TM materials. The authors are also grateful to Dr. Malcolm David Murray for providing the methods to construct the phantom.

1. Phantom Design
A drawing of the preclinical multimodality phantom is shown in Figure 1 7, 8. The size of the phantom is 38 mm in diameter and 115 mm in length to allow the phantom to be scanned in various animal scanners. The phantom contains five tumor-simulating test objects (diameter: 14, 10, 7, 4 and 2 mm) placed at a depth of 10 mm within the phantom.
2. Silicone Mold Construction
Silicone molds are prepare...

<ol>
	<li>Prasad, S. R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=CT+tumor+measurement+for+therapeutic+response+assessment:+Comparison+of+unidimensional,+bidimensional,+and+volumetric+techniques-Initial+observations.">CT tumor measurement for therapeutic response assessment: Comparison of unidimensional, bidimensional, and volumetric techniques-Initial observations.</a> Radiology. 225 (2), 416-419 (2002).</li><li>Cortes, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Comparison+of+unidimensional+and+bidimensional+measurement+in+metastatic+non-small+cell+lung+cancer.">Comparison of unidimensional and bidimensional measurement in metastatic non-small cell lung cancer.</a> Br. J. Cancer. 87 (2), 158-160 (2002).</li><li>Saini, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Radiologic+measurement+of+tumor+size+in+clinical+trials:+past,+present,+and+future.">Radiologic measurement of tumor size in clinical trials: past, present, and future.</a> AJR Am. J. Roentgenol. 176 (2), 333-334 (2001).</li><li>Suzuki, C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Radiologic+measurements+of+tumor+response+to+treatment:+practical+approaches+and+limitations.">Radiologic measurements of tumor response to treatment: practical approaches and limitations.</a> Radiographics. 28 (2), 329-344 (2008).</li><li>Therasse, P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=RECIST+revisited:+A+review+of+validation+studies+on+tumour+assessment.">RECIST revisited: A review of validation studies on tumour assessment.</a> Eur. J. Cancer. 42 (8), 1031-1039 (2006).</li><li>O'Connor, P. B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Quantitative+imaging+biomarkers+in+the+clinical+development+of+targeted+therapeutics:+current+and+future+perspectives.">Quantitative imaging biomarkers in the clinical development of targeted therapeutics: current and future perspectives.</a> Lancet Oncol. 9 (8), 766-776 (2008).</li><li>Lee, Y. C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Preclinical+multimodality+phantom+design+for+quality+assurance+of+tumor+size+measurement.">Preclinical multimodality phantom design for quality assurance of tumor size measurement.</a> BMC Med. Phys. 11 (1), (2011).</li><li>Lee, Y. C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=QA+procedures+for+multimodality+preclinical+tumor+drug+response+testing.">QA procedures for multimodality preclinical tumor drug response testing.</a> Med. Phys. 37 (9), 4806-4816 (2010).</li><li>Park, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Measuring+response+in+solid+tumors:+comparison+of+RECIST+and+WHO+response+criteria.">Measuring response in solid tumors: comparison of RECIST and WHO response criteria.</a> Jpn. J. Clin. Oncol. 33 (10), 533-537 (2003).</li><li>Eisenhauer, E. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=New+response+evaluation+criteria+in+solid+tumors:+revised+RECIST+guideline+(version+1.1).">New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1).</a> Eur. J. Cancer. 45 (2), 228-247 (2009).</li><li>D'Souza, W. D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Tissue+mimicking+materials+for+a+multi-imaging+modality+prostate+phantom.">Tissue mimicking materials for a multi-imaging modality prostate phantom.</a> Med. Phys. 28 (4), 688-700 (2001).</li><li>Mitchell, M. D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Agarose+as+a+tissue+equivalent+phantom+material+for+NMR+images.">Agarose as a tissue equivalent phantom material for NMR images.</a> Magn. Reson. Imaging. 4 (3), 263-266 (1986).</li></ol>

The goal of this article was to provide the methods for making TM materials for multimodality imaging and constructing a preclinical multimodality phantom as a QA tool for accurate tumor size measurement using different modalities in multiple institutions. As previously mentioned, TM materials were originally developed by Dr. Ernest L. Madsen's laboratory at the University of Wisconsin Madison for a multi-imaging modality prostate phantom. We modified Dr. Madsen's TM material protocols for our own purpose in order to hav...

