The aim of the experiment was to create and validate a clinically relevant tumor growth model (using C38 colon adenocarcinoma), focusing on the effect of angiogenesis. Unable to load your collection due to an error, Unable to load your delegates due to an error. In a 2001 study utilizing MRI, it was concluded that 85% of tumors needed a measurement other than length and the width to yield an accurate volume[5]; caliper-based values do not provide this other measurement. A direct 3d measurement tool such as the TM900 does not induce such method sensitivity but cannot exclude operator dependency of the obtained values. Figure 12. 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]. 2023 Jan 20;42(1):25. doi: 10.1186/s13046-022-02578-w. Zhao R, Chen P, Qu C, Liang J, Cheng Y, Sun Z, Tian H. Cell Death Discov. 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. 2 0 obj https://doi.org/10.1371/journal.pone.0142190, Editor: Francesco Bertolini, Results from a vaccine trial from AstraZeneca. et al. Caliper Measurement. In Phase I, mice were sacrificed when the tumor reached a lethal size; it was on the 24th day of the experiment. 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). 37, 331337 (2011). Competing interests: The authors have the following interests: Coauthors PK and DG are employed by Gedeon Richter Ltd. Avastin (bevacizumab) is manufactured by Genentech, Inc., South San Francisco, California, USA; EU patent expiry in 2019 in the US and 2022 in EU. First way is the caliper measurement; in that case tumor diameters (width, length) are measured with digital caliper. For more information about PLOS Subject Areas, click In Phase I, we have investigated tumor growth without therapy with two types of mouse tumor. 20, the red dots that represent scanner-based measurements are closer to the black dotted (objective) line than the blue squares that represent caliper-based measurements. In this study, the researchers measured the same tumors with calipers and the scanner for a about month and a half. 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. {(Q~J9}=ow[5nkW"C; >tDve+7K,}g?A Average of tumor volumes for every measurement days of the experiment can be seen in Fig 8. Russo, J. Tumor size was measured every 3 days using a digital caliper and computed according to the ellipsoidal calculation formula: V . 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. by Mammog raphy (c.c) . Materials and methods: The murine CaNT subcutaneous xenograft model was used. Performed the experiments: JS ZS PK DG. 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. A patented algorithm running in the TumorManagerTM program calculates the tumor volume by creating a 3D surface map of the tumor (red-colored surface in Figure 12.). 2017 May 1;176:35-41. doi: 10.1016/j.lfs.2017.03.013. A quiet and modestly T2-weighted spin-echo scan was acquired at 4.7T (TE = 15 msec, TR = 1100 msec, 0.5 mm isotropic . This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. In order to assess interobserver variation, each . PubMed Central 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. Bevacizumab is a humanized monoclonal antibody, therefore the effectivity of bevacizumab therapy in mice is not trivial. However, most serious questions are: for how long and continuous or not? https://doi.org/10.1371/journal.pone.0142190.g007. 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 . 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 . M}{Gt{zj|&cXx[k?CZ
~AjTxMr0 '~ix$mj/)9?$
t-o6MkVXs's}^E6-^_Yrv#w&r7w@WsQs]#G g$Cn. 15, 115121 (2009). The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Disclaimer. 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. Tumor volumes have been calculated for all A431 tumors by the conventional caliper/formula method and by ultrasound with the ARTIDA system. Recommended administration of bevacizumab is one 5 10 mg/kg dose for 23 weeks [1]. As the height values of the tumors deviate from those of the width, the caliper-based volume values of those tumors begin to mirror real-life measurements less closely. The post hoc test resulted in the following. volume42,pages 217224 (2013)Cite this article. The authors say special thanks to Katalin Dezs MD. The problems with tumor volume measurements by calipers 3.1 Tumor growth: Height is not equal to the width of the tumor . Yes Autopsy revealed only minimal local tumor; however death was not caused by tumor. The caliper-based findings can lead researchers to believe that the drug is less effective than it actually is because the change in tumor volume between the control and treatment groups is smaller. The explanation of the effectiveness of low dose VEGF therapy is the following ([3944]). Mammary tumors seemed to take on an oblate spheroid geometry. In Phase IV, control group members received no bevacizumab. 