For more information about PLOS Subject Areas, click For various tumors in mice, only one can be approximated in volume by an ellipsoid. In the first subphase (Phase III/1), control group members (5 immunocompetent mice) received 10 mg per kg body weight bevacizumab, while case group members (5 immunocompetent mice) received one-tenth dose of control dose spread over 18 days. () and were used with the parameters displayed in Table 1Parameters for Gompertz growth were taken from Benzekry et al. 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). Using an extremely low dosage (as in our study), there is a high probability that these adverse effects can be minimized. Epub 2013 Jul 11. 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]. Figure 14. here. 2001 Jan 15;19(2):551-7. doi: 10.1200/JCO.2001.19.2.551. Eichelerger, L.E. Importantly, these measured size differences are real; they are not due to a miscalculation by the algorithm but due to the pressing of the tumor mass into the body. PLoS ONE 10(11): & Deshayes, J.L. Mice in Phase III/3 control and case groups, and mice in Phase IV case1 and case2 groups received bevacizumab. eCollection 2022. van Elsland DM, Duijster JW, Zhang J, Stvenin V, Zhang Y, Zha L, Xia Y, Franz E, Sun J, Mughini-Gras L, Neefjes J. Tumor volumes are calculated from digital caliper raw data by using the formula:Volume (mm3) = (l x w2) / 2. Considering the possibility of precise tumor volume determination and the effective quasi-continuous drug administration, it opens a new treatment choice based on closed-loop control. 22, 921929 (2003). A solution to these problems is the TumorImagerTM scanner. The first column shows the tumor values which were calculated using the two-dimensional mathematical model; the second column represents the protocol-based tumor volumes. Influence of breast cancer histology on the relationship between ultrasound and pathology tumor size measurements. Cancer 83, 621628 (1998). Since the real geometric object assumed to represent the tumor is a parallelepiped (rather than an ellipsoid), the flat bottom surface of it will leave a larger section of the tumor below than the interpolated surface following the body contour of the animal as seen in Figure 10, below. With a caliper measurement, the angle at which the tool is held over the tumor will affect the obtained value, thus inducing an extra operator and manipulation sensitivity in the final results. In order to estimate tumor volume by external caliper, the greatest longitudinal diameter (length) and the greatest transverse diameter (width) were determined while mice were scruffed and conscious. 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. 55, 74108 (2005). 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 . In Phase III/3, MRI-measured tumor volume values are available which can be used as reference values for caliper-measured data. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. The defined shape of an actual tumor (red) and the shape measured by a caliper (blue box). Compute the volume assuming perfect ellipsoids. 8600 Rockville Pike This results in the inclusion of sections of the parallelepipeds volume that does not exist in the actual tumor. J. Ultrasound Med. Quantity of the optimal solvent administration was also examined in this subphase. This can happen if the mouse is pressed into the mask or if the body is stretched when held. Role of real-time sonography in assessment of breast diseases: a review of 200 cases (Abstr). https://doi.org/10.1371/journal.pone.0142190.g006. This site needs JavaScript to work properly. Secondly, the aspect of side-effects are not inconsiderable. 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]. Autopsy revealed only minimal local tumor; however death was not caused by tumor. Ultrasonographic, thermographic and histologic evaluation of MNU-induced mammary tumors in female Sprague-Dawley rats. The volume calculation algorithm relies on the surface interpolated based on the surrounding healthy tissue. Effects of different applied voltages of irreversible electroporation on prostate cancer in a mouse model. Competing interests: The authors have the following interests: Coauthors PK and DG are employed by Gedeon Richter Ltd. Avastin (bevacizumab) is manufactured by Genentech, Inc., South San Francisco, California, USA; EU patent expiry in 2019 in the US and 2022 in EU. In each case the reference value is the MRI-measured tumor volume. A two-dimensional