Can the Kuznetsov Model Replicate and Predict Cancer Growth in Humans? Even though all the three diameters can be measured, the estimation of the volume has quite a large error. In the case of Phase III/3 and Phase IV, period of time was specified according to the previous phases (Phase I and Phase III/1); mice were sacrificed on the 23rd day of the experiment. All mice were implanted with HT-29 human colorectal adenocarcinoma. Wrote the paper: JS ZS PK LK. Tumor volume in subcutaneous mouse xenografts measured by microCT is more accurate and reproducible than determined by 18 F-FDG-microPET or external caliper. 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. Hoffman-Goetz, L. et al. Provided by the Springer Nature SharedIt content-sharing initiative, Bulletin of the National Research Centre (2022), Lab Animal (Lab Anim) In another, 7,286 tumors were measured and 99.97% of those exhibited smaller heights than widths. 54, 401414 (1975). 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. However mice which were treated with a quasi-continuous therapy (one-tenth dose of control dose spread over 18 days, i.e. CA Cancer J. Clin. ISSN 1548-4475 (online) obtained using vernier calipers (c.c) Vol. Figure 2. Figure 3. https://doi.org/10.1371/journal.pone.0142190.g007. Tumor segmentation by TumorImager-2TM. Average of tumor volumes for every measurement days of the experiment can be seen in Fig 8. Tumor Volume Measurement Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. Ultrasonography as the Gold Standard for In Vivo Volumetric Determination of Chemically-induced Mammary Tumors. Tumor cells form and expand subcutaneously in the cavity they are injected, into between the layers of the skin. The parameters V m = 83 mm 3, = 0.84 and = 0.21 from the literature were used [].. For \( {y}_i^j \) eqs. Yes 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. (Budapest, Hungary). 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. A possible solution for height approximation [23] is: In several recent studies ([21, 22]), tumor volume is calculated assuming ellipsoid shape: 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. CAS Internet J. Surg. https://doi.org/10.1371/journal.pone.0142190.g004. Berg, W.A. Yes PMID: 11208850. They found that caliper and ultrasonography measurements were significantly correlated but that tumor volumes calculated using different formulas varied substantially. Our results provide a theoretical background for a much more effective bevacizumab treatment using optimized administration. Figure 15. 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. 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). 19, 6170 (1989). Statistical evaluations of agreement between two methods for measuring a quantitative variable. This formula was the starting point of our examination to find an appropriate mathematical model. 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. Designed by Analyzed the data: JS ZS PK DG DAD LK. Bethesda, MD 20894, Web Policies Yes Clin. Under these conditions, the formula for the volume of a tumor becomes. The variables for the volume of a tumor, as measured by a caliper, are determined by a, b, and c in Figure 1, where length L is 2a, width W is 2b, and height H is c. VT, the volume of a tumor is determined by. PubMedGoogle Scholar. Breast cancer measurements with magnetic resonance imaging, ultrasonography, and mammography. J. Clin. 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. Diagnostic accuracy of mammography, clinical examination, US, and MR imaging in preoperative assessment of breast cancer. 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. calipers and Water Displacement methods Tumor mimicking objects Vol. 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. National Library of Medicine Accurately measure the tumor (in cm) using a caliper. The width of a fully formed tumor will be much larger than its height. Tumor growth can take place under such conditions; however delivery of chemotherapeutic drugs is obstructed. 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. Based on the experimental data, model identification can be carried out which describes the mathematical model of the investigated biological process. Faustino-Rocha AI, Gama A, Oliveira PA, Vanderperren K, Saunders JH, Pires MJ, Ferreira R, Ginja M. Life Sci. & Russo, I.H. (8) Pritt, B., Ashikaga, T., Oppenheimer, R.G. Measurement by Caliper In order to estimate tumor volume by external caliper, the greatest longitudinal diameter (length) and the Mice were monitored daily by personnel experienced in recognizing signs of morbidity (illness, injury, or abnormal behavior) also in weekends and holidays. endobj Epub 2014 May 28. Mammary tumors similar to those observed in women can be induced in rats by intraperitoneal administration of N-methyl-N-nitrosourea. 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%. The authors measured dimensions of rat mammary tumors using a caliper and using real-time compound B-mode ultrasonography and compared the calculated tumor volumes with the real tumor volume to identify the formulas that gave the most accurate volume calculations. Significance of rat mammary tumors for human risk assessment. 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. To validate our results which come from the experiments where mouse tumor vascularization was inhibited with humanized VEGF, we evaluated the results of Phase IV, where immunocompromized (SCID) mice were used with human colorectal adenocarcinoma (HT-29) xenografts. . (6) (7). The height and topography of the tumor is not taken into account in a caliper measurement. Figure 13. Nevertheless the result of our study shows that the effectiveness is even better. Since 2004, the target therapy of bevacizumab (Avastin) is widely used to treat colorectal [9], kidney [10], cervical [34], ovarian [35], non-small cell lung cancers [5], melanoma [14] and certain brain tumors (e.g. The dose depends mainly on weight. In this study, the authors measured dimensions of rat mammary tumors using a caliper and using real-time compound B-mode ultrasonography. The cause of death was tumor toxicity; however, none of the clinical criteria for euthanasia could be observed at these animals. This estimation has the same disadvantage as ellipsoid estimation, i.e. Parkin, D.M., Bray, F., Ferlay, J. Fornage, B.D., Toubas, O. Caliper Measurement. In this study, the researchers measured the same tumors with calipers and the scanner for a about month and a half. Cancer Inst. Treat. The volume calculation algorithm relies on the surface interpolated based on the surrounding healthy tissue. Tumor volumes are calculated from digital caliper raw data by using the formula:Volume (mm3) = (l x w2) / 2. One common measure of efficacy is the T/C ratio, the ratio of tumor volume in control versus treated mice at a specified 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. Verma, R. et al. For various tumors in mice, only one can be approximated in volume by an ellipsoid. Scientific Reports Preclinical evaluation of LU 79553: a novel bis-naphthalimide with potent antitumor activity. 