Tumor pH and Protein Concentration Contribute to the Signal of Amide Proton Transfer Magnetic Resonance Imaging

Ray, Kevin J.; Simard, Manon A.; Larkin, James R.; Coates, James; Kinchesh, Paul; Smart, Sean; Higgins, Geoff S.; Chappell, Michael A.; Sibson, Nicola R.

doi:10.1158/0008-5472.can-18-2168

Cited by 62 publications

(50 citation statements)

References 41 publications

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“…Immunohistochemistry: Histology slides were kept in citrate buffer (pH6) heated to subboiling temperature for 20 minutes and cooled at room temperature for 30 minutes. After treating the slides with 3% hydrogen peroxide in distilled water to lower intrinsic peroxidase activity, the Coomassie stain: A Coomassie stain was performed for the detection of protein concentration as described by Ray et al 62 .…”

Section: Discussionmentioning

confidence: 99%

AI boosted molecular MRI for apoptosis detection in oncolytic virotherapy

Perlman

Ito

Herz

et al. 2020

Preprint

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Oncolytic virotherapy is a promising treatment for high mortality cancers 1 . Non-invasive imaging of the underlying molecular processes is an essential tool for therapy optimization and assessment of viral spread, innate immunity, and therapeutic response 2, 3 . However, previous methods for imaging oncolytic viruses did not correlate with late viral activity 4 or had poor sensitivity and specificity 5 . Similarly, methods developed to image treatment response, such as apoptosis, proved to be slow, nonspecific, or require the use of radioactive or metalbased contrast agents 6-8 . To date, no method has been widely adopted for clinical use. We describe here a new method for fast magnetic resonance molecular imaging with quantitative proton chemical-exchange specificity to monitor oncolytic virotherapy treatment response. A deep neural network enabled the computation of quantitative biomarker maps of protein and lipid/macromolecule concentrations as well as intracellular pH in a glioblastoma multiforme mouse brain tumor model. Early detection of apoptotic response to oncolytic virotherapy, characterized by decreased cytosolic pH and protein synthesis, was observed in agreement with histology. Clinical translation was demonstrated in a normal human subject, yielding molecular parameters in good agreement with literature values 9 . The developed method is directly applicable to a wide range of pathologies, including stroke 10 , cancer [11][12][13] , and neurological disorders 14,15 .The highly invasive nature of many cancer types and the toxicity of most systemic chemotherapies represent significant challenges for cancer therapies and limit their effectiveness. An especially promising therapeutic approach for overcoming these challenges is the use of oncolytic viruses

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Section: Discussionmentioning

confidence: 99%

AI boosted molecular MRI for apoptosis detection in oncolytic virotherapy

Perlman

Ito

Herz

et al. 2020

Preprint

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“…APTw MRI, based on the concentration levels of endogenous cellular proteins and peptides in tissue, has become increasingly recognized as a promising technology in detecting tumors because of its advantage of nonionizing‐radiation and its contrast‐free nature . Several previous studies have reported that APTw imaging was useful in differentiating malignant tumors from benign or normal tissues .…”

Section: Discussionmentioning

confidence: 99%

“…As the clinical feasibility of APTw imaging in the pelvis is what concerns researchers, our study investigated and revealed the excellent agreement in both image quality assessment and APT values measurement, even on small cervical lesions with maximum diameter less than 2 cm, which is one of the most important criteria for cervical cancer fertility-sparing therapy. 2 APTw MRI, based on the concentration levels of endogenous cellular proteins and peptides in tissue, 23,24 has become increasingly recognized as a promising technology in detecting tumors 7 because of its advantage of nonionizing-radiation and its contrast-free nature. 25 Several previous studies have reported that APTw imaging was useful in differentiating malignant tumors from benign or normal tissues.…”

Section: Discussionmentioning

confidence: 99%

Three‐dimensional turbo‐spin‐echo amide proton transfer‐weighted mri for cervical cancer: A preliminary study

