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Supplemental Movie 2: Animated EVAC streamlines (grey lines), showing the path taken by interstitial fluid, overlaid on vascular perfusion measurements (colour scale, measured in vivo using arterial spin labelling) and the location of blood vessels (yellow structures, measured ex vivo using micro-CT). The data were acquired in an LS174T colorectal carcinoma tumour xenograft.

Additional data describing the reproducibility of convectionMRI data, and a figure showing the convectionMRI acquisition sequence.

Several distinct fluid flow phenomena occur in solid tumors, including intravascular blood flow and interstitial convection. Interstitial fluid pressure is often raised in solid tumors, which can limit drug delivery. To probe low-velocity flow in tumors resulting from raised interstitial fluid pressure, we developed a novel MRI technique named convection-MRI, which uses a phase-contrast acquisition with a dual-inversion vascular nulling preparation to separate intra- and extravascular flow. Here, we report the results of experiments in flow phantoms, numerical simulations, and tumor xenograft models to investigate the technical feasibility of convection-MRI. We observed a significant correlation between estimates of effective fluid pressure from convection-MRI with gold-standard, invasive measurements of interstitial fluid pressure in mouse models of human colorectal carcinoma. Our results show how convection-MRI can provide insights into the growth and responsiveness to vascular-targeting therapy in colorectal cancers.Significance: A noninvasive method for measuring low-velocity fluid flow caused by raised fluid pressure can be used to assess changes caused by therapy. Cancer Res; 78(7); 1859–72. ©2018 AACR.

Supplemental Movie 4: Animated EVAC streamlines (grey lines), showing the path taken by interstitial fluid, overlaid on vascular perfusion measurements (colour scale, measured in vivo using arterial spin labelling) and the location of blood vessels (yellow structures, measured ex vivo using micro-CT). The data were acquired in an SW1222 colorectal carcinoma tumour xenograft.

Supplemental Movie 1: Schematic movie illustrating the physical principles underpinning the convection-MRI sequence

Supplemental Movie 5: Interstitial convection, measured using EVAC-MRI and animated using a particle simulation (left), compared with MRI signal enhancement with time, following injection with a contrast agent (Gd-DTPA), in an LS174T tumour.

High-resolution copy of Figure 6b. Fluid flow measured in vivo with convectionMRI is shown as grey streamlines and perfusion is shown as a colorscale. The location of blood vessels is represented by yellow volume renderings, acquired using ex vivo microvascular casting and imaged with micro-CT.

Supplemental Movie 3: Animated EVAC streamlines (grey lines), showing the path taken by interstitial fluid, overlaid on vascular perfusion measurements (colour scale, measured in vivo using arterial spin labelling) and the location of blood vessels (yellow structures, measured ex vivo using micro-CT). The data were acquired in an LS174T colorectal carcinoma tumour xenograft.

Several distinct fluid flow phenomena occur in solid tumors, including intravascular blood flow and interstitial convection. Interstitial fluid pressure is often raised in solid tumors, which can limit drug delivery. To probe low-velocity flow in tumors resulting from raised interstitial fluid pressure, we developed a novel MRI technique named convection-MRI, which uses a phase-contrast acquisition with a dual-inversion vascular nulling preparation to separate intra- and extravascular flow. Here, we report the results of experiments in flow phantoms, numerical simulations, and tumor xenograft models to investigate the technical feasibility of convection-MRI. We observed a significant correlation between estimates of effective fluid pressure from convection-MRI with gold-standard, invasive measurements of interstitial fluid pressure in mouse models of human colorectal carcinoma. Our results show how convection-MRI can provide insights into the growth and responsiveness to vascular-targeting therapy in colorectal cancers. Significance: A noninvasive method for measuring low-velocity fluid flow caused by raised fluid pressure can be used to assess changes caused by therapy. Cancer Res; 78(7); 1859–72. ©2018 AACR.

Several distinct fluid flow phenemena occur in solid tumours, including intravascular blood flow and interstitial convection. To probe low-velocity flow in tumors resulting from raised interstitial fluid pressure, we have developed a novel magnetic resonance imaging (MRI) technique named convection-MRI. It uses a phase-contrast acquisition with a dual-inversion vascular nulling preparation to separate intra- and extra-vascular flow. Here, we report the results of experiments in flow phantoms, numerical simulations and tumor xenograft models to investigate the technical feasibility of convection-MRI. We report a good correlation between estimates of effective fluid pressure from convection-MRI with gold-standard, invasive measurements of interstitial fluid pressure in mouse models of human colorectal carcinoma and show that convection-MRI can provide insights into the growth and response to vascular-targeting therapy in colorectal cancers.

