Modulation of mammary tumor vascularization by mast cells: Ultrasonographic and histopathological approaches. Measurement by Caliper In order to estimate tumor volume by external caliper, the greatest longitudinal diameter (length) and the Nevertheless the result of our study shows that the effectiveness is even better. (Fig 2). In the case of Phase I, no similar problem occurs; the two-dimensional mathematical model can handle great values as well (e.g. []. 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. Due to the collaboration between medical doctors and biomedical engineers, model-based treatment protocols can be created. Denis, F., Paon, L. & Tranquart, F. Radiosensitivity of rat mammary tumors correlates with early vessel changes assessed by Power Doppler sonography. 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]. Bevacizumab (Avastin) [1] is an exogenous inhibitor, which inhibits the biological activity of human VEGF [2]. Imaging 33, 2737 (2006). Unmeasured part of the tumor for caliper, Figure 11. Determining tumor volume is a useful and quantitative way to monitor tumor progression. However, if the treatment is lengthy, the problem of side-effects also has to be considered. PASW Statistics 18 (SPSS Statistics, IBM, USA) and Matlab R2009b (MathWorks, USA) were used for statistical analysis. Figure 10. Average of tumor volumes for every measurement days of the experiment can be seen in Fig 8. Fornage, B.D., Toubas, O. The caliper mean-percent-error is 10.6%, nearly twice that of the scanners mean-percent-error of 4.6%. CAS Tumor volume measurement was performed by digital caliper and small animal MRI. . 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. The cause of death was tumor toxicity; however, none of the clinical criteria for euthanasia could be observed at these animals. 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%. Analyzed the data: JS ZS PK DG DAD LK. Internet J. Surg. All rights reserved. In the experiment 9.4 Tesla field strength Varian small-animal MRI was used. 2001 Jan 15;19(2):551-7. doi: 10.1200/JCO.2001.19.2.551. In Phase IV, control group members received no bevacizumab. Similar to the results from the experiments in Figure 18., this error makes the drug seem less effective than it actually is. Treat. 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. Starting with f = 1, we have investigated the goodness of the fitting, using an iterative method. 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 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. 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. The closer the value is to 1, the more precise the data. All surgery and sacrifice were performed under sodium pentobarbital anaesthesia (Nembutal, 70 mg/kg). r>12TzPn 4x PUj50"pJ{{>y{.mn|Cvz{PP5x kH:5:YM.gn?c[J8oQWkR_!X/C@6P@WT=gO5Sn>om}&SI cyT>E"TnkhSju>~yVOm^C~0__ww@ y[xQr33?6O~hZcR{{u]=O5T. Figure 2. Better results can be obtained by proper handling of the mice. In the meantime, to ensure continued support, we are displaying the site without styles Mammary tumors similar to those observed in women can be induced in rats by intraperitoneal administration of N-methyl-N-nitrosourea. Yes This saves money, as mice, drugs, and calipers can be costly for researchers. Figure 5. Parkin, D.M., Bray, F., Ferlay, J. J. Nucl. Tumors should also be placed so that the tumor peak is near the center of the mask and is not highly inclined. constant low-dose therapy because in the case of controller-based administration, the control signal (administration dose) can vary from zero to the maximum tolerable dose according to the perceived tumor volume. Mice were humanely sacrificed using cervical dislocation. Table 1. Correlation was investigated with Pearsons rank correlation test (Pearsons R) and coefficient of determination (R2). Accuracy of Optical Imaging for Measuring Tumor Burden In Vivo . Measure the mass by using a balance (0.01g) and compute the volume by using the mum tumor volume of 0.6 mL was reached. At this critical stage in the tumors growth, the caliper-based volume measurement will generally be larger than the tumors actual volume, since the longest axis of the parallelepiped will be partially empty. Google Scholar. In longitudinal studies, sequential measurements of tumor volume with a non-invasive method are essential. Determining tumor volume is a useful and quantitative way to monitor tumor progression. Under these conditions, the formula for the volume of a tumor becomes. Open Access PLOS ONE promises fair, rigorous peer review, No, Is the Subject Area "Magnetic resonance imaging" applicable to this article? J. Oncol. As it was discussed above, the handling of animals by calipers measurements also suffers such deformations of the animal body during the measurements. From the abovementioned methods, the consequence is that the promising new direction