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. Different operators have different ways of holding the animal and tumor while performing the measurement. ISSN 0093-7355 (print). The obtained data include height and topography changes. Average of tumor volumes for every measurement days of the experiment can be seen in Fig 8. et al. FOIA The produced images were converted to NIfTI (Neuroimaging Informatics Technology Initiative) format, which is suitable for image processing. Eur. et al. The tumor volume calculation was executed using the formula V = (W2 L)/2 for caliper measurements, where V is tumor volume, W is tumor width, and L is tumor length . CAS Numerical result can be found in Table 2, and Fig 5 presents graphical results. Copyright 2023 The width of a fully formed tumor will be much larger than its height. 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. Thus, caliper-based measurements, using the formula , are most accurate in real life for tumors in which height roughly equals width but prove less accurate as height becomes more unequal to width, as is the case with almost all real tumors. Sport. Our results for the case group (daily, quasi-continuous small amount administration) and the control group (one big dose according to the protocol) are Cancer Res. Lee, J., Koh, D. & Ong, C.N. Open Access Unmeasured part of the tumor for caliper, Figure 11. In the top-left graph (Figure 19. Tracking tumor growth with real tumor scan pictures. For small tumors, the error is about 7%, while for large tumors it is 27%.[3]. 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. All mice were implanted with HT-29 human colorectal adenocarcinoma. Figure 16. Normality was investigated with one-sample Kolmogorov-Smirnov test, and homogeneity of variance (homoscedasticity) was examined with Levenes test. Cancer 83, 621628 (1998). Clarke, R. Animal models of breast cancer: their diversity and role in biomedical research. Please enable it to take advantage of the complete set of features! J. Clin. One of them died on the 18th day, and another one on the 23rd day. 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. To validate our results which come from the experiments where mouse tumor vascularization was inhibited with humanized VEGF, we evaluated the results of Phase IV, where immunocompromized (SCID) mice were used with human colorectal adenocarcinoma (HT-29) xenografts. All rights reserved. by Mammog raphy (c.c) . This means that continuous, low dose antiangiogenic factor (VEGF) administration is needed. in The Laboratory Mouse (eds. Med. When using a handheld direct 3D measurement instrument such as the Peira TM900, the obtained value is independent from the angle position of the tool on the tumor. Mice were killed after 38 days. NCI CPTC Antibody Characterization Program. Using the above mentioned iterative method, the resulted equation is The first group did not receive therapy, the second group received one 200 g bevacizumab dose for a treatment period (protocol-based therapy), and the third group received 1.1 g bevacizumab every day (quasi-continuous therapy). This approach presents an alternative to calipers which, although cheap, fast, and easy to use, introduce many biases for tumor volume estimation. 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. Preclinical evaluation of LU 79553: a novel bis-naphthalimide with potent antitumor activity. Open Access A structured light-based system for scanning subcutaneous tumors in laboratory animals. In this phase, 5 immunocompetent mice in control group, and 9 immunocompetent mice in case group were used. 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. The tumor burden is evaluated by volume calculation using caliper measurement. The caliper mean-percent-error is 10.6%, nearly twice that of the scanners mean-percent-error of 4.6%. 2 0 obj BMC Med. This means that the daily treatment with one-twelfth total dose resulted in significantly smaller tumors than the protocol-based treatment. The other eight tumors exhibit forms that cannot be compared to a perfect ellipsoid. The site is secure. In Phase III/3, case group members received one-tenth dose of control dose intraperitoneally spread over 18 days. Modulation of mammary tumor vascularization by mast cells: Ultrasonographic and histopathological approaches. Due to the collaboration between medical doctors and biomedical engineers, model-based treatment protocols can be created. 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.). In this way, the targeted therapy can be used in a much more individualized form. Russo, J. Discover a faster, simpler path to publishing in a high-quality journal. Quantity of the optimal solvent administration was also examined in this subphase. 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). On the bottom left graph in Fig. 22, 921929 (2003). VC refers to tumor volume values calculated through the formula VT = 0.5 L W2, and VCH refers to those through the formula VT = 0.5 L W H. VS refers to measurements taken by the scanner, and % Inc. refers to the percent increase between VS and VCH. 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. https://doi.org/10.1038/laban.254. Using a caliper, growth of the tumor in height is not measured as only width and length changes will . The parameters V m = 83 mm 3, = 0.84 and = 0.21 from the literature were used [].. For \( {y}_i^j \) eqs. 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. Mice in Phase III/3 control and case groups, and mice in Phase IV case1 and case2 groups received bevacizumab. That is independent from the use of a direct optical 3D measurement tool or a caliper. One can see that the two-dimensional mathematical model fits to the MRI-measured values, while the protocol-based values present totally different curve. %PDF-1.4 39, 720 (1996). Figure 18. 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]. Pollok, K.E. Traditionally their volume growth has been monitored by using a mechanical caliper. Ultrasound Med. It can be carried out in vivo during the experiment due to the subcutaneous localization of the tumor. 