Hua Li^{1,2}, Lori R. Arlinghaus^{1,2}, A. Bapsi Chakravarthy^{3}, Vandana G. Abramson^{2}, John C. Gore^{1,2}, and Junzhong Xu^{1,2}

We report a new MRI method termed IMPULSED (Imaging Microstructural Parameters Using Limited Spectrally Edited Diffusion) to quantitatively characterize mean cell size and density in solid tumors simultaneously and the first application of this method in breast cancer patients.

Theory: Fig. 1 shows the pulse sequences used to
acquire diffusion data over a range of length scales. In addition to conventional
pulsed gradient spin echo (PGSE) acquisitions for probing long length scales,
the IMPULSED method also uses oscillating gradient spin echo (OGSE) acquisitions
to sample short length scales. This combination enables detection and
separation of restricted diffusion effects from sub- to supra-cellular length
scales, providing more comprehensive information on tissue microstructure than
single measurements of ADC. The diffusion weighted signals are modeled as *S*=*v*_{in}*S*_{in}+(1-*v*_{in})*S*_{ex}, where *v*_{in} is the water volume fraction of intracellular
space, and *S*_{in} and *S*_{ex} are the signal
magnitudes per volume from the intra- and extracellular spaces, respectively.
We have derived and validated analytical
expressions of *S*_{in} by assuming spherical cancer cells, and the
extracellular hindered diffusion coefficient *D*_{ex}= $$$ \sqrt{1-v_{in}} $$$ *D*_{in} for long
diffusion times and randomly packed spherical cells [1]. All signals were fit to analytical
equations pixel wise [2], so that parametric maps of mean cell size *d*, cell density ρ, and intracellular diffusion coefficient *D*_{in} of tumors could be obtained.

Human imaging: IMPULSED imaging was performed on breast cancer patients prior to surgery using a Philips Achieva 3T scanner with a 16-channel breast coil. TR/TE=4000/103ms; FOV=192×192mm; reconstructed in-plane resolution = 1.3×1.3 mm; 10 slices; slice thickness=5 mm; NEX=4; single shot EPI; SENSE factor=3; fat suppression with SPAIR and other imaging parameters are provided in Table 1. Note that the maximum gradient strength used was < 60 mT/m, which is available on most clinical scanners. The total scan time ≈ 5 mins. In addition, ADC measurements using PGSE acquisitions with Δ = 50 and 30 ms were performed to further investigate the ADC dependence on diffusion times.

[1] A. Szafer, J. Zhong, J.C. Gore, Theoretical model for water diffusion in tissues, Magn Reson Med, 33 (1995) 697-712.

[2] X. Jiang, H. Li, J. Xie, E.T. McKinley, P. Zhao, J.C. Gore, J. Xu, In vivo imaging of cancer cell size and cellularity using temporal diffusion spectroscopy, Magn Reson Med, (2016).

[3] U. Del Monte, Does the cell number 10(9) still really fit one gram of tumor tissue?, Cell Cycle, 8 (2009) 505-506.

[4] A.T. Van, S.J. Holdsworth, R. Bammer, In vivo investigation of restricted diffusion in the human brain with optimized oscillating diffusion gradient encoding, Magn Reson Med, 71 (2014) 83-94.

Fig.1 Diagrams of IMPULSED pulse sequences
on regular whole-body MRI system. Note oscillating trapezoidal gradients are
used to maximum b values but keep sampling spectra similar to traditional
cosine waveforms [4].

Fig 2. Tumor ADC dependence on different diffusion times. The error-bars
represent the standard deviations over the tumor region shown in Fig 4.

Fig
3.
The ROI-based diffusion-weighted signal attenuations of a representative human
breast tumor. Markers are mean signals and the error bars represent standard
deviations. The solid lines are fitted results.

Fig 4. IMPULSED-derived maps of mean cell size (left), cell density
(middle), and intracellular diffusion coefficient Din (right) overlaid on a
high-resolution fat-suppressed T2-weighted of a breast cancer patient.

Table 1
Summary of diffusion parameters used in IMPULSED measurements on a human MRI
system. N: number of cycles in each diffusion gradient.