Cancer Res. Calculate the correct dose of STELFONTA once you have the volume of the tumor in cm 3, using the Dose Calculator. 120, 386391 (2003). Berg, W.A. The article discusses two results. 2022 Dec 5;10:998013. doi: 10.3389/fchem.2022.998013. constant low-dose therapy because in the case of controller-based administration, the control signal (administration dose) can vary from zero to the maximum tolerable dose according to the perceived tumor volume. Additionally, we explore the impact of six different tumour . Tumor was located in the last third of the back of the mouse in every case. Figure 19. In that caseeven though all the three diameters can be measuredthe estimation of the volume has quite a large error. 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. Tumor volume was measured with digital caliper as well. 12, 881885 (2005). 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. Figure 13. CA Cancer J. Clin. 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. ), the more correlated a given group (scanner or caliper estimations) is to the black line (r2 = 1), the more accurate the tumor volume measurements are. 1.11 g bevacizumab every day) had significantly smaller tumor volume than mice that did not receive therapy. 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. Modern Pathol. (3), Another relatively new but not widely used approach to estimate tumor volume is to assume hemi-ellipsoid shape [24]. Cancer Res. Provided by the Springer Nature SharedIt content-sharing initiative, Bulletin of the National Research Centre (2022), Lab Animal (Lab Anim) here. Timing wise both methods perform the same. Epub 2017 Mar 21. In this study, the authors measured dimensions of rat mammary tumors using a caliper and using real-time compound B-mode ultrasonography. 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. official website and that any information you provide is encrypted 29 September 2022, Bulletin of Mathematical Biology Pairwise comparison was done by Tukeys honest significant difference test to find those samples, which have significantly different means. 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. The problems with tumor volume measurements by calipers 3.1 Tumor growth: Height is not equal to the width of the tumor . Bevacizumab administration was started on the 7th day in both cases. 58, 264270 (2008). Preclinical evaluation of LU 79553: a novel bis-naphthalimide with potent antitumor activity. Determining tumor volume is a useful and quantitative way to monitor tumor progression. 20, the red dots that represent scanner-based measurements are closer to the black dotted (objective) line than the blue squares that represent caliper-based measurements. (6) (7). In addition, even though there is about a 20% difference between the low-dose treatment group for the scanner measurements, the caliper-based measurements do not show any effect for this dose. Girit, I.C., Jure-Kunkel, M. & McIntyre, K.W. Importantly, these measured size differences are real; they are not due to a miscalculation by the algorithm but due to the pressing of the tumor mass into the body. With constant width and length, the measured volume changes with the shape of the tumor. & Hafstrm, L. Estimation of liver tumor volume using different formulasan experimental study in rats. 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%. All surgery and sacrifice were performed under sodium pentobarbital anaesthesia (Nembutal, 70 mg/kg), and all efforts were made to minimize suffering. BMC Med. The specific roles of these authors are articulated in the author contributions section. Care should be taken not to stretch the mouse whether using one or two hands to hold the mouse during a scan. PubMed Tumors this large are typically beyond the maximum size allowed by the Institutional Animal Care and Use Committees protocols (IACUC). In this study, the authors measured dimensions of rat mammary tumors using a caliper and using real-time compound B-mode ultrasonography. 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. CAS Numerical result can be found in Table 2, and Fig 5 presents graphical results. Yes Therefore, its formula will always overestimate the tumor volume until the height equals its width, as seen in Figure 3. Small MRI measurements were done in the Preclinical Imaging Center of Gedeon Richter Plc. 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). Mammary tumors seemed to take on an oblate spheroid geometry. 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. No, Is the Subject Area "Magnetic resonance imaging" applicable to this article? No, Is the Subject Area "Renal cancer" applicable to this article? Google Scholar. In Phase II, the toxicology investigation of the applied angiogenic inhibitor (bevacizumab) was performed; there was no tumor implantation into mice in this phase. N-nitrosomethylurea as mammary gland carcinogen in rats. Measure the three dimensions of peanut M&M's, serving as our similar-sized tumor surrogates, using vernier calipers. Then we calculated the Coefficient of Variance between such measurements for both measurements to compare average inter-operator differences. Quantity of the optimal solvent administration was also examined in this subphase. 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. Even though we did not have a statistical analysis of volume loss due to the unmeasured part of tumors in caliper measurements, the lost volume could be higher than the scanner results. & Pisani, P. Global cancer statistics, 2002. A solution to these problems is the TumorImagerTM scanner. 26 December 2022, Bulletin of Mathematical Biology After sacrificing mice, tumors were removed, and their mass was measured. Firstly, since the tumor is assumed to be an ellipsoid shape, and the tumors morphology often deviates significantly from this as it grows, this method will produce errors as big as 18.4%. The other way to measure tumor volume is the usage of small animal MRI, a non-invasive in vivo technology giving the possibility of a more precise volume measurement [29]. Click through the PLOS taxonomy to find articles in your field. 