ISSN 1548-4475 (online) In Phase IV, case2 group members received 1.11 g bevacizumab (with 45 l 0.9% NaCl solution) every day form the 8th day for 15 days. The scanner-based measurements yield a higher correlation in this sense than caliper-based measurements. Thus, caliper-based measurements are less accurate the more the height of the stack deviates from its width. To reduce the time of analysis one could e.g. Tumor Volume Formula for Caliper Measurements, 3. contracts here. Small MRI measurements were done in the Preclinical Imaging Center of Gedeon Richter Plc. Our results for the case group (daily, quasi-continuous small amount administration) and the control group (one big dose according to the protocol) are Mammary tumors seemed to take on an oblate spheroid geometry. () and were used with the parameters displayed in Table 1Parameters for Gompertz growth were taken from Benzekry et al. The C38 colorectal carcinoma line was maintained by serial subcutaneous transplantations in C57Bl/6 mice. Using the mathematical model, different dosage algorithms can be designed for antiangiogenic cancer therapy [1619]. Monaco performed the dose calculation of the VMAT treatment plans with the dose calculation grid of 3.0 mm by utilizing the Monte Carlo algorithm. PubMed 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 depth. Hence, the first step has to be the vasculature normalization with the reconstruction of the balance of pro- and antiangiogenic factors. & Robinson, S.P. We found out that due to this unmeasured part, the dissected tumor volumes were about 6% larger than the scan results. Cell Rep Med. A tumor tends to be flat early into its growth, and later as time advances, the treatment groups tumors may shrink especially in height if the compound of interest is effective. Kobayashy, T. et al. Traditionally their volume growth has been monitored by using a mechanical caliper. European Institute of Oncology, ITALY, Received: February 3, 2015; Accepted: October 19, 2015; Published: November 5, 2015, Copyright: 2015 Spi et al. 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]. The scan images obtained are only for the external surface of the tumor. Hedrich, H.J. For ultrasonography measurements, we calculated tumor volume . In order to estimate tumor volume by external caliper, the greatest longitudinal diameter (length) and the greatest transverse diameter (width) were determined while mice were scruffed and conscious. Determining tumor volume is a useful and quantitative way to monitor tumor progression. These images were applied to calculate vascularization area by using ImageJ (NIH, USA) [33] software (Fig 4). Even the same operator, with different trials or at different moments in time does not always hold the animal in exactly the same way. The mathematical relationship between MRI-measured tumor volume and mass was investigated to estimate accurate tumor volume using caliper-measured data. Our hypothesis is that the effectiveness of a lower dosage with a quasi-continuous therapy can be comparable with the protocol therapy. % @0u !7oyc5/Ck Tumor area was determined with flood fill algorithm [31] from the slides; by knowing the volume of a voxel, tumor volume was calculated from these two values. [2]no matter how accurately the length and width of the tumor are measured. Normality was investigated with one-sample Kolmogorov-Smirnov test; each sample has normal distribution (ppI = 0.883, ppIII/3_case = 0.716, ppIII/3_control = 0.869). 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). Bevacizumab (Avastin) [1] is an exogenous inhibitor, which inhibits the biological activity of human VEGF [2]. 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. 54, 401414 (1975). 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. 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). Preclinical Imaging Center, Gedeon Richter Plc., Budapest, Hungary, Affiliation Evaluation of prostate volume by transabdominal ultrasonography with modified ellipsoid formula at different stages of benign prostatic hyperplasia. M}{Gt{zj|&cXx[k?CZ ~AjTxMr0 '~ix$mj/)9?$ t-o6MkVXs's}^E6-^_Yrv#w&r7w@WsQs]#G g$Cn. All surgery and sacrifice were performed under sodium pentobarbital anaesthesia (Nembutal, 70 mg/kg). Usually, 3.0 x 10 6 cells are needed per injection. We also compared the tumor volumes measured by calipers to compare them with the scanner measurements. In the meantime, to ensure continued support, we are displaying the site without styles Thank you for visiting nature.com. 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. 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 . Breathing was monitored with piezoelectric transducer; temperature of the body was measured by rectal thermometer. Tukeys HSD test resuled in significant difference between case1 and case2 groups (p = 0.038). In this study, the researchers measured the same tumors with calipers and the scanner for a about month and a half. The significant difference between quasi-continuous therapy (Phase III/3 case group) and tumor growth without treatment (Phase I) was proved with statistical analysis as well. Unable to load your collection due to an error, Unable to load your delegates due to an error. This effect is illustrated in the included video. 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. Fornage, B.D., Toubas, O. Cells should be suspended in a volume so that 300 l contains required number of cells per injection. Lab Anim 42, 217224 (2013). 35, 18341840 (2003). The tumor burden is evaluated by volume calculation using caliper measurement. Ergonomics 37, 217229 (1994). Normality was investigated with one-sample Kolmogorov-Smirnov test, and homogeneity of variance (homoscedasticity) was examined with Levenes test. Results from a vaccine trial from AstraZeneca. Comp. here. Eichelerger, L.E. 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. 01 July 2022. One can find datasets in the last column of Table 2. 12, 881885 (2005). The volume above the red area is not occupied by the tumor, as seen in Figure 8. For the most precise result, tumor mass values, which were measured at the end of the experiment, were compared in the statistical analysis. J. Nucl. ANOVA test showed significant difference between these means (p = 0.041, 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. Google Scholar. 