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Clinical applications of iron oxide nanoparticles for magnetic resonance imaging of brain tumors

Current neuroimaging provides detailed anatomic and functional evaluation of brain tumors, allowing for improved diagnostic and prognostic capabilities. Some challenges persist even with today’s advanced imaging techniques, including accurate delineation of tumor margins and distinguishing treatment effects from residual or recurrent tumor. Ultrasmall superparamagnetic iron oxide nanoparticles are an emerging tool that can add clinically useful information due to their distinct physiochemical features and biodistribution, while having a good safety profile. Nanoparticles can be used as a platform for theranostic drugs, which have shown great promise for the treatment of CNS malignancies. This review will provide an overview of clinical ultrasmall superparamagnetic iron oxides and how they can be applied to the diagnostic and therapeutic neuro-oncologic setting. Keywords: brain tumor • ferucarbotran • ferumoxtran • ferumoxytol • macrophage • MRI • ultrasmall superparamagnetic iron oxide nanoparticles

Neuroimaging plays an important role in patients with brain tumors. It provides for detailed anatomic evaluation of intracranial neoplasms for surgical localization and intervention, and it allows for biological and physiological characterization of these lesions to diagnose, prognosticate, assess treatment effects and monitor therapeutic responses. Several MRI techniques have been employed to acquire such information including imaging with gadolinium-based contrast agents, perfusion-weighted imaging, diffusionweighted imaging and proton magnetic resonance (MR) spectroscopy [1–10] . However, some challenges remain with current imaging that can impact survival and quality of life in patients with brain cancer. These challenges include the abilities to precisely delineate tumor margins for surgical resection (as tumor cells can often be found outside areas of enhancement or nonenhancing T2 signal abnormality); to differentiate benign postoperative changes (such as blood products and enhancement) from potential residual tumor following surgery; and to distinguish

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between treatment effects that arise from chemoradiation and true disease progression [11–17] . This article provides an overview of current clinical applications of ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles for use in MRI of brain tumors. We begin by introducing the physiochemical, biodistribution and safety profiles of these agents and then discuss their diagnostic capabilities in detecting and characterizing tumor, imaging treatment effects and monitoring response to therapy. Within this context, we review the preclinical and clinical data present in the literature. Finally, we highlight key therapeutic uses of iron oxide nanoparticles in the management of central nervous system neoplasms including delivery of drugs and monitoring stem cell therapies.

Michael Iv*,1, Nicholas Telischak1, Dan Feng2, Samantha J Holdsworth3, Kristen W Yeom2 & Heike E Daldrup-Link2 Department of Radiology, Stanford University & Stanford University Medical Center, Stanford, CA 94305, USA 2 Pediatric Radiology Section, Department of Radiology, Lucile Packard Children’s Hospital, Stanford University, Stanford, CA 94305, USA 3 Department of Radiology, Lucas Center, Stanford University, Stanford, CA 94305, USA *Author for correspondence: Tel.: +1 650 725 5384 Fax: +1 650 498 5374 miv@ stanford.edu 1

Iron oxide nanoparticles Iron oxide nanoparticles currently used in the clinical arena are classified into two groups based on their mean hydrodynamic particle size: superparamagnetic iron oxide (SPIO)

