105, 2023 (1983). 35, 18341840 (2003). In this phase, control group members received no treatment; case1 group members received one 200 g bevacizumab dose; while case2 group members received 1.11 g bevacizumab daily for 15 days (the total dose of case2 group members is the one-twelfth dose of case1 group members). Article Data Availability: All relevant data are within the paper. Davis, P.L. Lab Animal Cancer Inst. recurrent glioblastoma (rGBM) [36]) as a first or second line treatment, usually in combination with chemo- or immunotherapy. Table 1. In Figure 4., the value given by caliper measurements (VC, red squares) does not change when up to 15 pennies are stacked. Fj^P;7? Bookshelf & trukelj, B. N-methylnitrosourea induced breast cancer in rat, the histopathology of the resulting tumours and its drawbacks as a model. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. It was on the 10th day, since HT-29 colorectal adenocarcinoma grows slower in mice than C38 colon adenocarcinoma. This process not only deforms the tumor mass but also creates undesirable pain on the animal. 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. 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. A graph depicting tumor volume in mm3, as measured by a caliper compared to its actual volume, vs. days. . Verma, R. et al. 2022 Dec 5;10:998013. doi: 10.3389/fchem.2022.998013. The aim of this article is therefore to explain of the tumor volume formula and the problems associated with the caliper measurements. In this study, the authors measured dimensions of rat mammary tumors using a caliper and using real-time compound B-mode ultrasonography. sharing sensitive information, make sure youre on a federal 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. Tumor growth Tumor regression Number of Number of volume volume doublings Percentage additional halvings: Decrease in Percentage decrcase in increase Volume Area" Diameterb volume doubling number Volume Area" Diameterb Doubling of Halving of Volume 1 .o 100.0 58.7 26.0 Volume 1 .o 50.0 37.0 20.6 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. In Phase III/3, control group members received 200 g bevacizumab (with 455 l 0.9% NaCl solution) in one dose intraperitoneally on the 3rd day and on the 21st day. 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. & Wieder, H. Monitoring chemotherapy and radiotherapy of solid tumors. Treat. Experimentally induced mammary tumors in rats. 37, 331337 (2011). Yes bowel, and kidneys is when the tumor is located in . Combining Mechanisms of Growth Arrest in Solid Tumours: A Mathematical Investigation, Dramatic increase in volume versus length of invasive ductal carcinoma mimicking intramammary lymph node in a small nodular lesion, Alteration in Inflammasome Cytokine Profile and Functional Plasticity of Macrophage Phenotype in Arsenic(0) Nanoparticle Treated Murine Fibrosarcoma, Tumoral CD105 promotes immunosuppression, metastasis, and angiogenesis in renal cell carcinoma, Cancel That is independent from the use of a direct optical 3D measurement tool or a caliper. To overcome all of these difficulties (continuity of the administration and side-effects), model identification should be determined and then a control algorithm (controller) can be designed for the created mathematical model. From the abovementioned methods, the consequence is that the promising new direction in tumor volume evaluation is the dimension reduction, namely to find a statistical constant which can replace the need of measuring the tumor height. Yes Biol. The site is secure. government site. 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). Studies using other methods of imaging have exposed the problems that calipers pose. J. Natl. 8600 Rockville Pike tumor height has to be approximated. (4). 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. and transmitted securely. In Phase III/3, case group members received one-tenth dose of control dose intraperitoneally spread over 18 days. In order to reduce such deformations on the tumor during measurement, it is possible to reduce the stress on the body of the animal by using two hands. contracts here. The dose depends mainly on weight. This process slightly stretches the body and deforms the tumor. The second subphase (Phase III/2) was similar to Phase III/1, mice received the same dosage of bevacizumab as in Phase III/1, however sample size was higher (6 immunocompetent mice in control group, 12 immunocompetent mice in case group), and bevacizumab administration started earlier, on the 3rd day of the experiment. In the experiment 9.4 Tesla field strength Varian small-animal MRI was used. Clipboard, Search History, and several other advanced features are temporarily unavailable. Typical side-effects and adverse events are arterial and venous thromboembolic events, bleeding, hypertension, febrile neutropenia, infections, proteinuria, mucositis, and hand-foot syndrome. 