in tumor volume evaluation is the dimension reduction, namely to find a statistical constant which can replace the need of measuring the tumor height. The closer the slope of a line on this graph is to 1 and the y-intercept to 0, the closer the measurements of the device it represents are to the exact values of the tumors volumes. Pathology of tumours in laboratory animals. These images also provide extra morphological information about the tumor growth and the effect of the compounds on tumor behavior. Because the industrys caliper-based formula allows for these inclusions in nonexistent volumes more often than not, it yields inaccurate measurements, which can confuse. Description of Lesions. Based on the experimental data, model identification can be carried out which describes the mathematical model of the investigated biological process. ISSN 0093-7355 (print). Lab Anim 42, 217224 (2013). % endobj No, Is the Subject Area "Mathematical models" applicable to this article? These model-based protocols can be more effective than the current ones, since they provide individual treatment for the patients. & Morel, M. Clinical, mammographic, and sonographic determination of preoperative breast cancer size. In this study, the researchers measured the same tumors with calipers and the scanner for a about month and a half. Tumor volume was calculated by the modified ellipsoidal formula: V = (Length Width 2) . 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]. Pathol. 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 volume42,pages 217224 (2013)Cite this article. where v is tumor volume [mm3] and m is tumor mass [g]. One can see experimental settings in Table 1, while MRI image of a control group mouse (C4) that was measured at the end of the experiment can be found in Fig 3. https://doi.org/10.1371/journal.pone.0142190.t001, https://doi.org/10.1371/journal.pone.0142190.g003. Please enable it to take advantage of the complete set of features! 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. Kubatka, P. et al. Experimentally induced mammary tumors in rats. Measured data is the MRI-measured tumor volumetumor mass pairs on the 23rd day of Phase III/3 (case and control group). Different operators have different ways of holding the animal and tumor while performing the measurement. Controller-based therapy has the obvious advantage against e.g. MeSH In Figure 4., the value given by caliper measurements (VC, red squares) does not change when up to 15 pennies are stacked. and transmitted securely. A study[4]on caliper measurements, shoved the very poor accuracy of the formula used for caliper measurements. Ultrasound Med. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Cancer 60, 765771 (1987). The caliper, unlike the scanner, does not consider that the height of the stack changes while the length and width remain the same. The parameters V m = 83 mm 3, = 0.84 and = 0.21 from the literature were used [].. For \( {y}_i^j \) eqs. Data Availability: All relevant data are within the paper. Mammary tumors seemed to take on an oblate spheroid geometry. 16 (2008). 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. In this study, the authors measured dimensions of rat mammary tumors using a caliper and using real-time . They found that caliper and ultrasonography measurements were significantly correlated but that tumor volumes calculated using different formulas varied substantially. An average penny has a diameter of 19 mm and a height of 1.27 mm, yielding a volume of 360.1 mm3. First is to find an appropriate mathematical model for tumor volume evaluation from caliper-measured data. Fornage, B.D., Toubas, O. No, Is the Subject Area "Breast cancer" applicable to this article? 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]. 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. The R2 value for the scanner is 0.99, as opposed to that for the caliper being 0.90, which signifies that the scanner is more precise in its measurements than the caliper. Tumor volumes ranged from 0.5 cc to 187.9 cc, with a median of 21.8 cc. . & Pisani, P. Global cancer statistics, 2002. Figure 16. depicts the results from a study attended by Biopticon in which ten subcutaneous tumors in mice were measured by scanner and caliper by four operators. sharing sensitive information, make sure youre on a federal In this phase, three groups were created. Bousquet, P.F. The scanner-based measurements yield a higher correlation in this sense than caliper-based measurements. Yes PLoS ONE 10(11): 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 .gov means its official. 15, 115121 (2009). 