All mice were implanted with HT-29 human colorectal adenocarcinoma. Unauthorized use of these marks is strictly prohibited. Bevacizumab (Avastin) [1] is an exogenous inhibitor, which inhibits the biological activity of human VEGF [2]. 2023 Jan 20;42(1):25. doi: 10.1186/s13046-022-02578-w. Zhao R, Chen P, Qu C, Liang J, Cheng Y, Sun Z, Tian H. Cell Death Discov. 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. PLoS ONE 10(11): Internet J. Surg. The other eight tumors exhibit forms that cannot be compared to a perfect ellipsoid. A quiet and modestly T2-weighted spin-echo scan was acquired at 4.7T (TE = 15 msec, TR = 1100 msec, 0.5 mm isotropic . Unmeasured part of the tumor for caliper, Figure 11. This effect is illustrated in the included video. In the case of Phase I and Phase IV, there were no MRI measurements. 35, 18341840 (2003). & trukelj, B. N-methylnitrosourea induced breast cancer in rat, the histopathology of the resulting tumours and its drawbacks as a model. We compared tumor volumes estimated in vivo by BLI and FLI, to those calculated by caliper measurements and found a good correlation between these two techniques (Figure 4). In the case1 group, one mouse died on the 17th day. Tumor volume was calculated by the modified ellipsoidal formula: V = (Length Width 2) . Disclaimer. Influence of breast cancer histology on the relationship between ultrasound and pathology tumor size measurements. The figure shows the results of a mouse (C4) from control group (first row), and a mouse (E9) from case group (second row). 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. The results of the three investigated cases using C38 mouse colon adenocarcinoma (Phase I, Phase III/3 control group, and Phase III/3 case group) were compared using tumor volume values from MRI measurements (Phase III/3 control and case groups, 23rd day) and evaluated data (Phase I MRI tumor volume calculated from linear curve fit, 24th day). This formula was the starting point of our examination to find an appropriate mathematical model. 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 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 depth. 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. CAS Based on the experimental data, model identification can be carried out which describes the mathematical model of the investigated biological process. No, Is the Subject Area "Magnetic resonance imaging" applicable to this article? This means that mice which were treated with the recommended bevacizumab protocol (one 200 g bevacizumab dose for an 18-day therapy) did not have significantly smaller tumor volume than mice which did not receive therapy at all. Figure 18. shows the results of an experiment in which mice were given different doses of a drug and their tumors were measured both with a caliper or TumorImager scanner. . 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. In this study, the authors measured dimensions of rat mammary tumors using a caliper and using real-time compound B-mode ultrasonography. Harris, R.E., Alshafie, G.A., Abou-Issa, H. & Seibert, K. Chemopreventive of breast cancer in rats by celecoxib, a ciclooxygenase 2 inhibitor. Click through the PLOS taxonomy to find articles in your field. et al. broad scope, and wide readership a perfect fit for your research every time. 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). Make sure you get accurate measurements for length, width and height. Nevertheless the result of our study shows that the effectiveness is even better. Similarly, Zhang et al. Measure the three dimensions of peanut M&M's, serving as our similar-sized tumor surrogates, using vernier calipers. The obtained data include height and topography changes. The dose depends mainly on weight. & Russo, I.H. In the case of C38 colon adenocarcinoma, first, the subcutaneously transplanted piece of tumor has to disintegrate, and after that the new tumor colony (which needs to be measured) can begin to grow from the disintegrated tumor cells. The volume calculation algorithm relies on the surface interpolated based on the surrounding healthy tissue. In order to understand inter-operator differences between operators making both caliper and scanner measurements, we conducted experiments in which multiple numbers of operators measured several tumors both with caliper and scanner. n5). In Phase I, Phase II and Phase III, eight weeks old male C57Bl/6 mice with implanted C38 mouse colorectal carcinoma was used. Preclinical evaluation of LU 79553: a novel bis-naphthalimide with potent antitumor activity. & Pisani, P. Global cancer statistics, 2002. Kobayashy, T. et al. e0142190. 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. Figure 16. depicts the results from a study attended by Biopticon in which ten subcutaneous tumors in mice were measured by scanner and caliper by four operators. & Deshayes, J.L. 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. Secondly, the aspect of side-effects are not inconsiderable. Accuracy of Optical Imaging for Measuring Tumor Burden In Vivo . A graph depicting tumor volume in mm3, as measured by a caliper compared to its actual volume, vs. days. Berg, W.A. Then we calculated the Coefficient of Variance between such measurements for both measurements to compare average inter-operator differences. 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). 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 more correlated a given group (scanner or caliper estimations) is to the black line (r2 = 1), the more accurate the tumor volume measurements are. Predicting tumor volume in radical prostatectomy specimens from patients with prostate cancer. Tumor segmentation by TumorImager-2TM. No, Is the Subject Area "Colorectal cancer" applicable to this article? where f is a constant which belongs to a certain tumor type. In Phase II, the toxicology investigation of the applied angiogenic inhibitor (bevacizumab) was performed; there was no tumor implantation into mice in this phase. J. Nucl. Bizberg Themes, By Memorial Sloan Kettering Cancer Center. Caliper instructions are provided as well as an introduction to ellipsoids. McCormick, D.L., Adamowski, C.B., Fiks, A. 2 0 obj The athymic (nude) mouse is a useful model for studying the biology and response to therapies of human tumors in vivo. Sci Rep. 2022 Dec 26;12(1):22336. doi: 10.1038/s41598-022-25258-3. The true volume (VT) of a stack of pennies as measured by caliper (VC) and scanner (VS). the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Autopsy revealed large metastasis in the lung, this is the suspected cause of the death. The https:// ensures that you are connecting to the 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]. Because the industrys caliper-based formula allows for these inclusions in nonexistent volumes more often than not, it yields inaccurate measurements, which can confuse. Correspondence to Tumor measurement by TumorImager-2TM. Med. 2022 Dec 5;10:998013. doi: 10.3389/fchem.2022.998013. Almost 90% of the establishments that make tumor volume measurements using calipers use a modified version of the ellipsoid formula, under the incorrect assumption that a tumor is always a perfect ellipsoid. In longitudinal studies, sequential measurements of tumor volume with a non-invasive method are essential. Lab Anim 42, 217224 (2013). No animals were sacrificed before the experimental endpoint. 