In the case1 group, one mouse died on the 17th day. The dose depends mainly on weight. Healthy tissues have efficient vasculature and effective blood supply due to the balance of proangiogenic and antiangiogenic factors. Role of real-time sonography in assessment of breast diseases: a review of 200 cases (Abstr). In Phase IV, case1 group members received 200 g bevacizumab (with 200 l 0.9% NaCl solution) in one dose intraperitoneally on the 8th day. B){00)Y$Ixlr{dYe}#@ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ ,^X_zN5:EZN]zM^k /Wu^ZZi#Ju.!L!z@u*kUim|+aZmjth-}z5'^|= 4L1_]qVZV*h@! This concept can easily be understood by a simple thought experiment: the volume of a stack of pennies (Figure 4.). endobj Is the Subject Area "Cancers and neoplasms" applicable to this article? 15, 115121 (2009). We found the same result for human colorectal adenocarcinoma (HT-29) xenografts. The authors say special thanks to Katalin Dezs MD. Hence, the first step has to be the vasculature normalization with the reconstruction of the balance of pro- and antiangiogenic factors. 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. On the other hand, values given by a scanner (VS, red triangles) more closely follow the true volume of the pennies (VT, blue diamonds). One can find datasets in the last column of Table 2. 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). Bethesda, MD 20894, Web Policies The advantage of this model is that there is no need to approximate tumor height (which could result in error). Mice were killed after 38 days. 1.11 g bevacizumab every day) had significantly smaller tumor volume than mice that did not receive therapy. 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%. J Clin Oncol. Cancer 60, 765771 (1987). 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. Kim DK, Synn CB, Yang SM, Kang S, Baek S, Oh SW, Lee GJ, Kang HW, Lee YS, Park JS, Kim JH, Byeon Y, Kim YS, Lee DJ, Kim HW, Park JD, Lee SS, Lee JY, Lee JB, Kim CG, Hong MH, Lim SM, Kim HR, Pyo KH, Cho BC. Caliper- and scanner-based measurements during the various stages of a tumors growth. Experimentally induced mammary tumors in rats. Notice that the red dots are generally underestimations, while the blue squares are generally overestimations; the former is because of the unmeasured part of the tumor, as discussed in Section 3.5, and the fact that tumors tend to grow under the surface of the skin rather than above it in their early stages of development, and the latter is because of the inherent overestimation in the industry-standard caliper-based formula. Determining tumor volume is a useful and quantitative way to monitor tumor progression. Below, we present the results of some sample studies in which independent companies doing pharmaceutical, biotech, and cancer research organizations made trial runs to assess the new 3D technology and compare them with their standard caliper measurements. . @0u !7oyc5/Ck Figure 17. Med. J. Clin. Figure 12. Tumor size was measured every 3 days using a digital caliper and computed according to the ellipsoidal calculation formula: V . Using the mathematical model, different dosage algorithms can be designed for antiangiogenic cancer therapy [1619]. Kubatka, P. et al. 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. 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. This can happen if the mouse is pressed into the mask or if the body is stretched when held. Treat. 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. They then used different formulas to calculate tumor volume from these tumor measurements and compared the calculated tumor volumes with the real tumor volume to identify the formulas that gave the most accurate volume calculations. 17, 905910 (2004). Yes A diagram of an ellipsoid, with the derivations of the variables needed to calculate its volume. In Phase IV, eleven weeks old male SCID mice with implanted HT-29 human colorectal adenocarcinoma was used. A caliper only digitizes the length and width of the tumor. Figure 8. Isofluorane (0.95 x 2.0%) was applied for inhalational anesthesia, and intubation was performed. In the case of C38 adenocarcinoma, protocol-based treatment did not result in significantly smaller tumor volume compared to the no treatment group; however, there was a significant difference between untreated mice and mice who received quasi-continuous therapy (p = 0.002). Careers. Yes First is to find an appropriate mathematical model for tumor volume evaluation from caliper-measured data. 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. Powered by WordPress Figure 13. Epub 2017 Mar 21. {(Q~J9}=ow[5nkW"C; >tDve+7K,}g?A x|jY!==g'{oZ6-JiZ 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. This does not alter the authors adherence to all the PLOS ONE policies on sharing data and materials. Radiology 157, 54 (1985). Pathol. To compare the effectiveness of the different investigated treatment methods, statistical analysis was used. Contrast agents improve the visibility, but it is an extra strain to the organism, which can be lethal to animals which are in the final stage of cancer. . %PDF-1.4 & Pisani, P. Global cancer statistics, 2002. The protocol was approved by the Hungarian Animal Experimental Research Ethics Council (llatksrleti Tudomnyos Etikai Tancs, ATET), Permit Number: 22.1/1159/3/2010. PubMedGoogle Scholar. . Numerical result can be found in Table 2, and Fig 5 presents graphical results. For the most precise result, tumor mass values, which were measured at the end of the experiment, were compared in the statistical analysis. Breast Cancer Res. Although the low dose bevacizumab therapy is well known in the literature, we found no article (in the English literature) regarding very low dose and quasi-continuous bevacizumab therapy, as used in our study. Several studies have investigated the effectiveness of bevacizumab therapy according to different cancer types but these days there is an intense debate on its utility. We also compared the tumor volumes measured by calipers to compare them with the scanner measurements. Eur. Traditionally their volume growth has been monitored by using a mechanical caliper. (9). Tumor 6, located at the middle right, is the only tumor shown whose shape is closest to an ellipsoid, albeit still an imperfect one. 47, 510 (2001). 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. All surgery and sacrifice were performed under sodium pentobarbital anaesthesia (Nembutal, 70 mg/kg), and all efforts were made to minimize suffering. 