Tumor Perfusion Measurements Research Articles

Non-invasive measurement of oxygen metabolism. Part 1: Historical review and state of the art

Oxygen metabolism is a key factor in the life of a living organism. The article is the first part of a review of methods for measuring oxygen metabolism.Purpose. The aim of this review is to present an insight into the evolution of methods for measuring oxygen metabolism in a way from global to local measurement of brain perfusion. The role of the 15O isotope as the “gold standard” for measuring oxygen metabolism using positron emission tomography (PET) is described. We also provide a case report of brain tumor perfusion measurements from our clinic.Materials and methods. More than 200 Pubmed publications were studied with the keywords “positron emission tomography + O-15”. Relevant publications that do not contain these keywords or contain them in a different wording were also analyzed. A clinical case of a brain tumor perfusion using CT perfusion, MR-ASL and PET with H215O is provided.Results. The evolution of methods for measuring perfusion, oxygen extraction, and oxygen metabolism, is described. More than 50 papers are cited depicting key advances in measurement technologies. Examples of the use of PET with H215O in fundamental research and clinical practice are given.Conclusion. The obvious value of oxygen-isotope PET data is combined with the invasiveness (in some cases), technical complexity and high cost of the procedure. The second part of the review will be devoted to alternative methods for measuring oxygen metabolism, which are developing in the 21st century and which are intended for wide clinical use.

Imaging Hallmarks of the Tumor Microenvironment in Glioblastoma Progression.

Glioblastoma progression involves multifaceted changes in vascularity, cellularity, and metabolism. Capturing such complexities of the tumor niche, from the tumor core to the periphery, by magnetic resonance imaging (MRI) and spectroscopic imaging (MRSI) methods has translational impact. In human-derived glioblastoma models (U87, U251) we made simultaneous and longitudinal measurements of tumor perfusion (Fp), permeability (Ktrans), and volume fractions of extracellular (ve) and blood (vp) spaces from dynamic contrast enhanced (DCE) MRI, cellularity from apparent diffusion coefficient (ADC) MRI, and extracellular pH (pHe) from an MRSI method called Biosensor Imaging of Redundant Deviation in Shifts (BIRDS). Spatiotemporal patterns of these parameters during tumorigenesis were unique for each tumor. While U87 tumors grew faster, Fp, Ktrans, and vp increased with tumor growth in both tumors but these trends were more pronounced for U251 tumors. Perfused regions between tumor periphery and core with U87 tumors exhibited higher Fp, but Ktrans of U251 tumors remained lowest at the tumor margin, suggesting primitive vascularization. Tumor growth was uncorrelated with ve, ADC, and pHe. U87 tumors showed correlated regions of reduced ve and lower ADC (higher cellularity), suggesting ongoing proliferation. U251 tumors revealed that the tumor core had higher ve and elevated ADC (lower cellularity), suggesting necrosis development. The entire tumor was uniformly acidic (pHe 6.1-6.8) early and throughout progression, but U251 tumors were more acidic, suggesting lower aerobic glycolysis in U87 tumors. Characterizing these cancer hallmarks with DCE-MRI, ADC-MRI, and BIRDS-MRSI will be useful for exploring tumorigenesis as well as timely therapies targeted to specific vascular and metabolic aspects of the tumor microenvironment.

Preoperative localization of the sensorimotor cortex and measurement of tumor perfusion in a single acquisition using ASL technique

Resting state fMRI (rs-fMRI) using arterial spin labelling (ASL) technique was performed for the preoperative localization of the sensorimotor cortex in a patient with lymphoma and the results were compared to those of task-based (tb) and rs-fMRI studies using blood oxygenation level-dependent (BOLD) sequence. Rs-fMRI using ASL showed similar results in the regions of the sensorimotor network to those of tb- and rs-fMRI fMRI using BOLD. ASL technique has a potential in clinical practice because all of brain perfusion imaging, cerebral blood flow measurement, and rs-fMRI study can be performed at a single acquisition.

