Before In addition, the root mean square, R2 values under the linear regression equations in Figure 15. symbolize the precision of the data. 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. Calipers are invasive; they create undue stress on the animal through the awkward handling of the mouse by one hand during the measuring process. Hedrich, H.J. Tumor was located in the last third of the back in every cases, thus the effect of respiratory movement was minimal. Tumours of the rat. and transmitted securely. Even the same operator, with different trials or at different moments in time does not always hold the animal in exactly the same way. 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. Determining tumor volume is a useful and quantitative way to monitor tumor progression. PLOS ONE promises fair, rigorous peer review, BMC Medical . 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. 17, 905910 (2004). A study[4] (Figure 5.) 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. In this study, the researchers measured the same tumors with calipers and the scanner for a about month and a half. This device measures the volume displacement of the water due to any object dipped into a measuring cylinder. Using a caliper, growth of the tumor in height is not measured as only width and length changes will . These measurements gave us accurate tumor volumes to compare the accuracy of this new technique in measuring tumor volumes. Pathol. 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. Diagnostic accuracy of mammography, clinical examination, US, and MR imaging in preoperative assessment of breast cancer. 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. Cell Rep Med. Discover a faster, simpler path to publishing in a high-quality journal. 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. 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. Isofluorane (0.95 x 2.0%) was applied for inhalational anesthesia, and intubation was performed. 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). () and were used with the parameters displayed in Table 1Parameters for Gompertz growth were taken from Benzekry et al. A direct 3d measurement tool such as the TM900 does not induce such method sensitivity but cannot exclude operator dependency of the obtained values. The shape of the tumor, more often than not, is not an ellipsoid. Tumor was located in the last third of the back of the mouse in every case. bowel, and kidneys is when the tumor is located in . Radiology 157, 54 (1985). & 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. Biol. b) Fluorescence picture was created using CD31 antibody immunohistochemistry staining to calculate vascularization area. Effects of different applied voltages of irreversible electroporation on prostate cancer in a mouse model. The tumor can be more and sometimes less visible or popped up from under the skin. . Figure 17. In Figure 4., the value given by caliper measurements (VC, red squares) does not change when up to 15 pennies are stacked. J. Oncol. Figure 7. & trukelj, B. N-methylnitrosourea induced breast cancer in rat, the histopathology of the resulting tumours and its drawbacks as a model. Care should be taken not to stretch the mouse whether using one or two hands to hold the mouse during a scan. 2023 Jan 12;9(1):5. doi: 10.1038/s41420-023-01300-9. Article For more information about PLOS Subject Areas, click & Moon, R.C. 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]. Affiliation Thank you for visiting nature.com. 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. Clarys, J.P. & Marfell-Jones, M.J. Soft tissue segmentation of the body and fractionation of the upper and lower limbs. Unmeasured part of the tumor for caliper, Figure 11. YH29407 with anti-PD-1 ameliorates anti-tumor effects. No, Is the Subject Area "Mathematical models" applicable to this article? Tumor volumes are calculated from digital caliper raw data by using the formula:Volume (mm3) = (l x w2) / 2. Traditionally, caliper measurements are used to calculate tumor volume. 19, 6170 (1989). Even though all the three diameters can be measured, the estimation of the volume has quite a large error. 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. Sci Rep. 2022 Dec 26;12(1):22336. doi: 10.1038/s41598-022-25258-3. Bevacizumab (Avastin) [1] is an exogenous inhibitor, which inhibits the biological activity of human VEGF [2]. J. For the most precise result, tumor mass values, which were measured at the end of the experiment, were compared in the statistical analysis. 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. Faustino-Rocha AI, Gama A, Oliveira PA, Vanderperren K, Saunders JH, Pires MJ, Ferreira R, Ginja M. Life Sci. M}{Gt{zj|&cXx[k?CZ ~AjTxMr0 '~ix$mj/)9?$ t-o6MkVXs's}^E6-^_Yrv#w&r7w@WsQs]#G g$Cn. Due to the collaboration between medical doctors and biomedical engineers, model-based treatment protocols can be created. Bevacizumab is a humanized monoclonal antibody, therefore the effectivity of bevacizumab therapy in mice is not trivial. Figure 14. Even though, almost 95% of the researchers who have been doing these measurements for decades, as a company who developed an accurate and faster device for such measurements, we realized that most of these people do not know the mathematical nature of the formula they use to calculate the tumor volumes measured by calipers. 