2009, 18 (2009). Modern Pathol. Open Access Please enable it to take advantage of the complete set of features! After staining, fluorescence pictures were done from the slides using confocal microscope (BIO-RAD MRC-1024). sharing sensitive information, make sure youre on a federal Faustino-Rocha AI, Gama A, Oliveira PA, Vanderperren K, Saunders JH, Pires MJ, Ferreira R, Ginja M. Life Sci. Our results provide a theoretical background for a much more effective bevacizumab treatment using optimized administration. 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. Int. Google Scholar. In both cases, the height of the tumor will be much smaller than its length or width (Figure 2.). Davis, P.L. We have administered 10 mg/kg body weight intraperitoneally, which means 200 g bevacizumab per a mouse, since the mass of the mice in the experiment was approximately 20 g (in the case of C57Bl/6 and SCID mice as well). After sacrificing mice, tumors were removed, and their mass was measured. Pritt, B., Ashikaga, T., Oppenheimer, R.G. Normality was investigated with one-sample Kolmogorov-Smirnov test, and homogeneity of variance (homoscedasticity) was examined with Levenes test. 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. Clin. 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. Furthermore, caliper-based measurements cause undue stress on the animal and, by extension, the tumor, which can further distort measurements. 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. Evaluated the accuracy of common four formulas given in the literature to estimate xenograft tumor volumes based on manual caliper measurements and proposed formula (0,45 L*W*H) could estimate tumor volumes as good as prolate ellipsoid formula. Yes 2023 Jan 12;9(1):5. doi: 10.1038/s41420-023-01300-9. 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. In Phase I, 12 mice were implanted with C38 colon adenocarcinoma. 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. Provided by the Springer Nature SharedIt content-sharing initiative, Bulletin of the National Research Centre (2022), Lab Animal (Lab Anim) A structured light-based system for scanning subcutaneous tumors in laboratory animals. %PDF-1.4 When using calipers there is dependency in the measured data of the positioning by the operator of the tool on the xenograft. We have investigated different methods to find the best tumor volume estimation since it creates the possibility for precise and effective drug administration with a much lower dose than in the protocol. One can see from Table 2 that the goodness of the fit is different in the case of Phase I (tumor growth without therapy) and in the case of Phase III/3 (tumor growth with antiangiogenic therapy). In vivo measurements of tumor metabolism and growth after administration of enzastaurin using small animal FDG positron emission tomography. 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. Of course, for the closed-loop design frequent and precise tumor volume measuremets are required, thus the problem of tumor volume measurement has to be solved as well. 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 other eight tumors exhibit forms that cannot be compared to a perfect ellipsoid. A smaller standard deviation in a set of measurements suggests a lesser possibility of error. PLOS ONE promises fair, rigorous peer review, However, it has to be taken into consideration that in several cases using antiangiogenic therapy, tumor shape is irregular (berry-shaped). Sci. 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). Yang, C.H., Wang, S.J., Lin, A.T.L., Jen, Y.M. Accurately measure the tumor (in cm) using a caliper. by water displace ment (c.c) Vol. Tumor volume was measured with digital caliper as well. 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 3-D illustration can be found in Fig 7. a) berry-shaped tumor; b) x-diameter of the tumor; c) y-diameter of the tumor; d) z-diameter of the tumor; e) berry-shaped tumor with ellipsoidal estimation. https://doi.org/10.1371/journal.pone.0142190.g002. 120, 386391 (2003). Fj^P;7? In Phase IV, the first measurement occurred when the tumors have reached an average volume of 5060 mm3 (according to the xenograft protocol [20]). 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. Pairwise comparison was done by Tukeys honest significant difference test to find those samples, which have significantly different means. Make sure you get accurate measurements for length, width and height. Yes Watch our 2-minute video overview. A graph depicting tumor volume in mm3, as measured by a caliper compared to its actual volume, vs. days. Effects of holding an animal on tumor volume while scanning. 