Intravital Monitoring of Vasculature After Targeted Gene Therapy Alone or Combined With Tumor Irradiation.

Vascular-targeted therapies exhibit radiosensitizing effects by remodeling tumor vasculature, thus facilitating the increased oxygenation of the remaining tumor tissue. To examine these phenomena, the effects of antiendoglin gene therapy alone and in combination with irradiation were monitored for 5 consecutive days on a murine mammary adenocarcinoma (TS/A) tumor model growing in a dorsal window chamber. The vascularization of the tumors was assessed by the determination of the tumor vascular area and by measurement of tumor perfusion by using laser Doppler flowmetry to provide insight into intratumoral gene electrotransfer effects. The changes in the vascular area after this specific therapy correlated with laser Doppler measurements, indicating that either of the methods can be used to demonstrate the induced changes in the vascularization and perfusion of tumors. Gene electrotransfer with an endothelial-specific promoter resulted in a vascular-targeted effect on tumor vasculature within the first 24 hours and did not restore within 5 days. The combination with the irradiation did not result in a more pronounced vascular effect, and irradiation alone only abrogated the formation of new vessels and prevented an increase in the tumor perfusion over time. The results indicate that tumors grown in a dorsal window chamber facilitate intravital measurements of the vascularization of tumors and blood perfusion, enabling the monitoring of the antiangiogenic or vascular disruptive effects of different therapies.

Comparison of Voxel-Wise Tumor Perfusion Changes Measured With Dynamic Contrast-Enhanced (DCE) MRI and Volumetric DCE CT in Patients With Metastatic Brain Cancer Treated with Radiosurgery.

Dynamic contrast-enhanced (DCE)-MRI metrics are evaluated against volumetric DCE-CT quantitative parameters as a standard for tracer-kinetic validation using a common 4-dimensional temporal dynamic analysis platform in tumor perfusion measurements following stereotactic radiosurgery (SRS) for brain metastases. Patients treated with SRS as part of Research Ethics Board-approved clinical trials underwent volumetric DCE-CT and DCE-MRI at baseline, then at 7 and 21 days after SRS. Temporal dynamic analysis was used to create 3-dimensional pharmacokinetic parameter maps for both modalities. Individual vascular input functions were selected for DCE-CT and a population function was used for DCE-MRI. Semiquantitative and pharmacokinetic DCE parameters were assessed using a modified Tofts model within each tumor at every time point for both modalities for characterization of perfusion and capillary permeability, as well as their dependency on precontrast relaxation times (TRs), T10, and input function. Direct voxel-to-voxel Pearson analysis showed statistically significant correlations between CT and magnetic resonance which peaked at day 7 for Ktrans (R = 0.74, P ≤ .0001). The strongest correlation to DCE-CT measurements was found with DCE-MRI analysis using voxel-wise T10 maps (R = 0.575, P < .001) instead of assigning a fixed T10 value. Comparison of histogram features showed statistically significant correlations between modalities over all tumors for median Ktrans (R = 0.42, P = .01), median area under the enhancement curve (iAUC90) (R = 0.55, P < .01), and median iAUC90 skewness (R = 0.34, P = .03). Statistically significant, strong correlations were found for voxel-wise Ktrans, iAUC90, and ve values between DCE-CT and DCE-MRI. For DCE-MRI, the implementation of voxel-wise T10 maps plays a key role in ensuring the accuracy of heterogeneous pharmacokinetic maps.

Oxygen-Enhanced MRI Accurately Identifies, Quantifies, and Maps Tumor Hypoxia in Preclinical Cancer Models.

