Clinical Translation of Tumor Acidosis Measurements with AcidoCEST MRI

Abstract

Purpose We optimized acido-chemical exchange saturation transfer (acidoCEST) magnetic resonance imaging (MRI), a method that measures extracellular pH (pHe), and translated this method to the radiology clinic to evaluate tumor acidosis. Procedures A CEST-FISP MRI protocol was used to image a flank SKOV3 tumor model. Bloch fitting modified to include the direct estimation of pH was developed to generate parametric maps of tumor pHe in the SKOV3 tumor model, a patient with high-grade invasive ductal carcinoma, and a patient with metastatic ovarian cancer. The acidoCEST MRI results of the patient with metastatic ovarian cancer were compared with DCE MRI and histopathology. Results The pHe maps of a flank model showed pHe measurements between 6.4 and 7.4, which matched with the expected tumor pHe range from past acidoCEST MRI studies in flank tumors. In the patient with metastatic ovarian cancer, the average pHe value of three adjacent tumors was 6.58, and the most reliable pHe measurements were obtained from the right posterior tumor, which favorably compared with DCE MRI and histopathological results. The average pHe of the kidney showed an average pHe of 6.73 units. The patient with high-grade invasive ductal carcinoma failed to accumulate sufficient agent to generate pHe measurements. Conclusions Optimized acidoCEST MRI generated pHe measurements in a flank tumor model and could be translated to the clinic to assess a patient with metastatic ovarian cancer.

Preliminary Results that Assess Metformin Treatment in a Preclinical Model of Pancreatic Cancer Using Simultaneous [18F]FDG PET and acidoCEST MRI

“…3c, d, Figs. S1–S3) [7, 26]. For comparison, the absolute magnitudes of both CEST signals at 5.6 and 4.2 ppm are dependent on concentration, so that Bloch fitting of the magnitude of the CEST spectrum is largely responsible for estimating concentration.…”

“…CEST MR images were analyzed on a pixelwise basis using customized software developed with MATLAB R2016b (MathWorks, Inc., Natick, MA) [7]. For each mouse, the average of four pre-injection and six post-injection MR images were spatially smoothed with Gaussian filtering.…”

“…We have developed a version of this molecular imaging technique to monitor tumor glycolysis that causes lactic acid production and secretion, which is known as acidoCEST MRI [5–7]. Other researchers have developed similar CEST MRI methods that have been used to measure pHe in tumors, kidneys, and bladder, which further demonstrates the feasibility of this MRI technique [8–12].…”

“…1c–f) [19]. The chemical exchange rate of each type of amide proton on iopamidol has different dependencies on pH, so that an analysis of the CEST effects from both amide protons can measure pH [7]. In practice, the saturation frequency is iterated among many values to generate a CEST spectrum that is analyzed to measure pH (Fig.…”

Controlling Water Exchange Kinetics and Improving ParaCEST Imaging

“…The above is only one method for calculating pH utilizing a CEST agent, and there are many different calculations and approaches that researchers have come up with. 148,159,160,164,[166][167][168][169][170][171][172][173][174][175][176][177] Each method has its own list of parameters, some being held and some being allowed to fluctuate in calculations.…”