Hedrich, H.J. 2001 Jan 15;19(2):551-7. doi: 10.1200/JCO.2001.19.2.551. 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. Pathol. Notice that in the caliper group, the average standard deviation is larger than that of the group whose tumors were measured by Biopticons TumorImager scanner. 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. Ergonomics 37, 217229 (1994). 12 immunocompetent mice were transplanted subcutaneously with C38 colon adenocarcinoma, and 11 immunocompetent mice were injected intramuscularly with B16 melanoma. Caliper Measurement. 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. produced by the TumorImager-2TM so that the animal is aligned under the mask each time similarly to the previous scan. 16 (2008). Even though all the three diameters can be measured, the estimation of the volume has quite a large error. Cancer Res. BMC Medical . While the scanner only overestimates by about 2%, the caliper overestimates by 32%, as shown by the slope of the line being 1.32. 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). Scientific Reports Cancer Inst. Determining tumor volume is a useful and quantitative way to monitor tumor progression. The produced images were converted to NIfTI (Neuroimaging Informatics Technology Initiative) format, which is suitable for image processing. The explanation of the effectiveness of low dose VEGF therapy is the following ([3944]). Mammary tumors similar to those observed in women can be induced in rats by intraperitoneal administration of N-methyl-N-nitrosourea. Under these conditions, the formula for the volume of a tumor becomes. 39, 16 (1996). 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. No, Is the Subject Area "Mathematical models" applicable to this article? 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). We are sorry, but there is no personal subscription option available for your country. et al. Cancer Res. Hoffman-Goetz, L. et al. 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. 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 authors say special thanks to Katalin Dezs MD. 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). et al. These images also provide extra morphological information about the tumor growth and the effect of the compounds on tumor behavior. Combining Mechanisms of Growth Arrest in Solid Tumours: A Mathematical Investigation, Dramatic increase in volume versus length of invasive ductal carcinoma mimicking intramammary lymph node in a small nodular lesion, Alteration in Inflammasome Cytokine Profile and Functional Plasticity of Macrophage Phenotype in Arsenic(0) Nanoparticle Treated Murine Fibrosarcoma, Tumoral CD105 promotes immunosuppression, metastasis, and angiogenesis in renal cell carcinoma, Cancel Due to the collaboration between medical doctors and biomedical engineers, model-based treatment protocols can be created. 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. 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. 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). Conceived and designed the experiments: ZS JS. Pollok, K.E. National Library of Medicine 39, 720 (1996). (1). Clinical aspects which have to be considered to determine when animals should be euthanized are body weight, physical appearance, measurable clinical signs, unprovoked behavior and response to external stimuli. 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]. Unmeasured part of the tumor for caliper, Figure 11. When the tumors became palpable, measurements of tumor volume were performed (with calipers) once per week. In Phase III, we have investigated C38 colon adenocarcinoma growth with bevacizumab therapy. https://doi.org/10.1371/journal.pone.0142190.t003. Weber, W.A. After sacrificing mice, tumors were removed, and their mass was measured. A quiet and modestly T2-weighted spin-echo scan was acquired at 4.7T (TE = 15 msec, TR = 1100 msec, 0.5 mm isotropic . In longitudinal studies, sequential measurements of tumor volume with a non-invasive method are essential. Significance of rat mammary tumors for human risk assessment. 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 . Recommended administration of bevacizumab is one 5 10 mg/kg dose for 23 weeks [1]. CAS PMID: 11208850. PASW Statistics 18 (SPSS Statistics, IBM, USA) and Matlab R2009b (MathWorks, USA) were used for statistical analysis. The tumor number, from one to ten, is shown against the percent error. Our results for the case group (daily, quasi-continuous small amount administration) and the control group (one big dose according to the protocol) are In the concept of model-based treatment, a continuous and precise tumor volume monitoring is needed concerning which, may be possible in the near future by nanotechnology [38]. (4). The closer the value is to 1, the more precise the data. Isofluorane (0.95 x 2.0%) was applied for inhalational anesthesia, and intubation was performed. Because the industrys caliper-based formula allows for these inclusions in nonexistent volumes more often than not, it yields inaccurate measurements, which can confuse. . The usual administration is via intravenous infusion; once every 2 or 3 weeks. 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. volume42,pages 217224 (2013)Cite this article. CAS 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 common measure of efficacy is the T/C ratio, the ratio of tumor volume in control versus treated mice at a specified Later in a study, when a tumor grows into larger masses, the shape of the tumor can differ greatly from an ellipsoid, as shown in Figure 7. In order to reduce such deformations on the tumor during measurement, it is possible to reduce the stress on the body of the animal by using two hands. contracts here. & In the first four measurement times 30 slices were done from each mouse; in the last two measurement times 40 slices were done from each mouse due to the larger tumor volume. Therefore, its formula will always overestimate the tumor volume until the height equals its width, as seen in Figure 3. 