There is a clinical need for noninvasive biomarkers of tumor hypoxia for prognostic and predictive studies, radiotherapy planning, and therapy monitoring. Oxygen-enhanced MRI (OE-MRI) is an emerging imaging technique for quantifying the spatial distribution and extent of tumor oxygen delivery in vivo. In OE-MRI, the longitudinal relaxation rate of protons (ΔR1) changes in proportion to the concentration of molecular oxygen dissolved in plasma or interstitial tissue fluid. Therefore, well-oxygenated tissues show positive ΔR1. We hypothesized that the fraction of tumor tissue refractory to oxygen challenge (lack of positive ΔR1, termed "Oxy-R fraction") would be a robust biomarker of hypoxia in models with varying vascular and hypoxic features. Here, we demonstrate that OE-MRI signals are accurate, precise, and sensitive to changes in tumor pO2 in highly vascular 786-0 renal cancer xenografts. Furthermore, we show that Oxy-R fraction can quantify the hypoxic fraction in multiple models with differing hypoxic and vascular phenotypes, when used in combination with measurements of tumor perfusion. Finally, Oxy-R fraction can detect dynamic changes in hypoxia induced by the vasomodulator agent hydralazine. In contrast, more conventional biomarkers of hypoxia (derived from blood oxygenation-level dependent MRI and dynamic contrast-enhanced MRI) did not relate to tumor hypoxia consistently. Our results show that the Oxy-R fraction accurately quantifies tumor hypoxia noninvasively and is immediately translatable to the clinic.

On the Use of DSC-MRI for Measuring Vascular Permeability.

Contrast agent extravasation has been shown to confound brain tumor perfusion measurements with DSC-MR imaging, necessitating the use of correction techniques (eg, Weisskoff, Bjornerud). Leakage parameters (K2 and K(a)) postulated to reflect vessel permeability can be extracted from these correction methods; however, the biophysical interpretation of these parameters and their relationship to commonly used MR imaging measures of vascular permeability (eg, contrast agent volume transfer constant, [K(trans)]) remain unclear. Given that vascular density, as assessed by blood volume, and vascular permeability, as reflected by K(trans) (and potentially K2 or K(a)), report on unique and clinically informative vascular characteristics, there is a compelling interest to simultaneously assess these features. We acquired multiecho DSC-MR imaging data, allowing the simultaneous computation and voxelwise comparison of single- and dual-echo derived measures of K2, K(a) and K(trans) in patients with glioma. This acquisition enabled the investigation of competing T1 and T2* leakage effects and TE dependency on these parameters. K2 and K(a) displayed nonsignificant (P = .150 and P = .060, respectively) voxelwise linear correlations with K(trans), while a significant (P < .001) inverse relationship was observed between K2 and Ka (coefficient of determination [r(2)] = 0.466-0.984). Significantly different (P < .005) mean estimates were found between voxels exhibiting predominately T1 and T2* effects for K2 and K(a). K(trans), however, was observed to be similar between these voxels (0.109 versus 0.092 minutes(-1)). Significant differences (P < .001) in extracellular-extravascular volume fraction (v(e)) (0.285 versus 0.167) were also observed between cohorts. Additionally, K2 and K(a) were found to have a significant quadratic relationship (P = .031 and P = .005, respectively) with v(e). Estimates of vascular permeability in brain tumors may be simultaneously acquired from multiple-echo DSC-MR imaging via K(trans); however, caution should be used in assuming a similar relationship for K2 and K(a).