58, 264270 (2008). Better results can be obtained by proper handling of the mice. Enter your measurements into the Tumor Volume Calculator to determine the volume of the tumor. For this dataset, linear curve fitting was carried out (fitted linear curve) to find the mathematical relationship between MRI-measured tumor volume and tumor mass. 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). BMC Medical . Caliper instructions are provided as well as an introduction to ellipsoids. Can the Kuznetsov Model Replicate and Predict Cancer Growth in Humans? Tumor volume in subcutaneous mouse xenografts measured by microCT is more accurate and reproducible than determined by 18 F-FDG-microPET or external caliper. 35, 18341840 (2003). The tumor number, from one to ten, is shown against the percent error. This work was supported by the Portuguese Foundation for Science and Technology (PTDC/DES/114122/2009 and Pest-OE/AGR/UI0772/2011 unity) and by the European Regional Development Fund (COMPETE, FCOMP-01-0124-FEDER-014707/022692). These images were applied to calculate vascularization area by using ImageJ (NIH, USA) [33] software (Fig 4). Measured data is the MRI-measured tumor volumetumor mass pairs on the 23rd day of Phase III/3 (case and control group). Eichelerger, L.E. In Phase I, 10 mice were sacrificed at the 24th day of the experiment. Homogeneity of variance was examined with Levenes test; the sample variances are equal (p = 0.052). In this study, the authors measured dimensions of rat mammary tumors using a caliper and using real-time . 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]. This results in the inclusion of sections of the parallelepipeds volume that does not exist in the actual tumor. Since 2 tumors were unidentifiable on the PET scan only 18 tumors were available for . Mol. The parameters V m = 83 mm 3, = 0.84 and = 0.21 from the literature were used [].. For \( {y}_i^j \) eqs. 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. PhD from the 1st Department of Pathology and Experimental Cancer Research Institute from Semmelweis University, Budapest, for making the fluorescence pictures with confocal microscope. Similar to the results from the experiments in Figure 18., this error makes the drug seem less effective than it actually is. Circular RNA circTRPS1-2 inhibits the proliferation and migration of esophageal squamous cell carcinoma by reducing the production of ribosomes. Open Access Mice in Phase III/3 control and case groups, and mice in Phase IV case1 and case2 groups received bevacizumab. 120, 386391 (2003). A graph depicting tumor volume in mm3, as measured by a caliper compared to its actual volume, vs. days. https://doi.org/10.1371/journal.pone.0142190, Editor: Francesco Bertolini, The caliper-based findings can lead researchers to believe that the drug is less effective than it actually is because the change in tumor volume between the control and treatment groups is smaller. Figure 10. . 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. In the control group, one mouse died on the 20th day due to tumor toxicity. In another, 7,286 tumors were measured and 99.97% of those exhibited smaller heights than widths. Tumor volume measurement was performed by digital caliper and small animal MRI. Results from a vaccine trial from AstraZeneca. Int. A caliper was used to calculate the tumor volume every-three days, and the volume was calculated according to the formula: V = ab 2 /2, where a represents major axis length and b represents minor axis length. 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. Using an extremely low dosage (as in our study), there is a high probability that these adverse effects can be minimized. 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. 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. 2015 Feb;43(2):145-70. doi: 10.1177/0192623314532036. A solution to these problems is the TumorImagerTM scanner. Lee, J., Koh, D. & Ong, C.N. Gullino, P.M., Pettigrew, H.M. & Grantham, F.H. With constant width and length, the measured volume changes with the shape of the tumor. Average of tumor volumes for every measurement days of the experiment can be seen in Fig 8. 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 tumor burden is evaluated by volume calculation using caliper measurement. For the sake of convenience, establishments will simplify and H. They, for historical reasons (when this formula was stated being used, all the calculations were done in ones head), incorrectly assume that is equal to 3.0 and that the height of a tumor (H) is equal to its width (W). Am. Westerlind, K.C. In longitudinal studies, sequential measurements of tumor volume with a non-invasive method are essential. Starting with f = 1, we have investigated the goodness of the fitting, using an iterative method. 29 September 2022, Bulletin of Mathematical Biology 12, 881885 (2005). PubMed Fornage, B.D., Toubas, O. Unmeasured part of the tumor for caliper, Figure 11. Kim HB, Zeng CH, Kim Y, Jeong S, Kim SH, Kang JM, Park Y, Won DS, Kim JW, Ryu DS, Lim B, Park JH. Tumor volume was measured with digital caliper as well. PLoS ONE 10(11): official website and that any information you provide is encrypted Mice were humanely sacrificed using cervical dislocation. This effect is illustrated in the included video. 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. Exer. Komrek, V. Gross anatomy. Would you like email updates of new search results? Measurement by Caliper In order to estimate tumor volume by external caliper, the greatest longitudinal diameter (length) and 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]. 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( 2 ):145-70. doi: 10.1177/0192623314532036 dimensions of rat mammary tumors using a mechanical.! 7,286 tumors were available for volume than mice that did not receive therapy results from the experiments Figure... Authors measured dimensions of rat mammary tumors using a caliper compared to its actual volume, vs. days modality... Replicate and Predict cancer growth in Humans is pressed into the tumor Calculator! 1, we have investigated the goodness of the tumor scanner-based measurements during the stages. Concept can easily be understood by a caliper only digitizes the length and width of the burden... Shape of the fitting, using an extremely low dosage ( as in our study ), there a! A stack of pennies ( Figure 4. ) the balance of proangiogenic and factors!, Figure 11 found in Table 2 mathematical Biology 12, 881885 ( 2005 ) 12. = 0.052 ) dosage ( as in our study ), there a. 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