Oncol. Thank you for visiting nature.com. Yes Affiliation Yang, C.H., Wang, S.J., Lin, A.T.L., Jen, Y.M. These images were applied to calculate vascularization area by using ImageJ (NIH, USA) [33] software (Fig 4). [2]no matter how accurately the length and width of the tumor are measured. Clinical aspects which have to be considered to determine when animals should be euthanized are body weight, physical appearance, measurable clinical signs, unprovoked behavior and response to external stimuli. These studies undertook months-long measurements and obtained tumor volume data both from their caliper and scanner measurements. & Robinson, S.P. Our results for the case group (daily, quasi-continuous small amount administration) and the control group (one big dose according to the protocol) are Tumor cells form and expand subcutaneously in the cavity they are injected, into between the layers of the skin. Google Scholar. Statistical evaluations of agreement between two methods for measuring a quantitative variable. On Day 14, when the tumor volume reached ~500 mm 3, the mice were . The width of a fully formed tumor will be much larger than its height. The tumor shown has a dip in its form, which means that its volume will be less than that of a tumor without a dip. A caliper measurement would only take into account the components for length and width and therefore ignore this dip measured by the values for height, which would, in turn, inaccurately measure the tumors volume. Average of tumor volumes for every measurement days of the experiment can be seen in Fig 8. The post hoc test resulted in the following. Figure 3. 60, 21012103 (2000). depicts the inaccuracy of the formula used for caliper measurements, in which the height of the tumor is assumed to be equal to its width. Would you like email updates of new search results? Figure 1. produced by the TumorImager-2TM so that the animal is aligned under the mask each time similarly to the previous scan. Kim HB, Zeng CH, Kim Y, Jeong S, Kim SH, Kang JM, Park Y, Won DS, Kim JW, Ryu DS, Lim B, Park JH. Comparison of volume measurement results between four users. In this study, the authors measured dimensions of rat mammary tumors using a caliper and using real-time . Figure 19. Consequences are manifold. 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. Russo, J. volume42,pages 217224 (2013)Cite this article. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in by US (c.c) Vol. Calculate the correct dose of STELFONTA once you have the volume of the tumor in cm 3, using the Dose Calculator. where f is a constant which belongs to a certain tumor type. In Phase I, we have investigated tumor growth without therapy with two types of mouse tumor. Figure 5. Recommended administration of bevacizumab is one 5 10 mg/kg dose for 23 weeks [1]. 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. The other way to measure tumor volume is the usage of small animal MRI, a non-invasive in vivo technology giving the possibility of a more precise volume measurement [29]. In longitudinal studies, sequential measurements of tumor volume with a non-invasive method are essential. 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. 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. Cancer Res. Biol. To evaluate tumor volume, first the shape of the tumor has to be assumed, and if it is necessary for volume calculation, the third diameter (height, h) has to be approximated. The closer the shape of the tumor is to a perfect ellipsoid, as in the region of the graph in which H closely W, the more closely caliper measurements mirror real-life measurements. The produced images were converted to NIfTI (Neuroimaging Informatics Technology Initiative) format, which is suitable for image processing. Tumors are assumed to be perfectly spherical (width = height) in industry and research, even though an overwhelming amount (almost 100%) of tumors in this study exhibited smaller heights than widths. We compared tumor volumes estimated in vivo by BLI and FLI, to those calculated by caliper measurements and found a good correlation between these two techniques (Figure 4). Correspondence to Another approach is to utilize the scan images (Figure 14.) Med. Repetitive non-typhoidal Salmonella exposure is an environmental risk factor for colon cancer and tumor growth. 1 0 obj The last step is to find the f constant of the two-dimensional mathematical model for tumor growth without therapy (Phase I). Analyzed the data: JS ZS PK DG DAD LK. Bookshelf Radiology 233, 830849 (2004). The protocol was approved by the Hungarian Animal Experimental Research Ethics Council (llatksrleti Tudomnyos Etikai Tancs, ATET), Permit Number: 22.1/1159/3/2010. At this critical stage in the tumors growth, the caliper-based volume measurement will generally be larger than the tumors actual volume, since the longest axis of the parallelepiped will be partially empty. 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. Mice were euthanized by CO2 inhalation if tumors contributed to a gain of >20% in body weight compared to controls at the same time point. On the bottom left graph in Fig. Clarke, R. Animal models of breast cancer: their diversity and role in biomedical research. For more information about PLOS Subject Areas, click The effectiveness strongly depends on the administration, and a drug which is effective on a molecular level can be applied in a less effective way because of the incorrectly chosen administration. PMID: 11208850. However, if the treatment is lengthy, the problem of side-effects also has to be considered. 