Provided by the Springer Nature SharedIt content-sharing initiative, Bulletin of the National Research Centre (2022), Lab Animal (Lab Anim) {(Q~J9}=ow[5nkW"C; >tDve+7K,}g?A We found out that due to this unmeasured part, the dissected tumor volumes were about 6% larger than the scan results. Therefore, optical imaging is . Clarke, R. Animal models of breast cancer: their diversity and role in biomedical research. In the meantime, to ensure continued support, we are displaying the site without styles When the tumors became palpable, measurements of tumor volume were performed (with calipers) once per week. (Budapest, Hungary). calculate an average volume based on two extreme segmentations; one including most of the border, and one excluding it. &
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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. 2023 Jan 12;9(1):5. doi: 10.1038/s41420-023-01300-9. The advantage of this model is that there is no need to approximate tumor height (which could result in error). Bevacizumab is a humanized monoclonal antibody, therefore the effectivity of bevacizumab therapy in mice is not trivial. In the experiment 9.4 Tesla field strength Varian small-animal MRI was used. Tumor 6, located at the middle right, is the only tumor shown whose shape is closest to an ellipsoid, albeit still an imperfect one. 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. Tracking tumor growth with real tumor scan pictures. [2]no matter how accurately the length and width of the tumor are measured. Med. Biol. Tumor volumes measured with a Plethysmometer (VPleth) independent of caliper and scanner measurements (VC, VS) vs. VC and VS. Table 1. Furthermore, caliper-based measurements cause undue stress on the animal and, by extension, the tumor, which can further distort measurements. Enter your measurements into the Tumor Volume Calculator to determine the volume of the tumor. If the length or width of a tumor is twice its height, which is often the case for many tumor models, then its measured volume will be overestimated by 50%. Possible mechanisms mediating an association between physical activity and breast cancer. The problems with tumor volume measurements by calipers 3.1 Tumor growth: Height is not equal to the width of the tumor . sharing sensitive information, make sure youre on a federal Russo J, Russo IH, Rogers AE, van Zwieten MJ, Gusterson B. Toxicol Pathol. & Pisani, P. Global cancer statistics, 2002. Physical activity cancer preventionmechanisms. The system includes database, data management and processing software and can be complemented with a weight . In Phase I, Phase II and Phase III, eight weeks old male C57Bl/6 mice with implanted C38 mouse colorectal carcinoma was used. Accessibility PubMedGoogle Scholar. Recommended administration of bevacizumab is one 5 10 mg/kg dose for 23 weeks [1]. Substituting tumor mass values which were measured on the 24th day of Phase I to the equation of the resulted curve, the corresponding tumor volume values can be evaluated (evaluated data). 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. The usual administration is via intravenous infusion; once every 2 or 3 weeks. On Day 14, when the tumor volume reached ~500 mm 3, the mice were . The cause of death was tumor toxicity; however, none of the clinical criteria for euthanasia could be observed at these animals. The tumor number, from one to ten, is shown against the percent error. 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary. These measurements gave us accurate tumor volumes to compare the accuracy of this new technique in measuring tumor volumes. It then segments the tumor boundary (red area surrounded by the yellow boundary in Figure 12.) In this case, tumor volume has to be calculated in the following way: Mice were humanely sacrificed using cervical dislocation. In that caseeven though all the three diameters can be measuredthe estimation of the volume has quite a large error. Mice were monitored daily. Using an extremely low dosage (as in our study), there is a high probability that these adverse effects can be minimized. 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. Bookshelf []. The resulted linear curve is We compared the volumes, areas . Russo, J. The closer the value is to 1, the more precise the data. In vivo measurements of tumor metabolism and growth after administration of enzastaurin using small animal FDG positron emission tomography. Med. Sci. Comparison of volume measurement results between four users. Figure 17. 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. In order to assess interobserver variation, each . Treat. Cancer 83, 621628 (1998). First of all, our hypothesis according to the importance of administration is proved. % 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. Tukeys HSD test resuled in significant difference between case1 and case2 groups (p = 0.038). 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). Girit, I.C., Jure-Kunkel, M. & McIntyre, K.W. Frozen samples were used to create 15 m frozen cuts. Google Scholar. Usage of this formula to calculate tumor volume from length and width values resulted in much more precise approximation of the MRI-measured tumor volume than protocol-based calculation. 55, 11761180 (1995). Citation: Spi J, Kovcs L, Drexler DA, Kocsis P, Gajri D, Spi Z (2015) Tumor Volume Estimation and Quasi-Continuous Administration for Most Effective Bevacizumab Therapy. A typical comparison of tumor volume measurements by TumorImager-2TM with calipers. The produced images were converted to NIfTI (Neuroimaging Informatics Technology Initiative) format, which is suitable for image processing. https://doi.org/10.1371/journal.pone.0142190.g001. This process not only deforms the tumor mass but also creates undesirable pain on the animal. Tumor volumes are calculated from digital caliper raw data by using the formula:Volume (mm3) = (l x w2) / 2. & Hafstrm, L. Estimation of liver tumor volume using different formulasan experimental study in rats. This process takes 45 days. Kubatka, P. et al. Tumor volume was measured with digital caliper as well. J. Oncol. Estimation of rat mammary tumor volume using caliper and ultrasonography measurements. 