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]. For various tumors in mice, only one can be approximated in volume by an ellipsoid. After staining, fluorescence pictures were done from the slides using confocal microscope (BIO-RAD MRC-1024). Tumor volume was calculated by the modified ellipsoidal formula: V = (Length Width 2) . Traditionally their volume growth has been monitored by using a mechanical caliper. Therefore, optical imaging is . Westerlind, K.C. No animals were sacrificed before the experimental endpoint. YH29407 with anti-PD-1 ameliorates anti-tumor effects. 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%. 2009, 18 (2009). Secondly, the aspect of side-effects are not inconsiderable. The scanner-based measurements yield a higher correlation in this sense than caliper-based measurements. Breast Cancer Res. 120, 386391 (2003). 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 . Yes Figure 5. 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. Article 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. Determining tumor volume is a useful and quantitative way to monitor tumor progression. These model-based protocols can be more effective than the current ones, since they provide individual treatment for the patients. Monitoring tumor volume through a direct 3D measurement will include changes in all three directions, height, width and length thus resulting in more accurate realistic data. We have found in our previous study [32] that measurements without contrast agents resulted in high quality images, where tumor can be circumscribed precisely, thus the usage of contrast is unnecessary. The significant difference between quasi-continuous therapy (Phase III/3 case group) and tumor growth without treatment (Phase I) was proved with statistical analysis as well. Russo, J. Traditionally, caliper measurements are used to calculate tumor volume. Usually, 3.0 x 10 6 cells are needed per injection. Correspondence to These measurements gave us accurate tumor volumes to compare the accuracy of this new technique in measuring tumor volumes. 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]. Statistical evaluations of agreement between two methods for measuring a quantitative variable. 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). Tumor size was measured every 3 days using a digital caliper and computed according to the ellipsoidal calculation formula: V . A smaller standard deviation in a set of measurements suggests a lesser possibility of error. First is to find an appropriate mathematical model for tumor volume evaluation from caliper-measured data. It can be carried out in vivo during the experiment due to the subcutaneous localization of the tumor. The specific roles of these authors are articulated in the author contributions section. In the light of the above mentioned, linear curve fitting was carried out to find the mathematical relationship between MRI-measured tumor volume and tumor mass (Phase III/3 case and control groups). Tumor morphology was investigated using standard Haematoxylin Eosin staining on the samples stored in formalin. Figure 12. & Russo, I.H. Mammary tumors similar to those observed in women can be induced in rats by intraperitoneal administration of N-methyl-N-nitrosourea. calipers and Water Displacement methods Tumor mimicking objects Vol. Breast Cancer Res. Harris, R.E., Alshafie, G.A., Abou-Issa, H. & Seibert, K. Chemopreventive of breast cancer in rats by celecoxib, a ciclooxygenase 2 inhibitor. 47, 510 (2001). Examination of tumor growth belongs not only to the basic medical research, but to the biomedical engineering field as well. Accurately measure the tumor (in cm) using a caliper. b) Fluorescence picture was created using CD31 antibody immunohistochemistry staining to calculate vascularization area. Ergonomics 37, 217229 (1994). CA Cancer J. Clin. HHS Vulnerability Disclosure, Help In addition, we have found that the quasi-continuous administration of bevacizumab is effective against tumor growth of C38 colon adenocarcinoma, in contrast to protocol-based treatment. 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. Pathology of tumours in laboratory animals. 