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Review Iv, Telischak, Feng, Holdsworth, Yeom & Daldrup-Link and ultrasmall superparamagnetic iron oxide (USPIO) particles. SPIOs have a mean particle diameter greater than 50 nm, whereas USPIOs have a mean diameter of less than 50 nm [18] . Due largely in part to their smaller size and longer blood half-life, USPIOs are better suited for neuro-oncologic imaging [19] and are the focus of this review. USPIO particle design is similar between available formulations but key differences exist in the nature of the coating, particle size and particle charge. As a class, USPIOs are characterized by high longitudinal (r1 = 1/T1) and transverse (r2 = 1/T2) relaxivities. These ‘T1- and T2-reducing’ agents can be used to represent the degree of contrast agent uptake within a tissue [20–22] . Higher relaxivity agents allow for improved quality of imaging and lesion depiction [22,23] . There are currently three USPIOs that are undergoing clinical evaluation as a MR contrast agent: ferumoxtran-10, ferumoxytol and ferucarbotran C [21,24–26] . Table 1 summarizes the physiochemical features of these USPIOs, none of which is approved for therapeutic or diagnostic use in children. Ferumoxtran-10 (Sinerem™; Guerbet, Paris, France and Combidex™, AMI-227; Advanced Magnetics, MA, USA) is a first-generation USPIO that has to be administered as a slow infusion in order to avoid hypotensive side effects. It has the longest blood half-life of the three USPIOs. The agent has been used in Phase I to Phase III clinical trials, primarily for lymph node imaging [27–30] , but did not achieve US FDA approval due to inconclusive impact on patient management and was discontinued by the pharmaceutical industry. Recently, ferumoxtran-10 has been re-introduced to clinical trials in Europe. Ferumoxytol (Feraheme™, AMI-7228, Advanced Magnetics) is a second-generation USPIO with a carboxymethyl dextran coating that allows for administration as a bolus without mast cell degranulation [31] . Of the three USPIOs, ferumoxytol has the fastest r1 and r2 relaxivity, allowing for improved lesion detection compared with the other agents. On 30 June 2009, the US FDA approved ferumoxytol for the treatment of iron deficiency anemia in adults with chronic kidney disease [32] . More recently, the agent was also approved for anemia treatment in Canada and several countries in Europe. Thus, ferumoxytol has the advantage of being immediately and widely available for clinical imaging of inflammation and tumors through utilization as an ‘off label’ agent. Ferucarbotran C (Supravist™, SHU 555 C, Schering AG) is a carboxy-dextran-coated USPIO and has the smallest hydrodynamic diameter of the three USPIOs. This agent has been approved for clinical use in Europe, but was recently discontinued by the pharmaceutical industry.

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Biodistribution & metabolism After intravenous injection, USPIO nanoparticles circulate in the lumen of blood vessels (vascular phase), transiently escaping sequestration and phagocytosis by macrophages of the reticuloendothelial system (RES), which is comprised of the liver, spleen, lymph nodes and bone marrow (Figure 1) . This phenomenon leads to a prolonged blood half-life compared with the larger SPIO. USPIOs do not extravasate across intact vascular endothelia into the interstitial space because of their relatively large size [24,26,33] . As such, USPIOs (particularly ferumoxytol due to its ability to be administered as a bolus) can serve as good vascular blood pool agents during the first-pass (arterial) and equilibrium (delayed) phases of imaging (Figure 2) [34–38] . In tumors or other tissues with increased microvascular permeability, the nanoparticles gradually cross a disrupted blood–tissue barrier and enter the interstitium (‘interstitial phase’), where they exert T1 and T2 signal effects on MR [24,26,33] . The positive T1 signal effect (increased signal intensity on T1) is dependent on the quantity of protons and their degree of interaction with USPIOs [24,39–41] . Therefore, T1-effects are more pronounced for interstitial compared with intracellular iron. On the other hand, the negative T2 and T2* signal effect (decreased signal intensity on T2- and T2*-weighted MR images) is less dependent on iron oxide compartmentalization (Figure 3) [42] . While the exact route of transport of USPIOs across an altered blood–brain barrier has not yet been fully elucidated, proposed mechanisms that may help to explain increased vascular permeability in tumors include presence of endothelial fenestrations and/or interendothelial junctions and increased transport of particles via a single vesicle or chain of vesicles through endothelial cells [43–47] . Moreover, the rate of USPIO leakage across the blood–brain barrier also depends on the histologic type of tumor; for example, Beaumont et al. observed that during a specific time frame, ferumoxtran-10 remained intravascular in a rat C6 glioma model but extravasated in a RG2 glioma model [48] . Several hours to days after USPIO administration, nanoparticles are slowly phagocytosed by macrophages in the tumor interstitium (‘cellular phase’) [33] . Iron oxides in macrophages cause a predominant T2 and T2* effect but have a markedly diminished T1-effect compared with that of the interstitial phase [39,49] . Some residual ‘free’ iron oxide particles in the interstitium diffuse back into the blood pool once their interstitial concentration exceeds their blood concentration. Other ‘free’ iron oxides may be retained in necrotic tumor areas resulting in a marked T1-effect, which may help to dif-

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60‡ 24‡ 6h 35 min 20 At 0.47T and 39°C. At 0.47T and 40°C. Data taken from [21,24,25,26]. ‡

Carboxy-dextran Ferucarbotran C (Supravist™; Schering AG, Berlin, Germany) SHU 555 C

