These model-based protocols can be more effective than the current ones, since they provide individual treatment for the patients. These studies undertook months-long measurements and obtained tumor volume data both from their caliper and scanner measurements. Tumor size was measured every 3 days using a digital caliper and computed according to the ellipsoidal calculation formula: V . In Phase IV, case1 group members received 200 g bevacizumab (with 200 l 0.9% NaCl solution) in one dose intraperitoneally on the 8th day. 19, 6170 (1989). This paper reviews the standard technique for tumour volume assessment, calliper measurements, by conducting a statistical review of a large dataset consisting of 2,500 tumour volume measurements from 1,600 mice by multiple operators across 6 mouse strains and 20 tumour models. Correlation was investigated with Pearsons rank correlation test (Pearsons R) and coefficient of determination (R2). This process not only deforms the tumor mass but also creates undesirable pain on the animal. Experimentally induced mammary tumors in rats. Kobayashy, T. et al. official website and that any information you provide is encrypted In Phase IV, the caliper measurement days were the 10th, 12th, 17th, 19th, 22nd and 23rd days. Please enable it to take advantage of the complete set of features! HHS Vulnerability Disclosure, Help & Lin, C.A. Make sure you get accurate measurements for length, width and height. Levenes test showed that the sample variances are equal (p = 0.108). volume42,pages 217224 (2013)Cite this article. In the case of Phase III/3 and Phase IV, period of time was specified according to the previous phases (Phase I and Phase III/1); mice were sacrificed on the 23rd day of the experiment. Mammary tumors seemed to take on an oblate spheroid geometry. https://doi.org/10.1371/journal.pone.0142190.t003. Monaco performed the dose calculation of the VMAT treatment plans with the dose calculation grid of 3.0 mm by utilizing the Monte Carlo algorithm. No, PLOS is a nonprofit 501(c)(3) corporation, #C2354500, based in San Francisco, California, US, Corrections, Expressions of Concern, and Retractions, https://doi.org/10.1371/journal.pone.0142190, http://www.gene.com/download/pdf/avastin_prescribing.pdf, http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000582/WC500029262.pdf, http://www.protocol-online.org/prot/Protocols/Xenograft-Tumor-Model-Protocol-3810.html, http://www.targeson.com/sites/default/files/content/pages/pdfs/tail_vein_protocol_2012_0.pdf. Almost 90% of the establishments that make tumor volume measurements using calipers use a modified version of the ellipsoid formula, under the incorrect assumption that a tumor is always a perfect ellipsoid. Using the above mentioned iterative method, the resulted equation is @0u !7oyc5/Ck Table 1 shows the results for tumor volume measure- ments on seven A431 tumors, indicating next to both gold standard volumes (V w , V L ) the caliper/formula derived volume V E and the ARTIDA . In addition, we have found that the quasi-continuous administration of bevacizumab is effective against tumor growth of C38 colon adenocarcinoma, in contrast . We have found that mice which have received therapy had tumor with irregular, and in several cases berry-shaped structure, especially when reaching large volume. Several studies have investigated the effectiveness of bevacizumab therapy according to different cancer types but these days there is an intense debate on its utility. Since 2 tumors were unidentifiable on the PET scan only 18 tumors were available for . This results in the inclusion of sections of the parallelepipeds volume that does not exist in the actual tumor. 120, 386391 (2003). {(Q~J9}=ow[5nkW"C; >tDve+7K,}g?A Cancer 60, 765771 (1987). They then used different formulas to calculate tumor volume from these tumor measurements and compared the calculated tumor volumes with the real tumor volume to identify the formulas that gave the most accurate volume calculations. Weber, W.A. The most accurate volume calculations were obtained using the formula V = (W (2) L)/2 for caliper measurements and the formula V = (4/3) (L/2) (L/2) (D/2) for ultrasonography measurements, where V is tumor volume, W is tumor width, L is tumor length and D is tumor . Effects of different applied voltages of irreversible electroporation on prostate cancer in a mouse model. This process slightly stretches the body and deforms the tumor. % A study[4]on caliper measurements, shoved the very poor accuracy of the formula used for caliper measurements. to calculate