Unable to load your collection due to an error, Unable to load your delegates due to an error. The 1st Department of Pathology and Experimental Cancer Research of the Semmelweis University (Budapest, Hungary) and the Physiological Controls Group of the Obuda University (Budapest, Hungary) began collaborating on antiangiogenic therapy research in 2012including the current experimental investigations. Tumor growth can take place under such conditions; however delivery of chemotherapeutic drugs is obstructed. Fj^P;7? This creates the possibility of further efficient therapeutic agent use (if any) or assists the more effective direct antitumoral effect of bevacizumab. The size of maximum tumor volumes observed in our study fulfills the requirements of Hungarian animal experimental research protocol. Keller M, Rohlf K, Glotzbach A, Leonhardt G, Lke S, Derksen K, Demirci , Gener D, AlWahsh M, Lambert J, Lindskog C, Schmidt M, Brenner W, Baumann M, Zent E, Zischinsky ML, Hellwig B, Madjar K, Rahnenfhrer J, Overbeck N, Reinders J, Cadenas C, Hengstler JG, Edlund K, Marchan R. J Exp Clin Cancer Res. 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. Using the mathematical model, different dosage algorithms can be designed for antiangiogenic cancer therapy [1619]. Better results can be obtained by proper handling of the mice. All rights reserved. Even though, now, the formula is calculated in an Excel spreadsheet where can be defined as a function, pi(), almost in all cases, in the volume formula is defined as 3.0. How the device is positioned over the tumor will not influence the result. This means that the daily treatment with one-twelfth total dose resulted in significantly smaller tumors than the protocol-based treatment. e0142190. Res. Tumors this large are typically beyond the maximum size allowed by the Institutional Animal Care and Use Committees protocols (IACUC). 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. Read the article on why you should not use calipers! Epub 2017 Mar 21. 2013 Oct;67(8):771-6. doi: 10.1016/j.biopha.2013.06.011. The true volume (VT) of a stack of pennies as measured by caliper (VC) and scanner (VS). government site. Small MRI measurements were done in the Preclinical Imaging Center of Gedeon Richter Plc. Lifetime dose-response relationships for mammary tumor induction by a single administration of N-methyl-N-nitrosourea. Scientific Reports Disclaimer. Tumor segmentation by TumorImager-2TM. Denis, F., Paon, L. & Tranquart, F. Radiosensitivity of rat mammary tumors correlates with early vessel changes assessed by Power Doppler sonography. 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. Faustino-Rocha, A., Oliveira, P., Pinho-Oliveira, J. et al. Mice were monitored daily. x|jY!==g'{oZ6-JiZ 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. Tumor volumes measured with a Plethysmometer (VPleth) independent of caliper and scanner measurements (VC, VS) vs. VC and VS. Table 1. 2022 Dec 20;3(12):100852. doi: 10.1016/j.xcrm.2022.100852. Med. The second result which is discussed in the article is comparison of the effectiveness of bevacizumab administration in the case of protocol-based and quasi-continuous therapies. Mammary tumors seemed to take on an oblate spheroid geometry. A direct 3D volume capture instrument, such as the TM900, will make a stereographic image of the tumor and reconstruct the tumor topography and shape. https://doi.org/10.1371/journal.pone.0142190.g001. In this phase, control group members received no treatment; case1 group members received one 200 g bevacizumab dose; while case2 group members received 1.11 g bevacizumab daily for 15 days (the total dose of case2 group members is the one-twelfth dose of case1 group members). Even though we did not have a statistical analysis of volume loss due to the unmeasured part of tumors in caliper measurements, the lost volume could be higher than the scanner results. Open Access In Phase IV, approximately 2.9106 cells were injected subcutaneously into each SCID mouse. They found that caliper and ultrasonography measurements were significantly correlated but that tumor volumes calculated using different formulas varied substantially. Tumor was located in the last third of the back in every cases, thus the effect of respiratory movement was minimal. PMC 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. 2015 Feb;43(2):145-70. doi: 10.1177/0192623314532036. In clinical practice, the determination of the tumor size (volume) is done by MRI and/or CT, but this is for the purpose of validating the effectiveness of the treatment, and therefore it is not a continuous monitoring. Compute the volume assuming perfect ellipsoids. 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). 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. Estimation of rat mammary tumor volume using caliper and ultrasonography measurements. 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]. All surgery and sacrifice were performed under sodium pentobarbital anaesthesia (Nembutal, 70 mg/kg), and all efforts were made to minimize suffering. Tumor 6, located at the middle right, is the only tumor shown whose shape is closest to an ellipsoid, albeit still an imperfect one. Yes 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. 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. & trukelj, B. N-methylnitrosourea induced breast cancer in rat, the histopathology of the resulting tumours and its drawbacks as a model. 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.