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10–14 h 67 min 28–32 6.4–7.2 Carboxy-dextran Ferumoxytol (Feraheme™; Advanced Magnetics) AMI7228

Dextran T-10 Ferumoxtran-10 (Sinerem™; Guerbert, Paris, France; Combidex™; Advanced Magnetics, MA, USA) AMI-227

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Blood Blood half-life in half-life in rodents humans Hydrodynamic size (nm) Size of crystal core (nm) Coating Name

Safety Since the development of the first USPIO over two decades ago, USPIOs have been tested and used as a MR contrast agent in thousands of patients [50] . They are generally well-tolerated when used in single dose. Bernd et al. examined 37 Phase I to Phase III clinical trials for ferumoxtran-10 in 1777 adults. A total of 23.2% of all patients had at least one adverse event, 86.3% of which were graded as mild to moderate in severity. Common adverse events included back pain, pruritus, headache and urticaria. About 2.6% of the patients developed severe adverse events, although only 0.42% of these events were considered to be treatmentrelated (e.g., decreased oxygen saturation, chest pain, dyspnea and skin rash). There were 12 deaths, but only one was attributed to ferumoxtran-10 (anaphylactic shock) [55] . These findings are consistent with a previous Phase III trial in 152 adults, in which 28% of all patients had one or more adverse effects [28] . Other USPIOs have similar safety profiles. A Phase II clinical trial showed that 22% of 63 subjects receiving feruglose (Clariscan™, Amersham Health, UK) developed mild-to-moderate adverse events, and no subject developed serious adverse effects [56] . Ferucarbotran C was also well tolerated in all subjects in a Phase I clinical trial [57,58] . While most USPIOs have only been tested as contrast agents using a single dose, ferumoxytol showed a satisfactory safety profile in adult patients with

Table 1. Physiochemical features of ultrasmall superparamagnetic iron oxide nanoparticles.†

ferentiate these necrotic areas from intracellular iron oxides [Golovko et al., Unpublished Data] . Following phagocytosis, intracellular nanoparticles in macrophages are slowly metabolized and cleared by the RES with biodegradation predominantly occurring within lysosomes [33,50–53] . Elemental iron (ferritin) contained within the nanoparticles is incorporated into the body’s iron stores or is transferred to plasma transferrin for incorporation into hemoglobin within red blood cells. The dextran coat of ferumoxtran-10 is cleaved by intracellular dextranases and excreted almost exclusively through the kidneys. The small remainder is excreted in feces [21,54] . The carboxymethyl dextran coating of ferumoxytol is negligibly degraded by dextranases when it is used to treat anemia, and the amount of low molecular weight dextrans actually released from the coating and retained in the kidneys is probably quite low although this has not yet been well defined [Claire Corot & Jean-Marc Idee, Pers. Comm.] . Due to this overall slow metabolic process, MR signal intensities of RES tissues gradually return to baseline after several weeks [33] . There is currently no data available that reports how long USPIOs are retained in tumors.

r1 relaxivity r2 (mM -1s-1) relaxivity (mM -1s-1)

Iron oxides for neuro-oncology

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Figure 1. Biodistribution of ultrasmall superparamagnetic iron oxide nanoparticles. Ultrasmall superparamagnetic iron oxides (USPIOs) distribute and remain in the intravascular space early after injection (vascular phase). Tumors that cause increased permeability allow for slow leakage of these particles into the interstitial space (interstitial phase). An intact blood–brain barrier shields USPIOs from entering the interstitium of normal brain tissue. Over time, USPIOs are progressively phagocytosed by cellular agents such as tumor-associated macrophages/microglia, astrocytes (not shown) and, to a lesser extent, primary tumor cells (cellular phase). The blood–brain barrier is depicted in a simplified form for illustration purposes.

chronic kidney disease when used in a two-dose regime [32] . An FDA report following its approval as an iron supplement showed that out of 1726 subjects recruited in three randomized clinical trials, 3.7% of patients developed adverse events associated with hypersensitivity (e.g., rash, urticaria, pruritus, wheezing) and only 0.2% developed serious hypersensitivity reactions (anaphylaxis). Although hypotension is another concerning side effect with iron oxide use, it only occurred in 1.9% of all subjects. It is more common with rapid bolus injections and can be alleviated or avoided with slow injections. Other common but less-severe adverse events (observed in greater than 1% of subjects) included nausea, dizziness, peripheral

