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Intravoxel Incoherent Motion Diffusion-weighted Imaging for Monitoring the Immune Response to Cyclophosphamide in C57BL/6 Mice with GL261 gliomas1Medical image center, The First Affiliated Hospital of Jinan University, Guangzhou, China, 2MR Research China, GE Healthcare, Beijing, China
Synopsis
It is known that the intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) has been widely applied to the detection and characterization of tumors. However, there were no studies to investigate the use of IVIM-DWI in the evaluation of anti-neoplastic agents induced immune response. In this work, to assess whether IVIM-DWI can predict the immune response to anti-neoplastic agents, six C57BL/6 mice with GL261 mouse gliomas were applied using Metronomic cyclophosphamide. Our results indicated that IVIM-DWI is sensitive to detect the Cyclophosphamide-induced Immune Response.
Introduction
Currently, IVIM-DWI has been widely applied to the investigation of detection and characterization of renal, pancreatic, breast tumors, and so on[1] . The potential values of IVIM-DWI in the evaluation of imaging features and assessment of the immune response of radio-chemotherapy in clinical patients were demonstrated in previous studies [2-4]. In other published articles, it had provide proof-of-concept that single-agent chemotherapy delivered on an optimized metronomic schedule can eradicate large, established tumors and induce long-term immune memory.[4] However, to the best of our knowledge, there were no studies to investigate the use of IVIM-DWI in the evaluation of anti-neoplastic agents induced immune response in an experimental research. In this work, to assess whether IVIM-DWI can predict the immune response to anti-neoplastic agents, six C57BL/6 mice with GL261 mouse gliomas were applied using Metronomic cyclophosphamide.Materials
A total of 12 mice with GL261 glioma cells were randomly allocated to either the control group (n = 6) or the CPA-treated group [Microsoft1] [cw2] (n = 6). Mice in the treatment group were administered with CPA monohydrate every 6 days at a dose of 140 mg/kg-body weight per injection (CPA-140) as specified. Mice bearing GL261 underwent IVIM DWI scan (Signa HDxt, GE Medical System, USA) at baseline (T0) and 6 (T6) and 12 days (T12) after treatment with Metronomic cyclophosphamide (N = 6) with a custom-built-4-channel receiver coil with 3cm inner diameter. The IVIM DWI sequence was obtained using a single-shot echo-planar imaging with 12 b-values of 0, 20, 50, 100, 150, 200, 400, 600, 800, 1200, 1600, and 2000 s/mm2 (Fig. 1). The following parameters were used for this sequence: TR/TE, 3000 ms /102.4 ms; flip angle, 90°; matrix, 64 × 64; field of view, 80 × 80 mm2; section thickness, 2.9 mm; NEX, 4; and total scanning time, 6 mins and 35 s. After all experiments, there were two rats died in the control group. Region of interests (ROI) were placed on the lesions based on IVIM images by one experienced radiologists, then the ROIs were copied onto IVIM metrics (apparent diffusion coefficient, ADC; true diffusion coefficient, D.) and mean values were recorded. The results were then analyzed by Wilcoxon rank-sum tests.Result
At baseline, there was no statistical significance between the two groups of the ADC and D values (Table 1). However, the ADC and D value of the treatment group were significant higher than that in control group at both T6 and T12 (Table 1). Furthermore, the ADC and D values of the treatment group showed an increasing trend, while ADC and D values in control group showed a decreasing trend. Finally, the tumor volume of the treatment group began to decrease or not increase significantly at T6, while the control group showed a significant increasing trend.Discussion and Conclusion
The results of significantly increased ADC and D values in treatment group may associate with reduced diffusion of water molecules, which may be induced by degeneration, necrosis, apoptosis and nuclear fragmentation of tumor cells for effective anti-tumor therapy. In addition, the higher ADC and D values in the treatment group after treatment suggested that pre-treatment ADC and D can predict short-term efficacy. Theoretically, the ADC involved both the diffusion and perfusion information, while the D value reflects the diffusion of pure water molecules, so it is lower than the ADC value. In this work, we find that the D value was lower than the ADC value, which was consistent with the theory, and also with Wang [5]. Overall, our study indicate that the ADC and D parameter could predict early immune response to anti- neoplastic treatment. In this way, we can use the MRI to evaluate the immune response to anti- neoplastic treatment with clinical chemotherapy in tumor patients.Acknowledgements
No acknowledgement found.References
1. Cui, Y., et al., Intravoxel Incoherent Motion Diffusion-weighted Magnetic Resonance Imaging for Monitoring the Early Response to ZD6474 from Nasopharyngeal Carcinoma in Nude Mouse. Sci Rep, 2015. 5: p. 16389.
2. Cho, G.Y., et al., Intravoxel incoherent motion (IVIM) histogram biomarkers for prediction of neoadjuvant treatment response in breast cancer patients. Eur J Radiol Open, 2017. 4: p. 101-107.
3. Antonios, J.P., et al., Detection of immune responses after immunotherapy in glioblastoma using PET and MRI. Proc Natl Acad Sci U S A, 2017. 114(38): p. 10220-10225.
4. Wu, J. and D.J. Waxman, Metronomic cyclophosphamide eradicates large implanted GL261 gliomas by activating antitumor Cd8(+) T-cell responses and immune memory. Oncoimmunology, 2015. 4(4): p. e1005521.
5.Wang, Y.C., et al., Assessing the Early Response of Advanced Cervical Cancer to Neoadjuvant Chemotherapy Using Intravoxel Incoherent Motion Diffusion-weighted Magnetic Resonance Imaging: A Pilot Study. Chin Med J (Engl), 2016. 129(6): p. 665-71.
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