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. Analyzed the data: JS ZS PK DG DAD LK. N-nitrosomethylurea as mammary gland carcinogen in rats. Cell Rep Med. Small MRI measurements were done in the Preclinical Imaging Center of Gedeon Richter Plc. Article In Phase III/3, control group members received 200 g bevacizumab (with 455 l 0.9% NaCl solution) in one dose intraperitoneally on the 3rd day and on the 21st day. The problems with tumor volume measurements by calipers, 3.1 Tumor growth: Height is not equal to the width of the tumor, 3.3 Caliper measurements are time-consuming, 3.4 Caliper measurements ignore a larger volume, https://ugobasile.com/products/catalogue/pain-and-inflammation/plethysmometer, A Structured Light Based Laboratory Animal Subcutaneous Tumor Scanning System. 1 0 obj 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). Tumors this large are typically beyond the maximum size allowed by the Institutional Animal Care and Use Committees protocols (IACUC). 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%. 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. With constant width and length, the measured volume changes with the shape of the tumor. Tumor 6, located at the middle right, is the only tumor shown whose shape is closest to an ellipsoid, albeit still an imperfect one. PLOS ONE promises fair, rigorous peer review, Pere, M., Cerar, A. 55, 11761180 (1995). & Lin, C.A. 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. Pathology of tumours in laboratory animals. Tumor size was measured every 3 days using a digital caliper and computed according to the ellipsoidal calculation formula: V . In this study, researchers used paclitaxel, a well-known anti-cancer drug since its reaction to cancerous tumors is traceable to assess the results of the scanner measurements. 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. Pathol. In that caseeven though all the three diameters can be measuredthe estimation of the volume has quite a large error. In this phase, three groups were created. 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. Mammary tumors seemed to take on an oblate spheroid geometry. One of them died on the 18th day, and another one on the 23rd day. Conceived and designed the experiments: ZS JS. After staining, fluorescence pictures were done from the slides using confocal microscope (BIO-RAD MRC-1024). YH29407 with anti-PD-1 ameliorates anti-tumor effects. 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. CAS Cancer Res. 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. Correlation was investigated with Pearsons rank correlation test (Pearsons R) and coefficient of determination (R2). Figure 16. 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]. () and were used with the parameters displayed in Table 1Parameters for Gompertz growth were taken from Benzekry et al. Our results for the case group (daily, quasi-continuous small amount administration) and the control group (one big dose according to the protocol) are A study[4]on caliper measurements, shoved the very poor accuracy of the formula used for caliper measurements. and transmitted securely. The advantage of this model is that there is no need to approximate tumor height (which could result in error). In vivo measurements of tumor metabolism and growth after administration of enzastaurin using small animal FDG positron emission tomography. 22, 921929 (2003). 105, 2023 (1983). 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. Generally, to make caliper measurements, the measurer first traps the tail of the mouse under her fingers, then, grabs the neck of the mouse, and aligns the mouse in her hand in a way to expose the tumor for length and width measurements. In the top-left graph (Figure 19. Treat. The tumor dimensions are L, W, and H. The volume of an ellipsoid VE, using the variables as shown in Figure 1., is. NCI CPTC Antibody Characterization Program. This is a preview of subscription content, access via your institution. Research and Innovation Center of Obuda University, Physiological Controls Group, Obuda University, Budapest, Hungary, Affiliation 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. In addition, the root mean square, R2 values under the linear regression equations in Figure 15. symbolize the precision of the data. (5) 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. When tumor cells become able to produce proangiogenic factors (the process is called as angiogenic switch), it will result in abnormal and inefficient vascular network (with high vascular permeability and poor perfusion) due to the hurried process of vessel formation. In Phase IV, approximately 2.9106 cells were injected subcutaneously into each SCID mouse. Measurements with small animal MRI were done on the 4th, 8th, 11th, 15th, 18th and 23rd days of the experiment in Phase III/3. Eichelerger, L.E. The site is secure. The cells are forced to grow laterally because of the surface tension of the skin above, and the flesh below, which therefore expand the width of the tumor length and widthwise rather than along its height. Levenes test showed that the sample variances are equal (p = 0.108). PubMedGoogle Scholar. in The Laboratory Mouse (eds. Autopsy revealed only minimal local tumor; however death was not caused by tumor. Consequences are manifold. 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. Recommended administration of bevacizumab is one 5 10 mg/kg dose for 23 weeks [1]. 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. M}{Gt{zj|&cXx[k?CZ ~AjTxMr0 '~ix$mj/)9?$ t-o6MkVXs's}^E6-^_Yrv#w&r7w@WsQs]#G g$Cn. Breast Cancer Res. Weber, W.A. PhD from the 1st Department of Pathology and Experimental Cancer Research Institute from Semmelweis University, Budapest, for making the fluorescence pictures with confocal microscope.
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