mathematical model was created from the experimental results of BALB/c mice with KHJJ tumor line [25]: Measured data is the MRI-measured tumor volumetumor mass pairs on the 23rd day of Phase III/3 (case and control group). The technique of using calipers to measure the volume of a tumor has problems associated with both the instrument itself and the methods used in calculating volume[1]. J. Nucl. Fj^P;7? Imaging 16, 816 (2008). and JavaScript. By using a caliper, one will measure width and length of the tumor and then calculate the volume using a standard formula, such as /6 x W x W x L or 1/2 x W x W x L thus assuming a standard and constant shape of the tumor. In the case2 group, one mouse died on the 8th day, before the therapy (bevacizumab administration) started. In Phase IV, approximately 2.9106 cells were injected subcutaneously into each SCID mouse. https://doi.org/10.1038/laban.254. Position of the mouse was fixed to minimize the movement of the animal. Bousquet, P.F. {(Q~J9}=ow[5nkW"C; >tDve+7K,}g?A Girit, I.C., Jure-Kunkel, M. & McIntyre, K.W. These images also provide extra morphological information about the tumor growth and the effect of the compounds on tumor behavior. 16 (2008). Pathology of tumours in laboratory animals. Can the Kuznetsov Model Replicate and Predict Cancer Growth in Humans? N-nitrosomethylurea as mammary gland carcinogen in rats. Care should be taken not to stretch the mouse whether using one or two hands to hold the mouse during a scan. Bevacizumab (Avastin) [1] is an exogenous inhibitor, which inhibits the biological activity of human VEGF [2]. Open Access Clinical criteria that establish when the endpoint have to be carried out: a) if tumors contributed to a gain of >20% in body weight compared to controls at the same time point; b) tumors that ulcerate, become necrotic or infected; c) any animal found unexpectedly to be moribund, cachectic, or unable to obtain food or water. When tumor cells become able to produce proangiogenic factors (the process is called as angiogenic switch), it will result in abnormal and inefficient vascular network (with high vascular permeability and poor perfusion) due to the hurried process of vessel formation. . Denis, F., Paon, L. & Tranquart, F. Radiosensitivity of rat mammary tumors correlates with early vessel changes assessed by Power Doppler sonography. 105, 2023 (1983). Examination of tumor growth belongs not only to the basic medical research, but to the biomedical engineering field as well. . (1). The lines on the graphs have a slope of 1, signifying that it represents caliper-based measurements in which height equals width. Article Hoffman-Goetz, L. et al. The cells are forced to grow laterally because of the surface tension of the skin above, and the flesh below, which therefore expand the width of the tumor length and widthwise rather than along its height. https://doi.org/10.1371/journal.pone.0142190.g005, https://doi.org/10.1371/journal.pone.0142190.t002, To find the f constant for tumor growth without therapy (Phase I), first reliable tumor volume values had to be found, since there was no MRI measurement in Phase I. Beside tumor diameters, tumor mass was measured and vascularization area was calculated in the case of the removed tumors. Figure 18. shows the results of an experiment in which mice were given different doses of a drug and their tumors were measured both with a caliper or TumorImager scanner. Am. Yes For the most precise result, tumor mass values, which were measured at the end of the experiment, were compared in the statistical analysis. Provided by the Springer Nature SharedIt content-sharing initiative, Bulletin of the National Research Centre (2022), Lab Animal (Lab Anim) Lab Anim 42, 217224 (2013). 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. Weber, W.A. A tumor image, its 3D shape and all geometrical data are automatically calculated and stored. The volume above the red area is not occupied by the tumor, as seen in Figure 8. Forbes, D., Blom, H., Kostomitsopoulos, N., Moore, G. & Perretta, G. Euroguide: On the Accommodation and Care of Animals Used for Experimental and Other Scientific Purposes (Federation of European Laboratory Animal Science Associations, London, 2007). Contrast agents improve the visibility, but it is an extra strain to the organism, which can be lethal to animals which are in the final stage of cancer. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). broad scope, and wide readership a perfect fit for your research every time. 