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. Figure 14. HHS Vulnerability Disclosure, Help Consequently, when tumor mass data is unavailable (during the experiment), tumor volume value can be validated with MRI; in that way outlier data points (which were calculated using the two-dimensional mathematical model) can be filtered out. Tumor morphology was investigated using standard Haematoxylin Eosin staining on the samples stored in formalin. In this case, tumor volume has to be calculated in the following way: Google Scholar. MeSH Mammary tumors seemed to take on an oblate spheroid geometry. produced by the TumorImager-2TM so that the animal is aligned under the mask each time similarly to the previous scan. Lee, J., Koh, D. & Ong, C.N. Comparison of clinical assessment, mammography and ultrasound in pre-operative estimation of primary breast-cancer size: a practical approach. (Fig 2). Comparison of volume measurement results between four users. Controller-based therapy has the obvious advantage against e.g. For both one has to have the ease of hand and get used to manipulation of the instrument. . Comp. Modulation of mammary tumor vascularization by mast cells: Ultrasonographic and histopathological approaches. and JavaScript. When the tumors became palpable, measurements of tumor volume were performed (with calipers) once per week. Cancer 83, 621628 (1998). 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). The tumor can be more and sometimes less visible or popped up from under the skin. Cancer Res. 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. BMC Med. To reduce the time of analysis one could e.g. et al. 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). 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. This process not only deforms the tumor mass but also creates undesirable pain on the animal. 2001 Jan 15;19(2):551-7. doi: 10.1200/JCO.2001.19.2.551. 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. Tumor volume was calculated by the modified ellipsoidal formula: V = (Length Width 2) . No, Is the Subject Area "Mathematical models" applicable to this article? Better results can be obtained by proper handling of the mice. A caliper only digitizes the length and width of the tumor. The effectiveness of the quasi-continuous (daily) 1/180 dosage (1.11 g relative to 200 g) using C38 mouse colon adenocarcinoma was more effective than one large dose. Forbes, D., Blom, H., Kostomitsopoulos, N., Moore, G. & Perretta, G. Euroguide: On the Accommodation and Care of Animals Used for Experimental and Other Scientific Purposes (Federation of European Laboratory Animal Science Associations, London, 2007). J. Using a caliper, growth of the tumor in height is not measured as only width and length changes will affect the calculated volume. Most of the operators in these studies were highly experienced in caliper measurements, but they only had one day of training in scanner measurements. In this study, the authors measured dimensions of rat mammary tumors using a caliper and using real-time . Value of prostate volume measurement using transabdominal ultrasonography for the improvement of prostate-specific antigen-based cancer detection. et al. The obtained data include height and topography changes. Determining tumor volume is a useful and quantitative way to monitor tumor progression. Our results for the case group (daily, quasi-continuous small amount administration) and the control group (one big dose according to the protocol) are First of all, our hypothesis according to the importance of administration is proved. to calculate several estimates of tumor volume using the equations for the volume of a sphere ([4 /3]r3), Here r is average of a, b and c the volume of an 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 . In addition, the root mean square, R2 values under the linear regression equations in Figure 15. symbolize the precision of the data. The study was carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Due to the collaboration between medical doctors and biomedical engineers, model-based treatment protocols can be created. Examining the relationship between MRI-measured tumor volume and tumor mass values, we have found a very strong linear correlation (R = 0.998, R2 = 0.996, p < 0.0001). 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. 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. In one trial, 208 tumors were measured, and 98.94% of those tumors exhibited much smaller heights than widths. Finding the mathematical relationship between MRI-measured tumor volume and tumor mass creates the possibility to estimate tumor volume from caliper-measured data. Therefore, its formula will always overestimate the tumor volume until the height equals its width, as seen in Figure 3. In Phase I, 12 mice were implanted with C38 colon adenocarcinoma. On the bottom left graph in Fig. Pathol. Notice that the caliper-based measurements have a larger standard deviation. Each dot, in addition to signifying a real-life tumors width and height, also signifies through the right y-axis what percentage of a caliper-based measurement with the same width it is. One can find datasets in Table 3. Tumor volume was measured in two different ways. In addition, the mice were weighed . Comput. 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. Ultrasonographic, thermographic and histologic evaluation of MNU-induced mammary tumors in female Sprague-Dawley rats. 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. Mammary tumors seemed to take on an oblate spheroid geometry. 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