Despite advances in the multimodality treatment strategies, the prognosis of patients with glioblastoma (GBM) remains poor with a median survival of only 12-15 months for newly diagnosed GBM and 3-6 months for recurrent GBMs.¹ Recently,² tumor treating fields (TTFields), a new frontier in cancer therapy, have been approved by FDA for the treatment of newly diagnosed and recurrent GBMs. TTFields deliver low intensity, intermediate frequency alternating electric fields directly to the brain inhibiting cell division and causing neoplastic cell death with minimal effect on the quiescent cells.³ Due to its unique mechanism of action, this novel treatment modality has shown promise in pilot clinical trials in patients with both treatment naïve and recurrent GBMs.⁴ Several studies have shown the potential of diffusion tensor imaging (DTI)⁵, perfusion weighted imaging (PWI)⁶ and proton MR spectroscopy⁷ in evaluating treatment response to different therapeutic regimens in patients with gliomas. However, until now, no study has investigated the treatment response to TTFields in gliomas using advanced MR imaging. The purpose of study was to monitor the effects of TTFields in GBM patients using DTI, PWI and 3D-echoplanar spectroscopic imaging (EPSI).One patient with newly diagnosed GBM and 3 patients with recurrent GBM previously treated with standard of care maximal safe resection and chemo-radiation therapy received TTFields (intensity~0.7V/cm and frequency~200kHz). Patients underwent baseline (prior to TTFields) and 2 follow-up (one and two months post initiation of TTFields) MR imaging on a 3T MR system. DTI data were acquired using 30 directions with a single-shot spin-echo EPI with parallel imaging (acceleration factor=2), TR/TE=5000/86ms; NEX=3; in-plane resolution=1.72 × 1.72mm², slice thickness=3mm, b= 0, 1000s/mm². After motion and eddy current correction of raw DTI data, parametric maps (MD, FA) were generated using in-house developed algorithm.⁸ For PWI, T2* weighted gradient-echo EPI sequence was acquired prior to and during the course of a bolus of contrast agent using the following parameters: TR/TE = 2000/45ms, in-plane resolution=1.72 × 1.72mm², 20 slices with thickness= 3 mm. Forty-five sequential measurements were acquired for each section, with a temporal resolution of 2.1 s. Leakage corrected CBV maps were constructed using Nordic ICE program. Scan parameters for 3D-EPSI were: TR/TE = 1550/17.6ms, spatial points=50×50×18, voxel size=5.6×5.6×10mm³. Water suppression using frequency-selective saturation pulses and inversion-recovery nulling of lipid signal (TI=198ms) was performed. EPSI acquisition also included an interleaved water reference imaging to perform signal normalization, and eddy current correction. EPSI data were processed offline using metabolic imaging and data analysis system (MIDAS) package^.9 DTI, CBV maps and FLAIR images were co-registered to post-contrast T1-weighted images and a semi-automated routine⁸ was used to segment the contrast-enhancing region of tumor. Median values of MD, FA, rCBV and Cho/Cr were computed at each time point. The 90^th percentile rCBV (rCBV_max) values were also measured. Percent changes of each parameter between baseline and follow-up time points were evaluated.Clinically, all four patients were stable at 2 month follow-up. Percent changes in MD, FA and rCBVmax from baseline to post TTFields at one and two month follow-up periods are shown in Fig 1. An increasing trend in MD accompanied by a steady decline in FA was noted in most patients at the 2 month follow-up time point. The rCBVmax was either stable or decreased in three patients and in one patient, it initially increased at one-month and then stabilized at the 2 month time point. The median Cho/Cr value did not demonstrate any specific trend as it decreased in one and increased in another patient. No particular trend in the percent variation in volume from contrast enhancing regions was observed. In vitro³ studies in cell lines and in vivo¹⁰ studies in cancer xenograft models have shown TTFields arrests neoplastic cellular proliferation by disrupting normal polymerization-depolymerization process of microtubules during mitosis. The inhibited cellular growth may account for large increase in MD and decrease in FA as observed in the current study. Reducing trends in rCBV_max at the follow-up may be associated with reduced vascularity and tissue perfusion within the tumor bed after the therapy. These changes occurred prior to significant changes in tumor volume, which is typically used to assess response in these tumors, indicating the potential value of DTI and PWI in assessing early treatment response to this novel therapeutic paradigm. However, these early findings need to be corroborated in a larger patient cohort.