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. produced by the TumorImager-2TM so that the animal is aligned under the mask each time similarly to the previous scan. J Clin Oncol. 2 0 obj Using a caliper, growth of the tumor in height is not measured as only width and length changes will . The means of the samples are mpIV_control = 0.65, mpIV_case1 = 0.70, mpIV_case2 = 0.46. Unable to load your collection due to an error, Unable to load your delegates due to an error. & Weaver, D.L. No, Is the Subject Area "Cancer treatment" applicable to this article? The width of a fully formed tumor will be much larger than its height. Tumor volume (and the third diameter) has to be approximated, assuming a certain shape for the tumor. First is to find an appropriate mathematical model for tumor volume evaluation from caliper-measured data. Significance of rat mammary tumors for human risk assessment. Figure 5. Cancer Res. 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 In clinical practice, the determination of the tumor size (volume) is done by MRI and/or CT, but this is for the purpose of validating the effectiveness of the treatment, and therefore it is not a continuous monitoring. 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 CAS It then segments the tumor boundary (red area surrounded by the yellow boundary in Figure 12.) Mice were humanely sacrificed using cervical dislocation. 37, 331337 (2011). Sci. PubMedGoogle Scholar. Tumor as a 3-D object has three diameters (width, length and height); however in vivo only two diameters can be measured by caliper (width, w and length, l). Comp. @L Pk5*Gj@>Sk%SLL4w^c{j[hP(/h8HP_ @Ch( Get the most important science stories of the day, free in your inbox. During the scan, a mouse should be held in a relaxed manner without stretching its skin to cause unwanted deformation of the tumor body. Unmeasured part of the tumor for caliper, Figure 11. In one trial, 208 tumors were measured, and 98.94% of those tumors exhibited much smaller heights than widths. Cancer 60, 765771 (1987). P`e+"JF^ : 4:p7]k
=
Jy}! Diagnostic accuracy of mammography, clinical examination, US, and MR imaging in preoperative assessment of breast cancer. For ultrasonography measurements, we calculated tumor volume . Thus, caliper-based measurements are less accurate the more the height of the stack deviates from its width. Based on the experimental data, model identification can be carried out which describes the mathematical model of the investigated biological process. Linear regression analysis to identify an equation that can be used to calculate tumor depth from tumor length as measured by caliper. Current standard technique for volume determination of subcutaneously xenografted tumors in vivo is by external caliper where tumor volume is calculated by use of the modified ellipsoid formula 1/2(Length Width 2)[1,2]. Each dot, in addition to signifying a real-life tumors width and height, also signifies through the right y-axis what percentage of a caliper-based measurement with the same width it is. In addition, even though there is about a 20% difference between the low-dose treatment group for the scanner measurements, the caliper-based measurements do not show any effect for this dose. 2. Isofluorane (0.95 x 2.0%) was applied for inhalational anesthesia, and intubation was performed. Med. government site.
This problem can be explained by our observation, namely tumors which were grown without therapy have more symmetric and solid closed shape, in contrast to tumors which were grown under antiangiogenic therapy. tumor height has to be approximated. Substituting tumor mass values which were measured on the 24th day of Phase I to the equation of the resulted curve, the corresponding tumor volume values can be evaluated (evaluated data). Traditionally their volume growth has been monitored by using a mechanical caliper. We have found that there is significant difference between the means of the samples (p = 0.002, using 0.05 level of significance). A survey of recent literature revealed the use of 19 different formulas for determining the size of subcutaneous tumors grown as xenografts in nude mice (2 for determining tumor area, 3 for tumor diameter, and 14 for calculating tumor volume). Sport. J. Natl. Similar to the results from the experiments in Figure 18., this error makes the drug seem less effective than it actually is. 39, 720 (1996).
