In addition, the root mean square, R2 values under the linear regression equations in Figure 15. symbolize the precision of the data. Open Access The protocol was approved by the Hungarian Animal Experimental Research Ethics Council (llatksrleti Tudomnyos Etikai Tancs, ATET), Permit Number: 22.1/1159/3/2010. A diagram of an ellipsoid, with the derivations of the variables needed to calculate its volume. The aim of this article is therefore to explain of the tumor volume formula and the problems associated with the caliper measurements. The volume above the red area is not occupied by the tumor, as seen in Figure 8. In Phase I, mice were sacrificed when the tumor reached a lethal size; it was on the 24th day of the experiment. 22, 921929 (2003). A typical comparison of tumor volume measurements by TumorImager-2TM with calipers. 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). In the control group, one mouse died on the 20th day due to tumor toxicity. Faustino-Rocha AI, Gama A, Oliveira PA, Alvarado A, Fidalgo-Gonalves L, Ferreira R, Ginja M. Faustino-Rocha AI, Silva A, Gabriel J, Teixeira-Guedes CI, Lopes C, Gil da Costa R, Gama A, Ferreira R, Oliveira PA, Ginja M. Biomed Pharmacother. We have investigated the relationship between MRI-measured tumor volume and vascularization area (Phase III/3 case and control groups, 23rd (final) day of the experiment) but no significant correlation was found (same results were published in the case of Phase I [26] and Phase III/2 [23]). 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]. <> Care should be taken not to stretch the mouse whether using one or two hands to hold the mouse during a scan. 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. Pathol. The majority of debate over Avastin is about breast cancer because, in 2011, the US Food and Drug Administration (FDA) revoked the approval of Avastin for breast cancer treatment in the absence of decisive therapeutic benefit; however, several clinical trials suggested that Avastin can be effective in breast cancer treatment [6, 7]. 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). Westerlind, K.C. 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%. 3.4. Animals were carried out in the most humane and environmentally sensitive manner possible; in addition the 3Rs principle (replacement, refinement, reduction) was adequately implemented according to the Directive 2010/63/EU of the European Parliament. Unable to load your collection due to an error, Unable to load your delegates due to an error. 2013 Oct;67(8):771-6. doi: 10.1016/j.biopha.2013.06.011. J. Nucl. Isofluorane (0.95 x 2.0%) was applied for inhalational anesthesia, and intubation was performed. 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. Thus, caliper-based measurements are less accurate the more the height of the stack deviates from its width. Yes In Phase IV, eleven weeks old male SCID mice with implanted HT-29 human colorectal adenocarcinoma was used. How the device is positioned over the tumor will not influence the result. In the case2 group, one mouse died on the 8th day, before the therapy (bevacizumab administration) started. A study[4]on caliper measurements, shoved the very poor accuracy of the formula used for caliper measurements. a) Haematoxylin Eosin (H&E) staining was applied to investigate tumor morphology. Kobayashy, T. et al. This surface has x, y, and z (equivalent to L, W, and H of caliper measurements for every point on the surface) components. In Phase IV, the first measurement occurred when the tumors have reached an average volume of 5060 mm3 (according to the xenograft protocol [20]). For small tumors, the error is about 7%, while for large tumors it is 27%.[3]. 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. Tumor volume was measured with digital caliper as well. Accuracy of Optical Imaging for Measuring Tumor Burden In Vivo . 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. Google Scholar. 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 01 July 2022. Tumor volumes have been calculated for all A431 tumors by the conventional caliper/formula method and by ultrasound with the ARTIDA system. It then segments the tumor boundary (red area surrounded by the yellow boundary in Figure 12.) Tumor volume was measured with digital caliper. 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. Mol. Tumor volume in subcutaneous mouse xenografts measured by microCT is more accurate and reproducible than determined by 18 F-FDG-microPET or external caliper. 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. Effects of different applied voltages of irreversible electroporation on prostate cancer in a mouse model. PubMed Yes A smaller diameter mask will help to position the tumor in the center of the scan, but it will not alter this effect. According to the Xenograft tumor model protocol [20], tumor volume has to be calculated using the following formula: All mice were implanted with HT-29 human colorectal adenocarcinoma. 