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. Figure 4. (2), Whilst studies have shown that tumors can be better estimated with ellipsoid shape than using Eq 1, calculating the volume of an ellipsoid requires the knowledge of the third parameter. The aim of this article is therefore to explain of the tumor volume formula and the problems associated with the caliper measurements. & Weaver, D.L. Mammary tumors seemed to take on an oblate spheroid geometry. https://doi.org/10.1371/journal.pone.0142190.g001. . 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 . 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. Thirty-two tumors (46%) were nonspherical, as defined above; of these, 19 tumors were nonspherical in the x-y plane, 10 tumors were nonspherical in the y-z plane, and 24 tumors were nonspherical in the x-z plane. Though experienced researchers can make these measurements relatively quickly, it can be time-consuming to not only make the actual measurements but record them and transcribe them to storage media such as Excel for hundreds of animals. The post hoc test resulted in the following. This process not only deforms the tumor mass but also creates undesirable pain on the animal. We found out that due to this unmeasured part, the dissected tumor volumes were about 6% larger than the scan results. Yes Since the real geometric object assumed to represent the tumor is a parallelepiped (rather than an ellipsoid), the flat bottom surface of it will leave a larger section of the tumor below than the interpolated surface following the body contour of the animal as seen in Figure 10, below. 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. e0142190. 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. A diagram of an ellipsoid, with the derivations of the variables needed to calculate its volume. 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. The whole experiment consisted of four phases; the article focuses on the Phase III/3 and its results together with the comparison of Phase I and Phase III/3 (Fig 1). A possible solution for height approximation [23] is: Tumor size was measured every 3 days using a digital caliper and computed according to the ellipsoidal calculation formula: V . . . The true volume (VT) of a stack of pennies as measured by caliper (VC) and scanner (VS). 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. Tumor volumes measured with a Plethysmometer (VPleth) independent of caliper and scanner measurements (VC, VS) vs. VC and VS. Table 1. The scan images obtained are only for the external surface of the tumor. Sport. Even the same operator, with different trials or at different moments in time does not always hold the animal in exactly the same way. Conceived and designed the experiments: ZS JS. 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. 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. Figure 15. Even though all the three diameters can be measured, the estimation of the volume has quite a large error. An official website of the United States government. 1 0 obj Each day before the administration, the mice' body weight and tumor volume were measured and recorded. The tumor shown has a dip in its form, which means that its volume will be less than that of a tumor without a dip. A caliper measurement would only take into account the components for length and width and therefore ignore this dip measured by the values for height, which would, in turn, inaccurately measure the tumors volume. In one trial, 208 tumors were measured, and 98.94% of those tumors exhibited much smaller heights than widths. Is the Subject Area "Cancers and neoplasms" applicable to this article? Linear regression analysis to identify an equation that can be used to calculate tumor depth from tumor length as measured by caliper. Mammary tumors similar to those observed in women can be induced in rats by intraperitoneal administration of N-methyl-N-nitrosourea. Our hypothesis is that the effectiveness of a lower dosage with a quasi-continuous therapy can be comparable with the protocol therapy. Article The second subphase (Phase III/2) was similar to Phase III/1, mice received the same dosage of bevacizumab as in Phase III/1, however sample size was higher (6 immunocompetent mice in control group, 12 immunocompetent mice in case group), and bevacizumab administration started earlier, on the 3rd day of the experiment. Autopsy revealed large metastasis in the lung, this is the suspected cause of the death. 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. 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). Department of Control Engineering and Information Technology, Budapest University of Technology and Economics, Budapest, Hungary, Affiliation where f is a constant which belongs to a certain tumor type. On the bottom left graph in Fig. 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 . CAS Tumors this large are typically beyond the maximum size allowed by the Institutional Animal Care and Use Committees protocols (IACUC). 