Tumor volume determined by microCT, 18 F-FDG-PET and external caliper Tumor volume measured by microCT, PET and caliper all correlated (P < 0.001) with reference volume (figure 1).MicroCT versus reference volume (n = 20) had the best fit of line y = 1.01 0.04x - 6.1 6.3 (R 2 = 0.97; p < 0.001). Due to the collaboration between medical doctors and biomedical engineers, model-based treatment protocols can be created. 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. It means that knowing the tumor mass, tumor volume can be estimated with suitable accuracy; hence the lack of MRI measurement can be replaced in the case of Phase I. Consequently, when tumor mass data is unavailable (during the experiment), tumor volume value can be validated with MRI; in that way outlier data points (which were calculated using the two-dimensional mathematical model) can be filtered out. Mice were monitored daily. Similarly, we may have the possibility to a) measure the tumor volume using nanotechnology, b) create a pump for drug administration and c) design control algorithms for specific tumor types. A tumor tends to be flat early into its growth, and later as time advances, the treatment groups tumors may shrink especially in height if the compound of interest is effective. (9). In addition, calipers also place undue strain on the animal during measurement, assume conditions for a perfect ellipsoid (which most tumors are not), and can lead to unnecessary losses of money over time. Evaluated the accuracy of common four formulas given in the literature to estimate xenograft tumor volumes based on manual caliper measurements and proposed formula (0,45 L*W*H) could estimate tumor volumes as good as prolate ellipsoid formula. Bevacizumab is an exogenous inhibitor which inhibits the biological activity of human VEGF. 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. This process takes 45 days. One can find datasets in the last column of Table 2. J. Oncol. Different operators have different ways of holding the animal and tumor while performing the measurement. In the first four measurement times 30 slices were done from each mouse; in the last two measurement times 40 slices were done from each mouse due to the larger tumor volume. Open Access Faustino-Rocha AI, Gama A, Oliveira PA, Alvarado A, Fidalgo-Gonalves L, Ferreira R, Ginja M. Faustino-Rocha AI, Silva A, Gabriel J, Teixeira-Guedes CI, Lopes C, Gil da Costa R, Gama A, Ferreira R, Oliveira PA, Ginja M. Biomed Pharmacother. 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. The mathematical relationship between MRI-measured tumor volume and mass was investigated to estimate accurate tumor volume using caliper-measured data. We found the same result for human colorectal adenocarcinoma (HT-29) xenografts. According to angiogenic inhibitor administration, our hypothesis was that the effectiveness of a lower dosage with a quasi-continuous therapy can be comparable with the protocol therapy. Using the mathematical model, different dosage algorithms can be designed for antiangiogenic cancer therapy [1619]. No, Is the Subject Area "Mouse models" applicable to this article? Tumors were cut into two pieces for sample processing: one piece was stored in formalin, and the other piece was frozen using liquid nitrogen. According to the Xenograft tumor model protocol [20], tumor volume has to be calculated using the following formula: In this study, researchers used paclitaxel, a well-known anti-cancer drug since its reaction to cancerous tumors is traceable to assess the results of the scanner measurements. Comparison of clinical assessment, mammography and ultrasound in pre-operative estimation of primary breast-cancer size: a practical approach. This device measures the volume displacement of the water due to any object dipped into a measuring cylinder. Calipers are invasive; they create undue stress on the animal through the awkward handling of the mouse by one hand during the measuring process. The overestimation of caliper measurements is due mainly to the fact that the formula used is that of a parallelepiped, a shape unlike an ellipsoid actually represents the geometric body that is being measured. Treat. Clarys, J.P. & Marfell-Jones, M.J. Soft tissue segmentation of the body and fractionation of the upper and lower limbs. In a 2001 study utilizing MRI, it was concluded that 85% of tumors needed a measurement other than length and the width to yield an accurate volume[5]; caliper-based values do not provide this other measurement. This is a preview of subscription content, access via your institution. Homogeneity of variance was examined with Levenes test; the sample variances are equal (p = 0.052). It can be carried out in vivo during the experiment due to the subcutaneous localization of the tumor. In order to assess the accuracy of tumor measurements by the scanner, we measured the volume of many tumors with a caliper (VC) and with the scanner (VS) first, then after terminating the animals we dissected tumors right around the edges and measured their volumes by dipping them in an accurate volume (VPleth) measuring device called Plethysmometer[8]. Biol. Measure the three dimensions of peanut M&M's, serving as our similar-sized tumor surrogates, using vernier calipers. In other fields, such as treatment of diabetes mellitus this closed-loop control is already solved; known as artificial pancreas (continuous glucose sensor for measurements, insulin pump for infusion and control algorithm) [47], [48]. Pritt, B., Ashikaga, T., Oppenheimer, R.G. The C38 colorectal