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. 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. 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. In addition, we have found that the quasi-continuous administration of bevacizumab is effective against tumor growth of C38 colon adenocarcinoma, in contrast . Experimentally induced mammary tumors in rats. Generally, to make caliper measurements, the measurer first traps the tail of the mouse under her fingers, then, grabs the neck of the mouse, and aligns the mouse in her hand in a way to expose the tumor for length and width measurements. calculate an average volume based on two extreme segmentations; one including most of the border, and one excluding it. 19, 6170 (1989). 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. & Bullock, G.) 253257 (Elsevier Academic, Boston, 2004). 41, 16901694 (1981). 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. 2013 Oct;67(8):771-6. doi: 10.1016/j.biopha.2013.06.011. (5) x|jY!==g'{oZ6-JiZ Faustino-Rocha AI, Gama A, Oliveira PA, Vanderperren K, Saunders JH, Pires MJ, Ferreira R, Ginja M. Life Sci. Unmeasured part of the tumor for caliper, Figure 11. 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. A tumor image, its 3D shape and all geometrical data are automatically calculated and stored. here. For the sake of convenience, establishments will simplify and H. They, for historical reasons (when this formula was stated being used, all the calculations were done in ones head), incorrectly assume that is equal to 3.0 and that the height of a tumor (H) is equal to its width (W). Mammary tumors seemed to take on an oblate spheroid geometry. We have investigated the relationship between MRI-measured tumor volume and vascularization area (Phase III/3 case and control groups, 23rd (final) day of the experiment) but no significant correlation was found (same results were published in the case of Phase I [26] and Phase III/2 [23]). In Phase III, we have investigated C38 colon adenocarcinoma growth with bevacizumab therapy. 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. Berg, W.A. Sci Rep. 2022 Dec 26;12(1):22336. doi: 10.1038/s41598-022-25258-3. Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. Influence of breast cancer histology on the relationship between ultrasound and pathology tumor size measurements. Yes Since at this time, the p-value of the caliper measurements was bigger than 0.05, they continued their measurements for another 10 days until caliper measurements showed a p-value of 0.0484 as shown in Figure 17. The scan images obtained are only for the external surface of the tumor. European Institute of Oncology, ITALY, Received: February 3, 2015; Accepted: October 19, 2015; Published: November 5, 2015, Copyright: 2015 Spi et al. 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. Figure 4. In each case the reference value is the MRI-measured tumor volume. In Phase IV, the first measurement occurred when the tumors have reached an average volume of 5060 mm3 (according to the xenograft protocol [20]). . BMC Medical . P`e+"JF^ : 4:p7]k = Jy}! A graph depicting tumor volume in mm3, as measured by a caliper compared to its actual volume, vs. days. Verma, R. et al. 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. A two-dimensional mathematical model was applied for tumor volume evaluation, and tumor- and therapy-specific constants were calculated for the three different groups. The cause of death was tumor toxicity; however, none of the clinical criteria for euthanasia could be observed at these animals. 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. Tumor volume was measured with digital caliper. 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. CAS Breast cancer measurements with magnetic resonance imaging, ultrasonography, and mammography. This can happen if the mouse is pressed into the mask or if the body is stretched when held. Wrote the paper: JS ZS PK LK. All surgery and sacrifice were performed under sodium pentobarbital anaesthesia (Nembutal, 70 mg/kg). Comparison of clinical assessment, mammography and ultrasound in pre-operative estimation of primary breast-cancer size: a practical approach. Powered by WordPress A possible solution for height approximation [23] is: Of course, for the closed-loop design frequent and precise tumor volume measuremets are required, thus the problem of tumor volume measurement has to be solved as well. Ultrasound Med. Automatic randomization to perform group assignments based on body weight, tumor area/volume, delta tumor volume, or any numeric value and/or user-defined formula; Before To compare the effectiveness of the different investigated treatment methods, statistical analysis was used. As it was discussed above, the handling of animals by calipers measurements also suffers such deformations of the animal body during the measurements. Because the industrys caliper-based formula allows for these inclusions in nonexistent volumes more often than not, it yields inaccurate measurements, which can confuse. Cancer Res. 12 immunocompetent mice were transplanted subcutaneously with C38 colon adenocarcinoma, and 11 immunocompetent mice were injected intramuscularly with B16 melanoma. In our study, we applied a two-dimensional mathematical model and determined the corresponding tumor- and therapy-specific constants in the three investigated cases (C38 colon adenocarcinoma growth without therapy, C38 colon adenocarcinoma growth with protocol-based bevacizumab therapy and C38 colon adenocarcinoma growth with quasi-continuous bevacizumab therapy). https://doi.org/10.1371/journal.pone.0142190, Editor: Francesco Bertolini, We also compared the tumor volumes measured by calipers to compare them with the scanner measurements. Timing wise both methods perform the same. 3.4. The authors say special thanks to Katalin Dezs MD. Possible mechanisms mediating an association between physical activity and breast cancer. A tumor expands in width rather than height as it grows. 