Measurements of k with endogenous CEST MRI cannot substitute for pHe measurements with acidoCEST MRI. Whereas endogenous CEST MRI may still have good utility for evaluating some specific pathologies, exogenous acido-CEST MRI is more appropriate when evaluating pathologies based on pHe values. Magn Reson Med 79:2766-2772, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Differentiating pancreatitis from pancreatic cancer would improve diagnostic specificity, and prognosticating pancreatitis that progresses to pancreatic cancer would also improve diagnoses of pancreas pathology. The high glycolytic metabolism of pancreatic cancer can cause tumor acidosis, and different levels of pancreatitis may also have different levels of acidosis, so that extracellular acidosis may be a diagnostic biomarker for these pathologies. AcidoCEST MRI can noninvasively measure extracellular pH (pHe) in the pancreas and pancreatic tissue. We used acidoCEST MRI to measure pHe in a KC model treated with caerulein, which causes pancreatitis followed by development of pancreatic cancer. We also evaluated the KC model treated with PBS, and wild-type mice treated with caerulein or PBS as controls. The caerulein-treated KC cohort had lower pHe of 6.85–6.92 before and during the first 48 h after initiating treatment, relative to a pHe of 6.92 to 7.05 pHe units for the other cohorts. The pHe of the caerulein-treated KC cohort decreased to 6.79 units at 5 weeks when pancreatic tumors were detected with anatomical MRI, and sustained a pHe of 6.75 units at the 8-week time point. Histopathology was used to evaluate and validate the presence of tumors and inflammation in each cohort. These results showed that acidoCEST MRI can differentiate pancreatic cancer from pancreatitis in this mouse model, but does not appear to differentiate pancreatitis that progresses to pancreatic cancer vs. pancreatitis that does not progress to cancer.

Lung cancer diagnosis via imaging may be confounded by the presence of indolent infectious nodules in imaging studies. This issue is pervasive in the southwestern US where coccidioidomycosis (Valley Fever) is endemic. AcidoCEST MRI is a noninvasive imaging method that quantifies the extracellular pH (pHe) of tissues in vivo, allowing tumor acidosis to be used as a diagnostic biomarker. Using murine models of lung adenocarcinoma and coccidoidomycosis, we found that average lesion pHe differed significantly between tumors and granulomas. Our study shows that acidoCEST MRI is a promising tool for improving the specificity of lung cancer diagnosis.

Introduction: Our objective was to determine whether acidoCEST MRI—a novel, non-invasive MRI method that measures extracellular pH (pHe)—can differentiate between lung tumors and coccidioidomycosis (valley fever) granulomas within in vivo mouse models of lung cancer and valley fever. Methods: To develop a spontaneous murine lung tumor model, A/J mice received orthotopic injections of urethane to induce formation of lung adenocarcinomas. The Valley Fever Center for Excellence at the University of Arizona infected SW mice with a BSL 2-compatible mutant Coccidioides strain, Δcps1, to develop our preclinical valley fever model. All scans were performed with a Bruker BioSpin 7T MRI system. For all MRI scans, mice were anesthetized with 2.0% isofluorane, respiration and body temperature were monitoreduring scans, and body temperature was maintained at 37 °C. Respiration-triggering (gating) was used in all imaging sequences to compensate for motion artifacts in the lung. For optimal gating, the mouse's respiration rate was maintained at < 50 breaths per minute. Each mouse was scanned with acidoCEST MRI using 370 mg/mL Iopamidol (200 μL IV bolus, 400 μL/hr IV infusion). AcidoCEST MRI (3.5 μT, 300 ms imaging time, 6000 ms presaturation pulse) was performed according to previously published methods, updated with improved respiration gating. For acidoCEST MRI, the saturation pulse continued until terminated by the gating trigger. Spatial pHe maps of tumor and granuloma ROI were produced using Bloch fitting in Matlab 2014a. Average lesion pHe and iopamidol concentration we also recorded. Results: AcidoCEST MRI was successfully applied to the in vivo imaging of murine lung tumors and coccidioidomycosis granulomas. Lung tumors demonstrated successful uptake of the iopamidol contrast agent, with an average concentration of approximately 40 mM. pHe values in the tumor ROI ranged from 6.5 to 7.2 with an average value of 6.64. Granulomas demonstrated successful uptake of iopamidol with an average concentration of about 75 mM. pHe values in granulomas ranged from 7.2 to 7.4 with an average value of 7.29. Conclusion: AcidoCEST MRI may be used to quantify the pHe of murine lung tumors and coccidioidomycosis granulomas in vivo. Our results show that pHe is a promising biomarker for the differential diagnosis of coccidioidomycosis and lung cancer. Citation Format: Leila Renee Lindeman, Edward A. Randtke, Lisa F. Shubitz, Christine M. Howison, Kyle M. Jones, Mark D. Pagel. Imaging tissue extracellular pH for the differential diagnosis of coccidioidomycosis and lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3050.

