MRI

Workflow in Simultaneous PET/MRI Felipe de Galiza Barbosa, MD,* Gustav von Schulthess, MD, PhD,* and Patrick Veit-Haibach, MD*,† The advent of simultaneous PET/MRI brought a large amount of possibilities in research and clinical applications into hybrid imaging. Unlike in PET/CT protocols, the MR component provides an almost unlimited number of pulse sequences and possibilities of different protocols in PET/MRI. Nevertheless, there is an imperative to reduce excessive imaging protocols to realistic clinical practice imaging acquisition. The design of a concise and indication-adapted protocol that provides an efficient workflow in a clinical reality is necessary to transform PET/MRI to a cost-effective imaging modality in addition to PET/CT. The aim of the current article is to point out the main considerations regarding workflow, imaging protocols, and image analysis in simultaneous PET/MRI system in oncology and share our thoughts and experience in acquisition optimization compared with the current literature. Semin Nucl Med 45:332-344 C 2015 Elsevier Inc. All rights reserved.

Introduction

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linically available for approximately 25 years, PET and MRI are modalities that are very well established in clinical practice. The emergence of combined PET/CT was the foundation of the success of hybrid imaging. Consequently, stand-alone PET is no longer used clinically. In parallel, the last decades were also marked by the consolidation of the MRI as an imaging modality of great clinical importance. It is critical to understand that running a dual-modality hybrid system is substantially different from running two separate systems. Although the integration of PET and CT into a hybrid system was challenging but technically feasible, the integration of PET and MRI is much more demanding.1 The main technical challenges were development of PET system that is compatible to high magnetic field normally used in MRI and development

*Department of Nuclear Medicine, University Hospital Zurich, University of Zurich, Zurich, Switzerland. †Department of Diagnostic and Interventional Radiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland. Disclosure: Patrick Veit-Haibach received IIS grants from Bayer Healthcare, Germany; Siemens Medical Solutions, GE Healthcare, UK; and Roche Pharma, and speaker's fees from GE Healthcare. Gustav von Schulthess is a grant recipient from GE Healthcare. No other potential conflict of interest relevant to this article was reported. Address reprint requests to Patrick Veit-Haibach, Department of Medical Radiology, Nuclear Medicine, University Hospital Zurich, Switzerland. E-mail: [email protected]

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http://dx.doi.org/10.1053/j.semnuclmed.2015.03.007 0001-2998/& 2015 Elsevier Inc. All rights reserved.

of a MR scanner that guarantees a stable and homogenous magnetic field that leads to unaltered MR image quality in the presence of PET scintillation crystal detectors.2 The mutual interference of the MR magnetic fields and the PET detectors concerning image quality has been resolved, removing the main technical obstacle to build an integrated hybrid system. However, a second nontechnical challenge is to now migrate PET/MRI from a research tool to a clinical imaging modality. This needs dedicated hybrid imaging concepts and workflow considerations.3,4 Generally, one can differentiate between simultaneous and sequential systems in hybrid imaging.5,6 Sequential imaging systems require a shuttle system that moves patients from one modality to another without changing patient position. SPECT/CT and PET/CT systems are such sequential systems whereby the scanner bed also serves as the shuttle, and two vendors have introduced this approach for PET/MRI.6,7 In simultaneous imaging systems, images from both modalities can be acquired simultaneously without moving the patient. Two manufacturers have introduced such PET/MRI systems and they do not require a shuttle.8,9 Simultaneous systems do not exist with any other hybrid modality. The current article discusses the main issues concerning simultaneous PET/MRI system workflow and some specific imaging applications to help the readers understand the needs and requirements for clinically effective PET/MRI and the differences when compared with PET/CT– and MR–standalone imaging.

Workflow in simultaneous PET/MRI

General Aspects of Workflow in Imaging Whole-Body MRI Whole-body (WB) MRI has been used for approximately 10 years mainly for assessing and screening inflammatory and neoplastic diseases. It has being used both in adults and pediatric patients, being a good radiation-free imaging alternative to conventional imaging, which—together with its unsurpassed soft tissue contrast—is one of the major advantages. WB MRI has similar basic protocols in the literature, with few variations, which includes T1-weighted (T1w) and T2w fat-saturated (usually axially or coronally or both) imaging, the latter one often represented by a short-tau inversion recovery sequence, an excellent pathology-seeking sequence.10-12 Besides this basic protocol, the most frequently used additional sequence is diffusion-weighted imaging (DWI) with two b-values. These three sequences cover most basic WB MRI protocols.10,13 The most relevant protocol variations described in the literature are the addition of dedicated T2w sequences for the chest and liver regions and T1w sequences with contrast media,10,11 both with the aim to improve the detectability of small lesions. Although there are variations in the sequences of the WB MRI protocols, there seems to be a common sense that the study time should not be too long. The average scanning time in the latest literature protocols is 40 minutes, ranging from 3060 minutes.10,11,14,15 This current study time is a little longer than the MR organ imaging protocols (head and neck, thoracic region, abdomen, or pelvis) and seems to be usually tolerated by the patients. However, it is also known that WB protocols are not as sensitive and specific as dedicated organ-specific protocols because compromises on resolution and sequences selection have to be made. Furthermore, preparation and positioning time of the patient on the table takes approximately 10-15 minutes, and this is another important issue concerning workflow in hybrid imaging and not considered in those studies.

