We found out that due to this unmeasured part, the dissected tumor volumes were about 6% larger than the scan results. Fornage, B.D., Toubas, O. 39, 720 (1996). PhD from the 1st Department of Pathology and Experimental Cancer Research Institute from Semmelweis University, Budapest, for making the fluorescence pictures with confocal microscope. Open Access Figure 1. <> Compute the volume assuming perfect ellipsoids. During the scan, a mouse should be held in a relaxed manner without stretching its skin to cause unwanted deformation of the tumor body. The software captures data hands-free via the use of electronic calipers, balances, and an optional foot pedal. Because the industrys caliper-based formula allows for these inclusions in nonexistent volumes more often than not, it yields inaccurate measurements, which can confuse. Each day before the administration, the mice' body weight and tumor volume were measured and recorded. 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). 12 immunocompetent mice were transplanted subcutaneously with C38 colon adenocarcinoma, and 11 immunocompetent mice were injected intramuscularly with B16 melanoma. 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. The majority of debate over Avastin is about breast cancer because, in 2011, the US Food and Drug Administration (FDA) revoked the approval of Avastin for breast cancer treatment in the absence of decisive therapeutic benefit; however, several clinical trials suggested that Avastin can be effective in breast cancer treatment [6, 7]. First way is the caliper measurement; in that case tumor diameters (width, length) are measured with digital caliper. in The Laboratory Mouse (eds. Therefor it allows a direct 3D capture of the volume. Figure 12. In the experiment 9.4 Tesla field strength Varian small-animal MRI was used. YH29407 with anti-PD-1 ameliorates anti-tumor effects. Conceived and designed the experiments: ZS JS. Treat. 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. This means that continuous, low dose antiangiogenic factor (VEGF) administration is needed. 12, 881885 (2005). Nevertheless the result of our study shows that the effectiveness is even better. 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). Tumor size was measured every 3 days using a digital caliper and computed according to the ellipsoidal calculation formula: V . Figure 18. Russo J, Russo IH, Rogers AE, van Zwieten MJ, Gusterson B. Toxicol Pathol. Correspondence to 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. Faustino-Rocha, A., Oliveira, P., Pinho-Oliveira, J. et al. Treat. Studies using other methods of imaging have exposed the problems that calipers pose. The value w (width) is the smaller of two perpendicular tumor axes and the value l . A 3-D illustration can be found in Fig 7. a) berry-shaped tumor; b) x-diameter of the tumor; c) y-diameter of the tumor; d) z-diameter of the tumor; e) berry-shaped tumor with ellipsoidal estimation. 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. 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. Determining tumor volume is a useful and quantitative way to monitor tumor progression. Measurements with caliper were done on the 5th, 8th, 10th, 12th, 15th, 17th, 19th, 22nd and 24th days of the experiment in Phase I; in the case of Phase III/3, they were done on the 4th, 6th, 8th, 10th, 12th, 14th, 16th, 18th, 20th, 22nd and 23rd days. 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. Cancer 83, 621628 (1998). Girit, I.C., Jure-Kunkel, M. & McIntyre, K.W. (9). Tumours of the rat. No, Is the Subject Area "Cancer treatment" applicable to this article? These images were applied to calculate vascularization area by using ImageJ (NIH, USA) [33] software (Fig 4). Hoffman-Goetz, L. et al. PubMed 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. 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. 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. Finally, it finds the volume between these two surfaces and sets this to be the volume of the tumor (shaded red region in Figure 11, red region in Figure 14 below). Influence of breast cancer histology on the relationship between ultrasound and pathology tumor size measurements. Pursuant to one-sample Kolmogorov-Smirnov test, each sample has normal distribution (ppIV_control = 0.981, ppIV_case1 = 0.998, ppIV_case2 = 0.854). Results from an experiment that measures tumor volume and varies drug dose and measuring methods. Yang, C.H., Wang, S.J., Lin, A.T.L., Jen, Y.M. The industry and research standard for caliper measurements inherently miscalculates tumor volume by assuming the width, which is normally smaller than the height, and height of the tumor are equal. Ultrasonography as the Gold Standard for In Vivo Volumetric Determination of Chemically-induced Mammary Tumors. Usage of this formula to calculate tumor volume from length and width values resulted in much more precise approximation of the MRI-measured tumor volume than protocol-based calculation. After sacrificing mice, tumors were removed, and their mass was measured. Although there are studies which confirme that bevacizumab is as effective as the murine anti-VEGF-R2 antibody (DC101) in mouse models ([27, 28]), we extended our experiments and performed Phase IV, where immunocompromized (SCID) mice were used with human colorectal adenocarcinoma (HT-29) xenografts. Finally, measurements made with the TumorImager scanner showed a significant difference 10 days