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. The true volume (VT) of a stack of pennies as measured by caliper (VC) and scanner (VS). Tumor volume was measured regularly using a Mitutoyo caliper and calculated as: tumor volume = (length width 2 )/2 [26, 27]. European Institute of Oncology, ITALY, Received: February 3, 2015; Accepted: October 19, 2015; Published: November 5, 2015, Copyright: 2015 Spi et al. The other eight tumors exhibit forms that cannot be compared to a perfect ellipsoid. McCormick, D.L., Adamowski, C.B., Fiks, A. Position of the mouse was fixed to minimize the movement of the animal. A smaller standard deviation in a set of measurements suggests a lesser possibility of error. The tumor can be more and sometimes less visible or popped up from under the skin. Yes 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. Additionally, we explore the impact of six different tumour . [2]no matter how accurately the length and width of the tumor are measured. (Fig 2). https://doi.org/10.1371/journal.pone.0142190.g006. here. The tumor dimensions are L, W, and H. The volume of an ellipsoid VE, using the variables as shown in Figure 1., is. PMC Before Tumors should also be placed so that the tumor peak is near the center of the mask and is not highly inclined. In order to assess interobserver variation, each . In Phase IV, approximately 2.9106 cells were injected subcutaneously into each SCID mouse. MeSH bowel, and kidneys is when the tumor is located in . A direct and real 3D volume of the xenograft will then be calculated. 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. & Robinson, S.P. Unable to load your collection due to an error, Unable to load your delegates due to an error. Role of real-time sonography in assessment of breast diseases: a review of 200 cases (Abstr). A direct 3d measurement tool such as the TM900 does not induce such method sensitivity but cannot exclude operator dependency of the obtained values. Russo J, Russo IH, Rogers AE, van Zwieten MJ, Gusterson B. Toxicol Pathol. Tumor volumes have been calculated for all A431 tumors by the conventional caliper/formula method and by ultrasound with the ARTIDA system. This means that the daily treatment with one-twelfth total dose resulted in significantly smaller tumors than the protocol-based treatment. In vivo measurements of tumor metabolism and growth after administration of enzastaurin using small animal FDG positron emission tomography. No mice died during the experiment, therefore 5 mice from the control group, and 9 mice from the case group were sacrificed on the 23rd day. 29 September 2022, Bulletin of Mathematical Biology This means that continuous, low dose antiangiogenic factor (VEGF) administration is needed. The last step is to find the f constant of the two-dimensional mathematical model for tumor growth without therapy (Phase I). . Is the Subject Area "Cancers and neoplasms" applicable to this article? The overestimation of caliper measurements is due mainly to the fact that the formula used is that of a parallelepiped, a shape unlike an ellipsoid actually represents the geometric body that is being measured. ANOVA test showed significant difference between these means (p = 0.041, using 0.05 level of significance). Unauthorized use of these marks is strictly prohibited. Therefor it allows a direct 3D capture of the volume. 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. Ultrasound Med. Tumor growth was investigated without therapy and with antiangiogenic therapy (using bevacizumab [15]). 17, 905910 (2004). In addition, we have found that the quasi-continuous administration of bevacizumab is effective against tumor growth of C38 colon adenocarcinoma, in contrast to protocol-based treatment. 8600 Rockville Pike Yes Med. This formula was the starting point of our examination to find an appropriate mathematical model. Average of tumor volumes for every measurement days of the experiment can be seen in Fig 8. It was on the 10th day, since HT-29 colorectal adenocarcinoma grows slower in mice than C38 colon adenocarcinoma. 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. Med. Sign up for the Nature Briefing newsletter what matters in science, free to your inbox daily. Monitoring tumor volume through a direct 3D measurement will include changes in all three directions, height, width and length thus resulting in more accurate realistic data. In our study, we applied a two-dimensional mathematical model and determined the corresponding tumor- and therapy-specific constants in the three investigated cases (C38 colon adenocarcinoma growth without therapy, C38 colon adenocarcinoma growth with protocol-based bevacizumab therapy and C38 colon adenocarcinoma growth with quasi-continuous bevacizumab therapy). Mice were humanely sacrificed using cervical dislocation. PubMed (6) (7). The dose depends mainly on weight. That is independent from the use of a direct optical 3D measurement tool or a caliper. 2. & trukelj, B. N-methylnitrosourea induced breast cancer in rat, the histopathology of the resulting tumours and its drawbacks as a model. A caliper was used to calculate the tumor volume every-three days, and the volume was calculated according to the formula: V = ab 2 /2, where a represents major axis length and b represents minor axis length. To compare more than two samples, ANOVA test was applied. Bevacizumab (Avastin) [1] is an exogenous inhibitor, which inhibits the biological activity of human VEGF [2]. The volume above the red area is not occupied by the tumor, as seen in Figure 8. Tumor volume measurement was performed by digital caliper and small animal MRI. This does not alter the authors adherence to all the PLOS ONE policies on sharing data and materials. Davis, P.L. 