Ultrasound Imaging of Breast Tumor Perfusion and Neovascular Morphology

A novel image processing strategy is detailed for simultaneous measurement of tumor perfusion and neovascular morphology parameters from a sequence of dynamic contrast-enhanced ultrasound (DCE-US) images. After normalization and tumor segmentation, a global time–intensity curve describing contrast agent flow was analyzed to derive surrogate measures of tumor perfusion (i.e., peak intensity, time-to-peak intensity, area under the curve, wash-in rate, wash-out rate). A maximum intensity image was generated from these same segmented image sequences, and each vascular component was skeletonized via a thinning algorithm. This skeletonized data set and collection of vessel segments were then investigated to extract parameters related to the neovascular network and physical architecture (i.e., vessel-to-tissue ratio, number of bifurcations, vessel count, average vessel length and tortuosity). An efficient computation of local perfusion parameters was also introduced and operated by averaging time–intensity curve data over each individual neovascular segment. Each skeletonized neovascular segment was then color-coded by these local measures to produce a parametric map detailing spatial properties of tumor perfusion. Longitudinal DCE-US image data sets were collected in six patients diagnosed with invasive breast cancer using a Philips iU22 ultrasound system equipped with a L9-3 transducer and Definity contrast agent. Patients were imaged using US before and after contrast agent dosing at baseline and again at weeks 6, 12, 18 and 24 after treatment started. Preliminary clinical results suggested that breast tumor response to neoadjuvant chemotherapy may be associated with temporal and spatial changes in DCE-US-derived parametric measures of tumor perfusion. Moreover, changes in neovascular morphology parametric measures may also help identify any breast tumor response (or lack thereof) to systemic treatment. Breast cancer management from early detection to therapeutic monitoring is currently undergoing profound changes. Novel imaging techniques that are sensitive to the unique biological conditions of each individual tumor represent valuable tools in the pursuit of personalized medicine.

Combined measurement of tumor perfusion and glucose metabolism for improved tumor characterization in advanced cervical carcinoma

The aim of this pilot study was (1) to evaluate the combination of [(18)F]fluorodeoxyglucose (FDG) and [(15)O]water for detection of flow-metabolism mismatch in advanced cervical carcinomas, i.e., increased glycolysis at low blood flow, as a possible parameter for prediction of response to treatment, and (2) to propose a method for automated quantification of its spatial extent. The study retrospectively included 10women with advanced cervical carcinoma in whom PET with both FDG and [(15)O]water had been performed prior to therapy. The metabolically active tumor volume was delineated automatically in the FDG images. For computation of the regional blood flow in the tumor, a recovery corrected image-derived arterial input function was used. A tumor voxel was classified as mismatched when the voxel SUV of FDG was larger than the median tumor SUV and the voxel perfusion (K1) was smaller than the median perfusion. The absolute mismatch volume (aMMV) was defined as the volume of all mismatched voxels in ml, and the relative mismatch volume (rMMV) as the ratio of the aMMV to the metabolic tumor volume in percent. The tumors were quite heterogeneous with respect to both FDG uptake and perfusion. The aMMV clustered into 2 groups: "large aMMV" ≥ 10ml in 40 % of patients and "small aMMV" ≤ 5ml in 60 % of patients. The rMMV ranged from 12.7-24.9 %. There was no correlation between rMMV and metabolic tumor volume. There was a tendency (p = 0.126) for an association between rMMV and histological grading, rMMV being about 20 % higher in G3 than in G2 tumors. rMMV did not correlate with SUV or perfusion. These results suggest that combined PET with FDG and [(15)O]water allows detection and quantitative characterization of flow-metabolism mismatch in advanced cervical carcinomas.

Tumor perfusion imaging predicts the intra-tumoral accumulation of liposomes

Liposomes have proven to be a viable drug delivery strategy resulting in significant increases in tumor accumulation of drugs via exploitation of the enhanced permeability and retention (EPR) effect. However, significant variability has been observed in their bulk tumor accumulation and intra-tumoral distribution. The heterogeneous accumulation of liposomes in solid tumors is largely believed to result from the chaotic morphology and physiology of tumor blood vessels. Thus, tumor perfusion imaging may provide a novel method to predict the accumulation and resulting therapeutic effect of liposome formulations. In this study, dynamic contrast enhanced computed tomography (DCE-CT) was employed to quantitatively estimate the intra-tumoral distribution of perfusion and anatomical CT was used to map the spatio-temporal accumulation of a CT-liposome contrast agent. A statistically significant positive correlation was found between quantitative and semi-quantitative measures of tumor perfusion (i.e. Ktrans, vp, and AUCiox) and liposome accumulation (AUClipo and Cpeak) in two mouse xenograft models of human cervical cancer. Specifically, it was found that regions with higher Ktrans,vp, and AUCiox had greater liposome accumulation. These findings demonstrate that DCE-CT measurements of tumor perfusion may be an important technique for selecting patients that are likely to respond to liposome and potentially other nanoparticle-based therapies.

