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 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. 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. In Phase IV, the first measurement occurred when the tumors have reached an average volume of 5060 mm3 (according to the xenograft protocol [20]). https://doi.org/10.1371/journal.pone.0142190.g008. A study[4] (Figure 5.) How the device is positioned over the tumor will not influence the result. & Morel, M. Clinical, mammographic, and sonographic determination of preoperative breast cancer size. <> stream Radiology 157, 54 (1985). The scanner-based measurements yield a higher correlation in this sense than caliper-based measurements. However, it has to be taken into consideration that in several cases using antiangiogenic therapy, tumor shape is irregular (berry-shaped). 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. This saves money, as mice, drugs, and calipers can be costly for researchers. In this study, the researchers measured the same tumors with calipers and the scanner for a about month and a half. On the bottom left graph in Fig. endobj Mammary tumors similar to those observed in women can be induced in rats by intraperitoneal administration of N-methyl-N-nitrosourea. Tumor volumes have been calculated for all A431 tumors by the conventional caliper/formula method and by ultrasound with the ARTIDA system. Breathing was monitored with piezoelectric transducer; temperature of the body was measured by rectal thermometer. Investigating the results of Phase III/3 one can observe that the two-dimensional mathematical model has good estimation property when the tumor width and length values are small; however, for large tumor diameter values the estimation could result in significant error, the estimated value is greater than the measured one (outliers are E8, C2). Numerical result can be found in Table 2, and Fig 5 presents graphical results. 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. CAS While the scanner only overestimates by about 2%, the caliper overestimates by 32%, as shown by the slope of the line being 1.32. (Fig 2). Usually, 3.0 x 10 6 cells are needed per injection. A direct and real 3D volume of the xenograft will then be calculated. This results in the inclusion of sections of the parallelepipeds volume that does not exist in the actual tumor. In this phase, 5 immunocompetent mice in control group, and 9 immunocompetent mice in case group were used. 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. A direct 3d measurement tool such as the TM900 does not induce such method sensitivity but cannot exclude operator dependency of the obtained values. Timing wise both methods perform the same. 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. 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. (5) The site is secure. Copyright 2023 https://doi.org/10.1371/journal.pone.0142190, Editor: Francesco Bertolini, Med. Enter your measurements into the Tumor Volume Calculator to determine the volume of the tumor. The https:// ensures that you are connecting to the Mice were killed after 38 days. 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. 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. Even though, now, the formula is calculated in an Excel spreadsheet where can be defined as a function, pi(), almost in all cases, in the volume formula is defined as 3.0. Pritt, B., Ashikaga, T., Oppenheimer, R.G. PubMed Comparison of clinical assessment, mammography and ultrasound in pre-operative estimation of primary breast-cancer size: a practical approach. ANOVA test showed significant difference between these means (p = 0.041, using 0.05 level of significance). 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. Open Access The scan images obtained are only for the external surface of the tumor. Eichelerger, L.E. ISSN 1548-4475 (online) In Phase I, Phase II and Phase III, eight weeks old male C57Bl/6 mice with implanted C38 mouse colorectal carcinoma was used. Watch our 2-minute video overview. Lab Animal This dose was used for an 18-day treatment period in Phase III/3, and for a 15-day treatment in Phase IV. Therefore, optical imaging is . Figure 6. depicts three components used to measure the volume of a tumor: its length, represented by blue arrows, its width by green, and its height by yellow. The manipulation of the handheld tool is at least as easy as holding a measurement caliper. 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. J Clin Oncol. Google Scholar. Tumor area was determined with flood fill algorithm [31] from the slides; by knowing the volume of a voxel, tumor volume was calculated from these two values. J. <> Significance of rat mammary tumors for human risk assessment. The caliper mean-percent-error is 10.6%, nearly twice that of the scanners mean-percent-error of 4.6%. 37, 331337 (2011). @0u !7oyc5/Ck Davis, P.L. The effectiveness of bevacizumab administration was examined by statistical analysis. In Phase IV, control group members received no bevacizumab. 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. A two-dimensional mathematical model was applied for tumor volume evaluation, and tumor- and therapy-specific constants were calculated for the three different groups. 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). In Phase I, 10 mice were sacrificed at the 24th day of the experiment. Mammary tumors seemed to take on an oblate spheroid geometry. https://doi.org/10.1371/journal.pone.0142190.g007. Clarys, J.P. & Marfell-Jones, M.J. Soft tissue segmentation of the body and fractionation of the upper and lower limbs. 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 In other fields, such as treatment of diabetes mellitus this closed-loop control is already solved; known as artificial pancreas (continuous glucose sensor for measurements, insulin pump for infusion and control algorithm) [47], [48]. & Bullock, G.) 253257 (Elsevier Academic, Boston, 2004). This process slightly stretches the body and deforms the tumor. The tumor burden is evaluated by volume calculation using caliper measurement. Figure 10. 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. 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). & Weaver, D.L. In both cases, the height of the tumor will be much smaller than its length or width (Figure 2.). Figure 2. Med. In one trial, 208 tumors were measured, and 98.94% of those tumors exhibited much smaller heights than widths. Accessibility The shape of the tumor, more often than not, is not an ellipsoid. Tumor segmentation by TumorImager-2TM. The last step is to find the f constant of the two-dimensional mathematical model for tumor growth without therapy (Phase I). contracts here. The closer the value is to 1, the more precise the data. 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. Cancer 83, 621628 (1998). The whole experiment consisted of four phases; the article focuses on the Phase III/3 and its results together with the comparison of Phase I and Phase III/3 (Fig 1). 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. Possible mechanisms mediating an association between physical activity and breast cancer. 2. Tumor growth can take place under such conditions; however delivery of chemotherapeutic drugs is obstructed. 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