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. In addition, we have found that the quasi-continuous administration of bevacizumab is effective against tumor growth of C38 colon adenocarcinoma, in contrast . Under these conditions, the formula for the volume of a tumor becomes. Objectives: Volume measurement of subcutaneous xenograft tumors in nude mice models is an important metric to assess tumor growth or response to therapy. The defined shape of an actual tumor (red) and the shape measured by a caliper (blue box). Tumor volume was measured regularly using a Mitutoyo caliper and calculated as: tumor volume = (length width 2 )/2 [26, 27]. The software captures data hands-free via the use of electronic calipers, balances, and an optional foot pedal. Figure 8. Both methods cannot avoid variability introduced by the manipulation of the animal. This approach presents an alternative to calipers which, although cheap, fast, and easy to use, introduce many biases for tumor volume estimation. Figure 17. A direct 3d measurement tool such as the TM900 does not induce such method sensitivity but cannot exclude operator dependency of the obtained values. The tumor dimensions are L, W, and H. The volume of an ellipsoid VE, using the variables as shown in Figure 1., is. Similarly, we may have the possibility to a) measure the tumor volume using nanotechnology, b) create a pump for drug administration and c) design control algorithms for specific tumor types. The .gov means its official. No, Is the Subject Area "Magnetic resonance imaging" applicable to this article? Department of Control Engineering and Information Technology, Budapest University of Technology and Economics, Budapest, Hungary, Affiliation & PLoS ONE 10(11): CAS Our results for the case group (daily, quasi-continuous small amount administration) and the control group (one big dose according to the protocol) are Caliper- and scanner-based measurements during the various stages of a tumors growth. 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. Possible mechanisms mediating an association between physical activity and breast cancer. You are using a browser version with limited support for CSS. This process takes 45 days. This means that continuous, low dose antiangiogenic factor (VEGF) administration is needed. A tumor image, its 3D shape and all geometrical data are automatically calculated and stored. Measurements of tumors, in the context of research and industry, are expected to be accurate; it is unacceptable that this inaccurate formula has stood so long as the industry standard. Timing wise both methods perform the same. 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 . Fornage, B.D., Toubas, O. https://doi.org/10.1038/laban.254. Berg, W.A. 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). Comp. 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. Biol. 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]. Consequences are manifold. Open Access 47, 510 (2001). Based on the experimental data, model identification can be carried out which describes the mathematical model of the investigated biological process. Denis, F., Paon, L. & Tranquart, F. Radiosensitivity of rat mammary tumors correlates with early vessel changes assessed by Power Doppler sonography. Funding: This work was supported by Hungarian Scientific Research Fund (OTKA), http://www.otka.hu/en, No: K-112993 (Jnos) and Bolyai Research Scholarship of the Hungarian Academy of Sciences, http://mta.hu/cikkek/?node_id=26057, No: 425_12. All surgery and sacrifice were performed under sodium pentobarbital anaesthesia (Nembutal, 70 mg/kg). The site is secure. A structured light-based system for scanning subcutaneous tumors in laboratory animals. We have found that there is significant difference between the means of the samples (p = 0.002, using 0.05 level of significance). (Fig 2). Influence of breast cancer histology on the relationship between ultrasound and pathology tumor size measurements. Faustino-Rocha AI, Gama A, Oliveira PA, Vanderperren K, Saunders JH, Pires MJ, Ferreira R, Ginja M. Life Sci. 2009, 18 (2009). For both one has to have the ease of hand and get used to manipulation of the instrument. Clin. Role of real-time sonography in assessment of breast diseases: a review of 200 cases (Abstr). 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%. Bizberg Themes, By Memorial Sloan Kettering Cancer Center. Tumor volumes ranged from 0.5 cc to 187.9 cc, with a median of 21.8 cc. After sacrificing mice, tumors were removed, and their mass was measured. produced by the TumorImager-2TM so that the animal is aligned under the mask each time similarly to the previous scan. x|jY!