Fast and sensitive dynamic oxygen‐enhanced MRI with a cycling gas challenge and independent component analysis

Abstract

Purpose There is a critical need for non‐invasive imaging biomarkers of tumor oxygenation to assist in patient stratification and development of hypoxia targeting therapies. Using a cycling gas challenge and independent component analysis (ICA), we sought to improve the sensitivity and speed of existing oxygen enhanced MRI (OE‐MRI) techniques to detect changes in oxygenation with dynamically acquired T1W signal intensity images (dOE‐MRI). Methods Mice were implanted with SCCVII, HCT‐116, BT‐474, or SKOV3 tumors in the dorsal subcutaneous region and imaged at 7T. T1W images were acquired during a respiratory challenge with alternating 2‐minute periods of air and 100% oxygen for three cycles. Data were analyzed with ICA and oxygenation maps were generated and compared to corresponding histology sections stained for hypoxia (pimonidazole) and blood vessels (CD31). Results Cycling air‐oxygen‐air gas challenges were well tolerated and ICA permitted extraction of the oxygen‐enhancing component in all imaged tumors from four different models. Comparison with synthetic response functions showed that dOE‐MRI does not require any a‐priori knowledge of the physiological response. The fraction of O2‐negative dOE‐MRI voxels that correlate inversely with the ICA gas‐cycling component correspond well with the histological hypoxic fraction in SCCVII tumors (r = 0.91, p = 0.0016) but did not correlate in HCT‐116 tumors (r = 0.13, p = 0.81). Conclusions Using ICA and adding a cycling gas challenge extends the sensitivity of OE‐MRI and allows the oxygenation status of tumors to be assessed in as little as six minutes. These findings support further development of OE‐MRI as a biomarker of tumor oxygenation.

T1 based oxygen-enhanced MRI in tumours; a scoping review of current research

“…[13][14][15][16][17][18] (2) Verification that the distribution of hypoxic and normoxic areas seen with OE-MRI display intratumoural heterogeneity but with spatially coherent regions in keeping with patterns known to occur biologically. 5,[17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] (3) Correlation against histopathological hypoxia indicators such as pimonidazole staining, glucose transporter 1 (GLUT-1) expression and hypoxia-inducible factor 1-α (HIF-1α) expression. 17,29,31,32,34-38 (4) Verification of OE-MRI's ability to predict tumours more likely to display hypoxia induced treatment resistance.…”

Hypoxia and the phenomenon of immune exclusion

“…OE-MRI does not provide quantitative measures of oxygen per se but maps oxygen delivery in tissues with fully saturated haemoglobin [423,424]. Its potential was assessed in preclinical studies, in healthy individuals subjected to respiratory challenges and in patients with lung cancer and advanced cancer of the abdomen and pelvis [425][426][427].…”

Hypoxia and its therapeutic possibilities in paediatric cancers

“…53 Preclinical and clinical studies have demonstrated that the volume of oxygenrefractory voxels can be used to map and quantify hypoxic fractions across a range of tumour types. [54][55][56][57] OE-MRI revealed extensive tumour subregions that were refractory to oxygeninduced signal intensity changes in a syngeneic rat rhabdomyosarcoma model, again consistent with the presence of hypoxia. 49,50 Preliminary OE-MRI investigations in RH41 rhabdomyosarcoma xenografts also suggest a strong hypoxia signature in this tumour type ( Fig.…”