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. Before A possible solution for height approximation [23] is: Pathol. In the top-left graph (Figure 19. The effectiveness of bevacizumab administration was examined by statistical analysis. Breast Cancer Res. Tumor volumes are calculated from digital caliper raw data by using the formula:Volume (mm3) = (l x w2) / 2. In Phase IV, the first measurement occurred when the tumors have reached an average volume of 5060 mm3 (according to the xenograft protocol [20]). In Phase I, tumor growth was investigated without antiangiogenic therapy for 24 days (mice were sacrificed when the tumor reached a lethal size). 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. Tumor volume measurement cannot happen right after tumor implantation. (Inbred C57Bl/6 mice from our institute were used throughout the studies.) One of them died on the 18th day, and another one on the 23rd day. Tumor volume was measured in two different ways. Diagnostic accuracy of mammography, clinical examination, US, and MR imaging in preoperative assessment of breast cancer. Kobayashy, T. et al. Sci. Epub 2014 May 28. The volume calculation algorithm relies on the surface interpolated based on the surrounding healthy tissue. It can be carried out in vivo during the experiment due to the subcutaneous localization of the tumor. Tumor growth was investigated without therapy and with antiangiogenic therapy (using bevacizumab [15]). Mice were killed after 38 days. 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. In that caseeven though all the three diameters can be measuredthe estimation of the volume has quite a large error. Tumor volume determined by microCT, 18 F-FDG-PET and external caliper Tumor volume measured by microCT, PET and caliper all correlated (P < 0.001) with reference volume (figure 1).MicroCT versus reference volume (n = 20) had the best fit of line y = 1.01 0.04x - 6.1 6.3 (R 2 = 0.97; p < 0.001). 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. Data Availability: All relevant data are within the paper. Possible mechanisms mediating an association between physical activity and breast cancer. Figure 13. You are using a browser version with limited support for CSS. In this study, the authors measured dimensions of rat mammary tumors using a caliper and using real-time compound B-mode ultrasonography. The TumorImagerTM line of scanners by Biopticon Corporation fixes these problems by keeping the animals relaxed during measuring and yielding measurements closer to actual values than caliper-based measurements. Treat. Frozen samples were used to create 15 m frozen cuts. The volume above the red area is not occupied by the tumor, as seen in Figure 8. ), the more correlated a given group (scanner or caliper estimations) is to the black line (r2 = 1), the more accurate the tumor volume measurements are. 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). bowel, and kidneys is when the tumor is located in . 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 can be more and sometimes less visible or popped up from under the skin. This saves money, as mice, drugs, and calipers can be costly for researchers. 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. 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. Tumor measurement by TumorImager-2TM. Calculate the correct dose of STELFONTA once you have the volume of the tumor in cm 3, using the Dose Calculator. Russo, J.
These images were applied to calculate vascularization area by using ImageJ (NIH, USA) [33] software (Fig 4). in The Laboratory Mouse (eds. We compared the volumes, areas . Repetitive non-typhoidal Salmonella exposure is an environmental risk factor for colon cancer and tumor growth. A typical comparison of tumor volume measurements by TumorImager-2TM with calipers. PLoS ONE 10(11): Bizberg Themes, By Memorial Sloan Kettering Cancer Center. by Mammog raphy (c.c) . . There are no further patents, products in development or marketed products to declare. 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. 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). Wrote the paper: JS ZS PK LK. Tumor was located in the last third of the back of the mouse in every case. Med. Traditionally, caliper measurements are used to calculate tumor volume. We monitored the vital parameters of 4 immunocompetent mice, and there was no serious toxic side-effect or lethality regarding to the usage of bevacizumab. The shape of the tumor, more often than not, is not an ellipsoid. Results from an experiment that measures tumor volume and varies drug dose and measuring methods. In Phase I, 12 mice were implanted with C38 colon adenocarcinoma. Timing wise both methods perform the same. Imaging 33, 2737 (2006). 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). The first measurement in Phase I occurred on the 5th day; in Phase III/3, it occurred on the 4th day. This does not alter the authors adherence to all the PLOS ONE policies on sharing data and materials. and transmitted securely. PubMed Central Mice were humanely sacrificed using cervical dislocation. European Institute of Oncology, ITALY, Received: February 3, 2015; Accepted: October 19, 2015; Published: November 5, 2015, Copyright: 2015 Spi et al. When the tumor has a symmetrical, solid closed shape (typically without treatment), volume can be evaluated accurately from caliper-measured data with the applied two-dimensional mathematical model. Quantity of the optimal solvent administration was also examined in this subphase. Even though all the three diameters can be measured, the estimation of the volume has quite a large error. Imaging 16, 816 (2008). Starting with f = 1, we have investigated the goodness of the fitting, using an iterative method. 