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edema, headache, edema, vomiting, abdominal pain, chest pain, cough, pyrexia, back pain, muscle spasm and dyspnea [32] . The rates of adverse reactions observed with USPIOs are similar to but slightly higher than those seen with gadolinium-based contrast agents. For the latter, the frequency of all acute adverse events after administration ranges from less than 1 to 2.4%, the vast majority of which are mild in severity [59–61] . Individuals with a history of allergy or asthma or previous reaction to gadolinium had increased adverse reaction rates: 3.7 and 21.3%, respectively [60] . Severe anaphylactoid reactions, on the other hand, are extremely rare occurring in only 0.001–0.01% of cases [59] . In an accumu-



lated series of 20 million administered doses of a gadolinium chelate, there were 55 cases (72 h. GBM: Glioblastoma multiforme. Reproduced with permission from [31] .

sity of iron stained cells following MION administration was at the periphery of glioma xenografts, which correlated with the area of highest microvascular density. Since vascularization in most human gliomas is different, animal models are needed that better reflect human tumor physiology. However, the authors did make an important observation: iron oxide nanoparticle delivery to the tumor center could be significantly increased after bradykinin infusion, which increases permeability of the brain tumor barrier [80] . This intervention could be used for improved delivery of theranostic nanoparticles to tumors with limited tumor microvascular permeability. In comparison to animal and cell-culture models, clinical studies of human brain tumors evaluated with USPIO-enhanced imaging also suggest that USPIOs undergo intravascular and tumor interstitium uptake as well as subsequent intracellular compartmentalization. However, these studies have some variation in imaging and histologic


results when compared with the preclinical studies, in large part due to the heterogeneous population of brain tumors included in the studies [19,73–77,91,92] . Dosa et al. showed that T1 enhancement was seen in all 26 patients with benign (n = 3, comprised of two meningiomas and one pituitary adenoma) and malignant (n = 23, comprised of 19 primary gliomas, one angiocentric T-cell lymphoma and three secondary metastasis) tumors 24 h post-ferumoxytol injection, while T2 hypointensity was detected in only 16 patients 24 h after administration [91] . The authors did note that they observed minimal to no signal intensity changes at the tumor margin of the benign lesions although they did not further elaborate. A possible explanation for the lack of T2 signal seen in some of the masses may have been due to the relatively lower concentration of ferumoxytol used (17 ml or 510 mg diluted with 17 ml of saline regardless of body weight), which may not have been concentrated enough to produce distinct T2 signal


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Review Iv, Telischak, Feng, Holdsworth, Yeom & Daldrup-Link effects. In addition, six patients had enhancement on T1- and hypointensity on T2-weighted images 24 h post-ferumoxytol injection in areas around tumor that did not enhance with gadolinium, perhaps due to intracellular accumulation of iron oxide particles within macrophages. Following ferumoxtran-10 administration in five of seven patients with either anaplastic oligodendroglioma or glioblastoma, Neuwelt et al. also demonstrated areas of T1 enhancement on ferumoxtran-enhanced scans that were not present on the gadolinium-enhanced scans; the enhancement extended beyond the margin of the main tumor seen on the gadolinium images or was seen in new lesions altogether. In one of these patients with a multicentric anaplastic oligodendroglioma, three tumor foci that were identified on post-gadolinium images at five month follow-up had already been apparent on the initial preoperative post-ferumoxtran images, but not on preoperative postgadolinium images [76] . Extensive experience by this author and his group has shown that tumor and its margin are best detected by increased signal on USPIO-enhanced T1-weighted images while T2-weighted images were less sensitive [19,75,76] . In addition, it was noted that T2* images showed a ‘blooming effect’ (an apparent larger volume of tumor than seen on histology) due to magnetic susceptibility artifact induced by the iron oxide nanoparticles [75] . The appearance of brain metastasis often differs in morphology from that of a malignant glioma on imaging. The degree of enhancement observed within a lesion depends on the histologic type of tumor amongst other factors that can change the permeability of the blood–brain barrier such as abnormal vascularity or drug or radiation treatment [75] . Muldoon et al. observed that postferumoxtran enhancement was different in three intracerebral tumor models in rats (U87 glioblastoma, LX-1 SCLC [small-cell lung carcinoma] and CALU6 SCLC [a second SCLC tumor model]). Marked central ferumoxtran enhancement was seen with the LX-1 SCLC tumor, which is a rapidly growing tumor, while minimal enhancement was seen with the other two models, which are slower growing tumors [79] . Interestingly, the latter two models did show prominent gadolinium enhancement, suggesting some differential leakiness of the blood–brain barrier or lack of inflammatory activity. Clinical studies have reported on the appearance of metastatic disease in individual human patients following USPIO administration but the results have been variable with enhancement observed in some lesions but not in others [31,73,75–77,91] . Future studies with larger sample size and histologic correlation are needed to fully investigate the effect of USPIO in different metastatic tumors.

