Catheter was placed in the tail vein for injectionaccording to the mouse tail vein injection protocol [30]to investigate drug effect. Int. Similarly, Zhang et al. The technique of using calipers to measure the volume of a tumor has problems associated with both the instrument itself and the methods used in calculating volume[1]. Caliper instructions are provided as well as an introduction to ellipsoids. Repetitive non-typhoidal Salmonella exposure is an environmental risk factor for colon cancer and tumor growth. Tumor growth was investigated without therapy and with antiangiogenic therapy (using bevacizumab [15]). CA Cancer J. Clin. 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). 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. Figure 5. A study[4]on caliper measurements, shoved the very poor accuracy of the formula used for caliper measurements. Our study of the incised tumors in many mouse tumor models showed that this is mostly seen for very large tumors (Volume > ~1.5 cm3) where the tumors start bulging inward toward the flesh. Unauthorized use of these marks is strictly prohibited. As is the case with caliper measurements, if the tumor appears visibly flattened and is hard to see by eye then the mouse should be repositioned. 1 0 obj The tumor number, from one to ten, is shown against the percent error. 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. 35, 18341840 (2003). Cells should be suspended in a volume so that 300 l contains required number of cells per injection. Google Scholar. . With constant width and length, the measured volume changes with the shape of the tumor. n5). The tumor dimensions are L, W, and H. The volume of an ellipsoid VE, using the variables as shown in Figure 1., is. The parameters V m = 83 mm 3, = 0.84 and = 0.21 from the literature were used [].. For \( {y}_i^j \) eqs. 41, 16901694 (1981). This does not alter the authors adherence to all the PLOS ONE policies on sharing data and materials. In this case, tumor volume has to be calculated in the following way: The cause of death was tumor toxicity; however, none of the clinical criteria for euthanasia could be observed at these animals. 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. The closer the value is to 1, the more precise the data. Google Scholar. & trukelj, B. N-methylnitrosourea induced breast cancer in rat, the histopathology of the resulting tumours and its drawbacks as a model. The obtained data include height and topography changes. P`e+"JF^ : 4:p7]k = Jy}! A patented algorithm running in the TumorManagerTM program calculates the tumor volume by creating a 3D surface map of the tumor (red-colored surface in Figure 12.). 2022 Dec 20;3(12):100852. doi: 10.1016/j.xcrm.2022.100852. In the case of Phase I, no similar problem occurs; the two-dimensional mathematical model can handle great values as well (e.g. Data Availability: All relevant data are within the paper. (3), Another relatively new but not widely used approach to estimate tumor volume is to assume hemi-ellipsoid shape [24]. & Wieder, H. Monitoring chemotherapy and radiotherapy of solid tumors. 26 December 2022, Bulletin of Mathematical Biology where f is a constant which belongs to a certain tumor type. 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. The height and topography of the tumor is not taken into account in a caliper measurement. In addition, the root mean square, R2 values under the linear regression equations in Figure 15. symbolize the precision of the data. 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. The overestimation of caliper measurements is due mainly to the fact that the formula used is that of a parallelepiped, a shape unlike an ellipsoid actually represents the geometric body that is being measured. 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. Autopsy revealed large metastasis in the lung, this is the suspected cause of the death. BMC Medical . The data reveals that the mean volume of PTV is 60.8 53.9 cc where these targets exhibit no significant difference between each modality. 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. Homogeneity of variance was examined with Levenes test; the sample variances are equal (p = 0.052). 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary. 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. 2015 Feb;43(2):145-70. doi: 10.1177/0192623314532036. 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. This paper reviews the standard technique for tumour volume assessment, calliper measurements, by conducting a statistical review of a large dataset consisting of 2,500 tumour volume measurements from 1,600 mice by multiple operators across 6 mouse strains and 20 tumour models. Provided by the Springer Nature SharedIt content-sharing initiative, Bulletin of the National Research Centre (2022), Lab Animal (Lab Anim) For both one has to have the ease of hand and get used to manipulation of the instrument. PLOS ONE promises fair, rigorous peer review, Normality was investigated with one-sample Kolmogorov-Smirnov test; each sample has normal distribution (ppI = 0.883, ppIII/3_case = 0.716, ppIII/3_control = 0.869). Figure 16. Our results provide a theoretical background for a much more effective bevacizumab treatment using optimized administration. Figure 1. Russo J, Russo IH, Rogers AE, van Zwieten MJ, Gusterson B. Toxicol Pathol. 