Assessment of the change in tumor size is an important endpoint for evaluating the activity of anti-tumor drugs in both tumor shrinkage and disease progression 9, 10. World Health Organization (WHO) and Response Evaluation Criteria in Solid Tumors (RECIST) are the codified methods for the anatomic assessment of tumor lesions in imaging modalities such as ultrasound (US), computed tomography (CT) or magnetic resonance imaging (MRI). For WHO criteria, the product of tumor maximum diameter and its largest perpendicular diameter in the transverse plane for target regions is calculated 4. In contrast, for RECIST, the sum of longest diameters in the transverse plane for a limited number of target lesions is calculated 4. In spite of continuously growing interest in tumor therapeutic response assessment, there has been no preclinical quality assurance (QA) phantom/QA procedures for the imaging biomarker.
Considering that tumor size measurement based on WHO criteria and/or RECIST is the only imaging biomarker approved by the United States Food and Drug Administration (FDA), as a starting point of QA for any other imaging biomarkers, Lee et al. designed and constructed UTHSCSA/Gammex Mark 1 and Mark 2 phantoms for QA of tumor size measurement in collaboration with Gammex Inc 7. The Mark 1 phantom was a revised version of a Gammex commercial US phantom and thus, the size was too large to fit into animal CT and MR scanners. Also some tools in the Mark 1 phantom were unnecessary for tumor size measurement. The Mark 2 phantom was designed based on RECIST which is the most recent FDA-approved imaging biomarker. However, the size of the Mark 2 phantom was still too large for MR scanners, and CT and MR image quality of the phantom was not acceptable for accurate tumor size measurement 7.
The QA phantom described herein was re-designed to overcome shortcomings of the previous phantoms and constructed using modified tissue-mimicking (TM) materials and protocols developed in our lab. This paper describes the details of the protocols for phantom construction: First, methods are introduced for preparing the silicone molds needed for casting tumor-simulating test objects and for assembling a rotator for rotating a phantom to prevent gravitation sedimentation. Second, protocols for preparing TM materials modified from D'Souza et al.'s for US, CT and MR imaging are described 11. The physical properties of the TM materials were tested in each modality to ensure that the TM materials represented human soft tissues as observed in the images acquired with the various modalities, but the results are not displayed here. Third, the protocol for phantom construction is described. Lastly, US, CT and MR images of the phantom are presented as results.