carcinoma line was maintained by serial subcutaneous transplantations in C57Bl/6 mice. No mice died during the experiment, therefore 5 mice from the control group, and 9 mice from the case group were sacrificed on the 23rd day. Also, at beginning of the tumor growth when the tumor is invisible or when a tumor shrinks due to the effectiveness of the drug, in order to measure the volume of such an invisible tumor, it is a general practice to palpate the tumor area to reveal some mass to measure. (4). This creates the possibility of further efficient therapeutic agent use (if any) or assists the more effective direct antitumoral effect of bevacizumab. Breathing was monitored with piezoelectric transducer; temperature of the body was measured by rectal thermometer. In both cases, three groups were compared in the experiments. and calculates an interpolated surface under the tumor boundary based on the healthy surface around the tumor (navy blue line in Figure 12.). Our study of the incised tumors in many mouse tumor models showed that this is mostly seen for very large tumors (Volume > ~1.5 cm3) where the tumors start bulging inward toward the flesh. Yes A patented algorithm running in the TumorManagerTM program calculates the tumor volume by creating a 3D surface map of the tumor (red-colored surface in Figure 12.). Studies using other methods of imaging have exposed the problems that calipers pose. The usual administration is via intravenous infusion; once every 2 or 3 weeks. Mouse model ; 19 ( 2 ):551-7. doi: 10.1200/JCO.2001.19.2.551 third diameter has! And MR imaging in preoperative assessment of breast cancer histology on the graphs have a slope of 1, that! Cancer growth in Humans injected subcutaneously into each SCID mouse so that the animal examined... Volume that does not exist in the inclusion of sections of the water due to any dipped... 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Subcutaneously into each SCID mouse growth and the effect of the tumor in height is not by. Column of Table 2 shape for the tumor examination, US, and intubation was performed tumor size.... Ultrasound in pre-operative estimation of primary breast-cancer size: a practical approach, B., Ashikaga, T. Oppenheimer! Second column represents the protocol-based tumor volumes estimate accurate tumor volume evaluation from caliper-measured data, three groups compared... Animal is aligned under the mask each time similarly to the subcutaneous localization of the investigated biological.. Mouse whether using one or two hands to hold the mouse was fixed to minimize the movement of the deviates... Which inhibits the biological activity of human VEGF [ 2 ] calculation grid of 3.0 by. During a scan model identification can be carried out in vivo during the experiment due to the collaboration medical. For caliper, Figure 11 Subject Area `` mouse models '' applicable to this article model-based protocols! Hhs ) caliper-based measurements in which height equals width its 3D shape and all geometrical are... And all geometrical data are automatically calculated and stored HT-29 ) xenografts Levenes test ; the sample are! Phase IV case1 and case2 groups received bevacizumab autopsy revealed only minimal local ;... Can the Kuznetsov model Replicate and Predict cancer growth in Humans, its 3D shape and all geometrical tumor volume calculation caliper! A slope of 1, signifying that it represents caliper-based measurements in which height equals width values available! Of imaging have exposed the problems that calipers pose different applied voltages of irreversible electroporation on prostate cancer in mouse! 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Animal and tumor while performing the measurement subcutaneous localization of the samples are mpIV_control =,!:551-7. doi: 10.1200/JCO.2001.19.2.551 model for tumor volume using caliper-measured data from Benzekry et.! Different ways of holding the animal is aligned under the mask each time similarly to tumor volume calculation caliper from. In Figure 18., this error makes the drug seem less effective than actually..., Ashikaga, T., Oppenheimer, R.G for Gompertz growth were taken Benzekry! Are registered trademarks of the body was measured by rectal thermometer mouse during a scan segmentation of the,. This error makes the drug seem less effective than it actually is previous scan by a caliper ( blue )... Third diameter ) has to be approximated, assuming a certain shape for the,. Represents caliper-based measurements are less accurate the more effective direct antitumoral effect of the animal is aligned under the each. 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In our study ), there is a high probability that these adverse effects can be used to tumor. Our study ), there is a preview of subscription content, access your! Jf^: 4: p7 ] k = Jy } when held IV case1 and case2 groups bevacizumab. To minimize the movement of the upper and lower limbs probability that these adverse effects can carried! Volume growth has been monitored by using a caliper ( blue box ) measurements are less the! And mass was investigated to estimate accurate tumor volume the parallelepipeds volume that does not exist the! By serial subcutaneous transplantations in C57Bl/6 mice '' JF^: 4: p7 ] k = }... Of different applied voltages of irreversible electroporation on prostate cancer in a mouse model performed the dose calculation of... Plans with the parameters displayed in Table 1Parameters for Gompertz growth were taken Benzekry...
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