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. Healthy tissues have efficient vasculature and effective blood supply due to the balance of proangiogenic and antiangiogenic factors. Ultrasonographic, thermographic and histologic evaluation of MNU-induced mammary tumors in female Sprague-Dawley rats. In the light of the above mentioned, linear curve fitting was carried out to find the mathematical relationship between MRI-measured tumor volume and tumor mass (Phase III/3 case and control groups). Fornage, B.D., Toubas, O. Article Careers. <> The scan images obtained are only for the external surface of the tumor. In addition, the mice were weighed . One can see from Table 2 that the goodness of the fit is different in the case of Phase I (tumor growth without therapy) and in the case of Phase III/3 (tumor growth with antiangiogenic therapy). Table 1 shows the results for tumor volume measure- ments on seven A431 tumors, indicating next to both gold standard volumes (V w , V L ) the caliper/formula derived volume V E and the ARTIDA . A possible solution for height approximation [23] is: Lab Anim 42, 217224 (2013). 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. Correspondence to Comparison of clinical assessment, mammography and ultrasound in pre-operative estimation of primary breast-cancer size: a practical approach. One common measure of efficacy is the T/C ratio, the ratio of tumor volume in control versus treated mice at a specified In the concept of model-based treatment, a continuous and precise tumor volume monitoring is needed concerning which, may be possible in the near future by nanotechnology [38]. Figure 2. Physical activity cancer preventionmechanisms. Figure 14. CAS 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). Traditionally, caliper measurements are used to calculate tumor volume. However, it has to be taken into consideration that in several cases using antiangiogenic therapy, tumor shape is irregular (berry-shaped). the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in In the case1 group, one mouse died on the 17th day. These images were applied to calculate vascularization area by using ImageJ (NIH, USA) [33] software (Fig 4). Each dot, in addition to signifying a real-life tumors width and height, also signifies through the right y-axis what percentage of a caliper-based measurement with the same width it is. Unable to load your collection due to an error, Unable to load your delegates due to an error. Experimentally induced mammary tumors in rats. McCormick, D.L., Adamowski, C.B., Fiks, A. 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. Under these conditions, the formula for the volume of a tumor becomes. CAS Later in a study, when a tumor grows into larger masses, the shape of the tumor can differ greatly from an ellipsoid, as shown in Figure 7. Therefore, its formula will always overestimate the tumor volume until the height equals its width, as seen in Figure 3. 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. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). 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). Even though all the three diameters can be measured, the estimation of the volume has quite a large error. Measurements with small animal MRI were done on the 4th, 8th, 11th, 15th, 18th and 23rd days of the experiment in Phase III/3. Mice were monitored daily by personnel experienced in recognizing signs of morbidity (illness, injury, or abnormal behavior) also in weekends and holidays. 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. Timing wise both methods perform the same. 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. We found the same result for human colorectal adenocarcinoma (HT-29) xenografts. Med. 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). Value of prostate volume measurement using transabdominal ultrasonography for the improvement of prostate-specific antigen-based cancer detection. J. Ultrasound Med. We have investigated different methods to find the best tumor volume estimation since it creates the possibility for precise and effective drug administration with a much lower dose than in the protocol. Tumors are assumed to be perfectly spherical (width = height) in industry and research, even though an overwhelming amount (almost 100%) of tumors in this study exhibited smaller heights than widths. 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). A typical comparison of tumor volume measurements by TumorImager-2TM with calipers. Ergonomics 37, 217229 (1994). In clinical practice, the determination of the tumor size (volume) is done by MRI and/or CT, but this is for the purpose of validating the effectiveness of the treatment, and therefore it is not a continuous monitoring. Is the Subject Area "Cancers and neoplasms" applicable to this article? Mammary tumors similar to those observed in women can be induced in rats by intraperitoneal administration of N-methyl-N-nitrosourea. Tumor volume measurement cannot happen right after tumor implantation. Scientific Reports 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). Even the same operator, with different trials or at different moments in time does not always hold the animal in exactly the same way. Mice in Phase I and Phase IV control group received no bevacizumab. % J. Nucl. 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. Conceived and designed the experiments: ZS JS. The effectiveness strongly depends on the administration, and a drug which is effective on a molecular level can be applied in a less effective way because of the incorrectly chosen administration. Better results can be obtained by proper handling of the mice. Both methods cannot avoid variability introduced by the manipulation of the animal. and JavaScript. HHS Vulnerability Disclosure, Help Phase III contained three subphases, in every subphases two groups were created; control group received bevacizumab in one dose according to the protocol, while case group received substantially lower doses every day. Verma, R. et al. Girit, I.C., Jure-Kunkel, M. & McIntyre, K.W. . 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. 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). Initiative ) format, which is suitable for image processing by proper of! Is 27 %. [ 3 ] that the two-dimensional mathematical model fits the! Girit, I.C., Jure-Kunkel, M. & McIntyre, K.W: their diversity and role biomedical... Formula will always overestimate the tumor volume has quite a large error mice in III/3! 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