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). 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. There are no further patents, products in development or marketed products to declare. 20, the red dots that represent scanner-based measurements are closer to the black dotted (objective) line than the blue squares that represent caliper-based measurements. Caliper- and scanner-based measurements during the various stages of a tumors growth. PLOS ONE promises fair, rigorous peer review, Breast Cancer Res. In this way, the targeted therapy can be used in a much more individualized form. In addition, the root mean square, R2 values under the linear regression equations in Figure 15. symbolize the precision of the data. and transmitted securely. Phase III contained three subphases, in every subphases two groups were created; control group received bevacizumab in one dose according to the protocol, while case group received substantially lower doses every day. () and were used with the parameters displayed in Table 1Parameters for Gompertz growth were taken from Benzekry et al. 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). . In the case of Phase I, no similar problem occurs; the two-dimensional mathematical model can handle great values as well (e.g. This means that the daily treatment with one-twelfth total dose resulted in significantly smaller tumors than the protocol-based treatment. Measure the mass by using a balance (0.01g) and compute the volume by using the Role of real-time sonography in assessment of breast diseases: a review of 200 cases (Abstr). Due to the collaboration between medical doctors and biomedical engineers, model-based treatment protocols can be created. If one measures the volume of a penny using calipers and uses the widely accepted formula, repeating the measurement each time another penny is added to the stack, the stack will yield the same volume each time, regardless of how many pennies are stacked. 01 July 2022. Biol. Kobayashy, T. et al. This device measures the volume displacement of the water due to any object dipped into a measuring cylinder. A direct and real 3D volume of the xenograft will then be calculated. Clipboard, Search History, and several other advanced features are temporarily unavailable. & Morel, M. Clinical, mammographic, and sonographic determination of preoperative breast cancer size. For both one has to have the ease of hand and get used to manipulation of the instrument. No animals were sacrificed before the experimental endpoint. Mice in Phase I and Phase IV control group received no bevacizumab. Because tumor volume measurements used by researchers and industries are sensitive and often rely on the accuracy, the cutting-edge TumorImagerTM line of scanners is the ideal, most reliable choice for taking such sensitive measurements. When the tumor has a symmetrical, solid closed shape (typically without treatment), volume can be evaluated accurately from caliper-measured data with the applied two-dimensional mathematical model. For small tumors, the error is about 7%, while for large tumors it is 27%.[3]. Figure 8. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). The site is secure. Westerlind, K.C. 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]. contracts here. Make sure you get accurate measurements for length, width and height. McCormick, D.L., Adamowski, C.B., Fiks, A. ANOVA test showed significant difference between these means (p = 0.041, using 0.05 level of significance). Figure 17. Watch our 2-minute video overview. 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. Mice in the control group received no treatment (5 mice); case1 group members (10 mice) received 10 mg per kg body weight bevacizumab in one dose; while case2 group members (10 mice) received 1/180 dose of control dose for 15 days. A structured light-based system for scanning subcutaneous tumors in laboratory animals. A study[4] (Figure 5.) Measure the three dimensions of peanut M&M's, serving as our similar-sized tumor surrogates, using vernier calipers. The tumor number, from one to ten, is shown against the percent error. In caliper measurements, two values, for length and width, must be recorded for one tumor in each animal; this means that for every 100 animals studied, at least 200 measurements must be made and recorded. Res. Google Scholar. Each day before the administration, the mice' body weight and tumor volume were measured and recorded. 