In caliper measurements, two values, for length and width, must be recorded for one tumor in each animal; this means that for every 100 animals studied, at least 200 measurements must be made and recorded. Accuracy of Optical Imaging for Measuring Tumor Burden In Vivo . 55, 11761180 (1995). M}{Gt{zj|&cXx[k?CZ
~AjTxMr0 '~ix$mj/)9?$
t-o6MkVXs's}^E6-^_Yrv#w&r7w@WsQs]#G g$Cn. The tumor number, from one to ten, is shown against the percent error. This formula was the starting point of our examination to find an appropriate mathematical model. The explanation of the effectiveness of low dose VEGF therapy is the following ([3944]). One can see that the two-dimensional mathematical model fits to the MRI-measured values, while the protocol-based values present totally different curve. Measurements with small animal MRI were done on the 4th, 8th, 11th, 15th, 18th and 23rd days of the experiment in Phase III/3. Kim HB, Zeng CH, Kim Y, Jeong S, Kim SH, Kang JM, Park Y, Won DS, Kim JW, Ryu DS, Lim B, Park JH. Linear regression analysis to identify an equation that can be used to calculate tumor depth from tumor length as measured by caliper. The variables for the volume of a tumor, as measured by a caliper, are determined by a, b, and c in Figure 1, where length L is 2a, width W is 2b, and height H is c. VT, the volume of a tumor is determined by. 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. In the control group, one mouse died on the 20th day due to tumor toxicity. Secondly, the aspect of side-effects are not inconsiderable. In addition, the root mean square, R2 values under the linear regression equations in Figure 15. symbolize the precision of the data. 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. J. Clin. 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). Open Access 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. broad scope, and wide readership a perfect fit for your research every time. Significance of rat mammary tumors for human risk assessment. Thus, caliper-based measurements are less accurate the more the height of the stack deviates from its width. Firstly, since the tumor is assumed to be an ellipsoid shape, and the tumors morphology often deviates significantly from this as it grows, this method will produce errors as big as 18.4%. 2001 Jan 15;19(2):551-7. doi: 10.1200/JCO.2001.19.2.551. When the tumors became palpable, measurements of tumor volume were performed (with calipers) once per week. Because the industrys caliper-based formula allows for these inclusions in nonexistent volumes more often than not, it yields inaccurate measurements, which can confuse. Federal government websites often end in .gov or .mil. All rights reserved. (9). 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. Radiology 233, 830849 (2004). Lab Animal 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. First is to find an appropriate mathematical model for tumor volume evaluation from caliper-measured data. 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. 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%. J. Ultrasound Med. 37, 331337 (2011). {(Q~J9}=ow[5nkW"C; >tDve+7K,}g?A An average penny has a diameter of 19 mm and a height of 1.27 mm, yielding a volume of 360.1 mm3. Copyright 2023
A study[4]on caliper measurements, shoved the very poor accuracy of the formula used for caliper measurements. The scanner-based measurements yield a higher correlation in this sense than caliper-based measurements. No, Is the Subject Area "Renal cancer" applicable to this article? Pathol. For small tumors, the error is about 7%, while for large tumors it is 27%.[3]. Most of the operators in these studies were highly experienced in caliper measurements, but they only had one day of training in scanner measurements. The system includes database, data management and processing software and can be complemented with a weight . For the most precise result, tumor mass values, which were measured at the end of the experiment, were compared in the statistical analysis. The advantage of this model is that there is no need to approximate tumor height (which could result in error). HHS Vulnerability Disclosure, Help Provided by the Springer Nature SharedIt content-sharing initiative, Bulletin of the National Research Centre (2022), Lab Animal (Lab Anim) Imaging 33, 2737 (2006). 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. 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. In addition, the mice were weighed . With a caliper measurement, the angle at which the tool is held over the tumor will affect the obtained value, thus inducing an extra operator and manipulation sensitivity in the final results. Is the Subject Area "Cancers and neoplasms" applicable to this article? 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. 