55, 11761180 (1995). Lifetime dose-response relationships for mammary tumor induction by a single administration of N-methyl-N-nitrosourea. 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. One can see that the two-dimensional mathematical model fits to the MRI-measured values, while the protocol-based values present totally different curve. Hence, the first step has to be the vasculature normalization with the reconstruction of the balance of pro- and antiangiogenic factors. Pathol. . The size of maximum tumor volumes observed in our study fulfills the requirements of Hungarian animal experimental research protocol. 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. To compare more than two samples, ANOVA test was applied. 37, 19 (1996). Therefore, its formula will always overestimate the tumor volume until the height equals its width, as seen in Figure 3. The caliper, unlike the scanner, does not consider that the height of the stack changes while the length and width remain the same. Isofluorane (0.95 x 2.0%) was applied for inhalational anesthesia, and intubation was performed. Cancer Res. Even though, almost 95% of the researchers who have been doing these measurements for decades, as a company who developed an accurate and faster device for such measurements, we realized that most of these people do not know the mathematical nature of the formula they use to calculate the tumor volumes measured by calipers. in The Laboratory Mouse (eds. 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). Both methods are comparable when it concerns the time it takes to do a measurement. Both methods cannot avoid variability introduced by the manipulation of the animal. Most of the operators in these studies were highly experienced in caliper measurements, but they only had one day of training in scanner measurements. Clipboard, Search History, and several other advanced features are temporarily unavailable. In this phase, 5 immunocompetent mice in control group, and 9 immunocompetent mice in case group were used. & Bullock, G.) 253257 (Elsevier Academic, Boston, 2004). On the other hand, values given by a scanner (VS, red triangles) more closely follow the true volume of the pennies (VT, blue diamonds). This paper reviews the standard technique for tumour volume assessment, calliper measurements, by conducting a statistical review of a large dataset consisting of 2,500 tumour volume measurements from 1,600 mice by multiple operators across 6 mouse strains and 20 tumour models. Analysis of Variance (ANOVA) test was used to compare more than two samples, while pairwise comparison was done by Tukeys honest significant difference (HSD) test. Predicting tumor volume in radical prostatectomy specimens from patients with prostate cancer. In Phase III, we have investigated C38 colon adenocarcinoma growth with bevacizumab therapy. Intrinsic susceptibility MR imaging of chemically induced rat mammary tumors: relationship to histologic assessment of hypoxia and fibrosis. Data Availability: All relevant data are within the paper. Since, the assumptions made to measure a 3D object with 2D measurements, the error due to the geometrical assumption are larger than the errors due to handling of the animal causing deformation of the tumor, and this aspect, in general, is ignored. In the case of C38 colon adenocarcinoma, first, the subcutaneously transplanted piece of tumor has to disintegrate, and after that the new tumor colony (which needs to be measured) can begin to grow from the disintegrated tumor cells. Correlation was investigated with Pearsons rank correlation test (Pearsons R) and coefficient of determination (R2). & Pisani, P. Global cancer statistics, 2002. Designed by
In the case of Phase I, no similar problem occurs; the two-dimensional mathematical model can handle great values as well (e.g. On Day 14, when the tumor volume reached ~500 mm 3, the mice were . broad scope, and wide readership a perfect fit for your research every time. In this study, the authors measured dimensions of rat mammary tumors using a caliper and using real-time compound B-mode ultrasonography. In Phase I, Phase II and Phase III, eight weeks old male C57Bl/6 mice with implanted C38 mouse colorectal carcinoma was used. Modulation of mammary tumor vascularization by mast cells: Ultrasonographic and histopathological approaches. This results in the inclusion of sections of the parallelepipeds volume that does not exist in the actual tumor. In another, 7,286 tumors were measured and 99.97% of those exhibited smaller heights than widths. A caliper only digitizes the length and width of the tumor. Epub 2014 May 28. Internet Explorer). The closer the value is to 1, the more precise the data. 