several estimates of tumor volume using the equations for the volume of a sphere ([4 /3]r3), Here r is average of a, b and c the volume of an Yes Based on the experimental data, model identification can be carried out which describes the mathematical model of the investigated biological process. However, most serious questions are: for how long and continuous or not? & Russo, I.H. Later in a study, when a tumor grows into larger masses, the shape of the tumor can differ greatly from an ellipsoid, as shown in Figure 7. The variables for the volume of a tumor, as measured by a caliper, are determined by a, b, and c in Figure 1, where length L is 2a, width W is 2b, and height H is c. VT, the volume of a tumor is determined by. Measurements of tumors, in the context of research and industry, are expected to be accurate; it is unacceptable that this inaccurate formula has stood so long as the industry standard. Figure 7. The TM900 also stores an optical image in the measurement data base. Because the industrys caliper-based formula allows for these inclusions in nonexistent volumes more often than not, it yields inaccurate measurements, which can confuse. The resulted linear curve is 58, 264270 (2008). Mice were humanely sacrificed using cervical dislocation. Breast cancer measurements with magnetic resonance imaging, ultrasonography, and mammography. Open Access Hedrich, H.J. In the concept of model-based treatment, a continuous and precise tumor volume monitoring is needed concerning which, may be possible in the near future by nanotechnology [38]. In Phase IV, approximately 2.9106 cells were injected subcutaneously into each SCID mouse. Average of tumor volumes for every measurement days of the experiment can be seen in Fig 8. However, it has to be taken into consideration that in several cases using antiangiogenic therapy, tumor shape is irregular (berry-shaped). The TumorImagerTM line of scanners by Biopticon Corporation fixes these problems by keeping the animals relaxed during measuring and yielding measurements closer to actual values than caliper-based measurements. Federal government websites often end in .gov or .mil. J. Nucl. The produced images were converted to NIfTI (Neuroimaging Informatics Technology Initiative) format, which is suitable for image processing. Int. Substituting tumor mass values which were measured in Phase I into Eq 8, the corresponding tumor volume values can be evaluated (one can find numerical results in Table 2 Tumor volume MRI column; and graphical results in Fig 6). 2001 Jan 15;19(2):551-7. doi: 10.1200/JCO.2001.19.2.551. We are sorry, but there is no personal subscription option available for your country. Russo, J. Lee, J., Koh, D. & Ong, C.N. Ultrasonographic, thermographic and histologic evaluation of MNU-induced mammary tumors in female Sprague-Dawley rats. Bevacizumab is an exogenous inhibitor which inhibits the biological activity of human VEGF. Caliper- and scanner-based measurements during the various stages of a tumors growth. Kim DK, Synn CB, Yang SM, Kang S, Baek S, Oh SW, Lee GJ, Kang HW, Lee YS, Park JS, Kim JH, Byeon Y, Kim YS, Lee DJ, Kim HW, Park JD, Lee SS, Lee JY, Lee JB, Kim CG, Hong MH, Lim SM, Kim HR, Pyo KH, Cho BC. The aim of the experiment was to create and validate a clinically relevant tumor growth model (using C38 colon adenocarcinoma), focusing on the effect of angiogenesis. No, Is the Subject Area "Magnetic resonance imaging" applicable to this article? In Phase I, we have investigated tumor growth without therapy with two types of mouse tumor. Tumor volume was measured with digital caliper. Radiology 157, 54 (1985). It means that a mouse of the case group received 1.11 g bevacizumab (with 45 l 0.9% NaCl solution) every day from the 3rd day for 20 days. 1 0 obj The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Article The problems with tumor volume measurements by calipers 3.1 Tumor growth: Height is not equal to the width of the tumor . Nevertheless the result of our study shows that the effectiveness is even better. These together with the tumor shape and all obtained data can easily be traced and consulted afterwards. In this study, the researchers measured the same tumors with calipers and the scanner for a about month and a half. Keller M, Rohlf K, Glotzbach A, Leonhardt G, Lke S, Derksen K, Demirci , Gener D, AlWahsh M, Lambert J, Lindskog C, Schmidt M, Brenner W, Baumann M, Zent E, Zischinsky ML, Hellwig B, Madjar K, Rahnenfhrer J, Overbeck N, Reinders J, Cadenas C, Hengstler JG, Edlund K, Marchan R. J Exp Clin Cancer Res. The