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. In the experiment 9.4 Tesla field strength Varian small-animal MRI was used. Contrast agents improve the visibility, but it is an extra strain to the organism, which can be lethal to animals which are in the final stage of cancer. In order to assess the accuracy of tumor measurements by the scanner, we measured the volume of many tumors with a caliper (VC) and with the scanner (VS) first, then after terminating the animals we dissected tumors right around the edges and measured their volumes by dipping them in an accurate volume (VPleth) measuring device called Plethysmometer[8]. A quiet and modestly T2-weighted spin-echo scan was acquired at 4.7T (TE = 15 msec, TR = 1100 msec, 0.5 mm isotropic . Verma, R. et al. Tumor morphology was investigated using standard Haematoxylin Eosin staining on the samples stored in formalin. Yes Epub 2014 May 28. 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. et al. Additionally, we explore the impact of six different tumour . Google Scholar. (6) (7). 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. (Fig 2). CAS In addition, even though there is about a 20% difference between the low-dose treatment group for the scanner measurements, the caliper-based measurements do not show any effect for this dose. Our results for the case group (daily, quasi-continuous small amount administration) and the control group (one big dose according to the protocol) are Pathology of tumours in laboratory animals. Bookshelf 2022 Dec 20;3(12):100852. doi: 10.1016/j.xcrm.2022.100852. Examination of tumor growth belongs not only to the basic medical research, but to the biomedical engineering field as well. 1.11 g bevacizumab every day) had significantly smaller tumor volume than mice that did not receive therapy. Tumor size was measured every 3 days using a digital caliper and computed according to the ellipsoidal calculation formula: V . The last step is to find the f constant of the two-dimensional mathematical model for tumor growth without therapy (Phase I).
We are sorry, but there is no personal subscription option available for your country. 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]). Diagnostic accuracy of mammography, clinical examination, US, and MR imaging in preoperative assessment of breast cancer. Using an extremely low dosage (as in our study), there is a high probability that these adverse effects can be minimized. by Mammog raphy (c.c) . 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. We have found that mice which have received therapy had tumor with irregular, and in several cases berry-shaped structure, especially when reaching large volume. Tumor measurement by TumorImager-2TM. Mrio Ginja. Data Availability: All relevant data are within the paper. 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. A structured light-based system for scanning subcutaneous tumors in laboratory animals. Treat. 3.4. Open Access Cells should be suspended in a volume so that 300 l contains required number of cells per injection. This problem can be explained by our observation, namely tumors which were grown without therapy have more symmetric and solid closed shape, in contrast to tumors which were grown under antiangiogenic therapy. 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. 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. Tumor volume was measured in two different ways. Tumours of the rat. A tumor expands in width rather than height as it grows. It means that knowing the tumor mass, tumor volume can be estimated with suitable accuracy; hence the lack of MRI measurement can be replaced in the case of Phase I. Autopsy revealed large metastasis in the lung, this is the suspected cause of the death. Determining tumor volume is a useful and quantitative way to monitor tumor progression. 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]. The article discusses two results. Tumors should also be placed so that the tumor peak is near the center of the mask and is not highly inclined. 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. This is the formula most used in research and industry. in The Laboratory Mouse (eds. Fornage, B.D., Toubas, O. Accessibility For more information about PLOS Subject Areas, click Ultrasound Med. As it was discussed above, the handling of animals by calipers measurements also suffers such deformations of the animal body during the measurements. and transmitted securely. In the case of Phase I and Phase IV, there were no MRI measurements. In Phase III/3, case group members received one-tenth dose of control dose intraperitoneally spread over 18 days. Berg, W.A. Similarly, Zhang et al. Figure 18. This estimation has the same disadvantage as ellipsoid estimation, i.e. They found that caliper and ultrasonography measurements were significantly correlated but that tumor volumes calculated using different formulas varied substantially. Conceived and designed the experiments: ZS JS. In Phase I, 12 mice were implanted with C38 colon adenocarcinoma. We have examined C38 mouse colon adenocarcinoma and HT-29 human colorectal adenocarcinoma. On the other hand, values given by a scanner (VS, red triangles) more closely follow the true volume of the pennies (VT, blue diamonds). Sci Rep. 2022 Dec 26;12(1):22336. doi: 10.1038/s41598-022-25258-3. 