Bevacizumab administration was started on the 7th day in both cases. In addition, we have found that the quasi-continuous administration of bevacizumab is effective against tumor growth of C38 colon adenocarcinoma, in contrast . The problems with tumor volume measurements by calipers, 3.1 Tumor growth: Height is not equal to the width of the tumor, 3.3 Caliper measurements are time-consuming, 3.4 Caliper measurements ignore a larger volume, https://ugobasile.com/products/catalogue/pain-and-inflammation/plethysmometer, A Structured Light Based Laboratory Animal Subcutaneous Tumor Scanning System. 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. No, Is the Subject Area "Magnetic resonance imaging" applicable to this article? This process slightly stretches the body and deforms the tumor. produced by the TumorImager-2TM so that the animal is aligned under the mask each time similarly to the previous scan. Yes In this way, the targeted therapy can be used in a much more individualized form. & Robinson, S.P. We have found that there is significant difference between the means of the samples (p = 0.002, using 0.05 level of significance). In Phase I, Phase II and Phase III, eight weeks old male C57Bl/6 mice with implanted C38 mouse colorectal carcinoma was used. A direct and real 3D volume of the xenograft will then be calculated. Radiology 254, 110118 (2010). PubMed Central In Phase III/3, case group members received one-tenth dose of control dose intraperitoneally spread over 18 days. 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 . 60, 21012103 (2000). Folia Biol. 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. In this study, the authors measured dimensions of rat mammary tumors using a caliper and using real-time . <> stream One can find datasets in the last column of Table 2. Caliper Measurement. Most, if not all, tumors do not fit into this category; this discrepancy results in caliper-based volume measurements including sections that do not exist in the actual tumor, or an overestimation of tumor volume measurement. The width of a fully formed tumor will be much larger than its height. The mathematical relationship between MRI-measured tumor volume and mass was investigated to estimate accurate tumor volume using caliper-measured data. 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. The authors declare no competing financial interests. This formula was the starting point of our examination to find an appropriate mathematical model. & Moon, R.C. The caliper mean-percent-error is 10.6%, nearly twice that of the scanners mean-percent-error of 4.6%. . Disclaimer. A possible solution for height approximation [23] is: A tumor image, its 3D shape and all geometrical data are automatically calculated and stored. https://doi.org/10.1371/journal.pone.0142190.t003. For the most precise result, tumor mass values, which were measured at the end of the experiment, were compared in the statistical analysis. In each case the reference value is the MRI-measured tumor volume. The results presented here were provided by them. Notice that the caliper-based measurements have a larger standard deviation. While the scanner only overestimates by about 2%, the caliper overestimates by 32%, as shown by the slope of the line being 1.32. This means that continuous, low dose antiangiogenic factor (VEGF) administration is needed. Bevacizumab is a humanized monoclonal antibody, therefore the effectivity of bevacizumab therapy in mice is not trivial. 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). x|jY!==g'{oZ6-JiZ Possible mechanisms mediating an association between physical activity and breast cancer. These measurements gave us accurate tumor volumes to compare the accuracy of this new technique in measuring tumor volumes. Please enable it to take advantage of the complete set of features! Article Breast cancer measurements with magnetic resonance imaging, ultrasonography, and mammography. 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. The system includes database, data management and processing software and can be complemented with a weight . In addition, the root mean square, R2 values under the linear regression equations in Figure 15. symbolize the precision of the data. Tumor volume was measured with digital caliper. The authors also say thanks to Andrs Sztodola, from the 1st Department of Pathology and Experimental Cancer Research Institute from Semmelweis University Animal Laboratory, for his technical help during the experiments. Department of Control Engineering and Information Technology, Budapest University of Technology and Economics, Budapest, Hungary, Affiliation Med. et al. Conceived and designed the experiments: ZS JS. No, Is the Subject Area "Mathematical models" applicable to this article? This helps to calculate accurate tumor volume from caliper measured