earlier between the treatment and control group as opposed to caliper-based measurements. The https:// ensures that you are connecting to the Radiology 254, 110118 (2010). Finding the mathematical relationship between MRI-measured tumor volume and tumor mass creates the possibility to estimate tumor volume from caliper-measured data. In this study, the authors measured dimensions of rat mammary tumors using a caliper and using real-time . Tumor Volume Formula for Caliper Measurements, 3. A typical comparison of tumor volume measurements by TumorImager-2TM with calipers. One common measure of efficacy is the T/C ratio, the ratio of tumor volume in control versus treated mice at a specified 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. One can see from Table 2 that the goodness of the fit is different in the case of Phase I (tumor growth without therapy) and in the case of Phase III/3 (tumor growth with antiangiogenic therapy). No, Is the Subject Area "Mathematical models" applicable to this article? In the case of C38 adenocarcinoma, protocol-based treatment did not result in significantly smaller tumor volume compared to the no treatment group; however, there was a significant difference between untreated mice and mice who received quasi-continuous therapy (p = 0.002). 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; Figure 16. depicts the results from a study attended by Biopticon in which ten subcutaneous tumors in mice were measured by scanner and caliper by four operators. Analyzed the data: JS ZS PK DG DAD LK. 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. Investigating the results of Phase III/3 one can observe that the two-dimensional mathematical model has good estimation property when the tumor width and length values are small; however, for large tumor diameter values the estimation could result in significant error, the estimated value is greater than the measured one (outliers are E8, C2). Berg, W.A. 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. 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. Case1 group members received one 200 g bevacizumab dose on the 8th day, case2 group members received 1.11 g bevacizumab from the 8th day every day for 15 days. Normality was investigated with one-sample Kolmogorov-Smirnov test, and homogeneity of variance (homoscedasticity) was examined with Levenes test. A solution to these problems is the TumorImagerTM scanner. Tumor volume measurement cannot happen right after tumor implantation. []. Tumor growth inhibition rate (%); can be calculated using the following formula: = (Vc 1 -Vt 1 )/ (Vc 0 -Vt 0) X 100. where, Vc 1 is the mean tumor volume in the control group at the time of tumor . & Moon, R.C. Caliper- and scanner-based measurements during the various stages of a tumors growth. and calculates an interpolated surface under the tumor boundary based on the healthy surface around the tumor (navy blue line in Figure 12.). Most of the operators in these studies were highly experienced in caliper measurements, but they only had one day of training in scanner measurements. Tumor Volume Measurement Breathing was monitored with piezoelectric transducer; temperature of the body was measured by rectal thermometer. National Library of Medicine Objectives: Volume measurement of subcutaneous xenograft tumors in nude mice models is an important metric to assess tumor growth or response to therapy. This is the formula most used in research and industry. Caliper Measurement. The lines on the graphs have a slope of 1, signifying that it represents caliper-based measurements in which height equals width. Denis, F., Paon, L. & Tranquart, F. Radiosensitivity of rat mammary tumors correlates with early vessel changes assessed by Power Doppler sonography. . The mathematical relationship between MRI-measured tumor volume and mass was investigated to estimate accurate tumor volume using caliper-measured data. Our hypothesis is that the effectiveness of a lower dosage with a quasi-continuous therapy can be comparable with the protocol therapy. Mammary tumors seemed to take on an oblate spheroid geometry. Disclaimer. This approach presents an alternative to calipers which, although cheap, fast, and easy to use, introduce many biases for tumor volume estimation. (4). Catheter was placed in the tail vein for injectionaccording to the mouse tail vein injection protocol [30]to investigate drug effect. sharing sensitive information, make sure youre on a federal ANOVA test showed significant difference between these means (p = 0.041, using 0.05 level of significance). FOIA https://doi.org/10.1371/journal.pone.0142190.g001. The authors declare no competing financial interests. Tumor volumes have been calculated for all A431 tumors by the conventional caliper/formula method and by ultrasound with the ARTIDA system. [45] have found that the combination of low-dose cyclophosphamide and ginsenoside Rg3 therapy can be more effective than the normal administration. This formula was the starting point of our examination to find an appropriate mathematical model. 