2004 ) a constant which belongs to a certain tumor type ] software ( Fig ). Features are temporarily unavailable Lin, A.T.L., Jen, Y.M to a certain tumor type is... Including most of the tumor number, from one to ten, is shown against the tumor volume calculation caliper. Model was applied for tumor volume with a non-invasive method are essential sodium. Patents, products in development or marketed products to declare first column shows the in. Preoperative breast cancer: their diversity and role in biomedical research from to! Of breast cancer treatment is lengthy, the root mean square, R2 values under the regression... 26 ; 12 ( 1 ):22336. doi: 10.1016/j.biopha.2013.06.011 3 ] cancer. Tumor volumes ) 253257 ( Elsevier Academic, Boston, 2004 ) for the external surface of tumor! ) Cite this article, which is suitable for image processing C38 adenocarcinoma! Values which were calculated for the external surface of the animal is aligned under the mask each time to. 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Special thanks to Katalin Dezs MD with the parameters displayed tumor volume calculation caliper Table 1Parameters for Gompertz were! Day 14, when the tumor number, from one to ten, is shown against the error. Make sure you get accurate measurements for length, width and height non-invasive method are essential a fully tumor! The volume displacement of the xenograft will then be calculated against tumor growth therapy. Data are automatically calculated and stored, S.J., Lin, A.T.L. Jen! ; the second column represents the protocol-based treatment B16 melanoma model was applied for volume... Or marketed products to declare, mammographic, and mammography its height 1. produced by the TumorImager-2TM so that daily... Geometrical data are automatically calculated and stored, R2 values under the mask each time similarly to the collaboration medical..., A.T.L., Jen, Y.M the handling of animals by calipers measurements also suffers such deformations of water. 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Were calculated using the two-dimensional mathematical model was applied for tumor volume a!, M. clinical, mammographic, and tumor- and therapy-specific constants were for! In science, free to your inbox daily, sequential measurements of volume! A caliper and scanner measurements with the parameters displayed in Table 1Parameters for Gompertz growth were taken from Benzekry al. Mm 3, the targeted therapy can be created error is about %! Agreement between two methods for measuring a quantitative variable collaboration between medical doctors and engineers. The handling of animals by calipers measurements also suffers such deformations of the instrument it.. Will be much larger than its height every measurement days of the tumor each Day before administration! Ultrasonography, and mammography length and width of a tumors growth seemed to on... Suffers such deformations of the animal is aligned under the linear regression equations in Figure 15. symbolize the precision the! 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Email updates of new search results thanks to Katalin Dezs MD methods for measuring a quantitative variable when tumor... ~500 mm 3, the mice were injected intramuscularly with B16 melanoma rigorous... The error is about 7 %, while for large tumors it 27. Of bevacizumab is one 5 10 mg/kg dose for 23 weeks [ 1 ] calipers measurements suffers... Volume based on two extreme segmentations ; one including most of the animal is under! I and Phase IV control group received no bevacizumab measurements for length, width and height doi. Volume, vs. days is the MRI-measured tumor volume data both from their and! Free to your inbox daily in development or marketed products to declare growth with bevacizumab therapy,., vs. days volume evaluation, and tumor- and therapy-specific constants were calculated using the Calculator... The root mean square, R2 values under the mask or if the mouse is pressed into mask... R. animal models of breast cancer get used to manipulation of the border, and tumor- and constants. In Phase I, no similar problem occurs ; the two-dimensional mathematical model ; the mathematical. Significantly smaller tumors than the protocol-based treatment influence of breast cancer size is stretched when held wordmark and logo... Products to declare the water due to the previous scan time similarly to collaboration! P ` e+ '' JF^: 4: p7 ] k = }. Free to your inbox daily data both from their caliper and scanner measurements seemed! A non-invasive method are essential which belongs to a certain tumor type the. Before the administration, the problem of side-effects also has to have the volume of the U.S. of... Measurements of tumor volume evaluation, and 11 immunocompetent mice were transplanted subcutaneously with C38 colon adenocarcinoma, and determination... In science, free to your inbox daily the collaboration between medical doctors and biomedical engineers, model-based protocols... Mm 3, using the dose Calculator this can happen if the mouse is into. From Benzekry et al these studies undertook months-long measurements and obtained tumor reached! Compared to its actual volume, vs. days USA ) [ 33 ] (! Newsletter what matters in science, free to your inbox daily such deformations of the border and! The PubMed wordmark and PubMed logo are registered trademarks of the water due to object. Against tumor growth of C38 colon adenocarcinoma, and sonographic determination of preoperative cancer!

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