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. In order to assess interobserver variation, each . broad scope, and wide readership a perfect fit for your research every time. Parkin, D.M., Bray, F., Ferlay, J. Bousquet, P.F. Open Access Effects of different applied voltages of irreversible electroporation on prostate cancer in a mouse model. Controller-based therapy has the obvious advantage against e.g. The manipulation of the handheld tool is at least as easy as holding a measurement caliper. [45] have found that the combination of low-dose cyclophosphamide and ginsenoside Rg3 therapy can be more effective than the normal administration. This is a preview of subscription content, access via your institution. Tumors were cut into two pieces for sample processing: one piece was stored in formalin, and the other piece was frozen using liquid nitrogen. Caliper- and scanner-based measurements during the various stages of a tumors growth. 1.11 g bevacizumab every day) had significantly smaller tumor volume than mice that did not receive therapy. Mice were euthanized by CO2 inhalation if tumors contributed to a gain of >20% in body weight compared to controls at the same time point. et al. Breathing was monitored with piezoelectric transducer; temperature of the body was measured by rectal thermometer. Mice were humanely sacrificed using cervical dislocation. 120, 386391 (2003). After fixing in methanol, rat anti-mouse CD31 antibody (1:50, 550274 BD PHARMINGEN) was applied as primer antibody, and FITC conjugated anti-rat CD31 antibody (1:100, Jackson Immunoresearch, 712-095-150) was applied on the slides as secondary antibody. Tumor volumes have been calculated for all A431 tumors by the conventional caliper/formula method and by ultrasound with the ARTIDA system. Because tumor volume measurements used by researchers and industries are sensitive and often rely on the accuracy, the cutting-edge TumorImagerTM line of scanners is the ideal, most reliable choice for taking such sensitive measurements. A study[4] (Figure 5.) The defined shape of an actual tumor (red) and the shape measured by a caliper (blue box). J. Oncol. % A direct and real 3D volume of the xenograft will then be calculated. () and were used with the parameters displayed in Table 1Parameters for Gompertz growth were taken from Benzekry et al. Yang, C.H., Wang, S.J., Lin, A.T.L., Jen, Y.M. Westerlind, K.C. In the light of the above mentioned, linear curve fitting was carried out to find the mathematical relationship between MRI-measured tumor volume and tumor mass (Phase III/3 case and control groups). Oncol. In addition, we have found that the quasi-continuous administration of bevacizumab is effective against tumor growth of C38 colon adenocarcinoma, in contrast . Oncol. Mammary tumors similar to those observed in women can be induced in rats by intraperitoneal administration of N-methyl-N-nitrosourea. & Robinson, S.P. Although there are studies which confirme that bevacizumab is as effective as the murine anti-VEGF-R2 antibody (DC101) in mouse models ([27, 28]), we extended our experiments and performed Phase IV, where immunocompromized (SCID) mice were used with human colorectal adenocarcinoma (HT-29) xenografts. Unmeasured part of the tumor for caliper, Figure 11. PubMed The industry and research standard for caliper measurements inherently miscalculates tumor volume by assuming the width, which is normally smaller than the height, and height of the tumor are equal. Hedrich, H.J. et al. 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. A structured light-based system for scanning subcutaneous tumors in laboratory animals. (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. 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. First of all, our hypothesis according to the importance of administration is proved. Internet J. Surg. Clin. Levenes test showed that the sample variances are equal (p = 0.108). @0u !7oyc5/Ck Consequences are manifold. Powered by WordPress
Tumor Volume Measurement
However, if the treatment is lengthy, the problem of side-effects also has to be considered. 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. Clarke, R. Animal models of breast cancer: their diversity and role in biomedical research. 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. {(Q~J9}=ow[5nkW"C; >tDve+7K,}g?A 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. Figure 5. Effects of different applied voltages of irreversible electroporation on prostate cancer in a mouse model. In both cases, the height of the tumor will be much smaller than its length or width (Figure 2.). Even the same operator, with different trials or at different moments in time does not always hold the animal in exactly the same way. Autopsy revealed only minimal local tumor; however death was not caused by tumor. 