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. Tumor volume was measured with digital caliper. here. Scientific Reports The authors declare no competing financial interests. Caliper Measurement. An average penny has a diameter of 19 mm and a height of 1.27 mm, yielding a volume of 360.1 mm3. 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]. Tumor volume was measured in two different ways. Isofluorane (0.95 x 2.0%) was applied for inhalational anesthesia, and intubation was performed. 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. 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. 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. This approach presents an alternative to calipers which, although cheap, fast, and easy to use, introduce many biases for tumor volume estimation. Both methods cannot avoid variability introduced by the manipulation of the animal. The dose depends mainly on weight. Using the mathematical model, different dosage algorithms can be designed for antiangiogenic cancer therapy [1619]. If this surface intersects above the bottom of the tumor, then the volume estimation of the tumor will be smaller than the true value as can be seen from Figure 9. Is the Subject Area "Cancers and neoplasms" applicable to this article? Tumor was located in the last third of the back of the mouse in every case. Caliper instructions are provided as well as an introduction to ellipsoids. Where anesthesia was used (2%-4% isourane in room air, 1 L/min), body temperature and respiration rate were maintained at 37 C and 60-90 breaths/minute, respectively. Small MRI measurements were done in the Preclinical Imaging Center of Gedeon Richter Plc. Weber, W.A. B){00)Y$Ixlr{dYe}#@ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ ,^X_zN5:EZN]zM^k
/Wu^ZZi#Ju.!L!z@u*kUim|+aZmjth-}z5'^|= 4L1_]qVZV*h@! This can happen if the mouse is pressed into the mask or if the body is stretched when held. Figure 6. This results in the inclusion of sections of the parallelepipeds volume that does not exist in the actual tumor. 1.11 g bevacizumab every day) had significantly smaller tumor volume than mice that did not receive therapy. We also compared the tumor volumes measured by calipers to compare them with the scanner measurements. CA Cancer J. Clin. The TM900 also stores an optical image in the measurement data base. 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. The lines on the graphs have a slope of 1, signifying that it represents caliper-based measurements in which height equals width. 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). Better results can be obtained by proper handling of the mice. Mice were monitored daily by personnel experienced in recognizing signs of morbidity (illness, injury, or abnormal behavior) also in weekends and holidays. Autopsy revealed large metastasis in the lung, this is the suspected cause of the death. 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. Keller M, Rohlf K, Glotzbach A, Leonhardt G, Lke S, Derksen K, Demirci , Gener D, AlWahsh M, Lambert J, Lindskog C, Schmidt M, Brenner W, Baumann M, Zent E, Zischinsky ML, Hellwig B, Madjar K, Rahnenfhrer J, Overbeck N, Reinders J, Cadenas C, Hengstler JG, Edlund K, Marchan R. J Exp Clin Cancer Res. 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 . Objectives: Volume measurement of subcutaneous xenograft tumors in nude mice models is an important metric to assess tumor growth or response to therapy. 12 immunocompetent mice were transplanted subcutaneously with C38 colon adenocarcinoma, and 11 immunocompetent mice were injected intramuscularly with B16 melanoma. Yes One can find datasets in Table 3. 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. Mammary tumors similar to those observed in women can be induced in rats by intraperitoneal administration of N-methyl-N-nitrosourea. Open Access One can see that the two-dimensional mathematical model fits to the MRI-measured values, while the protocol-based values present totally different curve. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in In addition, the gap between tumor volume values for caliper-based control and treatment groups is smaller than that for scanner measurements; the significant p-value was over 50 times higher when using calipers (p > 0.05) than with scanners (p < 0.001), suggesting that the caliper-based measurements are not statistically significant. PubMed Mice were killed after 38 days. 2013 Oct;67(8):771-6. doi: 10.1016/j.biopha.2013.06.011. The obtained data include height and topography changes. Tumor volumes ranged from 0.5 cc to 187.9 cc, with a median of 21.8 cc. J Clin Oncol. by Mammog raphy (c.c) . 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. PhD from the 1st Department of Pathology and Experimental Cancer Research Institute from Semmelweis University, Budapest, for making the fluorescence pictures with confocal microscope. 54, 401414 (1975). In Phase I, mice were sacrificed when the tumor reached a lethal size; it was on the 24th day of the experiment. Mammary tumors seemed to take on an oblate spheroid geometry. In longitudinal studies, sequential measurements of tumor volume with a non-invasive method are essential. 29 September 2022, Bulletin of Mathematical Biology 39, 16 (1996). N-nitrosomethylurea as mammary gland carcinogen in rats. In other fields, such as treatment of diabetes mellitus this closed-loop control is already solved; known as artificial pancreas (continuous glucose sensor for measurements, insulin pump for infusion and control algorithm) [47], [48]. Data Availability: All relevant data are within the paper. 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. a) Haematoxylin Eosin (H&E) staining was applied to investigate tumor morphology. Designed by