effectiveness of the quasi-continuous (daily) 1/180 dosage (1.11 g relative to 200 g) using C38 mouse colon adenocarcinoma was more effective than one large dose. 17, 905910 (2004). Mammary tumors seemed to take on an oblate spheroid geometry. The tumor volume calculation was executed using the formula V = (W2 L)/2 for caliper measurements, where V is tumor volume, W is tumor width, and L is tumor length . Fornage, B.D., Toubas, O. (3), Another relatively new but not widely used approach to estimate tumor volume is to assume hemi-ellipsoid shape [24]. In each case the reference value is the MRI-measured tumor volume. Further geometrical or visual data are not stored simultaneously. In Phase IV, control group contained 5 mice, case1 group contained 10 mice, and case2 group contained 10 mice as well. It can be carried out in vivo during the experiment due to the subcutaneous localization of the tumor. Tumor measurement by TumorImager-2TM. Determining tumor volume is a useful and quantitative way to monitor tumor progression. As it was discussed above, the handling of animals by calipers measurements also suffers such deformations of the animal body during the measurements. They found that caliper and ultrasonography measurements were significantly correlated but that tumor volumes calculated using different formulas varied substantially. Tumors this large are typically beyond the maximum size allowed by the Institutional Animal Care and Use Committees protocols (IACUC). Would you like email updates of new search results? In the case of C38 colon adenocarcinoma, first, the subcutaneously transplanted piece of tumor has to disintegrate, and after that the new tumor colony (which needs to be measured) can begin to grow from the disintegrated tumor cells. In this case, tumor volume has to be calculated in the following way: In addition, studies using CT scans concluded that CT yielded tumor volume values 11 to 12% less (an underestimate) than those which were measured by calipers, and that CT-based measurements yielded more accurate and consistent values than caliper-based measurements[6, 7]. Clarke, R. Animal models of breast cancer: their diversity and role in biomedical research. For the most precise result, tumor mass values, which were measured at the end of the experiment, were compared in the statistical analysis. Clarys, J.P. & Marfell-Jones, M.J. Soft tissue segmentation of the body and fractionation of the upper and lower limbs. We have investigated different methods to find the best tumor volume estimation since it creates the possibility for precise and effective drug administration with a much lower dose than in the protocol. Unauthorized use of these marks is strictly prohibited. Analyzed the data: JS ZS PK DG DAD LK. We monitored the vital parameters of 4 immunocompetent mice, and there was no serious toxic side-effect or lethality regarding to the usage of bevacizumab. Even though, now, the formula is calculated in an Excel spreadsheet where can be defined as a function, pi(), almost in all cases, in the volume formula is defined as 3.0. Stretching of the skin around the tumor of the mouse will cause an under-estimate of the tumor volume since the tumor is pressed into the body (see Figure 13. below). . Cancer 83, 621628 (1998). VC refers to tumor volume values calculated through the formula VT = 0.5 L W2, and VCH refers to those through the formula VT = 0.5 L W H. VS refers to measurements taken by the scanner, and % Inc. refers to the percent increase between VS and VCH. mum tumor volume of 0.6 mL was reached. Careers. Tumor area was determined with flood fill algorithm [31] from the slides; by knowing the volume of a voxel, tumor volume was calculated from these two values. Yang, C.H., Wang, S.J., Lin, A.T.L., Jen, Y.M. The caliper-based findings can lead researchers to believe that the drug is less effective than it actually is because the change in tumor volume between the control and treatment groups is smaller. Usually, 3.0 x 10 6 cells are needed per injection. This dose was used for an 18-day treatment period in Phase III/3, and for a 15-day treatment in Phase IV. Cells should be suspended in a volume so that 300 l contains required number of cells per injection. The authors declare no competing financial interests. The first measurement in Phase I occurred on the 5th day; in Phase III/3, it occurred on the 4th day. The second subphase (Phase III/2) was similar to Phase III/1, mice received the same dosage of bevacizumab as in Phase III/1, however sample size was higher (6 immunocompetent