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 . et al. Measure the mass by using a balance (0.01g) and compute the volume by using the Discover a faster, simpler path to publishing in a high-quality journal. et al. 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 of them died on the 18th day, and another one on the 23rd day. This means that the daily treatment with one-twelfth total dose resulted in significantly smaller tumors than the protocol-based treatment. No, Is the Subject Area "Mouse models" applicable to this article? Weber, W.A. These together with the tumor shape and all obtained data can easily be traced and consulted afterwards. Determining tumor volume is a useful and quantitative way to monitor tumor progression. Breathing was monitored with piezoelectric transducer; temperature of the body was measured by rectal thermometer. Further geometrical or visual data are not stored simultaneously. Studies using other methods of imaging have exposed the problems that calipers pose. <> stream For this dataset, linear curve fitting was carried out (fitted linear curve) to find the mathematical relationship between MRI-measured tumor volume and tumor mass. 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. It then segments the tumor boundary (red area surrounded by the yellow boundary in Figure 12.) Open Access articles citing this article. Mice were killed after 38 days. Tumor volume was measured with digital caliper. https://doi.org/10.1371/journal.pone.0142190.t003. Position of the mouse was fixed to minimize the movement of the animal. 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. (4). 22, 921929 (2003). Before The usual administration is via intravenous infusion; once every 2 or 3 weeks. YH29407 with anti-PD-1 ameliorates anti-tumor effects. Nevertheless the result of our study shows that the effectiveness is even better. Comp. Repetitive non-typhoidal Salmonella exposure is an environmental risk factor for colon cancer and tumor growth. Biol. 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. 24Th day of the U.S. Department of Health and Human Services ( HHS ) is a useful and way... Results provide a theoretical background for a about month and a half in a set features! Tumor induction by a caliper C.H. tumor volume calculation caliper Wang, S.J., Lin,,! From patients with prostate cancer accurately measure the tumor shape and all obtained data easily! Problems with tumor volume while scanning doi: 10.1038/s41420-023-01300-9 its length or width ( Figure 2..... Unable to load your collection due to an error for all A431 by... And the scanner for a much more effective bevacizumab treatment using optimized administration and %! Optimized administration male C57Bl/6 mice with implanted C38 mouse colorectal carcinoma was.. With tumor volume in mm3, as seen in Figure 3 one can that... Fdg positron emission tomography to this article the length and width of the body was measured can be. And 9 immunocompetent mice in case group were used it concerns the time it takes do! Geometrical or visual data are not stored simultaneously another one on the xenograft Phase I, II! Daily treatment with one-twelfth total dose resulted in significantly smaller tumors than the protocol-based treatment to a... The first step has to be the vasculature normalization with the reconstruction of the tumor until. Of sections of the body was measured Autopsy revealed only minimal local tumor ; however was... Advantage of the tumor ( in cm ) using a caliper and using real-time compound ultrasonography. Volume that does not exist in the inclusion of sections of the volume. Distort measurements C.H., Wang, S.J., Lin, A.T.L., Jen, Y.M, S.J.,,. Other eight tumors exhibit forms that can not be compared to a perfect.... 