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Unlike malignant neoplasms, benign tumors tend to demonstrate minimal or no USPIO enhancement [91] . Varallyay et al. showed only slight to moderate ferumoxtran enhancement of low-grade gliomas, hamartoma, meningioma and pituitary adenoma as opposed to more prominent gadolinium enhancement observed with these lesions. This difference may be due to easier passage of smaller gadolinium molecules through an incompetent blood–brain barrier as opposed to larger USPIO molecules as well as a relative paucity of phagocytic cells capable of accumulating the iron oxide particles [19] . Mixed results were observed in a study of five patients with primary central nervous system lymphoma who were given ferumoxtran-10 [92] . Only one of the five subjects had more pronounced T1 and T2 signal changes post USPIO. In addition, Murillo et al. found variable enhancement in nonglial tumors with a tendency for more aggressive tumors such as lymphoma, metastasis and primitive neuroectodermal tumors to enhance more intensely after ferumoxtran-10 administration than with gadolinium (seen in five out of 22 patients) [75] . This may again relate to the degree of blood–brain barrier disruption. On the contrary, malignant glial neoplasms are more infiltrative and proliferative; they disrupt the blood–brain barrier, promote neoangiogenesis and recruit phagocytic inflammatory cells to the local environment, biological events that allow for increased signal on USPIO-enhanced images. TAM in malignant gliomas have been associated with tumor aggressiveness and tumor grade [88] . The vast majority of histochemistry studies performed in humans have overwhelmingly shown iron oxide accumulation within peritumoral and intratumoral reactive cells (macrophages/microglia and astrocytes), located primarily at the tumor margin, with minimal or no uptake within tumor cells [19,74–77] . Many of these studies only used cellular morphology at staining to determine specific cell types [19,74–76] . One study [77] did use CD68, a marker that is highly expressed on human monocytes and tissue macrophages [93] , in two patients with malignant brain tumors (anaplastic ependymoma and glioblastoma multiforme) to show iron deposits located in TAM while none was found in tumor cells nor in tumor interstitium. Therefore, ferumoxytol enhancement in human tumors can serve as a biomarker for TAM. Further studies in patients are needed to confirm evidence from preclinical studies that TAM enhancement correlates with tumor aggressiveness and prognosis. One early study, however, did show iron deposits within viable tumor cells and tumor interstitium in a patient with recurrent grade III/IV mixed cell glioma [73] , although it is unclear how tumor



cells were identified or if there was any assessment for the presence of TAM. The use of USPIOs in brain tumor imaging may offer additional advantages over routine imaging with gadolinium. First, due to its longer half-life, larger size and decreased diffusion coefficient, USPIOs can cause persistent tumor enhancement over several days thereby bypassing the need for additional contrast administration on short-term follow-up imaging. Gadolinium enhancement, on the other hand, peaks within minutes and resolves within hours leading to progressive blurring of tumor margins [73,74,76] . The prolonged ferumoxytol-tumor enhancement could be utilized to guide surgeries with intraoperative MR exams. The ability to accurately differentiate postsurgical changes following resection from residual tumor is yet another problem not entirely solved with today’s standard imaging. In general, an area of gadolinium enhancement that remains after resection of a tumor in the early postoperative period (during the first four days after surgery) is worrisome for residual tumor [16] . However, ‘benign’ surgically induced enhancement, possibly a result of blood–brain barrier breakdown and vascular injury, may also occur in the immediate postoperative period and complicates imaging interpretation [71,76] . In a preclinical study by Knauth et al., T1 enhancement with gadolinium was seen in all rat brains following the creation of surgically induced lesions. However, after MION injection, no signal change on T1-weighted imaging was detected in a similar group. This allowed for the detection of residual tumor using USPIO without the confounding presence of early postsurgical enhancement seen with gadolinium [94] . It is important to note, however, that some clinical studies have shown that the application of hemostatic and oxidizing agents (such as Surgicel or H2O2) during surgery can influence the signal of blood products in and around the resection cavity during the early postoperative period, often with resulting prolonged T1 hyperintense and T2 hypointense signal [16,17] . Residual USPIO enhancement may therefore be difficult to differentiate from applied hemostatic agents and subacute hemorrhage (which also appears T1 hyperintense) [76] , and future studies are needed to address this potential problem. Imaging treatment effects & therapy monitoring Dynamic susceptibility-weighted contrast-enhanced (DSC) perfusion MRI is a helpful diagnostic tool in brain tumor imaging and allows for the measurement of tumor angiogenesis, a biomarker that can be used to grade gliomas and assess the prognosis of patients with gliomas [1] . Relative cerebral blood volume (rCBV) is