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 . Affiliation 2. Both methods are comparable when it concerns the time it takes to do a measurement. sharing sensitive information, make sure youre on a federal Open Access Tumor was located in the last third of the back of the mouse in every case. The protocol was approved by the Hungarian Animal Experimental Research Ethics Council (llatksrleti Tudomnyos Etikai Tancs, ATET), Permit Number: 22.1/1159/3/2010. Because the industrys caliper-based formula allows for these inclusions in nonexistent volumes more often than not, it yields inaccurate measurements, which can confuse. Breast Cancer Res. Please enable it to take advantage of the complete set of features! . In Phase III/3, case group members received one-tenth dose of control dose intraperitoneally spread over 18 days. Significance of rat mammary tumors for human risk assessment. The produced images were converted to NIfTI (Neuroimaging Informatics Technology Initiative) format, which is suitable for image processing. In longitudinal studies, sequential measurements of tumor volume with a non-invasive method are essential. The volume above the red area is not occupied by the tumor, as seen in Figure 8. In Phase I, 10 mice were sacrificed at the 24th day of the experiment. Cancer Res. The usual administration is via intravenous infusion; once every 2 or 3 weeks. Bookshelf Med. 12 immunocompetent mice were transplanted subcutaneously with C38 colon adenocarcinoma, and 11 immunocompetent mice were injected intramuscularly with B16 melanoma. Even though all the three diameters can be measured, the estimation of the volume has quite a large error. The last step is to find the f constant of the two-dimensional mathematical model for tumor growth without therapy (Phase I). 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. Tumor Volume Formula for Caliper Measurements, 3. Open Access Hoffman-Goetz, L. et al. https://doi.org/10.1371/journal.pone.0142190.g006. On the other hand, values given by a scanner (VS, red triangles) more closely follow the true volume of the pennies (VT, blue diamonds). <> stream Can the Kuznetsov Model Replicate and Predict Cancer Growth in Humans? 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. Then we calculated the Coefficient of Variance between such measurements for both measurements to compare average inter-operator differences. Description of Lesions. Mice were killed after 38 days. One can find datasets in the last column of Table 2. 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. An official website of the United States government. tumor height has to be approximated. This site needs JavaScript to work properly. 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. 58, 264270 (2008). Exer. 47, 510 (2001). Cancer 83, 621628 (1998). No, Is the Subject Area "Colorectal cancer" applicable to this article? Performed the experiments: JS ZS PK DG. 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. Analysis of Variance (ANOVA) test was used to compare more than two samples, while pairwise comparison was done by Tukeys honest significant difference (HSD) test. 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). 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. While the scanner only overestimates by about 2%, the caliper overestimates by 32%, as shown by the slope of the line being 1.32. Different operators have different ways of holding the animal and tumor while performing the measurement. Mice were monitored daily. Care should be taken not to stretch the mouse whether using one or two hands to hold the mouse during a scan. In addition, studies using CT scans concluded that CT yielded tumor volume values 11 to 12% less (an underestimate) than those which were measured by calipers, and that CT-based measurements yielded more accurate and consistent values than caliper-based measurements[6, 7]. 16 (2008). This estimation has the same disadvantage as ellipsoid estimation, i.e. Biol. Determining tumor volume is a useful and quantitative way to monitor tumor progression. . Pathology of tumours in laboratory animals. Tumor cells form and expand subcutaneously in the cavity they are injected, into between the layers of the skin. Tukeys HSD test resuled in significant difference between case1 and case2 groups (p = 0.038). That is independent from the use of a direct optical 3D measurement tool or a caliper. Since 2 tumors were unidentifiable on the PET scan only 18 tumors were available for . PMID: 11208850. PhD from the 1st Department of Pathology and Experimental Cancer Research Institute from Semmelweis University, Budapest, for making the fluorescence pictures with confocal microscope. 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). In Phase IV, the caliper measurement days were the 10th, 12th, 17th, 19th, 22nd and 23rd days. In this phase, three groups were created. Calipers are invasive; they create undue stress on the animal through the awkward handling of the mouse by one hand during the measuring process. . The defined shape of an actual tumor (red) and the shape measured by a caliper (blue box). here. In Phase IV, approximately 2.9106 cells were injected subcutaneously into each SCID mouse. Nevertheless the result of our study shows that the effectiveness is even better. 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. A direct and real 3D volume of the xenograft will then be calculated. Effects of different applied voltages of irreversible electroporation on prostate cancer in a mouse model. The effectiveness of bevacizumab administration was examined by statistical analysis. et al. (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. J. Without prior training of users, this effect can lead to greater variability in intra and inter-user measurements. 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. 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). The majority of debate over Avastin is about breast cancer because, in 2011, the US Food and Drug Administration (FDA) revoked the approval of Avastin for breast cancer treatment in the absence of decisive therapeutic benefit; however, several clinical trials suggested that Avastin can be effective in breast cancer treatment [6, 7]. For injectionaccording to the mouse tail vein injection protocol [ 30 ] to investigate drug effect 4 ] on measurements... Unidentifiable on the PET scan only 18 tumors were unidentifiable on the PET scan 18. 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