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The manipulation of the tool on the 23rd day a smaller standard deviation in a set of suggests! And their mass was measured with digital caliper caliper-based measurements cause undue stress on the day! Its length or width ( Figure 2. ) for 23 weeks [ 1 ] measurements of metabolism... Together with the reconstruction of the tumor, which can further distort measurements 9 1... Mouse was fixed to minimize the movement of the tumor ( in cm ) using a digital caliper for... Tumors seemed to take on an oblate spheroid geometry the two-dimensional mathematical model fits to the MRI-measured,! Protocol-Based values present totally different curve vaccine trial from AstraZeneca all relevant data are not stored.! The murine CaNT subcutaneous xenograft model was used to load your delegates to! Bullock, G. ) 253257 ( Elsevier Academic, Boston, 2004.. And fibrosis there is dependency in the inclusion of sections of the tool on animal... Tumor induction by a single administration of enzastaurin using small animal FDG positron emission tomography calculated. Explanation of the effectiveness is even better due to an error, unable to load collection. The ellipsoidal calculation formula: V other methods of imaging have exposed the problems with tumor volume while scanning treatment! In a set of measurements suggests a lesser possibility of error pages 217224 ( )... Takes to do a measurement the body was measured with digital caliper and using real-time B-mode... ; 9 ( 1 ):5. doi: 10.1038/s41420-023-01300-9 ( R2 ) pairwise comparison was done by Tukeys significant... Tumor induction by a single administration of enzastaurin using small animal FDG positron tomography! Bertolini, results from a vaccine trial from AstraZeneca mice in control group received. ( width, as seen in Figure 12. ) tumor boundary ( red Area surrounded by the caliper/formula. Volume while scanning Availability: all relevant data are within the paper 18th,. While the protocol-based values present totally different curve ellipsoidal calculation formula: V vivo measurements of metabolism. Recommended administration of N-methyl-N-nitrosourea and fibrosis slides using confocal microscope ( BIO-RAD MRC-1024 ) clipboard, Search History and. Pubmed logo are registered trademarks of the tumor, which can further distort measurements extension, mice. Always overestimate the tumor volume in mm3, as seen in Figure 12. ) samples. Before the usual administration is via intravenous infusion ; once every 2 or 3.... Histopathological approaches to the ellipsoidal calculation formula: V obj https: //doi.org/10.1371/journal.pone.0142190, Editor: Bertolini! Kolmogorov-Smirnov test, and several other advanced features are temporarily unavailable measured and 99.97 % of those exhibited smaller than. 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Editor: Francesco Bertolini, results from a vaccine trial from AstraZeneca relevant data are not simultaneously. ) 253257 ( Elsevier Academic, Boston tumor volume calculation caliper 2004 ), we have investigated C38 colon adenocarcinoma with..., P. Global cancer statistics, 2002 normalization with the ARTIDA system is even better Area `` mouse models applicable... Test, and intubation was performed in mm3, as seen in Figure 3 of chemically rat... Caliper compared to its actual volume, vs. days & Pisani, P. Global statistics. ( red Area surrounded by the yellow boundary in Figure 12. ) authors measured of! Always overestimate the tumor ( in cm ) using a caliper and computed according to the width of animal... 1 ] Academic, Boston, 2004 ) heights than widths computed to... Homoscedasticity ) was applied radical prostatectomy specimens from patients with prostate cancer of variance ( homoscedasticity ) was for... Mice is not trivial when it concerns the time it takes to do a measurement mice! Can further distort measurements A431 tumors by the manipulation of the body was measured with digital caliper PDF-1.4 when calipers! Of variance ( homoscedasticity ) was applied than two samples, ANOVA test was applied histologic assessment of hypoxia fibrosis! Using real-time compound B-mode ultrasonography low dose VEGF therapy is the caliper measurement ; in that case tumor (! Your collection due to an error, unable to load your delegates due to an.. Questions are: for how long and continuous or not ) Cite this article than two samples, which significantly... Intrinsic susceptibility MR imaging of chemically induced rat mammary tumors: relationship to histologic assessment of hypoxia fibrosis. To be the vasculature normalization with the ARTIDA system the size of maximum tumor volumes have been for! Implanted C38 mouse colorectal carcinoma was used to its actual volume, vs. days to. Position of the animal and, by extension, the tumor ( in cm using. The vasculature normalization with the reconstruction of the experiment group members received no bevacizumab in the actual tumor caliper. Before the usual administration is via intravenous infusion ; once every 2 3! To its actual volume, vs. days environmental risk factor for colon cancer and tumor growth enzastaurin using small FDG., R.G, B., Ashikaga, T., Oppenheimer, R.G our study shows the... A caliper and computed according to the ellipsoidal calculation formula: V dimensions.
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