PET/CT Despite being a hybrid imaging machine, PET/CT imaging acquisition is split in into two components and is not acquired simultaneously. There exist various PET/CT protocols that are mainly related to the CT component. The most widespread basic CT acquisition is a free-breathing low-dose protocol used for anatomical and attenuation correction (AC) purposes. With current systems, it can be acquired in less than 30 seconds. When more accurate diagnostic information is needed, a standard CT with venous contrast media administration with or without oral contrast media administration is recommended.16 The enhanced CT scan prolongs the protocol by between 1 and 3 minutes, mainly because of the injection time required to achieve an adequately enhanced scanning phase. This latter part of the protocol influences patient preparation and overall workflow because the CT component does not contribute very much to the imaging time itself.

333 The PET data component requires 2-5 minutes per bed position. The number of bed positions depends on the patient's height, and with a standard patient and scanner, between six and eight positions are needed. Occasionally, one bed position requires additional images at a later time point to see a presumed increase of uptake (dual time point imaging). Another important consideration is the scan area. Two protocols are in use, head to proximal thigh (standard WB) or head to toe (total WB), depending on the indication (eg, lower limb melanoma or soft tissue tumors).16,17 This part is the most relevant when considering the PET scanning component, because it is the longest part of the study. Taking both components (CT and PET), study time overall ranges between 15 and 30 minutes. In summary, in PET/CT protocols, there is not much flexibility or possibility to reduce the acquisition time or increase the quality of anatomical correlation derived from the CT component, and the radiation dose is determined by the sensitivity of the PET scanner and the CT protocol chosen. The situation with PET/MRI is substantially different. MRI offers a better soft tissue contrast than CT does and potentially a range of relevant, partly quantitative information on tumor biology related to, for example, blood flow, vascular and tissue spaces, pH and hypoxia, cellularity, and (via magnetic resonance spectroscopy) metabolite concentrations—all without exposing the patient to ionizing radiation.18 Thus, combining MRI with PET information might give a more complete overview of the patient's disease state than PET/CT does.

Options for Time Savings in Hybrid Imaging PET/MRI systems are very costly, and thus, operating such a system efficiently requires optimized workflows. Based on the assumption that uploading and downloading and patient preparation before scan requires approximately 10-15 minutes for each imaging modality, this would be the time saved in a PET/MRI when compared with separate PET and MR examinations. Current standard WB MRI may take up to 60 minutes, but standard PET imaging can be done in ca 12-20 minutes. Thus, if the MRI time considerably exceeds the PET time, a PET/MRI is mostly used as a very expensive MRI modality because only the minority of imaging time would be used simultaneously (in this case, 40-48 minutes). Imaging protocols in PET/MRI therefore need to be optimized for their hybrid nature to achieve the highest diagnostic accuracy in a limited time. This optimization is possible because a hybrid system in many ways is a “single” system: sensitivity and specificity do not have to be optimized for each component individually, but only jointly for the hybrid system. In fact, as information coming from both components can be either complementary, confirmatory, or redundant,4 any protocol for a hybrid PET/MRI needs to try to minimize redundant information by suppressing those MR pulse sequences that largely prove to contribute redundancy. PET/CT has limited flexibility regarding acquisition parameters to avoid acquisition of redundant information. For example, there is a substantial body of literature showing that there is no need for contrast-enhanced CT in indications where

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Figure 1 A 62-year-old patient with breast cancer with multiple metastases in right liver lobe: unenhanced CT only (A), PET only (B), and PET/CT (C). The liver lesions are clearly seen on PET and PET/CT images but are not seen in unenhanced CT, demonstrating the lack of necessity of contrast media in such cases.

the main information is derived from the PET component (eg, breast cancer, lymphoma, and melanoma)19,20 (Fig. 1). Conversely, in indications with complex anatomy, contrastenhanced CT in PET/CT certainly increases diagnostic accuracy by adding complementary or confirmatory knowledge (liver lesions, abdominal malignancies, and head and neck cancers). Furthermore, other advanced technologies such as CT perfusion might be added to get information about tumor pathophysiology or to get additional prognostic information.21,22 When MR is added to the PET, it brings with it powerful capabilities with flexible pulse sequences, and we can safely assume that in the future, it can be tailored to different indications

optimizing diagnostic accuracy. But the choice of these sequences becomes an essential ingredient of a good workflow, as MR image acquisition time (for cost-effective equipment utilization) is limited.4 Very basic and standard pulse sequences have to provide at least as much information as low-dose unenhanced CT studies and should not result in a low quality when compared with PET/CT.23,24 MRI is certainly superior to CT in several indications—but because of acquisition of redundant information, the assumption that PET/MRI is superior to PET/CT in the same indications may not be warranted. There are a number of scenarios in clinical routine where PET/MRI “formally” is superior to PET/CT (Fig. 2), but the clinical information needed for a therapy decision mainly