2009, 18 (2009). Later in a study, when a tumor grows into larger masses, the shape of the tumor can differ greatly from an ellipsoid, as shown in Figure 7. This creates the possibility of further efficient therapeutic agent use (if any) or assists the more effective direct antitumoral effect of bevacizumab. Weber, W.A. Data Availability: All relevant data are within the paper. . This means that continuous, low dose antiangiogenic factor (VEGF) administration is needed. Eichelerger, L.E. . Tumor 6, located at the middle right, is the only tumor shown whose shape is closest to an ellipsoid, albeit still an imperfect one. 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. A study[4] (Figure 5.) As it was discussed above, the handling of animals by calipers measurements also suffers such deformations of the animal body during the measurements. In Phase III/3, control group contained 5 mice, case group contained 9 mice; all mice were implanted with C38 mouse colon adenocarcinoma. Another approach is to utilize the scan images (Figure 14.) Imaging 33, 2737 (2006). 17, 905910 (2004). The tumor number, from one to ten, is shown against the percent error. 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. The explanation of the effectiveness of low dose VEGF therapy is the following ([3944]). Bevacizumab (Avastin) [1] is an exogenous inhibitor, which inhibits the biological activity of human VEGF [2]. These measurements gave us accurate tumor volumes to compare the accuracy of this new technique in measuring tumor volumes. & Bullock, G.) 253257 (Elsevier Academic, Boston, 2004). Tumor growth was investigated without therapy and with antiangiogenic therapy (using bevacizumab [15]). 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 . Open Access The lines on the graphs have a slope of 1, signifying that it represents caliper-based measurements in which height equals width. The figure shows the results of a mouse (C4) from control group (first row), and a mouse (E9) from case group (second row). Fornage, B.D., Toubas, O. Controller-based therapy has the obvious advantage against e.g. Sport. Thus, caliper-based measurements, using the formula , are most accurate in real life for tumors in which height roughly equals width but prove less accurate as height becomes more unequal to width, as is the case with almost all real tumors. 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. The first column shows the tumor values which were calculated using the two-dimensional mathematical model; the second column represents the protocol-based tumor volumes. Breast Cancer Res. CAS HHS Vulnerability Disclosure, Help The closer the shape of the tumor is to a perfect ellipsoid, as in the region of the graph in which H closely W, the more closely caliper measurements mirror real-life measurements. The height and topography of the tumor is not taken into account in a caliper measurement. CAS Intrinsic susceptibility MR imaging of chemically induced rat mammary tumors: relationship to histologic assessment of hypoxia and fibrosis. Parkin, D.M., Bray, F., Ferlay, J. 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). 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. Wrote the paper: JS ZS PK LK. 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. When the tumors became palpable, measurements of tumor volume were performed (with calipers) once per week. . Comput. 2023 Jan 12;9(1):5. doi: 10.1038/s41420-023-01300-9. Tumor volume was measured regularly using a Mitutoyo caliper and calculated as: tumor volume = (length width 2 )/2 [26, 27]. (2), Whilst studies have shown that tumors can be better estimated with ellipsoid shape than using Eq 1, calculating the volume of an ellipsoid requires the knowledge of the third parameter. It means that knowing the tumor mass, tumor volume can be estimated with suitable accuracy; hence the lack of MRI measurement can be replaced in the case of Phase I. Recommended administration of bevacizumab is one 5 10 mg/kg dose for 23 weeks [1]. 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]. This results in the loss of information about its real growth.. With constant width and length, the measured volume does not change with the tumor shape. In Phase I, mice were sacrificed when the tumor reached a lethal size; it was on the 24th day of the experiment. One of them died on the 18th day, and another one on the 23rd day. Table 1 shows the results for tumor volume measure- ments on seven A431 tumors, indicating next to both gold standard volumes (V w , V L ) the caliper/formula derived volume V E and the ARTIDA . Traditionally, caliper measurements are used to calculate tumor volume. 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. mum tumor volume of 0.6 mL was reached. 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. Tumor volume was measured in two different ways. the tumor volume are made using digital calipers, and bio logical activity is quantified via the assessment of changes in tumor volume between treated and control mice. Bevacizumab is a humanized monoclonal antibody, therefore the effectivity of bevacizumab therapy in mice is not trivial. 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. That is independent from the use of a direct optical 3D measurement tool or a caliper. Pritt, B., Ashikaga, T., Oppenheimer, R.G. 41, 16901694 (1981). In Phase IV, approximately 2.9106 cells were injected subcutaneously into each SCID mouse. Materials and methods: The murine CaNT subcutaneous xenograft model was used. and calculates an interpolated surface under the tumor boundary based on the healthy surface around the tumor (navy blue line in Figure 12.). Figure 5. For more information about PLOS Subject Areas, click 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). A tumor image, its 3D shape and all geometrical data are automatically calculated and stored. Article Comparison of clinical assessment, mammography and ultrasound in pre-operative estimation of primary breast-cancer size: a practical approach. Better results can be obtained by proper handling of the mice. No, Is the Subject Area "Mathematical models" applicable to this article? 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