It was on the 10th day, since HT-29 colorectal adenocarcinoma grows slower in mice than C38 colon adenocarcinoma. In Phase III, we have investigated C38 colon adenocarcinoma growth with bevacizumab therapy. Pollok, K.E. et al. In Phase I, we have investigated tumor growth without therapy with two types of mouse tumor. Timing wise both methods perform the same. Yang, C.H., Wang, S.J., Lin, A.T.L., Jen, Y.M. A smaller diameter mask will help to position the tumor in the center of the scan, but it will not alter this effect. Med. 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. 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.). 37, 331337 (2011). 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. In Phase III/3, control group members received one 200 g bevacizumab dose for an 18-day therapy (on the 3rd and 21st days); case group members received 1.11 g bevacizumab every day for 20 days. Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. 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. In this case, tumor volume has to be calculated in the following way: Using a caliper, growth of the tumor in height is not measured as only width and length changes will . 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). Please enable it to take advantage of the complete set of features! A possible solution for height approximation [23] is: Breast Cancer Res. Estimation of rat mammary tumor volume using caliper and ultrasonography measurements. Tracking tumor growth with real tumor scan pictures. & Wieder, H. Monitoring chemotherapy and radiotherapy of solid tumors. PMC Using an extremely low dosage (as in our study), there is a high probability that these adverse effects can be minimized. This process slightly stretches the body and deforms the tumor. Pathology of tumours in laboratory animals. Copyright 2023 Russo J, Russo IH, Rogers AE, van Zwieten MJ, Gusterson B. Toxicol Pathol. Unmeasured part of the tumor for caliper, Figure 11. Consequences are manifold. 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. 26 December 2022, Bulletin of Mathematical Biology First way is the caliper measurement; in that case tumor diameters (width, length) are measured with digital caliper. In a study done in England, the researchers at the end of their experiment, dissected tumors and measured their weight with a precise balance, and used these weight values of the tumors to compare results of the caliper and the scanner measurements. 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. . & J. 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. Imaging 16, 816 (2008). An average penny has a diameter of 19 mm and a height of 1.27 mm, yielding a volume of 360.1 mm3. We have administered 10 mg/kg body weight intraperitoneally, which means 200 g bevacizumab per a mouse, since the mass of the mice in the experiment was approximately 20 g (in the case of C57Bl/6 and SCID mice as well). Ultrasonography as the Gold Standard for In Vivo Volumetric Determination of Chemically-induced Mammary Tumors. Figure 16. Kim HB, Zeng CH, Kim Y, Jeong S, Kim SH, Kang JM, Park Y, Won DS, Kim JW, Ryu DS, Lim B, Park JH. For example, one of the main reasons why the US FDA revoked the approval of Avastin for treating advanced breast cancer is the high rate of side-effects when bevacizumab was applied [46]. Consequently, when tumor mass data is unavailable (during the experiment), tumor volume value can be validated with MRI; in that way outlier data points (which were calculated using the two-dimensional mathematical model) can be filtered out. 01 July 2022. 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 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. To compare the effectiveness of the different investigated treatment methods, statistical analysis was used. 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. 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. M}{Gt{zj|&cXx[k?CZ ~AjTxMr0 '~ix$mj/)9?$ t-o6MkVXs's}^E6-^_Yrv#w&r7w@WsQs]#G g$Cn. Studies using other methods of imaging have exposed the problems that calipers pose. (1). 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). Tumor growth inhibition rate (%); can be calculated using the following formula: = (Vc 1 -Vt 1 )/ (Vc 0 -Vt 0) X 100. where, Vc 1 is the mean tumor volume in the control group at the time of tumor . 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. We have found in our previous study [32] that measurements without contrast agents resulted in high quality images, where tumor can be circumscribed precisely, thus the usage of contrast is unnecessary. A survey of recent literature revealed the use of 19 different formulas for determining the size of subcutaneous tumors grown as xenografts in nude mice (2 for determining tumor area, 3 for tumor diameter, and 14 for calculating tumor volume). Tumor Volume Measurement Bevacizumab (Avastin) [1] is an exogenous inhibitor, which inhibits the biological activity of human VEGF [2]. PubMedGoogle Scholar. 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. In each case the reference value is the MRI-measured tumor volume. YH29407 with anti-PD-1 ameliorates anti-tumor effects. The cause of death was tumor toxicity; however, none of the clinical criteria for euthanasia could be observed at these animals. CA Cancer J. Clin. 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. Cell Rep Med. 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. A graph depicting tumor volume in mm3, as measured by a caliper compared to its actual volume, vs. days. A two-dimensional mathematical model was applied for tumor volume evaluation, and tumor- and therapy-specific constants were calculated for the three different groups. 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. In the case of HT-29 adenocarcinoma, the daily treatment with one-twelfth total dose resulted in significantly smaller tumors than the protocol-based treatment (p = 0.038). In Phase IV, the caliper measurement days were the 10th, 12th, 17th, 19th, 22nd and 23rd days. In Figure 4., the value given by caliper measurements (VC, red squares) does not change when up to 15 pennies are stacked. They found that caliper and ultrasonography measurements were significantly correlated but that tumor volumes calculated using different formulas varied substantially. Using the above mentioned iterative method, the resulted equation is Mammary tumors seemed to take on an oblate spheroid geometry. Pritt, B., Ashikaga, T., Oppenheimer, R.G. & Pisani, P. Global cancer statistics, 2002. https://doi.org/10.1371/journal.pone.0142190.g001. Figure 12. Description of Lesions. bowel, and kidneys is when the tumor is located in . PubMed Russo, J. The site is secure. We compared the volumes, areas . 