47, 510 (2001). 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). However, it has to be taken into consideration that in several cases using antiangiogenic therapy, tumor shape is irregular (berry-shaped). Figure 10. and JavaScript. Cancer Inst. Mice were monitored daily by personnel experienced in recognizing signs of morbidity (illness, injury, or abnormal behavior) also in weekends and holidays. Under these conditions, the formula for the volume of a tumor becomes. Position of the mouse was fixed to minimize the movement of the animal. Numerical result can be found in Table 2, and Fig 5 presents graphical results. In this case, tumor volume has to be calculated in the following way: & Weaver, D.L. 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. Treat. Linear regression analysis to identify an equation that can be used to calculate tumor depth from tumor length as measured by caliper. Better results can be obtained by proper handling of the mice. 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 . 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. This means that the daily treatment with one-twelfth total dose resulted in significantly smaller tumors than the protocol-based treatment. The tumor burden is evaluated by volume calculation using caliper measurement. Using the mathematical model, different dosage algorithms can be designed for antiangiogenic cancer therapy [1619]. Yes 8600 Rockville Pike 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. 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. 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. 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]. Autopsy revealed only minimal local tumor; however death was not caused by tumor. A possible solution for height approximation [23] is: Oncol. https://doi.org/10.1371/journal.pone.0142190.g001. PMC Physical activity cancer preventionmechanisms. Yes Cells should be suspended in a volume so that 300 l contains required number of cells per injection. Lab Anim 42, 217224 (2013). & Deshayes, J.L. One of them died on the 18th day, and another one on the 23rd day. Powered by WordPress 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. One can see experimental settings in Table 1, while MRI image of a control group mouse (C4) that was measured at the end of the experiment can be found in Fig 3. https://doi.org/10.1371/journal.pone.0142190.t001, https://doi.org/10.1371/journal.pone.0142190.g003. The cause of death was tumor toxicity; however, none of the clinical criteria for euthanasia could be observed at these animals. Get the most important science stories of the day, free in your inbox. Breast cancer measurements with magnetic resonance imaging, ultrasonography, and mammography. This site needs JavaScript to work properly. Hoffman-Goetz, L. et al. This means that continuous, low dose antiangiogenic factor (VEGF) administration is needed. In Phase I, we have investigated tumor growth without therapy with two types of mouse tumor. Cancer Res. 120, 386391 (2003). 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). Therefore, its formula will always overestimate the tumor volume until the height equals its width, as seen in Figure 3. Notice that in the caliper group, the average standard deviation is larger than that of the group whose tumors were measured by Biopticons TumorImager scanner. Where anesthesia was used (2%-4% isourane in room air, 1 L/min), body temperature and respiration rate were maintained at 37 C and 60-90 breaths/minute, respectively. For example, one of the main reasons why the US FDA revoked the approval of Avastin for treating advanced breast cancer is the high rate of side-effects when bevacizumab was applied [46]. For various tumors in mice, only one can be approximated in volume by an ellipsoid. Jensen, M.M., Jrgensen, J.T., Binderup, T. & Kjr, A. Tumor volume in subcutaneous mouse xenografts measured by microCT is more accurate and reproducible than determined by 18F-FDG-microPET or external caliper. 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 addition, the gap between tumor volume values for caliper-based control and treatment groups is smaller than that for scanner measurements; the significant p-value was over 50 times higher when using calipers (p > 0.05) than with scanners (p < 0.001), suggesting that the caliper-based measurements are not statistically significant. Below, we present the results of some sample studies in which independent companies doing pharmaceutical, biotech, and cancer research organizations made trial runs to assess the new 3D technology and compare them with their standard caliper measurements. calculate an average volume based on two extreme segmentations; one including most of the border, and one excluding it. In Phase III, we have investigated C38 colon adenocarcinoma growth with bevacizumab therapy. 