The Potential of PET/MRI Imaging in Oncology: a Comment to a Summary Report of the First PET/MRI Workshop in Tuebingen in 2012

The Potential of PET/MRI Imaging in Oncology: a Comment to a Summary Report of the First PET/MRI Workshop in Tuebingen in 2012

Early Detection of Tumor Response Using 4D DCE-CT and DCE-MRI in Patients Treated With Radiosurgery for Brain Metastases

Early change in tumor perfusion following radiosurgery (RS) is a potential biomarker of response. But measurement of tumor perfusion using dynamic contrast enhanced (DCE) MRI has limitations in accuracy and precision, and DCE-CT is a standard for tracer-kinetic validation. A recent 4D temporal dynamic segmentation (TDS) method, which enables voxel-based, parametric analysis based on patient-specific dynamic behavior of contrast flow, might improve DCE-MRI analysis but its performance must be tested against DCE-CT.

Advanced Hepatocellular Carcinoma: Early evaluation of response to targeted therapy and prognostic value of Perfusion CT and Dynamic Contrast Enhanced-Ultrasound. Preliminary results

PurposeTo investigate whether there is any correlation between standard endpoints and tumor perfusion measurements with Perfusion CT and Dynamic Contrast-Enhanced Ultrasonography (DCE-US) in patients with advanced Hepatocellular Carcinoma (HCC) treated with targeted therapy. Materials and methodsNineteen patients were evaluated during targeted therapy (sorafenib n=16, sunitinib n=3). Changes in tumor perfusion measurements between baseline and month 1 were assessed and compared using RECIST progression criteria at month 2. ResultsMedian time to progression according to RECIST was 117 days and median time to death was 208 days. Perfusion CT values before treatment were significantly increased in HCC compared to the surrounding liver (n=17, P<.02). Eleven patients received complete examinations with both techniques at baseline and month 1. A non-significant decrease was found in all Perfusion CT values between RECIST nonprogressors (n=7) and progressors (n=4): mean Blood Volume: −27.9 vs. −11.1% and mean Blood Flow: −25.0 vs. −11.7% respectively. With DCE-US, opposite changes were found (mean Area Under the Curve AUC: −38.3 vs. 436.3%). RECIST progression at month 2 was significantly correlated with a threshold 40% decrease in AUC (P=.015). None of the patients with a decrease in AUC≥40% was a progressor at month 2. ConclusionDespite perfusion changes with both Perfusion CT and DCE-US in patients receiving treatment, only DCE-US at month 1 (with a decrease in the AUC of more than 40%) predicted non-progression at month 2 and may be a potential surrogate marker of tumor response during targeted therapy.

Hyperpolarized 13C Spectroscopy Detects Early Changes in Tumor Vasculature and Metabolism after VEGF Neutralization

No clinically validated biomarkers exist to image tumor responses to antiangiogenic therapy. Here, we report the utility of hyperpolarized (13)C magnetic resonance spectroscopy (MRS) to detect the early effects of anti-VEGF therapy. In two colorectal cancer xenograft models, displaying differential sensitivity to VEGF blockade, we compared hyperpolarized MRS with measurements of tumor perfusion using dynamic contrast agent-enhanced (DCE)-MRI and tumor cellularity using diffusion-weighted MRI of the apparent diffusion coefficient (ADC) of tissue water. In tumors sensitive to anti-VEGF therapy, (13)C flux between hyperpolarized [1-(13)C]pyruvate and [1-(13)C]lactate decreased after anti-VEGF therapy and correlated with reduced perfusion. Production of [1,4-(13)C(2)]malate from hyperpolarized [1,4-(13)C(2)]fumarate increased in parallel with tumor cell necrosis, preceding any change in tumor ADC. In contrast, tumors that were less sensitive to anti-VEGF therapy showed an increase in (13)C flux from hyperpolarized [1-(13)C]pyruvate and an increase in uptake of a gadolinium contrast agent, whereas tumor ADC decreased. Increased label flux could be explained by vascular normalization after VEGF blockade, increasing delivery of hyperpolarized [1-(13)C]pyruvate as observed. Despite the minimal response of these tumors to treatment, with only a minor increase in necrosis observed histologically, production of [1,4-(13)C(2)]malate from hyperpolarized [1,4-(13)C(2)]fumarate in therapy-resistant tumors also increased. Together, our findings show that hyperpolarized (13)C MRS detects early responses to anti-VEGF therapy, including vascular normalization or vascular destruction and cell death.