PURPOSE: To investigate the combined use of hyperoxia-induced ?R(2) * and ?R(1) as a noninvasive imaging biomarker of tumor hypoxia. MATERIALS AND METHODS: MRI was performed on rat GH3 prolactinomas (n = 6) and human PC3 prostate xenografts (n = 6) propagated in nude mice. multiple gradient echo and inversion recovery truefisp images were acquired from identical transverse slices to quantify tumor R(2) * and R(1) before and during carbogen (95% O(2) /5% CO(2) ) challenge, and correlates of ?R(2) * and ?R(1) assessed. RESULTS: Mean baseline R(2) * and R(1) were 119 � 7 s(-1) and 0.6 � 0.03 s(-1) for GH3 prolactinomas and 77 � 12 s(-1) and 0.7 � 0.02 s(-1) for PC3 xenografts, respectively. During carbogen breathing, mean ?R(2) * and ?R(1) were -20 � 8 s(-1) and 0.08 � 0.03 s(-1) for GH3 and -0.5 � 1 s(-1) and 0.2 � 0.08 s(-1) for the PC3 tumors, respectively. A pronounced relationship between ?R(2) * and ?R(1) was revealed. CONCLUSION: Considering the blood oxygen-hemoglobin dissociation curve, fast R(2) * suggested that GH3 prolactinomas were more hypoxic at baseline, and their carbogen response dominated by increased hemoglobin oxygenation, evidenced by highly negative ?R(2) *. PC3 tumors were less hypoxic at baseline, and their response to carbogen dominated by increased dissolved oxygen, evidenced by highly positive ?R(1) . Because the two biomarkers are sensitive to different oxygenation ranges, the combination of ?R(2) * and ?R(1) may better characterize tumor hypoxia than each alone. J. Magn. Reson. Imaging 2013;. � 2013 Wiley Periodicals, Inc.

The aim of this study was to use the combined carbogen-ultrasmall superparamagnetic iron oxide (CUSPIO) magnetic resonance imaging (MRI) method, which uses spatial correlations in independent susceptibility imaging biomarkers, to investigate and compare the impact of tumor size and anatomical site on vascular structure and function in vivo. Mice bearing either subcutaneous or orthotopic PC3 LN3 prostate tumors were imaged at 7 T, using a multi-gradient echo sequence to quantify R2∗, before and during carbogen (95% O2/5% CO2) breathing, and subsequently following intravenous administration of USPIO particles. Carbogen and USPIO-induced changes in R2∗ were used to inform on hemodynamic vasculature and fractional blood volume (%), respectively. The CUSPIO imaging data were also segmented to identify and assess five categories of R2∗ response. Small and large subcutaneous and orthotopic tumor cohorts all exhibited significantly (P

The recently described combined carbogen USPIO (CUSPIO) magnetic resonance imaging (MRI) method uses spatial correlations in independent imaging biomarkers to assess specific components of tumor vascular structure and function. Our study aimed to evaluate CUSPIO biomarkers for the assessment of tumor response to antiangiogenic therapy. CUSPIO imaging was performed in subcutaneous rat C6 gliomas before and 2 days after treatment with the potent VEGF-signaling inhibitor cediranib (n = 12), or vehicle (n = 12). Histological validation of Hoechst 33342 uptake (perfusion), smooth muscle actin staining (maturation), pimonidazole adduct formation (hypoxia) and necrosis were sought. Following treatment, there was a significant decrease in fractional blood volume (-43%, p < 0.01) and a significant increase in hemodynamic vascular functionality (treatment alteredδ R 2* carbogen from 1.2 to -0.2 s -1, p < 0.05). CUSPIO imaging revealed an overall significant decrease in plasma perfusion (-27%, p < 0.05) following cediranib treatment, that was associated with selective effects on immature blood vessels. The CUSPIO responses were associated with a significant 15% reduction in Hoechst 33342 uptake (p < 0.05), but no significant difference in vascular maturation or necrosis. Additionally, treatment with cediranib resulted in a significant 40% increase in tumor hypoxia (p < 0.05). The CUSPIO imaging method provides novel and more specific biomarkers of tumor vessel maturity and vascular hemodynamics, and their response to VEGF-signaling inhibition, compared to current MR imaging biomarkers utilized in the clinic. Such biomarkers may prove effective in longitudinally monitoring tumor vascular remodeling and/or evasive resistance in response to antiangiogenic therapy. © 2011 UICC.