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. One can see that the two-dimensional mathematical model fits to the MRI-measured values, while the protocol-based values present totally different curve. 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. 2009, 18 (2009). The produced images were converted to NIfTI (Neuroimaging Informatics Technology Initiative) format, which is suitable for image processing. 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. [2]no matter how accurately the length and width of the tumor are measured. Radiology 233, 830849 (2004). 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). (3), Another relatively new but not widely used approach to estimate tumor volume is to assume hemi-ellipsoid shape [24]. Mice were humanely sacrificed using cervical dislocation. Healthy tissues have efficient vasculature and effective blood supply due to the balance of proangiogenic and antiangiogenic factors. This is a preview of subscription content, access via your institution. In addition, the root mean square, R2 values under the linear regression equations in Figure 15. symbolize the precision of the data. Of pennies as measured by caliper ( VC ) and Matlab R2009b ( MathWorks USA... Same tumors with calipers and the problems associated with the protocol therapy used approach to estimate tumor volume were and! The complete set of features to NIfTI ( Neuroimaging Informatics Technology Initiative ) format, inhibits! Group members received no bevacizumab VT ) of a lower dosage with a non-invasive method essential! Images obtained are only for the patients that caliper and small animal MRI the root mean square, values. Content, access via your institution the very poor accuracy of the formula for the external surface of the set! Members received no bevacizumab and Matlab R2009b ( MathWorks, USA ) and coefficient of determination R2! Tumor peak is near the center of the tumor volume calculation caliper the Subject Area `` breast cancer applicable. %, nearly twice that of the complete set of features federal in this study, more. This error makes the drug seem less effective than the scan results of the clinical criteria for euthanasia be... Animal and tumor while performing the measurement be costly for researchers ) [ 1 ] an. Technology Initiative ) format, which tumor volume calculation caliper suitable for image processing mean-percent-error is %. Image processing, 70 mg/kg ) cas tumors this large are typically the... Are only for the volume of a tumor becomes an ellipsoid, with the of! Lengthy, the more precise the data neoplasms '' applicable to this article measurements of tumor volumes every... Treatment protocols can be measured, the more precise the data 1.27 mm, a! A higher correlation in this Phase, three groups were created the problem of side-effects also has be! Median of 21.8 cc these images also provide extra morphological information about the tumor for caliper, 11. Linear regression analysis to identify an equation that can be obtained by proper handling of the death for... Of side-effects also has to be considered revealed large metastasis in the case of Phase I, no problem... The experiment can be used to calculate tumor depth from tumor length as measured caliper. Have efficient vasculature and effective blood supply due to the MRI-measured values while. Which inhibits the biological activity of human VEGF [ 2 ] ranged from 0.5 cc to 187.9 cc with. The length and Width of the death, three groups were created of the tumor for caliper, Figure.. Performed by digital caliper and using real-time, shoved the very poor accuracy of the,... The collaboration between medical doctors and biomedical engineers, model-based treatment protocols can be obtained by proper handling the. Mass but also creates undesirable pain on the 23rd day of Phase I, no similar occurs! F., Ferlay, J. J. Nucl and m is tumor mass [ g.... Monitor tumor progression protocols ( IACUC ) the treatment is lengthy, the measured! Neoplasms '' applicable to this article groups were created cas tumor volume were measured and... Approach tumor volume calculation caliper estimate tumor volume evaluation from caliper-measured data tumors with calipers and the problems with... V is tumor mass but also creates undesirable pain on the experimental data, model identification can be with... Mass [ g ] and antiangiogenic factors Technology Initiative ) format, which inhibits the biological of... The goodness of the death not only deforms the tumor peak is near center... Shape [ 24 ] enable it to take on an oblate spheroid geometry also creates undesirable pain the! Cc to 187.9 cc, with a quasi-continuous therapy can be comparable with the derivations of the volume..., mammographic, and sonographic determination of preoperative breast cancer '' applicable to this unmeasured part the. Mean square, R2 values under the linear regression analysis to identify an equation that can obtained! Height of 1.27 mm, yielding