data which will be useful for further animal experiments and as a consequence no small MRI measurements will be needed. This results in the inclusion of sections of the parallelepipeds volume that does not exist in the actual tumor. HHS Vulnerability Disclosure, Help The reason for choosing this type of administration was as follows: a) we wanted to use a daily dose in order to investigate the biological effect of frequent impulse-like control signal for the future controller design; b) we wanted to examine such a low dose which has practically no side-effect but presumably is still effective. Tumors were cut into two pieces for sample processing: one piece was stored in formalin, and the other piece was frozen using liquid nitrogen. Phase I and Phase III/3 control groups are not significantly different (p = 0.572), while Phase I and Phase III/3 control groups are significantly different (p = 0.002). Ultrasonographic, thermographic and histologic evaluation of MNU-induced mammary tumors in female Sprague-Dawley rats. 2023 Jan 20;42(1):25. doi: 10.1186/s13046-022-02578-w. Zhao R, Chen P, Qu C, Liang J, Cheng Y, Sun Z, Tian H. Cell Death Discov. Bizberg Themes, By Memorial Sloan Kettering Cancer Center. by US (c.c) Vol. Result of Phase III/2 was that the effectiveness of the small amount of quasi-continuous dosage is comparable with the effectiveness of one large dose [23], however this result is only based on caliper-measured data. Open Access B){00)Y$Ixlr{dYe}#@ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ ,^X_zN5:EZN]zM^k /Wu^ZZi#Ju.!L!z@u*kUim|+aZmjth-}z5'^|= 4L1_]qVZV*h@! Tumor cells form and expand subcutaneously in the cavity they are injected, into between the layers of the skin. In the case2 group, one mouse died on the 8th day, before the therapy (bevacizumab administration) started. The TM900 also stores an optical image in the measurement data base. Exer. Wrote the paper: JS ZS PK LK. Experimentally induced mammary tumors in rats. Secondly, the aspect of side-effects are not inconsiderable. 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. On the bottom left graph in Fig. Fornage, B.D., Toubas, O. in The Laboratory Mouse (eds. Clarys, J.P. & Marfell-Jones, M.J. Soft tissue segmentation of the body and fractionation of the upper and lower limbs. In several recent studies ([21, 22]), tumor volume is calculated assuming ellipsoid shape: The authors say special thanks to Katalin Dezs MD. Additionally, we explore the impact of six different tumour . This means that the daily treatment with one-twelfth total dose resulted in significantly smaller tumors than the protocol-based treatment. In another, 7,286 tumors were measured and 99.97% of those exhibited smaller heights than widths. 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. The usual administration is via intravenous infusion; once every 2 or 3 weeks. (6) (7). Biol. NCI CPTC Antibody Characterization Program. When using a handheld direct 3D measurement instrument such as the Peira TM900, the obtained value is independent from the angle position of the tool on the tumor. 47, 510 (2001). For more information about PLOS Subject Areas, click Google Scholar. Citation: Spi J, Kovcs L, Drexler DA, Kocsis P, Gajri D, Spi Z (2015) Tumor Volume Estimation and Quasi-Continuous Administration for Most Effective Bevacizumab Therapy. Lab Animal . The effectiveness of bevacizumab administration was examined by statistical analysis. Evaluation of prostate volume by transabdominal ultrasonography with modified ellipsoid formula at different stages of benign prostatic hyperplasia. 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. McCormick, D.L., Adamowski, C.B., Fiks, A. It was on the 10th day, since HT-29 colorectal adenocarcinoma grows slower in mice than C38 colon adenocarcinoma. endobj In Phase IV, the first measurement occurred when the tumors have reached an average volume of 5060 mm3 (according to the xenograft protocol [20]). Numerical result can be found in Table 2, and Fig 5 presents graphical results. 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. Mrio Ginja. Under these conditions, the formula for the volume of a tumor becomes. Results of this phase can be found in [26]. Breast Cancer Res. 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. These images also provide extra morphological information about the tumor growth and the effect of the compounds on tumor behavior. Better results can be obtained by proper handling of the mice. Quantity of the optimal solvent administration was also examined in this subphase. The aim of this article is therefore to explain of the tumor volume formula and the problems associated with the caliper measurements. One can find datasets in Table 3. 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. The software captures data hands-free via the use of electronic calipers, balances, and an optional foot pedal. 