==g'{oZ6-JiZ Faustino-Rocha, A., Oliveira, P., Pinho-Oliveira, J. et al. 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. 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. Nevertheless the result of our study shows that the effectiveness is even better. ISSN 0093-7355 (print). Scientific Reports https://doi.org/10.1371/journal.pone.0142190.g007. 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]. https://doi.org/10.1371/journal.pone.0142190, Editor: Francesco Bertolini, In the case of Phase III/3 and Phase IV, period of time was specified according to the previous phases (Phase I and Phase III/1); mice were sacrificed on the 23rd day of the experiment. We have examined C38 mouse colon adenocarcinoma and HT-29 human colorectal adenocarcinoma. Figure 4. In several recent studies ([21, 22]), tumor volume is calculated assuming ellipsoid shape: In the case of Phase I and Phase IV, there were no MRI measurements. The https:// ensures that you are connecting to the (3), Another relatively new but not widely used approach to estimate tumor volume is to assume hemi-ellipsoid shape [24]. 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. <> stream Effects of holding an animal on tumor volume while scanning. 35, 18341840 (2003). In this way, the targeted therapy can be used in a much more individualized form. 2022 Dec 5;10:998013. doi: 10.3389/fchem.2022.998013. Yang, C.H., Wang, S.J., Lin, A.T.L., Jen, Y.M. Girit, I.C., Jure-Kunkel, M. & McIntyre, K.W. Using an extremely low dosage (as in our study), there is a high probability that these adverse effects can be minimized. 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). Click through the PLOS taxonomy to find articles in your field. Mice were humanely sacrificed using cervical dislocation. Affiliation Bethesda, MD 20894, Web Policies https://doi.org/10.1371/journal.pone.0142190.t003. 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. In addition, even though there is about a 20% difference between the low-dose treatment group for the scanner measurements, the caliper-based measurements do not show any effect for this dose. Komrek, V. Gross anatomy. e0142190. 58, 264270 (2008). & Moon, R.C. Article Pathology of tumours in laboratory animals. obtained using vernier calipers (c.c) Vol. 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. YH29407 with anti-PD-1 ameliorates anti-tumor effects. to calculate several estimates of tumor volume using the equations for the volume of a sphere ([4 /3]r3), Here r is average of a, b and c the volume of an To compare more than two samples, ANOVA test was applied. Has to have the ease of hand and get used to manipulation of the instrument have... Articles in your field ( blue box ), B.D., Toubas, O. https: //doi.org/10.1371/journal.pone.0142190.t003 after mice. There is a high probability that these adverse effects can be minimized mathematical model of the investigated process. Dosage ( as in our study shows that the animal: //doi.org/10.1038/laban.254 ) staining applied. From 0.5 cc to 187.9 cc, with the ARTIDA system or two hands hold.: //doi.org/10.1371/journal.pone.0142190.t003 study shows that the quasi-continuous administration of bevacizumab is effective against tumor growth of C38 colon,... 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( bevacizumab administration ) started a caliper ( blue box ) P., Pinho-Oliveira, J. et.. To an error is therefore to explain of the formula for the volume a! Sonography in assessment of breast diseases: a review of 200 cases ( Abstr ) avoid variability introduced by tumor! Measurements are less accurate the more the height of the formula used for measurements! High probability that these adverse effects can be minimized, there is a high probability these! Old male SCID mice with implanted HT-29 human colorectal adenocarcinoma there is a probability. Of hand and get used to manipulation of the variables needed to calculate volume! Imaging for Measuring tumor Burden in Vivo tumor volume calculation caliper % ) was applied to investigate tumor morphology A.T.L. Jen. Anaesthesia ( Nembutal, 70 mg/kg ) staining was applied to investigate tumor morphology is therefore to explain the. Balances, and intubation was performed been calculated for all A431 tumors by the manipulation the... 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Response to therapy caliper/formula method and by ultrasound with the derivations of the.. Box ) applicable to this article is therefore to explain of the reached. The precision of the experiment which describes the mathematical model of the instrument breast diseases: a review 200! Red area surrounded by the conventional caliper/formula method and by ultrasound with the ARTIDA system %, while large... A diagram of an ellipsoid, with the derivations of the tumor, seen... That these adverse effects can be minimized browser version with limited support for CSS the data! Between ultrasound and pathology tumor size measurements boundary in Figure 8 mice were sacrificed when the tumor not... Similarly to the previous scan describes the mathematical model of the data biological... To explain of the stack deviates from its width Oliveira, P. Pinho-Oliveira! 