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. 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]. Almost 90% of the establishments that make tumor volume measurements using calipers use a modified version of the ellipsoid formula, under the incorrect assumption that a tumor is always a perfect ellipsoid. In that caseeven though all the three diameters can be measuredthe estimation of the volume has quite a large error. 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%. and calculates an interpolated surface under the tumor boundary based on the healthy surface around the tumor (navy blue line in Figure 12.). Frozen samples were used to create 15 m frozen cuts. 2001 Jan 15;19(2):551-7. doi: 10.1200/JCO.2001.19.2.551. Even though all the three diameters can be measured, the estimation of the volume has quite a large error. A smaller diameter mask will help to position the tumor in the center of the scan, but it will not alter this effect. Clipboard, Search History, and several other advanced features are temporarily unavailable. Another approach is to utilize the scan images (Figure 14.) & Pisani, P. Global cancer statistics, 2002. Careers. Contributed reagents/materials/analysis tools: ZS PK LK. https://doi.org/10.1371/journal.pone.0142190.g004. Orthotopic xenograft tumor models, which are more difficult to establish, are close to the clinical behavior of malignant tumors in terms of location of the primary tumor site, the tumor progression, the tumor micro-environment, cell migration and metastasis [1 . At some point, the scanner measurements showed a p-value between the treatment group in question and the control, 0.05, which generally experiments stops for a 95% confidence level measurements. (Fig 2). Russo, J. Effects of different applied voltages of irreversible electroporation on prostate cancer in a mouse model. It can be carried out in vivo during the experiment due to the subcutaneous localization of the tumor. No, Is the Subject Area "Breast cancer" applicable to this article? Department of Control Engineering and Information Technology, Budapest University of Technology and Economics, Budapest, Hungary, Affiliation <> stream Substituting tumor mass values which were measured in Phase I into Eq 8, the corresponding tumor volume values can be evaluated (one can find numerical results in Table 2 Tumor volume MRI column; and graphical results in Fig 6). Yes https://doi.org/10.1371/journal.pone.0142190.g005, https://doi.org/10.1371/journal.pone.0142190.t002, To find the f constant for tumor growth without therapy (Phase I), first reliable tumor volume values had to be found, since there was no MRI measurement in Phase I. Beside tumor diameters, tumor mass was measured and vascularization area was calculated in the case of the removed tumors. Disclaimer. Unauthorized use of these marks is strictly prohibited. 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. 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. 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]). Most, if not all, tumors do not fit into this category; this discrepancy results in caliper-based volume measurements including sections that do not exist in the actual tumor, or an overestimation of tumor volume measurement. 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. FOIA Int. No, Is the Subject Area "Cancer treatment" applicable to this article? (1). 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. et al. Yes 39, 16 (1996). However mice which were treated with a quasi-continuous therapy (one-tenth dose of control dose spread over 18 days, i.e. {(Q~J9}=ow[5nkW"C; >tDve+7K,}g?A 8600 Rockville Pike First is to find an appropriate mathematical model for tumor volume evaluation from caliper-measured data. Physical activity cancer preventionmechanisms. In Phase I, Phase II and Phase III, eight weeks old male C57Bl/6 mice with implanted C38 mouse colorectal carcinoma was used. In Figure 4., the value given by caliper measurements (VC, red squares) does not change when up to 15 pennies are stacked. Biol. Clinical criteria that establish when the endpoint have to be carried out: a) if tumors contributed to a gain of >20% in body weight compared to controls at the same time point; b) tumors that ulcerate, become necrotic or infected; c) any animal found unexpectedly to be moribund, cachectic, or unable to obtain food or water. Figure 4. Provided by the Springer Nature SharedIt content-sharing initiative, Bulletin of the National Research Centre (2022), Lab Animal (Lab Anim) Measure the mass by using a balance (0.01g) and compute the volume by using the Bizberg Themes, By Memorial Sloan Kettering Cancer Center. Better results can be obtained by proper handling of the mice. Figure 12. The authors declare no competing financial interests. 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. CAS 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. 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. depicts the inaccuracy of the formula used for caliper measurements, in which the height of the tumor is assumed to be equal to its width. All mice were implanted with HT-29 human colorectal adenocarcinoma. Folia Biol. This estimation has the same disadvantage as ellipsoid estimation, i.e. Front Chem. Experimentally induced mammary tumors in rats. To overcome all of these difficulties (continuity of the administration and side-effects), model identification should be determined and then a control algorithm (controller) can be designed for the created mathematical model. Tumor volumes are calculated from digital caliper raw data by using the formula:Volume (mm3) = (l x w2) / 2. J. Oncol. 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. All surgery and sacrifice were performed under sodium pentobarbital anaesthesia (Nembutal, 70 mg/kg), and all efforts were made to minimize suffering. Numerical result can be found in Table 2, and Fig 5 presents graphical results. Therefor it allows a direct 3D capture of the volume. J. Figure 6. Treat. CAS Med. 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