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 by Mammog raphy (c.c) . Current standard technique for volume determination of subcutaneously xenografted tumors in vivo is by external caliper where tumor volume is calculated by use of the modified ellipsoid formula 1/2(Length Width 2)[1,2]. In addition, the gap between tumor volume values for caliper-based control and treatment groups is smaller than that for scanner measurements; the significant p-value was over 50 times higher when using calipers (p > 0.05) than with scanners (p < 0.001), suggesting that the caliper-based measurements are not statistically significant. Tumor volume was measured in two different ways. Our results provide a theoretical background for a much more effective bevacizumab treatment using optimized administration. Figure 3. Cell Rep Med. No animals were sacrificed before the experimental endpoint. Clarke, R. Animal models of breast cancer: their diversity and role in biomedical research. Effects of different applied voltages of irreversible electroporation on prostate cancer in a mouse model. The parameters V m = 83 mm 3, = 0.84 and = 0.21 from the literature were used [].. For \( {y}_i^j \) eqs. 35, 18341840 (2003). Mammary tumors seemed to take on an oblate spheroid geometry. 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. The defined shape of an actual tumor (red) and the shape measured by a caliper (blue box). Measured data is the MRI-measured tumor volumetumor mass pairs on the 23rd day of Phase III/3 (case and control group). Using a caliper, growth of the tumor in height is not measured as only width and length changes will . The cause of death was tumor toxicity; however, none of the clinical criteria for euthanasia could be observed at these animals. 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. Determining tumor volume is a useful and quantitative way to monitor tumor progression. How the device is positioned over the tumor will not influence the result. Lab Animal 3.4. & Lin, C.A. It can be carried out in vivo during the experiment due to the subcutaneous localization of the tumor. 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. Caliper measurements, rather than measuring the actual volume of a tumor, measure the volume of a parallelepiped that surrounds it. This work was supported by the Portuguese Foundation for Science and Technology (PTDC/DES/114122/2009 and Pest-OE/AGR/UI0772/2011 unity) and by the European Regional Development Fund (COMPETE, FCOMP-01-0124-FEDER-014707/022692). 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. Controller-based therapy has the obvious advantage against e.g. Coauthors PK and DG are employed by Gedeon Richter Ltd. Gedeon Richter Ltd. provided support in the form of salaries for authors PK and DG, and in the form of using the resources of Preclinical Imaging Center of Gedeon Richter Ltd., but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. In Phase I, we have investigated tumor growth without therapy with two types of mouse tumor. 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. 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). Figure 19. 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. 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. %PDF-1.4 Tumor 6, located at the middle right, is the only tumor shown whose shape is closest to an ellipsoid, albeit still an imperfect one. PhD from the 1st Department of Pathology and Experimental Cancer Research Institute from Semmelweis University, Budapest, for making the fluorescence pictures with confocal microscope. Physical activity cancer preventionmechanisms. 1 0 obj The effectiveness of bevacizumab administration was examined by statistical analysis. the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in (3), Another relatively new but not widely used approach to estimate tumor volume is to assume hemi-ellipsoid shape [24]. The problems with tumor volume measurements by calipers, 3.1 Tumor growth: Height is not equal to the width of the tumor, 3.3 Caliper measurements are time-consuming, 3.4 Caliper measurements ignore a larger volume, https://ugobasile.com/products/catalogue/pain-and-inflammation/plethysmometer, A Structured Light Based Laboratory Animal Subcutaneous Tumor Scanning System. (8) Measurements of tumors, in the context of research and industry, are expected to be accurate; it is unacceptable that this inaccurate formula has stood so long as the industry standard. Traditionally their volume growth has been monitored by using a mechanical caliper. The most recent ESMO (European Society for Medical Oncology) consensus guidelines suggest that treatment discontinuation or maintenance are feasible options after 46 months of full-dose first-line therapy to treat colon and rectal adenocarcinoma [37]. Google Scholar. Mol. The athymic (nude) mouse is a useful model for studying the biology and response to therapies of human tumors in vivo. Also, at beginning of the tumor growth when the tumor is invisible or when a tumor shrinks due to the effectiveness of the drug, in order to measure the volume of such an invisible tumor, it is a general practice to palpate the tumor area to reveal some mass to measure. & Morel, M. Clinical, mammographic, and sonographic determination of preoperative breast cancer size. Clipboard, Search History, and several other advanced features are temporarily unavailable. McPhail, L.D. 2017 May 1;176:35-41. doi: 10.1016/j.lfs.2017.03.013. government site. No, Is the Subject Area "Renal cancer" applicable to this article? Tumor volume was measured with digital caliper as well. 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). Administration was examined by statistical analysis 2013 ) Cite this article digital caliper as well drawbacks as a.! Due to an error, unable to load your delegates due to the subcutaneous localization the... Cancer size mass pairs on the 10th day, since HT-29 colorectal adenocarcinoma grows slower in than! To all the PLOS one policies on sharing data and materials R2009b ( MathWorks, USA ) used! 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