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the most widely used quantitative parameter derived from perfusion imaging for the assessment of tumor vascular density and proliferation [1,95,96] . High rCBV values are associated with increased tumor vascularity and viable tumor as well as more rapid time to progression of disease [7,95–97] . rCBV has been shown to be helpful in differentiating residual or recurrent tumor from treatment effects due to chemoradiation [97–99] and can be used to monitor tumor response to anti angiogenic therapy [100–102] . Given these features, rCBV may be utilized to determine short- and longterm treatment strategies and to predict patient outcomes. Accurate measurement of tumor rCBV is, therefore, imperative. USPIOs are good blood pool agents on the basis of their long plasma half-life and macromolecular size, qualities that allow for longer circulation time in the intravascular space [21] . This allows for improved visualization of tumor vascularity and blood volume on MR [77,103–105] . In contrast to gadolinium, which is used in routine perfusion imaging, USPIOs do not cross a disrupted blood–brain barrier early after injection (minutes to hours) [31,101] . This is an important quality for a reliable vascular contrast agent as early leakage may result in underestimation of rCBV [101] . Of the USPIOs, ferumoxytol has emerged as a good candidate for perfusion imaging because of its ability to be injected as a bolus [34] . Dosa et al. showed higher rCBV values obtained with ferumoxytol than with gadolinium [91] . Comparable rCBV values were seen following ferumoxytol and gadolinium administration but only after leakage correction techniques were applied to the latter [97] . An alternative approach for obtaining CBV maps is steady-state susceptibility contrast imaging, which is feasible given ferumoxytol’s relatively long half-life and confinement to the intravascular space early after injection. Unlike with DSC imaging, the steady-state technique does not rely on bolus tracking, bolus arrival, or transit times, thereby, avoiding the need to determine arterial input function. Higher spatial resolution and distortion-free images can be obtained with the steady-state approach allowing for improved characterization and localization of malignant tumors associated with elevated cerebral blood volume [106,107] . Residual or recurrent tumor may be differentiated from chemoradiation-induced changes with rCBV measurements [97–99] . Gahramanov et al. evaluated patients with glioblastomas who underwent surgical resection and chemoradiation and had conventional MRI showing apparent tumor progression. With ferumoxytol, patients with areas of suspected tumor showing low rCBV (≤1.75) had significantly improved survival than in those patients with tumors


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Figure 6. Imaging of treatment effects (pseudoprogession) in a 73-year-old man with glioblastoma. Precontrast and gadoteridol-enhanced T1-weighted magnetic resonance images obtained before and 3 months after chemoradiotherapy demonstrate increased mass-like enhancement after treatment, concerning for disease progression. The enhancing area shows no increase in rCBV on perfusion color maps obtained with ferumoxytol (Fe-rCBV), gadoteridol (Gd-rCBV) and gadoteridol with leakage correction (Gd-rCBV LC) indicative of treatment effects (pseudoprogression) rather than true disease progression. The leakage map shows gadoteridol contrast leakage that can confound Gd-enhanced perfusion studies (arrow). No contrast leakage can be seen on the ferumoxytol (Fe) image. CRT: Chemoradiotherapy; rCBV: Relative cerebral blood volume. Reproduced with permission from [97] .

showing high rCBV (>1.75). Low rCBV indicated pseudoprogression (treatment effects), whereas high rCBV indicated viable tumor (Figure 6) . Similar results were seen after gadolinium administration. However, improved survival between the two rCBV groups became statistically significant with gadolinium only after leakage correction techniques were applied [97] . Thompson et al. also found that low rCBV (