41, 16901694 (1981). This formula was the starting point of our examination to find an appropriate mathematical model. Radiology 157, 54 (1985). The size of maximum tumor volumes observed in our study fulfills the requirements of Hungarian animal experimental research protocol. . In caliper measurements, two values, for length and width, must be recorded for one tumor in each animal; this means that for every 100 animals studied, at least 200 measurements must be made and recorded. Preclinical Imaging Center, Gedeon Richter Plc., Budapest, Hungary, Affiliation (Budapest, Hungary). Tumor cells form and expand subcutaneously in the cavity they are injected, into between the layers of the skin. Google Scholar. Inhibiting the glycerophosphodiesterase EDI3 in ER-HER2+ breast cancer cells resistant to HER2-targeted therapy reduces viability and tumour growth. sharing sensitive information, make sure youre on a federal 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. Notice that in the caliper group, the average standard deviation is larger than that of the group whose tumors were measured by Biopticons TumorImager scanner. In addition, the root mean square, R2 values under the linear regression equations in Figure 15. symbolize the precision of the data. 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. In addition, we have found that the quasi-continuous administration of bevacizumab is effective against tumor growth of C38 colon adenocarcinoma, in contrast . The tumor can be more and sometimes less visible or popped up from under the skin. This is a preview of subscription content, access via your institution. Figure 17. Yes (6) (7). In this study, the authors measured dimensions of rat mammary tumors using a caliper and using real-time compound B-mode ultrasonography. A caliper only digitizes the length and width of the tumor. Additionally, we explore the impact of six different tumour . Applying the two-dimensional mathematical model (described in Eq 5) the goal is to find the f constant which belongs to the C38 colon adenocarcinoma and the treatment type. Hoffman-Goetz, L. et al. Hence, the first step has to be the vasculature normalization with the reconstruction of the balance of pro- and antiangiogenic factors. In Phase IV, the first measurement occurred when the tumors have reached an average volume of 5060 mm3 (according to the xenograft protocol [20]). A structured light-based system for scanning subcutaneous tumors in laboratory animals. https://doi.org/10.1371/journal.pone.0142190.g002. Due to the collaboration between medical doctors and biomedical engineers, model-based treatment protocols can be 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 data reveals that the mean volume of PTV is 60.8 53.9 cc where these targets exhibit no significant difference between each modality. 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. 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. ISSN 0093-7355 (print). 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. In Phase III/3, case group members received one-tenth dose of control dose intraperitoneally spread over 18 days. Based on the experimental data, model identification can be carried out which describes the mathematical model of the investigated biological process. All surgery and sacrifice were performed under sodium pentobarbital anaesthesia (Nembutal, 70 mg/kg). 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. 54, 401414 (1975). PASW Statistics 18 (SPSS Statistics, IBM, USA) and Matlab R2009b (MathWorks, USA) were used for statistical analysis. Gullino, P.M., Pettigrew, H.M. & Grantham, F.H. 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. To evaluate tumor volume, first the shape of the tumor has to be assumed, and if it is necessary for volume calculation, the third diameter (height, h) has to be approximated. Biol. by Mammog raphy (c.c) . For more information about PLOS Subject Areas, click Thank you for visiting nature.com. N-nitrosomethylurea as mammary gland carcinogen in rats. This does not alter the authors adherence to all the PLOS ONE policies on sharing data and materials. Combining Mechanisms of Growth Arrest in Solid Tumours: A Mathematical Investigation, Dramatic increase in volume versus length of invasive ductal carcinoma mimicking intramammary lymph node in a small nodular lesion, Alteration in Inflammasome Cytokine Profile and Functional Plasticity of Macrophage Phenotype in Arsenic(0) Nanoparticle Treated Murine Fibrosarcoma, Tumoral CD105 promotes immunosuppression, metastasis, and angiogenesis in renal cell carcinoma, Cancel the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in 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 III/3, control group contained 5 mice, case group contained 9 mice; all mice were implanted with C38 mouse colon adenocarcinoma. The problems with tumor volume measurements by calipers 3.1 Tumor growth: Height is not equal to the width of the tumor . contracts here. 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. 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. Comparing ARTIDA-calculated tumor volumes to the volumes derived from the caliper/ellipsoid formula calculations and referenced to the gold standard volume determination method (with literature density values), as it is shown in Figure 2A. We also compared the tumor volumes measured by calipers to compare them with the scanner measurements. . 17, 905910 (2004). 8600 Rockville Pike Levenes test showed that the sample variances are equal (p = 0.108). volume42,pages 217224 (2013)Cite this article. Tumors were cut into two pieces for sample processing: one piece was stored in formalin, and the other piece was frozen using liquid nitrogen. No, PLOS is a nonprofit 501(c)(3) corporation, #C2354500, based in San Francisco, California, US, Corrections, Expressions of Concern, and Retractions, https://doi.org/10.1371/journal.pone.0142190, http://www.gene.com/download/pdf/avastin_prescribing.pdf, http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Scientific_Discussion/human/000582/WC500029262.pdf, http://www.protocol-online.org/prot/Protocols/Xenograft-Tumor-Model-Protocol-3810.html, http://www.targeson.com/sites/default/files/content/pages/pdfs/tail_vein_protocol_2012_0.pdf. 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