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). J Clin Oncol. Tumor cells form and expand subcutaneously in the cavity they are injected, into between the layers of the skin. Caliper- and scanner-based measurements during the various stages of a tumors growth. by water displace ment (c.c) Vol. Discover a faster, simpler path to publishing in a high-quality journal. Mammary tumors similar to those observed in women can be induced in rats by intraperitoneal administration of N-methyl-N-nitrosourea. Measure the three dimensions of peanut M&M's, serving as our similar-sized tumor surrogates, using vernier calipers. 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. 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). Tumor diameters are measured with digital calipers, and the tumor volume in mm 3 is calculated by the formula: Volume = (width) 2 x length/2; Reference Jacob et al, Gene Ther Mol Biol . Tumor volume was measured with digital caliper. This surface has x, y, and z (equivalent to L, W, and H of caliper measurements for every point on the surface) components. For this dataset, linear curve fitting was carried out (fitted linear curve) to find the mathematical relationship between MRI-measured tumor volume and tumor mass. Ultrasonography as the Gold Standard for In Vivo Volumetric Determination of Chemically-induced Mammary Tumors. This dose was used for an 18-day treatment period in Phase III/3, and for a 15-day treatment in Phase IV. In Phase I, 10 mice were sacrificed at the 24th day of the experiment. A caliper only digitizes the length and width of the tumor. Mol. & Hafstrm, L. Estimation of liver tumor volume using different formulasan experimental study in rats. and JavaScript. 2013 Oct;67(8):771-6. doi: 10.1016/j.biopha.2013.06.011. One can see that the two-dimensional mathematical model fits to the MRI-measured values, while the protocol-based values present totally different curve. Careers. An average penny has a diameter of 19 mm and a height of 1.27 mm, yielding a volume of 360.1 mm3. (8) The defined shape of an actual tumor (red) and the shape measured by a caliper (blue box). 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. One can find datasets in Table 3. Hoffman-Goetz, L. et al. Performed the experiments: JS ZS PK DG. Using the mathematical model, different dosage algorithms can be designed for antiangiogenic cancer therapy [1619]. 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). No, Is the Subject Area "Renal cancer" applicable to this article? However, it has to be taken into consideration that in several cases using antiangiogenic therapy, tumor shape is irregular (berry-shaped). All mice were implanted with HT-29 human colorectal adenocarcinoma. Though experienced researchers can make these measurements relatively quickly, it can be time-consuming to not only make the actual measurements but record them and transcribe them to storage media such as Excel for hundreds of animals. PhD from the 1st Department of Pathology and Experimental Cancer Research Institute from Semmelweis University, Budapest, for making the fluorescence pictures with confocal microscope. The size of maximum tumor volumes observed in our study fulfills the requirements of Hungarian animal experimental research protocol. This means that the daily treatment with one-twelfth total dose resulted in significantly smaller tumors than the protocol-based treatment. 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. PubMed For more information about PLOS Subject Areas, click Compute the volume assuming perfect ellipsoids. The obtained data include height and topography changes. Biol. If this surface intersects above the bottom of the tumor, then the volume estimation of the tumor will be smaller than the true value as can be seen from Figure 9. Hence, the first step has to be the vasculature normalization with the reconstruction of the balance of pro- and antiangiogenic factors. This formula was the starting point of our examination to find an appropriate mathematical model. Pairwise comparison was done by Tukeys honest significant difference test to find those samples, which have significantly different means. In addition, we have found that the quasi-continuous administration of bevacizumab is effective against tumor growth of C38 colon adenocarcinoma, in contrast . Using the above mentioned iterative method, the resulted equation is Tukeys HSD test resuled in significant difference between case1 and case2 groups (p = 0.038). They found that caliper and ultrasonography measurements were significantly correlated but that tumor volumes calculated using different formulas varied substantially. 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. e0142190. https://doi.org/10.1371/journal.pone.0142190.g001. Faustino-Rocha AI, Gama A, Oliveira PA, Vanderperren K, Saunders JH, Pires MJ, Ferreira R, Ginja M. Life Sci. 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