Perfusion MRI for Monitoring the Effect of Sorafenib on Experimental Prostate Carcinoma: A Validation Study

The purpose of this study was to investigate with immunohistochemical validation whether dynamic contrast-enhanced MRI with small-molecule contrast medium is useful for monitoring the effects of the multikinase inhibitor sorafenib on prostate carcinomas in rats. Copenhagen rats (n = 20) into which prostate carcinoma (MAT-Ly-Lu-B2) had been implanted subcutaneously were imaged on the day of implantation and 7 days later with 3-T dynamic gadobutrol-enhanced MRI. The therapy group (n = 10) received daily administration of 10 mg/kg body weight sorafenib. Quantitative measurements of tumor perfusion, tumor vascularity, and permeability-surface area product were calculated with a two-compartment model. Dynamic contrast-enhanced MRI values were correlated with immunohistochemical results for validation. Tumor perfusion in sorafenib-treated prostate carcinoma declined significantly from day 0 to day 7 (47.9 ± 36.8 mL/100 mL/min to 24.4 ± 18.6 mL/100 mL/min; p < 0.05). No significant effect on permeability-surface area product was observed in either the therapy or the control group (p > 0.05). Tumor vascularity decreased significantly (p < 0.05) from day 0 to day 7 under sorafenib treatment (15.6% ± 11.4% to 5.4% ± 2.1%). Immunohistochemical analysis revealed significantly lower tumor vascularity in the therapy than in the control group (rat endothelial cell antigen 1, 74.4 ± 16.9 cells vs 197 ± 75.4 cells; p < 0.05). In sorafenib-treated tumors, significantly more apoptotic cells (terminal deoxynucleotidyl transferase-mediated nick end labeling, 6923 ± 3761 vs 3167 ± 1500; p < 0.05) and significantly fewer proliferating cells (Ki-67, 10,198 ± 3064 vs 15,003 ± 3674; p < 0.05) were observed than in the control group. Modest but significant correlations were observed between tumor perfusion and immunohistochemical tumor cell apoptosis (r = -0.56; p < 0.05) and between tumor perfusion and immunohistochemical tumor vascularity (r = 0.56; p < 0.05). Tumor perfusion quantified with gadobutrol-enhanced dynamic contrast-enhanced MRI can be used as a noninvasive surrogate parameter for monitoring the antiangiogenic, antiproliferative, and proapoptotic effects of sorafenib on prostate carcinoma allografts as validated with immunohistochemical analysis.

Prediction of Locoregional Control in Head and Neck Squamous Cell Carcinoma with Serial CT Perfusion during Radiotherapy

Tumor hypoxia is a known factor of radioresistance in HNSCC. CTP is a noninvasive method of measuring tumor perfusion in vivo. The purpose of our study was to determine serial changes in tumor perfusion in HNSCC during a course of RT by using CTP and to correlate tumor perfusion measurements to LRC. A prospective study was performed in 15 patients with HNSCC receiving definitive RT who underwent serial CTP before RT; at weeks 2, 4, and 6 of RT; and 6 weeks after RT. The median follow-up was 28 months (range, 6-44 months). Thirteen patients achieved LRC, and 2 patients had LRF. Tumor perfusion parameters, including BF, BV, MTT, and CP, were obtained by using a deconvolution-based analysis. Pretreatment tumor BF was significantly higher in patients who achieved LRC, 118.0 mL/100 g/min, compared with those with LRF, 53.4 mL/100 g/min (P = .004). Similarly, pretreatment CP was higher in patients with LRC, 16.6 mL/100 g/min, compared with those with LRF, 7.7 mL/100 g/min (P = .02). At week 2 of RT, tumor BF parameters showed a 27.5% increase versus an 18.1% decrease from pretreatment BF values (P = .046) in patients with LRC and LRF, respectively. A decrease in BF and BV was observed in both groups 6 weeks after RT compared with these values at baseline scanning. An increase in tumor BF and CP by using CTP early during a course of RT predicts LRC in patients with HNSCC treated with RT.

