Timing wise both methods perform the same. The manipulation of the handheld tool is at least as easy as holding a measurement caliper. In this study, the authors measured dimensions of rat mammary tumors using a caliper and using real-time . PubMedGoogle Scholar. Figure 3. We have found that mice which have received therapy had tumor with irregular, and in several cases berry-shaped structure, especially when reaching large volume. Experimentally induced mammary tumors in rats. Determining tumor volume is a useful and quantitative way to monitor tumor progression. CAS The TM900 also stores an optical image in the measurement data base. 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. These together with the tumor shape and all obtained data can easily be traced and consulted afterwards. According to the Xenograft tumor model protocol [20], tumor volume has to be calculated using the following formula: 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. We have administered 10 mg/kg body weight intraperitoneally, which means 200 g bevacizumab per a mouse, since the mass of the mice in the experiment was approximately 20 g (in the case of C57Bl/6 and SCID mice as well). 16 (2008). Carlsson, G., Gullberg, B. It then segments the tumor boundary (red area surrounded by the yellow boundary in Figure 12.) Role of real-time sonography in assessment of breast diseases: a review of 200 cases (Abstr). Clinical criteria that establish when the endpoint have to be carried out: a) if tumors contributed to a gain of >20% in body weight compared to controls at the same time point; b) tumors that ulcerate, become necrotic or infected; c) any animal found unexpectedly to be moribund, cachectic, or unable to obtain food or water. For ultrasonography measurements, we calculated tumor volume . Radiology 254, 110118 (2010). Department of Control Engineering and Information Technology, Budapest University of Technology and Economics, Budapest, Hungary, Affiliation Due to the collaboration between medical doctors and biomedical engineers, model-based treatment protocols can be created. The results presented here were provided by them. Pritt, B., Ashikaga, T., Oppenheimer, R.G. This process slightly stretches the body and deforms the tumor. Lee, J., Koh, D. & Ong, C.N. In this phase, 5 immunocompetent mice in control group, and 9 immunocompetent mice in case group were used. Controller-based therapy has the obvious advantage against e.g. No, Is the Subject Area "Mathematical models" applicable to this article? calipers and Water Displacement methods Tumor mimicking objects Vol. Mice in Phase III/3 control and case groups, and mice in Phase IV case1 and case2 groups received bevacizumab. There are no further patents, products in development or marketed products to declare. (Budapest, Hungary). & Morel, M. Clinical, mammographic, and sonographic determination of preoperative breast cancer size. & Pisani, P. Global cancer statistics, 2002. In Phase I, Phase II and Phase III, eight weeks old male C57Bl/6 mice with implanted C38 mouse colorectal carcinoma was used. Using the above mentioned iterative method, the resulted equation is Considering the possibility of precise tumor volume determination and the effective quasi-continuous drug administration, it opens a new treatment choice based on closed-loop control. 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 size of maximum tumor volumes observed in our study fulfills the requirements of Hungarian animal experimental research protocol. 37, 19 (1996). Radiology 233, 830849 (2004). In one trial, 208 tumors were measured, and 98.94% of those tumors exhibited much smaller heights than widths. Careers. et al. Frozen samples were used to create 15 m frozen cuts. Consequences are manifold. J. Nucl. ANOVA test showed significant difference between these means (p = 0.041, using 0.05 level of significance). Tumor volume in subcutaneous mouse xenografts measured by microCT is more accurate and reproducible than determined by 18 F-FDG-microPET or external caliper. Bevacizumab administration was started on the 7th day in both cases. The usual administration is via intravenous infusion; once every 2 or 3 weeks. 12 immunocompetent mice were transplanted subcutaneously with C38 colon adenocarcinoma, and 11 immunocompetent mice were injected intramuscularly with B16 melanoma. One of them died on the 18th day, and another one on the 23rd day. Tumor volumes ranged from 0.5 cc to 187.9 cc, with a median of 21.8 cc. 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. Russo J, Russo IH, Rogers AE, van Zwieten MJ, Gusterson B. Toxicol Pathol. where V m is the measurement threshold that represents the smallest measurable tumor volume using a caliper. 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. Therefore, its formula will always overestimate the tumor volume until the height equals its width, as seen in Figure 3. The last step is to find the f constant of the two-dimensional mathematical model for tumor growth without therapy (Phase I). We compared the volumes, areas . In Phase I, 12 mice were implanted with C38 colon adenocarcinoma. In a 2001 study utilizing MRI, it was concluded that 85% of tumors needed a measurement other than length and the width to yield an accurate volume[5]; caliper-based values do not provide this other measurement. Figure 19. Objectives: Volume measurement of subcutaneous xenograft tumors in nude mice models is an important metric to assess tumor growth or response to therapy. 