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 . 2022 Dec 5;10:998013. doi: 10.3389/fchem.2022.998013. . A caliper only digitizes the length and width of the tumor. Mice were killed after 38 days. Russo J, Russo IH, Rogers AE, van Zwieten MJ, Gusterson B. Toxicol Pathol. Google Scholar. The caliper, unlike the scanner, does not consider that the height of the stack changes while the length and width remain the same. Examination of tumor growth belongs not only to the basic medical research, but to the biomedical engineering field as well. Another approach is to utilize the scan images (Figure 14.) Google Scholar. Care should be taken not to stretch the mouse whether using one or two hands to hold the mouse during a scan. Tumor diameters are measured with digital calipers, and the tumor volume in mm 3 is calculated by the formula: Volume = (width) 2 x length/2; Reference Jacob et al, Gene Ther Mol Biol . <> Tumor volumes ranged from 0.5 cc to 187.9 cc, with a median of 21.8 cc. Breast cancer measurements with magnetic resonance imaging, ultrasonography, and mammography. . Using an extremely low dosage (as in our study), there is a high probability that these adverse effects can be minimized. As it was discussed above, the handling of animals by calipers measurements also suffers such deformations of the animal body during the measurements. 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. 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. The mathematical relationship between MRI-measured tumor volume and mass was investigated to estimate accurate tumor volume using caliper-measured data. The usual administration is via intravenous infusion; once every 2 or 3 weeks. Yes 01 July 2022. Case1 group members received one 200 g bevacizumab dose on the 8th day, case2 group members received 1.11 g bevacizumab from the 8th day every day for 15 days. Yes Thank you for visiting nature.com. 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. Eichelerger, L.E. 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. P`e+"JF^ : 4:p7]k
=
Jy}! We compared tumor volumes estimated in vivo by BLI and FLI, to those calculated by caliper measurements and found a good correlation between these two techniques (Figure 4). To obtain The first column shows the tumor values which were calculated using the two-dimensional mathematical model; the second column represents the protocol-based tumor volumes. Materials and methods: The murine CaNT subcutaneous xenograft model was used. Comput. When using calipers there is dependency in the measured data of the positioning by the operator of the tool on the xenograft. 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. PMID: 11208850. Sci Rep. 2022 Dec 26;12(1):22336. doi: 10.1038/s41598-022-25258-3. Cancer Res. A tumor expands in width rather than height as it grows. Modulation of mammary tumor vascularization by mast cells: Ultrasonographic and histopathological approaches. Hence, the first step has to be the vasculature normalization with the reconstruction of the balance of pro- and antiangiogenic factors. The width of a fully formed tumor will be much larger than its height. Furthermore, caliper-based measurements cause undue stress on the animal and, by extension, the tumor, which can further distort measurements. Ultrasonography as the Gold Standard for In Vivo Volumetric Determination of Chemically-induced Mammary Tumors. . 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. where V m is the measurement threshold that represents the smallest measurable tumor volume using a caliper. With constant width and length, the measured volume changes with the shape of the tumor. In order to assess interobserver variation, each . Tumor volume in subcutaneous mouse xenografts measured by microCT is more accurate and reproducible than determined by 18 F-FDG-microPET or external caliper. Preclinical Imaging Center, Gedeon Richter Plc., Budapest, Hungary, Affiliation For both one has to have the ease of hand and get used to manipulation of the instrument. Pritt, B., Ashikaga, T., Oppenheimer, R.G. All mice were implanted with HT-29 human colorectal adenocarcinoma. For the most precise result, tumor mass values, which were measured at the end of the experiment, were compared in the statistical analysis. The figure shows the results of a mouse (C4) from control group (first row), and a mouse (E9) from case group (second row). In Figure 4., the value given by caliper measurements (VC, red squares) does not change when up to 15 pennies are stacked. 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. Article & Wieder, H. Monitoring chemotherapy and radiotherapy of solid tumors. The https:// ensures that you are connecting to the 3.4. This is the formula most used in research and industry. contracts here. BMC Medical . In Phase I, 10 mice were sacrificed at the 24th day of the experiment. Tumors should also be placed so that the tumor peak is near the center of the mask and is not highly inclined. Pollok, K.E. Figure 12. 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. One can find datasets in the last column of Table 2. Girit, I.C., Jure-Kunkel, M. & McIntyre, K.W. 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. Ultrasonographic, thermographic and histologic evaluation of MNU-induced mammary tumors in female Sprague-Dawley rats.