<table border="1">
	<tbody>
		<tr>
			<td>Reagent/Material</td>
			<td>&nbsp;</td>
			<td>&nbsp;</td>
			<td>&nbsp;</td>
		</tr>
		<tr>
			<td>PVC pipe</td>
			<td>N/A</td>
			<td>N/A</td>
			<td>Home Depot</td>
		</tr>
		<tr>
			<td>Bolt, nut, washer and metal plates</td>
			<td>N/A</td>
			<td>N/A</td>
			<td>Home Depot</td>
		</tr>
		<tr>
			<td>Acrylic plates and rods</td>
			<td>N/A</td>
			<td>N/A</td>
			<td>Plastic supply in San Antonio, TX</td>
		</tr>
		<tr>
			<td>Steel balls</td>
			<td>Nordex, Inc.</td>
			<td>AEC-M2-2, -4, -7, -10 and -14</td>
			<td>2, 4, 7, 10 and 14 mm diameter</td>
		</tr>
		<tr>
			<td>C-clamps</td>
			<td>Adjustable Clamp</td>
			<td>1420-C</td>
			<td>2 inch length</td>
		</tr>
		<tr>
			<td>Masking tape</td>
			<td>3M Industrial Adhesives and Tapes</td>
			<td>2600</td>
			<td>&nbsp;</td>
		</tr>
		<tr>
			<td>Duct tape</td>
			<td>3M Industrial Adhesives and Tapes</td>
			<td>S-3763SIL</td>
			<td>&nbsp;</td>
		</tr>
		<tr>
			<td>J-B KWIK</td>
			<td>J-B WELD Co.</td>
			<td>380238</td>
			<td>&nbsp;</td>
		</tr>
		<tr>
			<td>3M Scotch-Weld Epoxy Adhesive</td>
			<td>3M Industrial Adhesives and Tapes</td>
			<td>DP-100</td>
			<td>&nbsp;</td>
		</tr>
		<tr>
			<td>Silicone grease</td>
			<td>Permatex, Inc.</td>
			<td>22058</td>
			<td>&nbsp;</td>
		</tr>
		<tr>
			<td>Silicone glue</td>
			<td>DAP, Inc.</td>
			<td>688</td>
			<td>&nbsp;</td>
		</tr>
		<tr>
			<td>Silicone rubber compound</td>
			<td>Smooth-ON, Inc.</td>
			<td>Smooth-SilTM950 Part A and B</td>
			<td>A:B mix ratio = 10:1 by weight</td>
		</tr>
		<tr>
			<td>Brush</td>
			<td>N/A</td>
			<td>N/A</td>
			<td>Hobby Lobby</td>
		</tr>
		<tr>
			<td>Syringe</td>
			<td>Becton Dickinson</td>
			<td>309604</td>
			<td>10 ml</td>
		</tr>
		<tr>
			<td>Needle</td>
			<td>Becton Dickinson</td>
			<td>305156</td>
			<td>22-gauge 1.5 inch length</td>
		</tr>
		<tr>
			<td>Funnel</td>
			<td>N/A</td>
			<td>N/A</td>
			<td>&nbsp;</td>
		</tr>
		<tr>
			<td>Mesh filters</td>
			<td>Small parts, Inc.</td>
			<td>CMN-0010-C and CMN-0020-C</td>
			<td>10 and 20 &mu;m</td>
		</tr>
		<tr>
			<td>Whole milk</td>
			<td>N/A</td>
			<td>N/A</td>
			<td>HEB in San Antonio, TX</td>
		</tr>
		<tr>
			<td>Thimerosal</td>
			<td>Sigma-Aldrich Co.</td>
			<td>T5125</td>
			<td>&nbsp;</td>
		</tr>
		<tr>
			<td>Propanol</td>
			<td>Sigma-Aldrich Co.</td>
			<td>33538</td>
			<td>&nbsp;</td>
		</tr>
		<tr>
			<td>EDTA</td>
			<td>Sigma-Aldrich Co.</td>
			<td>431788</td>
			<td>&nbsp;</td>
		</tr>
		<tr>
			<td>CuCl2</td>
			<td>Sigma-Aldrich Co.</td>
			<td>459097</td>
			<td>&nbsp;</td>
		</tr>
		<tr>
			<td>Agarose</td>
			<td>Sigma-Aldrich Co.</td>
			<td>A0169</td>
			<td>&nbsp;</td>
		</tr>
		<tr>
			<td>BaSO4</td>
			<td>Sigma-Aldrich Co.</td>
			<td>B8675</td>
			<td>&nbsp;</td>
		</tr>
		<tr>
			<td>Glass beads</td>
			<td>Potters Industries, Inc.</td>
			<td>3000E</td>
			<td>&nbsp;</td>
		</tr>
		<tr>
			<td>PET/AL/LLDPE*</td>
			<td>Pechiney Plastic Packaging, Inc.</td>
			<td>Pechiney Spec 151</td>
			<td>Phantom cover material</td>
		</tr>
		<tr>
			<td>&nbsp;</td>
			<td>&nbsp;</td>
			<td>&nbsp;</td>
			<td>*Polyethylene terephthalate/aluminum/linear low density polyethylene</td>
		</tr>
		<tr>
			<td>Equipment</td>
			<td>&nbsp;</td>
			<td>&nbsp;</td>
			<td>&nbsp;</td>
		</tr>
		<tr>
			<td>Rotisserie motor</td>
			<td>Brinkmann</td>
			<td>812-7103-S</td>
			<td>Home Depot</td>
		</tr>
		<tr>
			<td>Water bath 1</td>
			<td>Precision, Inc.</td>
			<td>Model: 282, Serial #: 601091552</td>
			<td>&nbsp;</td>
		</tr>
		<tr>
			<td>Water bath 2</td>
			<td>VWR, Inc.</td>
			<td>Model: 1212, Serial #: 08119606</td>
			<td>&nbsp;</td>
		</tr>
		<tr>
			<td>Ultrasound</td>
			<td>Visualsonics</td>
			<td>Serial #: 770/120-259</td>
			<td>&nbsp;</td>
		</tr>
		<tr>
			<td>CT</td>
			<td>Gamma Medica-Ideas</td>
			<td>Serial #: GR 0050</td>
			<td>&nbsp;</td>
		</tr>
		<tr>
			<td>MRI</td>
			<td>Bruker</td>
			<td>Part #: W3301390, Serial #: 0030</td>
			<td>&nbsp;</td>
		</tr>
	</tbody>
</table>