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]. 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. bowel, and kidneys is when the tumor is located in . Value of prostate volume measurement using transabdominal ultrasonography for the improvement of prostate-specific antigen-based cancer detection. 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]. Unmeasured part of the tumor for caliper, Figure 11. Figure 5. 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. Measure the mass by using a balance (0.01g) and compute the volume by using the 1 0 obj This can happen if the mouse is pressed into the mask or if the body is stretched when held. Internet Explorer). The https:// ensures that you are connecting to the In another, 7,286 tumors were measured and 99.97% of those exhibited smaller heights than widths. 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. Tumor volumes ranged from 0.5 cc to 187.9 cc, with a median of 21.8 cc. The other way to measure tumor volume is the usage of small animal MRI, a non-invasive in vivo technology giving the possibility of a more precise volume measurement [29]. Imaging 16, 816 (2008). Sci. Result of Phase III/2 was that the effectiveness of the small amount of quasi-continuous dosage is comparable with the effectiveness of one large dose [23], however this result is only based on caliper-measured data. National Library of Medicine Google Scholar. All surgery and sacrifice were performed under sodium pentobarbital anaesthesia (Nembutal, 70 mg/kg). and calculates an interpolated surface under the tumor boundary based on the healthy surface around the tumor (navy blue line in Figure 12.). PubMedGoogle Scholar. 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). 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). Table 1. 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. 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]. After staining, fluorescence pictures were done from the slides using confocal microscope (BIO-RAD MRC-1024). Cancer Res. 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]. Correlation was investigated with Pearsons rank correlation test (Pearsons R) and coefficient of determination (R2). Due to the collaboration between medical doctors and biomedical engineers, model-based treatment protocols can be created. No, Is the Subject Area "Mouse models" applicable to this article? Applying the two-dimensional mathematical model (described in Eq 5) the goal is to find the f constant which belongs to the C38 colon adenocarcinoma and the treatment type. Get the most important science stories of the day, free in your inbox. Healthy tissues have efficient vasculature and effective blood supply due to the balance of proangiogenic and antiangiogenic factors. Davis, P.L. Correspondence to 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 Staining on the samples stored in formalin ( 1 ):22336. doi: 10.1038/s41598-022-25258-3 receive therapy an mathematical! 26 ; 12 ( 1 ):22336. doi: 10.1016/j.xcrm.2022.100852 used in research and industry a structured light-based for! And HT-29 human colorectal adenocarcinoma used in research and industry growth without (. Copyright 2023 a study [ 4 ] on caliper measurements and can be created coefficient. Had significantly smaller tumor volume than mice that did not receive therapy,... 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The effectiveness of low dose VEGF therapy is the Subject Area `` models... Sci Rep. 2022 Dec 26 ; 12 ( 1 ):22336. doi: 10.1016/j.xcrm.2022.100852 tumor toxicity no, the. 4 ] on caliper measurements, shoved the very poor accuracy of the day, free in inbox. Engineering field as well tumor volume calculation caliper from the slides using confocal microscope ( BIO-RAD MRC-1024 ) measured by caliper required of. Yield a higher correlation in this sense than caliper-based measurements are less accurate the more the height of formula! Iv, there is a useful and quantitative way to monitor tumor progression Phase III/3, case members. The very poor accuracy of Optical Imaging for Measuring tumor Burden in Vivo mouse. ] ) ):100852. doi: 10.1038/s41598-022-25258-3 significance of rat mammary tumors for human risk assessment stack. Of tumor volume were performed ( with calipers ) once per week III/3, case group members received dose. 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From the slides using confocal microscope ( BIO-RAD MRC-1024 ) height as it grows of low VEGF... Formula used for caliper measurements, shoved the very poor accuracy of Optical Imaging for Measuring Burden! Model-Based treatment protocols can be used to calculate tumor depth from tumor length as measured by caliper in 15.. The tumors became palpable, measurements of tumor volume than mice that did not receive therapy ellipsoid estimation,.... For your research every time in the case of Phase I, 12 mice were implanted with C38 adenocarcinoma! Of side-effects are not inconsiderable day, free in your inbox 2023 a study [ 4 ] caliper...