Vessel size index (Rv, μm) has been proposed as a quantitative magnetic resonance imaging (MRI) derived imaging biomarker in oncology, for the non-invasive assessment of tumour blood vessel architecture and vascular targeted therapies. Appropriate pre-clinical evaluation of Rv in animal tumour models will improve the interpretation and guide the introduction of the biomarker into clinical studies. The objective of this study was to compare Rv measured in vivo with vessel size measurements from high-resolution X-ray computed tomography (μCT) of vascular corrosion casts measured post mortem from the same tumours, with and without vascular targeted therapy. MRI measurements were first acquired from subcutaneous SW1222 colorectal xenografts in mice following treatment with 0 (n = 6), 30 (n = 6) or 200 mg/kg (n = 3) of the vascular disrupting agent ZD6126. The mice were then immediately infused with a low viscosity resin and, following polymerisation and maceration of surrounding tissues, the resulting tumour vascular casts were dissected and subsequently imaged using an optimised μCT imaging approach. Vessel diameters were not measurable by μCT in the 200 mg/kg group as the high dose of ZD6126 precluded delivery of the resin to the tumour vascular bed. The mean Rv for the three treatment groups was 24, 23 and 23.5 μm respectively; the corresponding μCT measurements from corrosion casts from the 0 and 30 mg/kg cohorts were 25 and 28 μm. The strong association between the in vivo MRI and post mortem μCT values supports the use of Rv as an imaging biomarker in clinical trials of investigational vascular targeted therapies., Highlights ► Non-invasive quantitation of vessel calibre in tumour xenografts in vivo ► Assessment of tumour vessel calibre response to a vascular disrupting agent ► Generation of vascular corrosion casts from the same tumours imaged by MRI ► Quantitation of vessel calibre from corrosion casts by microCT ► Excellent agreement between the in vivo MRI and post mortem microCT vessel calibres

A combined carbogen ultrasmall superparamagnetic iron oxide (USPIO) imaging protocol was developed and applied in vivo in two murine colorectal tumor xenograft models, HCT116 and SW1222, with established disparate vascular morphology, to investigate whether additional information could be extracted from the combination of two susceptibility MRI biomarkers. Tumors were imaged before and during carbogen breathing and subsequently following intravenous administration of USPIO particles. A novel segmentation method was applied to the image data, from which six categories of R(2)* response were identified, and compared with histological analysis of the vasculature. In particular, a strong association between a negative ?R(2)*(carbogen) followed by positive ?R(2)*(USPIO) with the uptake of the perfusion marker Hoechst 33342 was determined. Regions of tumor tissue where there was a significant ?R(2)*(carbogen) but no significant ?R(2)*(USPIO) were also identified, suggesting these regions became temporally isolated from the vascular supply during the experimental timecourse. These areas correlated with regions of tumor tissue where there was CD31 staining but no Hoechst 33342 uptake. Significantly, different combined carbogen USPIO responses were determined between the two tumor models. Combining ?R(2)*(carbogen) and ?R(2)*(USPIO) with a novel segmentation scheme can facilitate the interpretation of susceptibility contrast MRI data and enable a deeper interrogation of tumor vascular function and architecture.

Item does not contain fulltext PURPOSE: To evaluate and histologically qualify carbogen-induced DeltaR2 as a noninvasive magnetic resonance imaging biomarker of improved tumor oxygenation using a double 2-nitroimidazole hypoxia marker approach. METHODS AND MATERIALS: Multigradient echo images were acquired from mice bearing GH3 prolactinomas, preadministered with the hypoxia marker CCI-103F, to quantify tumor R2 during air breathing. With the mouse remaining positioned within the magnet bore, the gas supply was switched to carbogen (95% O2, 5% CO2), during which a second hypoxia marker, pimonidazole, was administered via an intraperitoneal line, and an additional set of identical multigradient echo images acquired to quantify any changes in tumor R2. Hypoxic fraction was quantified histologically using immunofluorescence detection of CCI-103F and pimonidazole adduct formation from the same whole tumor section. Carbogen-induced changes in tumor pO2 were further validated using the Oxylite fiberoptic probe. RESULTS: Carbogen challenge significantly reduced mean tumor R2 from 116 +/- 13 s(-1) to 97 +/- 9 s(-1) (P