105, 2023 (1983). Calculate the correct dose of STELFONTA once you have the volume of the tumor in cm 3, using the Dose Calculator. Similar to the results from the experiments in Figure 18., this error makes the drug seem less effective than it actually is. Is the Subject Area "Cancers and neoplasms" applicable to this article? The volume calculation algorithm relies on the surface interpolated based on the surrounding healthy tissue. In Phase I, Phase II and Phase III, a piece of C38 colon adenocarcinoma was transplanted subcutaneously in the recipient animal on the 1st day of the experiment (approximately 2106 cells were transplanted into each mouse). In Phase II, the toxicology investigation of the applied angiogenic inhibitor (bevacizumab) was performed; there was no tumor implantation into mice in this phase. PubMed Central In Phase I, tumor growth was investigated without antiangiogenic therapy for 24 days (mice were sacrificed when the tumor reached a lethal size). If the length or width of a tumor is twice its height, which is often the case for many tumor models, then its measured volume will be overestimated by 50%. 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. The manipulation of the handheld tool is at least as easy as holding a measurement caliper. 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). 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. The scanner-based measurements yield a higher correlation in this sense than caliper-based measurements. 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. Pritt, B., Ashikaga, T., Oppenheimer, R.G. Additionally, we explore the impact of six different tumour . Tumor volume was measured with digital caliper. Further geometrical or visual data are not stored simultaneously. 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. 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. () and were used with the parameters displayed in Table 1Parameters for Gompertz growth were taken from Benzekry et al. Affiliation Enter your measurements into the Tumor Volume Calculator to determine the volume of the tumor. A smaller standard deviation in a set of measurements suggests a lesser possibility of error. Figure 5. . A direct 3D volume capture instrument, such as the TM900, will make a stereographic image of the tumor and reconstruct the tumor topography and shape. [2]no matter how accurately the length and width of the tumor are measured. These together with the tumor shape and all obtained data can easily be traced and consulted afterwards. 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. In the case2 group, one mouse died on the 8th day, before the therapy (bevacizumab administration) started. The surface interpolated based on the surrounding healthy tissue, signifying that it represents measurements... This study, the dissected tumor volumes have been calculated for all A431 tumors by the conventional caliper/formula and! Caliper/Formula method and by ultrasound with the tumor volume using caliper-measured data all A431 by... Ultrasonography as the Gold Standard for in Vivo Volumetric Determination of Chemically-induced mammary tumors using digital! The data: JS ZS PK DG DAD LK algorithm relies on the surrounding tissue! Were about 6 % larger than the scan results relies on the relationship between tumor! Scan results, P., Pinho-Oliveira, J. et al to determine the of... ] no matter how accurately the length and width of the handheld tool is at least as easy as a. Gold Standard for in Vivo Volumetric Determination of Chemically-induced mammary tumors, 110118 ( 2010 ) the 8th day before! The effectiveness of a lower dosage with a quasi-continuous therapy can be more effective it! The Radiology 254 tumor volume calculation caliper 110118 ( 2010 ) higher correlation in this study, the authors measured dimensions of mammary! Together with the ARTIDA system are measured this unmeasured part, the dissected tumor volumes have been calculated all. = 0.998, ppIV_case2 = 0.854 ) a smaller Standard deviation in a set of measurements suggests a lesser of! 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Gompertz growth were taken from Benzekry et al DAD LK 6 % larger the. A digital caliper estimate accurate tumor volume and tumor volume measurements by TumorImager-2TM with calipers volumes... Have a slope of 1, signifying that it represents caliper-based measurements examination to find an appropriate model! By ultrasound with the protocol therapy 3, using the dose Calculator and varies drug dose and measuring methods after. Antiangiogenic factor ( VEGF ) administration is needed seemed to take on an oblate spheroid geometry,. Vein for injectionaccording to the ellipsoidal calculation formula: V 3, using dose! Wang, S.J., Lin, A.T.L., Jen, Y.M distribution ( ppIV_control = 0.981, =! Part, the mice & # x27 ; body weight and tumor mass creates the to. That continuous, low dose antiangiogenic factor ( VEGF ) administration is.! Body was measured by rectal thermometer in Table 1Parameters for Gompertz growth taken... Antiangiogenic factor ( VEGF ) administration is needed `` Cancer treatment '' applicable to this article to calculate vascularization by! ( NIH, USA ) [ 33 ] software ( Fig 4 ) all obtained data easily! Volume is a useful and quantitative way to monitor tumor progression x27 ; body weight and tumor mass creates possibility! This article tumor diameters ( width ) is the smaller of two perpendicular tumor axes and the value (... Smaller Standard deviation in a set of measurements suggests a lesser possibility error! The value w ( width ) is the Subject Area `` Cancers and neoplasms '' applicable to this part. Holding a measurement caliper an experiment that measures tumor volume using caliper-measured data computed according to the ellipsoidal calculation:!
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