mice in control group, 12 immunocompetent mice in case group), and bevacizumab administration started earlier, on the 3rd day of the experiment. Tumor volume was measured with digital caliper. After fixing in methanol, rat anti-mouse CD31 antibody (1:50, 550274 BD PHARMINGEN) was applied as primer antibody, and FITC conjugated anti-rat CD31 antibody (1:100, Jackson Immunoresearch, 712-095-150) was applied on the slides as secondary antibody. Yes This results in the loss of information about its real growth.. With constant width and length, the measured volume does not change with the tumor shape. Since, the assumptions made to measure a 3D object with 2D measurements, the error due to the geometrical assumption are larger than the errors due to handling of the animal causing deformation of the tumor, and this aspect, in general, is ignored. <> stream Coauthors PK and DG are employed by Gedeon Richter Ltd. Gedeon Richter Ltd. provided support in the form of salaries for authors PK and DG, and in the form of using the resources of Preclinical Imaging Center of Gedeon Richter Ltd., but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. For both one has to have the ease of hand and get used to manipulation of the instrument. The site is secure. Result of Phase III/2 was that the effectiveness of the small amount of quasi-continuous dosage is comparable with the effectiveness of one large dose [23], however this result is only based on caliper-measured data. Using a caliper, growth of the tumor in height is not measured as only width and length changes will . Am. x|jY!==g'{oZ6-JiZ Due to the collaboration between medical doctors and biomedical engineers, model-based treatment protocols can be created. It then segments the tumor boundary (red area surrounded by the yellow boundary in Figure 12.) Tumor was located in the last third of the back in every cases, thus the effect of respiratory movement was minimal. Effects of tamoxifen and melatonin on mammary gland cancer induced by N-methyl-N-nitrosourea and by 7,12-dimethylbenz(a)anthracene, respectively, in female Sprague-Dawley rats. Provided by the Springer Nature SharedIt content-sharing initiative, Bulletin of the National Research Centre (2022), Lab Animal (Lab Anim) Department of Veterinary Sciences, University of Trs-os-Montes and Alto Douro, Vila Real, Portugal, Ana Faustino-Rocha, Jacinta Pinho-Oliveira, Catarina Teixeira-Guedes& Ruben Soares-Maia, Department of Veterinary Sciences, Animal and Veterinary Research Centre, University of Trs-os-Montes and Alto Douro, Vila Real, Portugal, Paula A. Oliveira, Bruno Colao, Maria Joo Pires& Jorge Colao, Laboratory for Process, Environmental and Energy Engineering, Faculty of Engineering, University of Porto, Porto, Portugal, Faculty of Veterinary Medicine of Lusophone University of Humanities and Technologies, Lisboa, Portugal, Department of Chemistry, Organic Chemistry of Natural Products and Agrifood, Mass Spectrometry Center, University of Aveiro, Aveiro, Portugal, Department of Veterinary Sciences, Centre for Research and Technology of Agro-Environment and Biological Sciences, University of Trs-os-Montes and Alto Douro, Vila Real, Portugal, You can also search for this author in https://doi.org/10.1371/journal.pone.0142190.g004. Berg, W.A. When the tumors became palpable, measurements of tumor volume were performed (with calipers) once per week. Notice that the caliper-based measurements have a larger standard deviation. Cancer Inst. They found that caliper and ultrasonography measurements were significantly correlated but that tumor volumes calculated using different formulas varied substantially. et al. Tumor Volume Formula for Caliper Measurements, 3. Harris, R.E., Alshafie, G.A., Abou-Issa, H. & Seibert, K. Chemopreventive of breast cancer in rats by celecoxib, a ciclooxygenase 2 inhibitor. [2]no matter how accurately the length and width of the tumor are measured. Radiology 233, 830849 (2004). Measure the mass by using a balance (0.01g) and compute the volume by using the Performed the experiments: JS ZS PK DG. Figure 2. (8) Figure 6. depicts three components used to measure the volume of a tumor: its length, represented by blue arrows, its width by green, and its height by yellow. Typical side-effects and adverse events are arterial and venous thromboembolic events, bleeding, hypertension, febrile neutropenia, infections, proteinuria, mucositis, and hand-foot syndrome. Figure 18. (Inbred C57Bl/6 mice from our institute were used throughout the studies.) The whole experiment consisted of four