construction of a preclinical multimodality phantom using tissue-mimicking materials for quality assurance in tumor size measurement

World Health Organization (WHO) and the Response Evaluation Criteria in Solid Tumors (RECIST) working groups advocated standardized criteria for radiologic assessment of solid tumors in response to anti-tumor drug therapy in the 1980s and 1990s, respectively. WHO criteria measure solid tumors in two-dimensions, whereas RECIST measurements use only one-dimension which is considered to be more reproducible 1, 2, 3,4,5. These criteria have been widely used as the only imaging biomarker approved by the United States Food and Drug Administration (FDA) 6. In order to measure tumor response to anti-tumor drugs on images with accuracy, therefore, a robust quality assurance (QA) procedures and corresponding QA phantom are needed.
To address this need, the authors constructed a preclinical multimodality (for ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI)) phantom using tissue-mimicking (TM) materials based on the limited number of target lesions required by RECIST by revising a Gammex US commercial phantom 7. The Appendix in Lee et al. demonstrates the procedures of phantom fabrication 7. In this article, all protocols are introduced in a step-by-step fashion beginning with procedures for preparing the silicone molds for casting tumor-simulating test objects in the phantom, followed by preparation of TM materials for multimodality imaging, and finally construction of the preclinical multimodality QA phantom. The primary purpose of this paper is to provide the protocols to allow anyone interested in independently constructing a phantom for their own projects. QA procedures for tumor size measurement, and RECIST, WHO and volume measurement results of test objects made at multiple institutions using this QA phantom are shown in detail in Lee et al. 8.

Figure 3B and Figure 5 show two silicone molds for casting test objects, and the multimodality phantom, respectively. The length &times; width &times; depth of each mold is 109 mm &times; 37 mm &times; 21 mm and two molds are identical mirror-images. One mold has 1 mm holes where TM material can be inserted using a thin needle. Each mold has an additional five holes for alignment rods. The length &times; width &times; depth of the phantom is 115 mm &times; 38 mm &times; 24 mm and its ini...

Watch this Scientific Journal Video about Construction of a Preclinical Multimodality Phantom Using Tissue-mimicking Materials for Quality Assurance in Tumor Size Measurement at JoVE.com

Construction of a Preclinical Multimodality Phantom Using Tissue-mimicking Materials for Quality Assurance in Tumor Size Measurement

This paper describes in-house procedures of constructing a preclinical multimodality phantom made of tissue-mimicking (TM) materials for quality assurance (QA) of tumor size measurement in animal imaging modalities such as ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI).

World Health Organization (WHO) and the Response Evaluation Criteria in Solid Tumors (RECIST) working groups advocated standardized criteria for ...

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