Current molecular imaging of spinal tumors in clinical practice.

Energy metabolism measurements in spinal cord tumors, as well as in osseous spinal tumors/metastasis in vivo, are rarely performed only with molecular imaging (MI) by positron emission tomography (PET). This imaging modality developed from a small number of basic clinical science investigations followed by subsequent work that influenced and enhanced the research of others. Apart from precise anatomical localization by coregistration of morphological imaging and quantification, the most intriguing advantage of this imaging is the opportunity to investigate the time course (dynamics) of disease-specific molecular events in the intact organism. Most importantly, MI represents one of the key technologies in translational molecular neuroscience research, helping to develop experimental protocols that may later be applied to human patients. PET may help monitor a patient at the vertebral level after surgery and during adjuvant treatment for recurrent or progressive disease. Common clinical indications for MI of primary or secondary CNS spinal tumors are: (i) tumor diagnosis, (ii) identification of the metabolically active tumor compartments (differentiation of viable tumor tissue from necrosis) and (iii) prediction of treatment response by measurement of tumor perfusion or ischemia. While spinal PET has been used under specific circumstances, a question remains as to whether the magnitude of biochemical alterations observed by MI in CNS tumors in general (specifically spinal tumors) can reveal any prognostic value with respect to survival. MI may be able to better identify early disease and to differentiate benign from malignant lesions than more traditional methods. Moreover, an adequate identification of treatment effectiveness may influence patient management. MI probes could be developed to image the function of targets without disturbing them or as treatment to modify the target's function. MI therefore closes the gap between in vitro and in vivo integrative biology of disease. At the spinal level, MI may help to detect progression or recurrence of metastatic disease after surgical treatment. In cases of nonsurgical treatments such as chemo-, hormone- or radiotherapy, it may better assess biological efficiency than conventional imaging modalities coupled with blood tumor markers. In fact, PET provides a unique possibility to correlate topography and specific metabolic activity, but it requires additional clinical and experimental experience and research to find new indications for primary or secondary spinal tumors.

Tumor Blood Volume Determination by Using Susceptibility-corrected ΔR2* Multiecho MR

To evaluate a susceptibility-corrected multiecho magnetic resonance (MR) relaxometry technique for an accurate and robust determination of DeltaR2* as a noninvasive surrogate parameter of the perfused tumor blood volume. All experiments were approved by the institutional animal care committee. In a glass tube phantom with different superparamagnetic iron oxide (SPIO) particle concentrations and at tumor mice xenografts with DU-4475, HT-1080, and MDA-MB-435 tumors (n = 15 total, n = 5 per model) with different degrees of neovascularization after injection of different ultrasmall SPIO (USPIO) doses changes of the transverse relaxation rate (DeltaR2*) were determined by using a fixed echo time (TE) of 22 msec and a susceptibility-corrected multigradient-echo technique. The mean DeltaR2* value and the vascular volume fraction (VVF) of each tumor was determined and compared with independent in vivo fluorescent tumor perfusion measurements and histologic analysis helped determine microvessel density (MVD). Statistical differences were tested by using analysis of variance and linear correlations. For the phantom study, DeltaR2* maps calculated with a fixed TE of 22 msec showed a higher standard deviation of the noise index compared with the susceptibility-corrected multiecho technique. For the xenograft model, mean tumor DeltaR2* values (+/- standard error of the mean) showed significant differences between the various tumors (eg, DU-4475: 12.3 sec(-1) +/- 2.67, HT-1080: 36.47 sec(-1) +/- 5.84, and MDA-MB-435: 64.01 sec(-1) +/- 8.87 at 80 mumol of iron per kilogram; P < .05). DeltaR2* values increased dose dependently and in a linear fashion, resulting in reproducibly stable VVF measurements. Fluorescent tumor perfusion measurements and MVD counts corroborated the MR results. Susceptibility-corrected multiecho MR relaxometry allows a highly accurate and robust determination of DeltaR2* and VVF with an excellent dynamic range for tumor characterization at clinically relevant doses of USPIO.