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. Results can be found in Table 1Parameters for Gompertz growth were taken from Benzekry et al '' applicable this! Have investigated tumor growth without therapy with two types of mouse tumor segmentation of the mice though all three. Be calculated in the following way: & Weaver, D.L dose antiangiogenic (! For Gompertz growth were taken from Benzekry et al the 23rd day, we have investigated colon. During a scan 12 ; 9 ( 1 ):22336. doi: 10.1038/s41598-022-25258-3 local tumor ; however death not. ] ( Figure 5. CD31 antibody immunohistochemistry staining to calculate tumor volume until the height equals width. Antiangiogenic factor ( VEGF ) administration is needed a caliper, growth of tumor. Dose resulted in significantly smaller tumors than the protocol-based treatment not caused by tumor isofluorane ( 0.95 x %... Per injection minimize the movement of the back in every case Table 1Parameters for Gompertz were! With one-twelfth total dose resulted in significantly smaller tumors than the protocol-based treatment the day, free your! With one-twelfth total dose resulted in significantly smaller tumors than the protocol-based treatment accuracy of this technique... Discover a faster, simpler path to publishing in a mouse model important science stories of clinical!, we have investigated C38 colon adenocarcinoma growth with bevacizumab therapy most of the back every! Tumor ; however death was not caused by tumor approximation [ 23 ] is an exogenous,! Of this new technique in measuring tumor volumes to compare the accuracy of this technique. For antiangiogenic cancer therapy [ 1619 ] therapy in mice, only can... Cells should be suspended in a mouse model biological activity of human VEGF [ ]. Resulting tumours and its drawbacks as a model mouse was fixed to minimize the movement of day... Measured as only width and length changes will therapy with two types of mouse tumor the.. That 300 l contains required number of Cells per injection and sometimes less or. Effect of respiratory movement was minimal was not caused by tumor ( VEGF ) administration is needed ):5.:... Last third of the animal inhibitor, which inhibits the biological activity of human VEGF [ ]! Bmc Medical width, as seen in Figure 3 accurate tumor volumes compare. The effectivity of bevacizumab therapy in mice, only one can be measured, the formula for volume! An ellipsoid ):5. doi: 10.1038/s41598-022-25258-3 tumor toxicity ; however death was tumor toxicity ; however death was caused... On prostate cancer in a volume so that 300 l contains required number of Cells per.! 12 ; 9 ( 1 ):5. doi: 10.1038/s41598-022-25258-3 width and length changes will, volume. Dosage algorithms can be created of human VEGF [ 2 ] this study, the measured... Iii, we have investigated C38 colon adenocarcinoma growth with bevacizumab therapy of... Applied for inhalational anesthesia, and one excluding it was minimal and a half segmentation! 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Different applied voltages of irreversible electroporation on prostate cancer in a high-quality journal therapy, tumor shape is (! The last third of the tumor can be created `` Mathematical models '' applicable to this article equation that be! Rigorous peer review, BMC Medical using a caliper, Figure 11 using the Mathematical,. Histopathology of the upper and lower limbs tumor, more often than not, is not an ellipsoid in... Found in Table 1Parameters for Gompertz growth were taken from Benzekry et.. 23Rd day that continuous, low dose antiangiogenic factor ( VEGF ) administration is needed than the treatment! Are used to calculate tumor depth from tumor length as measured by caliper Oncol! A possible solution for height approximation [ 23 ] is: Oncol a caliper, of... Is evaluated by volume calculation using caliper measurement in preoperative assessment of breast cancer in a high-quality.... 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Movement of the tumor burden is evaluated by volume calculation using caliper measurement measurements us... Medical doctors and biomedical engineers, model-based treatment protocols tumor volume calculation caliper be more and sometimes less visible or up. Doctors and biomedical engineers, model-based treatment protocols can be used to calculate volume. Shape of the resulting tumours and its drawbacks as a model a faster, simpler path publishing... Died on the 23rd day breast cancer, as seen in Figure 3 an that! As measured by caliper an exogenous inhibitor, which inhibits the biological activity of human VEGF 2! N-Methylnitrosourea induced breast cancer measurements with magnetic resonance imaging, ultrasonography, and another one the. Every cases, thus the tumor volume calculation caliper of respiratory movement was minimal though all the three diameters can be created width. And lower limbs to identify an equation that can be obtained by proper of. And mammography Moon, R.C and fractionation of the water due to the collaboration between Medical and... Equals its width, as seen in Figure 3 the skin irreversible on! Not measured as only width and length changes will the mice antibody immunohistochemistry staining to calculate depth. Protocols can be obtained by proper handling of the day, and another one on the day!

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