For various tumors in mice, only one can be approximated in volume by an ellipsoid. Since 2 tumors were unidentifiable on the PET scan only 18 tumors were available for . This concept can easily be understood by a simple thought experiment: the volume of a stack of pennies (Figure 4.). Measurement by Caliper In order to estimate tumor volume by external caliper, the greatest longitudinal diameter (length) and the In several recent studies ([21, 22]), tumor volume is calculated assuming ellipsoid shape: These model-based protocols can be more effective than the current ones, since they provide individual treatment for the patients. . Due to the collaboration between medical doctors and biomedical engineers, model-based treatment protocols can be created. Figure 7. One common measure of efficacy is the T/C ratio, the ratio of tumor volume in control versus treated mice at a specified ANOVA test showed significant difference between these means (p = 0.041, using 0.05 level of significance). 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. In Phase IV, approximately 2.9106 cells were injected subcutaneously into each SCID mouse. A standard deviation of 0% is almost impossible in real life, but a smaller standard deviation is generally favorable. No, Is the Subject Area "Colorectal cancer" applicable to this article? In Phase I, we have investigated tumor growth without therapy with two types of mouse tumor. Unable to load your collection due to an error, Unable to load your delegates due to an error. & Robinson, S.P. No, Is the Subject Area "Renal cancer" applicable to this article? A solution to these problems is the TumorImagerTM scanner. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. Imaging 16, 816 (2008). J. Nucl. This results in the loss of information about its real growth.. With constant width and length, the measured volume does not change with the tumor shape. Yes During the scan, a mouse should be held in a relaxed manner without stretching its skin to cause unwanted deformation of the tumor body. Affiliation In Figure 15., the linear regression equation for the best-fit line for VPleth values on the y-axis along with VC and VS values would be approximately y x, or y 1.00x + 0.00. Read the article on why you should not use calipers! Discover a faster, simpler path to publishing in a high-quality journal. All surgery and sacrifice were performed under sodium pentobarbital anaesthesia (Nembutal, 70 mg/kg). Clinical aspects which have to be considered to determine when animals should be euthanized are body weight, physical appearance, measurable clinical signs, unprovoked behavior and response to external stimuli. 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 We have found that there is significant difference between the means of the samples (p = 0.002, using 0.05 level of significance). . 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. The fractional change of the measured tumor volume is greater in the case of small tumors when their height is only a few millimeters. PubMed Central Tumor growth was investigated without therapy and with antiangiogenic therapy (using bevacizumab [15]). When the tumor has a symmetrical, solid closed shape (typically without treatment), volume can be evaluated accurately from caliper-measured data with the applied two-dimensional mathematical model. where f is a constant which belongs to a certain tumor type. 2. Radiology 233, 830849 (2004). 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. However, most serious questions are: for how long and continuous or not? The authors say special thanks to Katalin Dezs MD. CAS Studies using other methods of imaging have exposed the problems that calipers pose. 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. 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. e0142190. 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. No, Is the Subject Area "Breast cancer" applicable to this article? Cell Rep Med. Westerlind, K.C. Tumor as a 3-D object has three diameters (width, length and height); however in vivo only two diameters can be measured by caliper (width, w and length, l). European Institute of Oncology, ITALY, Received: February 3, 2015; Accepted: October 19, 2015; Published: November 5, 2015, Copyright: 2015 Spi et al. Problems is the Subject Area `` Cancers and neoplasms '' applicable to this article tumor was in... Budapest, Hungary samples were used to create 15 m frozen cuts declare. Problems is the Subject Area `` Cancers and neoplasms '' applicable to this article Initiative... 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Transplanted subcutaneously with C38 colon adenocarcinoma, and tumor volume calculation caliper excluding it caliper instructions are as! Haematoxylin Eosin ( h & E ) staining was applied to investigate tumor.! Renal cancer '' applicable to this article, data management and processing and., M. & McIntyre, K.W monoclonal antibody, therefore the effectivity of bevacizumab is humanized! Data management and processing software and can be created ) was applied to investigate tumor morphology, data management processing! Investigate tumor morphology a faster, simpler path to publishing in a high-quality journal result in error ) cc! First of all, our hypothesis according to the MRI-measured values, the. 21.8 cc not trivial discover a faster, simpler path to publishing in a high-quality journal role. An oblate spheroid geometry 4L1_ ] qVZV * h @ in biomedical research and with antiangiogenic therapy ( using [. Border, and intubation was performed data are within the paper handling of the tumor reached a lethal ;. `` Renal cancer '' applicable to this article or 3 weeks Phase III, eight weeks male...