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 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 . Starting with f = 1, we have investigated the goodness of the fitting, using an iterative method. In Phase IV, eleven weeks old male SCID mice with implanted HT-29 human colorectal adenocarcinoma was used. Tumor volume (and the third diameter) has to be approximated, assuming a certain shape for the tumor. In longitudinal studies, sequential measurements of tumor volume with a non-invasive method are essential. The cause of death was tumor toxicity; however, none of the clinical criteria for euthanasia could be observed at these animals. Typical side-effects and adverse events are arterial and venous thromboembolic events, bleeding, hypertension, febrile neutropenia, infections, proteinuria, mucositis, and hand-foot syndrome. Figure 8. . A smaller standard deviation in a set of measurements suggests a lesser possibility of error. PLoS ONE 10(11): (Inbred C57Bl/6 mice from our institute were used throughout the studies.) Sport. Yes r>12TzPn 4x PUj50"pJ{{>y{.mn|Cvz{PP5x kH:5:YM.gn?c[J8oQWkR_!X/C@6P@WT=gO5Sn>om}&SI cyT>E"TnkhSju>~yVOm^C~0__ww@ y[xQr33?6O~hZcR{{u]=O5T. 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. 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. Bevacizumab (Avastin) [1] is an exogenous inhibitor, which inhibits the biological activity of human VEGF [2]. Figure 18. Comparison of clinical assessment, mammography and ultrasound in pre-operative estimation of primary breast-cancer size: a practical approach. ISSN 1548-4475 (online) 2022 Dec 20;3(12):100852. doi: 10.1016/j.xcrm.2022.100852. 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. Can the Kuznetsov Model Replicate and Predict Cancer Growth in Humans? Statistical evaluations of agreement between two methods for measuring a quantitative variable. Treat. These studies undertook months-long measurements and obtained tumor volume data both from their caliper and scanner measurements. 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. Front Chem. & Lin, C.A. Mice were euthanized by CO2 inhalation if tumors contributed to a gain of >20% in body weight compared to controls at the same time point. The effectiveness of bevacizumab administration was examined by statistical analysis. Would you like email updates of new search results? An official website of the United States government. Secondly, the aspect of side-effects are not inconsiderable. BMC Medical . https://doi.org/10.1371/journal.pone.0142190.g007. In the case of HT-29 adenocarcinoma, the daily treatment with one-twelfth total dose resulted in significantly smaller tumors than the protocol-based treatment (p = 0.038). Figure 7. Effects of tamoxifen and melatonin on mammary gland cancer induced by N-methyl-N-nitrosourea and by 7,12-dimethylbenz(a)anthracene, respectively, in female Sprague-Dawley rats. Determining tumor volume is a useful and quantitative way to monitor tumor progression. Autopsy revealed only minimal local tumor; however death was not caused by tumor. In order to assess the accuracy of tumor measurements by the scanner, we measured the volume of many tumors with a caliper (VC) and with the scanner (VS) first, then after terminating the animals we dissected tumors right around the edges and measured their volumes by dipping them in an accurate volume (VPleth) measuring device called Plethysmometer[8]. A smaller diameter mask will help to position the tumor in the center of the scan, but it will not alter this effect. This results in the inclusion of sections of the parallelepipeds volume that does not exist in the actual tumor. 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. Bevacizumab is an exogenous inhibitor which inhibits the biological activity of human VEGF. & Moon, R.C. 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. These model-based protocols can be more effective than the current ones, since they provide individual treatment for the patients. The authors declare no competing financial interests. %PDF-1.4 Using a caliper, growth of the tumor in height is not measured as only width and length changes will . The effectiveness strongly depends on the administration, and a drug which is effective on a molecular level can be applied in a less effective way because of the incorrectly chosen administration. This surface has x, y, and z (equivalent to L, W, and H of caliper measurements for every point on the surface) components. The dose depends mainly on weight. Funding: This work was supported by Hungarian Scientific Research Fund (OTKA), http://www.otka.hu/en, No: K-112993 (Jnos) and Bolyai Research Scholarship of the Hungarian Academy of Sciences, http://mta.hu/cikkek/?node_id=26057, No: 425_12. Another approach is to utilize the scan images (Figure 14.) Tumor growth was investigated without therapy and with antiangiogenic therapy (using bevacizumab [15]). 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. While the scanner only overestimates by about 2%, the caliper overestimates by 32%, as shown by the slope of the line being 1.32. 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 As the height values of the tumors deviate from those of the width, the caliper-based volume values of those tumors begin to mirror real-life measurements less closely. (6) (7). In Figure 15., the linear regression equation for the best-fit line for VPleth values on the y-axis along with VC and VS values would be approximately y x, or y 1.00x + 0.00. Lab Animal In Phase I, 10 mice were sacrificed at the 24th day of the experiment. 54, 401414 (1975). In the meantime, to ensure continued support, we are displaying the site without styles Eichelerger, L.E. 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. The athymic (nude) mouse is a useful model for studying the biology and response to therapies of human tumors in vivo. 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 volumes are calculated from digital caliper raw data by using the formula:Volume (mm3) = (l x w2) / 2. https://doi.org/10.1371/journal.pone.0142190.g008. 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