Introduction: Our objective was to accurately measure the extracellular pH (pHe) of lung tumors in vivo using an innovative, non-invasive imaging method known as acidoCEST MRI, to potentially improve the early detection of lung tumors via molecular imaging. Methods: A spontaneous murine lung tumor model was initiated through orthotopic injections of urethane in seven A/J mice to induce formation of lung adenocarcinomas. Starting at 8 weeks post injection, we performed coronal anatomical scans to monitor tumor growth with Bruker BioSpin 7T small animal MRI instrument. AcidoCEST MRI was then performed when tumors reached a diameter of 1 mm in one dimension at approximately 17 weeks post injection, followed by additional scans each month. For all MRI scans, mice were anesthetized with 2.0% isofluorane, the respiration rate was monitored, and body temperature was maintained at 37 °C. Respiration-triggering (gating) was used in all imaging sequences to compensate for motion artifacts in the lung. For optimal gating, the mouse's respiration rate was maintained at < 40 breaths per minute. Each mouse was scanned with acidoCEST MRI using 370 mg/mL iopamidol (200 μL IV bolus, 400 μL/hr IV infusion), using a 6 sec saturation period at 3.5 μT power, 300 ms acquisition time, with 468×468 μm spatial resolution, updated with improved respiration gating. Parametric maps of pixel-wise pHe values of the tumor were produced by fitting the Bloch-McConnell equations in Matlab 2014a. The average tumor pHe and concentration of iopamidol agent in the tumor tissue were recorded. Results: AcidoCEST MRI was successfully applied to the in vivo imaging of murine lung tumors. Our innovative, respiration-gated pulse sequence and Bloch-McConnell fitting method were essential to overcome the noise created by motion artifacts inherent in lung imaging. Lung tumors demonstrated successful uptake of the iopamidol contrast agent, with an average concentration of approximately 40 mM. The pH values in the tumor ranged from 6.5 to 7.0 with an average value of 6.64, demonstrating tumor acidosis. Anatomical MRI was used to monitor tumor growth from 1 mm diameter at 17 weeks post injection, to 4 mm diameter at 36 weeks post-injection. Conclusion: Our study has established that acidoCEST MRI can be used to quantify the pH of murine lung tumors in vivo, showing that this method is promising for improved early detection of lung tumors. These pHe measurements can be compared with tumor growth rates to determine how tumor acidosis correlates with aggressive phenotype. Tumor pHe measurements can also be related to concentration of the agent as a biomarker of vascular perfusion. Furthermore, the spatial heterogeneity of lung tumor pHe can be assessed with this noninvasive imaging method. Further pre-clinical studies are also warranted to determine if the acidoCEST MRI method is suitable for early therapy response monitoring. Citation Format: Leila R. Lindeman, Edward A. Randtke, Christine M. Howison, Kyle M. Jones, Mark D. Pagel. Quantification of murine lung tumor pH in vivo by acidoCEST MRI. [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 4249.