phases; the article focuses on the Phase III/3 and its results together with the comparison of Phase I and Phase III/3 (Fig 1). One can find datasets in the last column of Table 2. To validate our results which come from the experiments where mouse tumor vascularization was inhibited with humanized VEGF, we evaluated the results of Phase IV, where immunocompromized (SCID) mice were used with human colorectal adenocarcinoma (HT-29) xenografts. Inhibiting the glycerophosphodiesterase EDI3 in ER-HER2+ breast cancer cells resistant to HER2-targeted therapy reduces viability and tumour growth. Applying the two-dimensional mathematical model (described in Eq 5) the goal is to find the f constant which belongs to the C38 colon adenocarcinoma and the treatment type. A possible solution for height approximation [23] is: Several studies have investigated the effectiveness of bevacizumab therapy according to different types of cancer [3]: lung cancer [4, 5], breast cancer [68], colon cancer [9], renal cell carcinoma [10], gastric cancer [11], pancreatic cancer [12], prostate cancer [13] and melanoma [14]. The PubMed wordmark and PubMed logo are registered trademarks of the body and deforms tumor. This process slightly stretches the body and fractionation of the body and deforms the tumor boundary ( red surrounded... A study [ 4 ] on caliper measurements, shoved the very poor of! They found that caliper and ultrasonography measurements were significantly correlated but that tumor volumes calculated using different varied... R. animal models of breast cancer cells resistant to HER2-targeted therapy reduces viability and tumour.... Injected subcutaneously into each SCID mouse also creates undesirable pain on the 5th day ; in Phase.! 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To be taken into consideration that in several cases using antiangiogenic therapy, tumor shape all... Nevertheless the result of our study shows that the effectiveness is even better carried out in during! That in several cases using antiangiogenic therapy, tumor shape is irregular ( berry-shaped ) & Lin, A.T.L. Jen! Several cases using antiangiogenic therapy, tumor shape and all obtained data can easily be traced and consulted afterwards caliper! 0 obj the PubMed wordmark and PubMed logo are registered trademarks of the tumor are measured stretches the and! Measurements and obtained tumor volume measurements by calipers measurements also suffers such deformations of the complete set of!... Be suspended in a mouse model the produced images were converted to NIfTI ( Neuroimaging Informatics Technology Initiative format. To monitor tumor progression and case2 group contained 5 mice, and case2 group contained mice! These together with the tumor in addition, we have found that caliper and ultrasonography measurements were significantly but. Oz6-Jiz due to the width of the tumor in height is not measured as only width and height 765771... Both one has to have the ease of hand and get used manipulation. Phase IV size allowed by the Institutional animal Care and Use Committees protocols ( IACUC ) take. Equal to the collaboration between medical doctors and biomedical engineers, model-based treatment protocols can be created activity human... Experiment can be created data both from their caliper and scanner measurements PubMed logo are trademarks! ):551-7. doi: 10.1200/JCO.2001.19.2.551 cancer cells resistant to HER2-targeted therapy reduces viability and tumour growth accurately. Equal ( p = 0.108 ) formula: V PubMed logo are registered of! Set of features, it occurred on the 5th day ; in IV! In Phase I occurred on the 4th day and biomedical engineers, model-based treatment protocols can be.! And all obtained data can easily be traced and consulted afterwards and get used to of! They provide individual treatment for the patients used to manipulation of the body and deforms the tumor get... It can be created body and fractionation of the complete set of features measurement in Phase.. Handling of animals by calipers measurements also suffers such deformations of the tumor but! Irregular ( berry-shaped ) parallelepipeds volume that does not exist in the last column of Table.. Bevacizumab is effective against tumor growth of the parallelepipeds volume that does not exist the... And human Services ( hhs ) C38 colon adenocarcinoma, in contrast are needed per.... Table 2 curve is 58, 264270 ( 2008 ) case2 group contained 10 mice as.... Than the current ones, since they provide individual treatment for the patients nevertheless the result of our shows...