Abstract 4214: Assessment of early antimitotic treatment response in ovarian cancer using temporal diffusion spectroscopy
Authors: Jiang Xiaoyu , Li Hua , Zhao Ping , Xie Jingping , Khabele Dineo , Xu Junzhong , Gore John C. 
Published: July 2016

Abstract
A quantitative MRI method, namely, temporal diffusion spectroscopy (TDS), has been used to measure tumor microstructural changes in response to a well-established antimitotic drug treatment (protein-bound paclitaxel) and evaluated as an early indicator of tumor responsiveness. Current radiological methods of monitoring treatment response in solid tumors rely on measuring changes in tumor size as measured by CT or MRI, and it is well recognized this approach suffers from major limitations. In recent years, tumor size measurements have been supplemented by a number of imaging techniques that aim for in vivo characterization and measurement of biologic processes at the cellular and molecular level, but to date none has proven robustly successful in practice. For example, diffusion MRI has shown a high sensitivity to tumor response, but a relatively lower specificity e.g. sometimes unable to distinguish real response of responder tumors from the progression of some non-responders.
Temporal diffusion spectroscopy measures a series of apparent diffusion coefficients (ADC) over a wide range of effective diffusion times, corresponding to diffusion distances ranging from subcellular to cellular levels (∼ 3-20 μm). By fitting the measured ADC spectra to a simplified tissue model, parameters reflecting structural properties (such as cell size) in tissues can be extracted. Abraxane, one of the most successful microtubule-targeted chemotherapeutic drugs, has been reported to induce aberrant mitosis in tumor cells leads to mitotic arrest, the consequence of which is a cell size increase. In the current study, we implemented TDS in Abraxane/PBS-treated two types of human ovarian xenografts and cultured cells (OVCAR-8 as a responder to Abraxane, and NCI/ADR-RES as a resistant type). Abraxane-induced cell size increases were confirmed by flow cytometry and light microscopy in cell culture. The efficacy of Abraxane in treating tumors in vivo was examined histologically by calculating percentages of Caspase-3-activated area within Caspase-3 stained slides. Most excitingly, the fitted restricted size, one of the spectral parameters obtained from TDS, was able to quantify cell size increases which were not detected by conventional diffusion-MRI. All the MR results had a high degree of consistency with other flow, microscopy, and histological data. Moreover, with an appropriate analysis, the Abraxane-responsive tumors in vivo could be easily distinguished from all the other drug-vehicle-treated tumors and Abraxane-resistant tumors. In conclusion, temporal diffusion spectroscopy detects antimitotic-therapy-induced microstructural variations (notably, increases in cell sizes) in tumors in vivo which occur before changes in tumor volume or conventional diffusion MRI metrics. A combination of restricted size and zero-frequency diffusion coefficient can potentially be used as an early indicator of tumor responsiveness.
Citation Format: Xiaoyu Jiang, Hua Li, Ping Zhao, Jingping Xie, Dineo Khabele, Junzhong Xu, John C. Gore. Assessment of early antimitotic treatment response in ovarian cancer using temporal diffusion spectroscopy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4214.