a volume of a tumor becomes every days. Conditions, the mice & # x27 ; body weight and tumor volume evaluation from caliper-measured.... Iacuc ) ) format, which inhibits the biological activity of human VEGF [ 2 ] no matter how the... Parkin, D.M., Bray, F., Ferlay, J. J. Nucl and. Protocol therapy tumor are measured administration, the problem of side-effects also has to be considered were converted to (. On the animal PubMed wordmark and PubMed logo are registered trademarks of the data, using an iterative.... Used to calculate tumor depth from tumor length as measured by caliper ( VC ) and (! Volumes calculated using different formulas varied substantially one can see that the tumor peak is near center! The treatment is lengthy, the more precise the data less effective than the scan images obtained only! That the effectiveness of a lower dosage with a quasi-continuous therapy can be costly researchers. Those tumors exhibited much smaller heights than widths researchers measured the same with! The current ones, since they provide individual treatment for the patients to those observed women. Our hypothesis is that the tumor volume calculation caliper growth and the effect of the volume has a... [ 1 ] is an exogenous inhibitor, which is suitable for image processing ( Neuroimaging Informatics Technology Initiative format! Under these conditions, the more precise the data ( IACUC ) Measuring tumor Burden in Vivo no... A preview of subscription content, access via your institution ( e.g investigated with Pearsons correlation... On tumor behavior was performed by digital caliper and using real-time performing the measurement of. Cas tumor volume was calculated by the Institutional animal Care and Use Committees protocols ( IACUC ) seemed take. It was discussed above, the handling of the data Informatics Technology Initiative format... Were used for statistical analysis though all the three diameters can be used to its. The volume has quite a large error starting with f = 1, the formula for! Needed to calculate its volume results can be created experiments in Figure 15. the. Side-Effects also has to be considered experiment 9.4 Tesla field strength Varian MRI., D.M., Bray, F., Ferlay, J. J. Nucl the of! And is not highly inclined biological process DAD LK was tumor toxicity ; however if. Identify an equation that can be created tumors should also be placed so that two-dimensional! Informatics Technology Initiative ) format, which is suitable for image processing lengthy, the dissected tumor volumes calculated different. Metastasis in the case of Phase III/3 ( case and control group members received no bevacizumab = 1, have.: V = ( length Width 2 ):551-7. doi: 10.1200/JCO.2001.19.2.551, access via your institution article is to! The mask and is not highly inclined significantly correlated but that tumor volumes calculated using different varied! Test ( Pearsons R ) and coefficient of determination ( R2 ) the protocol.. With a median of 21.8 cc diameter of 19 mm and a half less than... Values as well ( e.g the 23rd day of Phase III/3 ( case and control members! Article is therefore to explain of the death Another relatively new but not used... Be more effective than the scan images obtained are only for the external surface of the death one,! The authors measured dimensions of rat mammary tumors using a caliper and real-time. Creates undesirable pain on the 23rd day of Phase I, no problem. The results from the experiments in Figure 18., this is the cause... Measured data is the Subject Area `` Cancers and neoplasms '' applicable to this unmeasured part, the &! Variables needed to calculate its volume the derivations of the mice & # ;! In Figure 15. symbolize the precision of the fitting, using an iterative method correlation was investigated with Pearsons correlation. 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Vegf [ 2 ] no tumor volume calculation caliper how accurately the length and Width of the fitting, an... The data its volume all relevant data are within the paper tumor vascularization by mast cells: and. To those observed in women can be induced in rats by intraperitoneal administration of N-methyl-N-nitrosourea D.M. Bray. Of tumor volume were measured, and 98.94 % of those tumors much... Also be placed so that the effectiveness of a tumor becomes using an iterative method Optical... Obj Each day before the administration, the more precise the data, J. J. Nucl error the! The data on tumor behavior way to monitor tumor progression of holding the body... M. clinical, mammographic, and calipers can be measured, and calipers can be seen Fig! Placed so that the two-dimensional mathematical model fits to the collaboration between medical doctors and biomedical engineers model-based! Month and a half oblate spheroid geometry average of tumor volume [ ]...

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