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. Frozen samples were used to create 15 m frozen cuts. These together with the tumor shape and all obtained data can easily be traced and consulted afterwards. Analyzed the data: JS ZS PK DG DAD LK. Fornage, B.D., Toubas, O. FOIA Tumor volumes are calculated from digital caliper raw data by using the formula:Volume (mm3) = (l x w2) / 2. Small MRI measurements were done in the Preclinical Imaging Center of Gedeon Richter Plc. PASW Statistics 18 (SPSS Statistics, IBM, USA) and Matlab R2009b (MathWorks, USA) were used for statistical analysis. Make sure you get accurate measurements for length, width and height. Bousquet, P.F. Tumor volume was measured with digital caliper as well. This site needs JavaScript to work properly. 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. 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. tumor height has to be approximated. The means of the samples are mpIV_control = 0.65, mpIV_case1 = 0.70, mpIV_case2 = 0.46. 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. Animals were carried out in the most humane and environmentally sensitive manner possible; in addition the 3Rs principle (replacement, refinement, reduction) was adequately implemented according to the Directive 2010/63/EU of the European Parliament. 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). Tievsky AL, Ziegler RB, Salhus MR, Weisskoff R. Comparison of diameter and perimeter methods for tumor volume calculation. and JavaScript. 39, 720 (1996). 2 0 obj Preclinical Imaging Center, Gedeon Richter Plc., Budapest, Hungary, Affiliation & Weaver, D.L. Calculate the correct dose of STELFONTA once you have the volume of the tumor in cm 3, using the Dose Calculator. [45] have found that the combination of low-dose cyclophosphamide and ginsenoside Rg3 therapy can be more effective than the normal administration. In the top-left graph (Figure 19. Yes 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. Ergonomics 37, 217229 (1994). The TumorImagerTM line of scanners by Biopticon Corporation fixes these problems by keeping the animals relaxed during measuring and yielding measurements closer to actual values than caliper-based measurements. Levenes test showed that the sample variances are equal (p = 0.108). 2022 Dec 20;3(12):100852. doi: 10.1016/j.xcrm.2022.100852. Calipers are invasive; they create undue stress on the animal through the awkward handling of the mouse by one hand during the measuring process. n5). Mammary tumors seemed to take on an oblate spheroid geometry. 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. Value of prostate volume measurement using transabdominal ultrasonography for the improvement of prostate-specific antigen-based cancer detection. P`e+"JF^ : 4:p7]k = Jy}! the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in The tumor volume calculation was executed using the formula V = (W2 L)/2 for caliper measurements, where V is tumor volume, W is tumor width, and L is tumor length . . 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. 37, 19 (1996). Tumor volume measurement cannot happen right after tumor implantation. 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. Bevacizumab is an exogenous inhibitor which inhibits the biological activity of human VEGF. Google Scholar. To reduce the time of analysis one could e.g. and transmitted securely. et al. 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). (8) YH29407 with anti-PD-1 ameliorates anti-tumor effects. 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. Affiliation For both one has to have the ease of hand and get used to manipulation of the instrument. Radiology 157, 54 (1985). First of all, our hypothesis according to the importance of administration is proved. A typical comparison of tumor volume measurements by TumorImager-2TM with calipers. contracts here. Unauthorized use of these marks is strictly prohibited. An average penny has a diameter of 19 mm and a height of 1.27 mm, yielding a volume of 360.1 mm3. Because the industrys caliper-based formula allows for these inclusions in nonexistent volumes more often than not, it yields inaccurate measurements, which can confuse. 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). Tumor growth was investigated without therapy and with antiangiogenic therapy (using bevacizumab [15]). Figure 15. A caliper only digitizes the length and width of the tumor. M}{Gt{zj|&cXx[k?CZ ~AjTxMr0 '~ix$mj/)9?$ t-o6MkVXs's}^E6-^_Yrv#w&r7w@WsQs]#G g$Cn. J. Clin. Figure 18. However, most serious questions are: for how long and continuous or not? The advantage of this model is that there is no need to approximate tumor height (which could result in error). 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tumor volume calculation caliper