Applications of Computed Tomography Angiography (CTA) in Neuroimaging

A novel image processing strategy is detailed for simultaneous measurement of tumor perfusion and neovascular morphology parameters from a sequence of dynamic contrast-enhanced ultrasound (DCE-US) images. After normalization and tumor segmentation, a global time–intensity curve describing contrast agent flow was analyzed to derive surrogate measures of tumor perfusion (i.e., peak intensity, time-to-peak intensity, area under the curve, wash-in rate, wash-out rate). A maximum intensity image was generated from these same segmented image sequences, and each vascular component was skeletonized via a thinning algorithm. This skeletonized data set and collection of vessel segments were then investigated to extract parameters related to the neovascular network and physical architecture (i.e., vessel-to-tissue ratio, number of bifurcations, vessel count, average vessel length and tortuosity). An efficient computation of local perfusion parameters was also introduced and operated by averaging time–intensity curve data over each individual neovascular segment. Each skeletonized neovascular segment was then color-coded by these local measures to produce a parametric map detailing spatial properties of tumor perfusion. Longitudinal DCE-US image data sets were collected in six patients diagnosed with invasive breast cancer using a Philips iU22 ultrasound system equipped with a L9-3 transducer and Definity contrast agent. Patients were imaged using US before and after contrast agent dosing at baseline and again at weeks 6, 12, 18 and 24 after treatment started. Preliminary clinical results suggested that breast tumor response to neoadjuvant chemotherapy may be associated with temporal and spatial changes in DCE-US-derived parametric measures of tumor perfusion. Moreover, changes in neovascular morphology parametric measures may also help identify any breast tumor response (or lack thereof) to systemic treatment. Breast cancer management from early detection to therapeutic monitoring is currently undergoing profound changes. Novel imaging techniques that are sensitive to the unique biological conditions of each individual tumor represent valuable tools in the pursuit of personalized medicine.

Magnetic resonance imaging as a biomarker in renal cell carcinoma

The ability to noninvasively discriminate the most common types of renal cell carcinoma (RCC) based on their magnetic resonance imaging (MRI) appearances or their magnetic resonance phenotypes is achievable. Intracellular lipids, a histologic characteristic of the clear cell RCC, can be identified on chemical shift MRI. Intratumoral hemosiderin deposition, as observed histologically with papillary RCC, correlates to the low signal intensity on T2-weighted images. In addition to morphologic imaging features, the different subtypes of RCC have distinct patterns of enhancement on dynamic contrast-enhanced MRI. Clear cell tumors demonstrate much greater enhancement than papillary and chromophobe RCCs during the corticomedullary and nephrographic phases. The MRI technique arterial spin labeling (ASL) uses magnetic fields to label the water protons in arterial blood and measures blood flow into tissue; quantitative images of blood flow can be generated without exogenous contrast media. Multiple measurements of tumor perfusion may be repeated before and after a physiologic or drug challenge (ie, antiangiogenic therapy). In RCC xenografts and in patients with metastatic RCC, ASL MRI assessments can be used to monitor blood flow changes in response to antiangiogenic therapies. High blood flow on ASL MRI in RCC xenografts correlates with viable tumor at histopathologic analysis, whereas zones of absent or diminished signal correspond to necrosis. ASL MRI has the potential to serve as a biomarker for patients with metastatic RCC by offering a noninvasive measure of tumor blood flow changes accompanying antiangiogenic therapy.