To evaluate and histologically qualify carbogen-induced ΔR2 as a noninvasive magnetic resonance imaging biomarker of improved tumor oxygenation using a double 2-nitroimidazole hypoxia marker approach.Multigradient echo images were acquired from mice bearing GH3 prolactinomas, preadministered with the hypoxia marker CCI-103F, to quantify tumor R2 during air breathing. With the mouse remaining positioned within the magnet bore, the gas supply was switched to carbogen (95% O2, 5% CO2), during which a second hypoxia marker, pimonidazole, was administered via an intraperitoneal line, and an additional set of identical multigradient echo images acquired to quantify any changes in tumor R2. Hypoxic fraction was quantified histologically using immunofluorescence detection of CCI-103F and pimonidazole adduct formation from the same whole tumor section. Carbogen-induced changes in tumor pO2 were further validated using the Oxylite fiberoptic probe.Carbogen challenge significantly reduced mean tumor R2 from 116 ± 13 s(-1) to 97 ± 9 s(-1) (P.05). This was associated with a significantly lower pimonidazole adduct area (2.3 ± 1%), compared with CCI-103F (6.3 ± 2%) (P.05). A significant correlation was observed between ΔR2 and Δhypoxic fraction (r=0.55, P.01). Mean tumor pO2 during carbogen breathing significantly increased from 6.3 ± 2.2 mm Hg to 36.0 ± 7.5 mm Hg (P.01).The combined use of intrinsic susceptibility magnetic resonance imaging with a double hypoxia marker approach corroborates carbogen-induced ΔR2 as a noninvasive imaging biomarker of increased tumor oxygenation.

To investigate the combined use of hyperoxia-inducedΔR(2) * and ΔR(1) as a noninvasive imaging biomarker of tumor hypoxia.MRI was performed on rat GH3 prolactinomas (n = 6) and human PC3 prostate xenografts (n = 6) propagated in nude mice. multiple gradient echo and inversion recovery truefisp images were acquired from identical transverse slices to quantify tumor R(2) * and R(1)before and during carbogen (95% O2 /5% CO2 ) challenge, and correlates of ΔR(2) * and ΔR(1) assessed.Mean baseline R(2) * and R(1) were 119 ± 7 s(-1) and 0.6 ± 0.03 s(-1) for GH3 prolactinomas and 77 ± 12 s(-1) and 0.7 ± 0.02 s(-1) for PC3 xenografts, respectively. During carbogen breathing, mean ΔR(2) * and ΔR(1) were -20 ± 8 s(-1) and 0.08 ± 0.03 s(-1) for GH3 and -0.5 ± 1 s(-1) and 0.2 ± 0.08 s(-1) for the PC3 tumors, respectively. A pronounced relationship betweenΔR(2) * and ΔR(1) was revealed.Considering the blood oxygen-hemoglobin dissociation curve, fast R2 * suggested that GH3 prolactinomas were more hypoxic at baseline, and their carbogen response dominated by increased hemoglobin oxygenation, evidenced by highly negative ΔR(2) *. PC3 tumors were less hypoxic at baseline, and their response to carbogen dominated by increased dissolved oxygen, evidenced by highly positive ΔR(1) . Because the two biomarkers are sensitive to different oxygenation ranges, the combination of ΔR(2) * and ΔR(1) may better characterize tumor hypoxia than each alone.

A combined carbogen ultrasmall superparamagnetic iron oxide (USPIO) imaging protocol was developed and applied in vivo in two murine colorectal tumor xenograft models, HCT116 and SW1222, with established disparate vascular morphology, to investigate whether additional information could be extracted from the combination of two susceptibility MRI biomarkers. Tumors were imaged before and during carbogen breathing and subsequently following intravenous administration of USPIO particles. A novel segmentation method was applied to the image data, from which six categories of R(2)* response were identified, and compared with histological analysis of the vasculature. In particular, a strong association between a negative ΔR(2)*(carbogen) followed by positive ΔR(2)*(USPIO) with the uptake of the perfusion marker Hoechst 33342 was determined. Regions of tumor tissue where there was a significant ΔR(2)*(carbogen) but no significant ΔR(2)*(USPIO) were also identified, suggesting these regions became temporally isolated from the vascular supply during the experimental timecourse. These areas correlated with regions of tumor tissue where there was CD31 staining but no Hoechst 33342 uptake. Significantly, different combined carbogen USPIO responses were determined between the two tumor models. Combining ΔR(2)*(carbogen) and ΔR(2)*(USPIO) with a novel segmentation scheme can facilitate the interpretation of susceptibility contrast MRI data and enable a deeper interrogation of tumor vascular function and architecture.