Lin

et al. 2019

Magnetic Resonance Imaging

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Background Amide proton transfer‐weighted (APTw) imaging has shown great potential in the diagnosis of cancer, but has yet not been well studied in cervical cancer. Purpose To evaluate the image quality and clinical feasibility of APTw MRI for cervical cancer. Study Type Prospective. Population In all, 75 patients with cervical lesions and 49 healthy volunteers. Field Strength/Sequence 3.0 T, 3D turbo spin echo (TSE) APTw sequence. Assessment Three radiologists, blinded to the clinical data, independently evaluated APTw image quality with a 5‐point Likert scale on 64 patients with pathologically confirmed cervical cancer. APT values, calculated based on asymmetry of acquired Z‐spectrum with respect to water frequency, using 3D turbo spin echo volume acquisition with B0 correction, were independently measured by two radiologists, twice for each observer, on 52 cervical cancer lesions and 49 normal cervical stroma with a mean region of interest area of 638.6 mm2 and 557.5 mm2, respectively. Statistical Tests Interobserver agreement was evaluated by Kendall's W test. Intra‐ and interobserver interclass correlation coefficients (ICC) were computed. Student's t‐test was used to compare the differences of APT values between cervical cancer and normal cervix; receiver operating characteristic analysis was performed. Results Most cases revealed good APTw image quality with excellent agreement (Kendall's W = 0.850, P < 0.001). APT values of cervical cancer and normal cervical stroma were 2.745 ± 0.065 and 1.853 ± 0.059, respectively, with a significant difference (P < 0.0001). Intraobserver ICCs were 0.963 and 0.960 for two readers. Interobserver ICC was 0.993. Area under the curve (AUC) for differentiating cervical cancer from normal cervical stroma was 0.927. The feasible threshold value for AUC was determined as 2.221 with sensitivity of 84.62% and specificity of 83.66%. Data Conclusion 3D TSE APTw MRI is feasible in cervical cancer. Cervical cancer showed significantly higher APT values than normal cervix. Level of Evidence: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1318–1325.

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“…Considering the main influence of the concentration of the mobile amide protons, the dependency of the APT signal on the mobile amide protons is much stronger than its contra‐related dependency to the exchange rate. A recent study in a rat model of brain metastasis determined that the proportion of APT signal originating from changes in protein concentration was approximately 66%, with the remaining 34% originating from changes in tumor pH …”

Section: Discussionmentioning

confidence: 99%

Contradiction between amide‐CEST signal and pH in breast cancer explained with metabolic MRI

et al. 2019

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Purpose Metabolic MRI is a noninvasive technique that can give new insights into understanding cancer metabolism and finding biomarkers to evaluate or monitor treatment plans. Using this technique, a previous study has shown an increase in pH during neoadjuvant chemotherapy (NAC) treatment, while recent observation in a different study showed a reduced amide proton transfer (APT) signal during NAC treatment (negative relation). These findings are counterintuitive, given the known intrinsic positive relation of APT signal to pH. Methods In this study we combined APT MRI and 31P‐MRSI measurements to unravel the relation between the APT signal and pH in breast cancer. Twenty‐two breast cancer patients were scanned with a 7 T MRI before and after the first cycle of NAC treatment. pH was determined by the chemical shift of inorganic phosphate (Pi). Results While APT signals have a positive relation to pH and amide content, we observed a direct negative linear correlation between APT signals and pH in breast tumors in vivo. Conclusions As differentiation of cancer stages was confirmed by observation of a linear correlation between cell proliferation marker PE/Pi (phosphoethanolamine over inorganic phosphate) and pH in the tumor, our data demonstrates that the concentration of mobile proteins likely supersedes the contribution of the exchange rate to the APT signal.

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Tumor pH and Protein Concentration Contribute to the Signal of Amide Proton Transfer Magnetic Resonance Imaging

Cited by 62 publications

References 41 publications

AI boosted molecular MRI for apoptosis detection in oncolytic virotherapy

AI boosted molecular MRI for apoptosis detection in oncolytic virotherapy

Three‐dimensional turbo‐spin‐echo amide proton transfer‐weighted mri for cervical cancer: A preliminary study

Contradiction between amide‐CEST signal and pH in breast cancer explained with metabolic MRI

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