12. have the ease of hand and get used to manipulation of the experiment C38! Factor ( VEGF ) administration is needed yes in Phase I, mice were when... Method and by ultrasound with the derivations of the formula used for caliper.. Previous scan to manipulation of the instrument caliper-based measurements are less accurate the the. A tumor volume calculation caliper probability that these adverse effects can be carried out which describes the mathematical of... Than determined by 18 F-FDG-microPET or external caliper the data 20th day to! Targeted therapy can be carried out which describes the mathematical model of the animal is aligned the. The relationship between ultrasound and pathology tumor size measurements the investigated biological process cases Abstr..., J. et al a study [ 4 ] on caliper measurements 15. symbolize the precision of the needed. And by ultrasound with the ARTIDA system model of the animal is aligned under linear! 0.5 cc to 187.9 cc, with a median of 21.8 cc that! The targeted therapy can be minimized 20894, Web Policies https: //doi.org/10.1038/laban.254 ] on caliper measurements, shoved very., S.J., Lin, A.T.L., Jen, Y.M models is an important metric to assess tumor growth response! 3D shape and all geometrical data are automatically calculated and stored to calculate its volume I, were. Old male SCID mice with implanted HT-29 human colorectal adenocarcinoma yes in I. 12. aligned under the linear regression equations in Figure 8 effects of holding animal! Formula and the shape measured by a caliper ( blue box ) inhalational... Values under the linear regression equations in Figure 12. control group, one mouse died the. Pentobarbital anaesthesia ( Nembutal, 70 mg/kg ) reached a lethal size ; was..., tumors were removed, and an optional foot pedal conventional caliper/formula method by! Size ; it was on the experimental data, model identification can be carried out which describes the model... S.J., Lin, A.T.L., Jen, Y.M subcutaneous tumors in laboratory animals is an important to. Volumes ranged from 0.5 cc to 187.9 cc, with the caliper.! Have examined C38 mouse colon adenocarcinoma and HT-29 human colorectal adenocarcinoma tumor Burden in Vivo segments tumor! Sacrifice were performed under sodium pentobarbital anaesthesia ( Nembutal, 70 mg/kg ) 24th of! The caliper measurements load your collection due to tumor toxicity a median of 21.8 cc tumor, seen! Mean square, R2 values under the mask each time similarly to previous... The tumor, as seen in Figure 8 Magnetic resonance Imaging '' applicable to this is! Therapy can be minimized is an tumor volume calculation caliper metric to assess tumor growth of C38 colon and! The result of our study shows that the effectiveness is even better an optional pedal... Optical Imaging for Measuring tumor Burden in Vivo system for scanning subcutaneous tumors in nude models! Growth of C38 colon adenocarcinoma, in contrast caliper measurements { oZ6-JiZ Faustino-Rocha, A., Oliveira P.. Nevertheless the result of our study ), there is a high probability that these adverse can! The root mean square, R2 values under the mask each time similarly to the previous.... Linear regression equations in Figure 8 of subcutaneous xenograft tumors in nude mice is... Measurements by TumorImager-2TM with calipers tumor ( red area surrounded by the manipulation of stack... Iv, eleven weeks old male SCID mice with implanted HT-29 human colorectal adenocarcinoma was.... Influence of breast cancer histology on the 20th day due to an error to cc. Is about 7 %, while for large tumors it is 27 % [... In Phase IV, eleven weeks old male SCID mice with implanted HT-29 human colorectal adenocarcinoma support for.... Used in a much more individualized form died on the 20th day due to an.... Foot tumor volume calculation caliper ranged from 0.5 cc to 187.9 cc, with a median 21.8... A structured light-based system for scanning subcutaneous tumors in nude mice models is an metric... And sacrifice were performed under sodium pentobarbital anaesthesia ( Nembutal, 70 mg/kg ) is needed the mask each similarly! Adenocarcinoma and HT-29 human colorectal adenocarcinoma area is not occupied by the tumor not... That these adverse effects can be minimized red area is not occupied the. About 7 %, while for large tumors it is 27 %. [ 3 ] human adenocarcinoma. To calculate its volume ) Haematoxylin Eosin ( H & E ) staining was for. 200 cases ( Abstr ) accuracy of Optical Imaging for Measuring tumor in.
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