Figure 2 A 71-year-old patient with metastatic rectal cancer with multiple liver nodules in both lobes: CT only (A), unenhanced MR T1w (B), PET only (C), PET/CT (D), and PET/MRI (E). Liver metastases are well seen on PET/CT and PET/ MRI. MRI only (B) also shows clearly the same liver lesions. Additional multiphase contrast-enhanced sequences or DWI would generate redundant information.

Workflow in simultaneous PET/MRI derives from the PET component. Thus, although the MR component shows additional information in a different way, the diagnosis is already made on PET/CT (mainly on the PET component). However, simultaneous PET/MRI studies have significant effect in research, as discussed in several articles in this special PET/MRI issue of Seminars in Nuclear Medicine. However, for standard clinical workup, the advantage is not as clear as for research applications yet.

Specific PET/MRI Workflow Considerations Scanning Implications for WB PET/MRI Simultaneous WB PET/MRI requires a different workflow than PET/CT does. PET/CT scans are acquired sequentially, first the CT and then PET data. In contrast, PET/MRI protocols have some basic common steps. The study begins with the MRI localizer (similar do the scan topogram in PET/CT) to define the axial range primarily for the AC. After that, the PET data are acquired in a step-and-shoot mode, which requires the number of bed positions (according to the body length to be covered) and the acquisition time for each bed position. The current scanner in our site has an axial range of 25.0 cm for one bed position with an overlap of 23% of bed positions. The PET acquisition time in general is very similar to PET/CT; however, based on the improved PET components, imaging times for the PET can partly be reduced while keeping the same image quality if required, or the tracer dose can be reduced. The basic MR pulse sequences are acquired during the PET data acquisition in the specific bed position. Depending on the protocol, PET acquisition times can be increased to acquire more and different pulse sequences in one bed position. Such scenarios are examples showing the necessity of previously setting up the scanning parameters to improve the workflow time. A WB PET scan requires usually less than 30 minutes, whereas many MRI protocols require a longer imaging time. Thus, a good choice of the pulse sequences used in PET/MRI is fundamental to achieve acceptable imaging times. The choice of MR sequences that are useful for AC are limited and have to be tailored to each body compartment.25 For the head, atlasbased techniques are available, which are based on a comparison of the acquired images with a database, generating the patient AC data. The most widely used AC for the body and also for the head is the two-point two-dimensional (2D) or 3D isotropic Dixon sequence, which can classify tissues into air, lung, fat, and soft tissue.26 Although Dixon-based AC is mostly accurate in detection and anatomical delineation of bone lesions, there remain issues in PET quantification unlike in PET/CT.27,28 More detailed explanations about quantification issues in current AC methods and possible future improvements are discussed in the article by Boss et al in PET/MR Part I. For each bed position, separate breath-hold two-point Dixon PS acquisitions are acquired, which usually take between 14 and 18 seconds. This sequence is preceded by scanning preparations that include shimming to optimize the

335 homogeneity of the magnetic field,29 which can take up to 40 seconds in the first station and then approximately 4-5 seconds for the next bed positions. Therefore, depending on the patient size, overall scanning preparation can take already 65-75 seconds in WB scanning. After acquiring the images for the MR-based AC (Dixon sequence), various pulse sequences can be used either for specific bed positions or for WB overview, while the PET data is acquired simultaneously. Depending on the clinical indication, the basic choice at this time point of the examination is 1. Either to acquire a WB PET/MRI protocol with multiple sequences (maybe even with contrast enhancement) or 2. To acquire a basic PET/MRI protocol for the WB with a selection of basic sequences, as discussed earlier, and then a dedicated contrast-enhanced protocol in one anatomical compartment (eg, head and neck, chest, and liver) (Fig. 3). The PET component has to be planned accordingly 1. Either the bed position time is adapted to the imaging time required by the MRI (eg, especially useful in the chest) or 2. The bedtime is always fixed for all stations. A new technology of acquiring WB MRI in oncology patients with a continuously moving table has shown comparable results concerning lesion detection and image quality when compared with the step-and-shoot approach but without significant improvements concerning acquisition time.30 Recently, it was shown that at least in theory, the same technique can be used to acquire MRI and PET data with a continuously moving table in a PET/MRI hybrid scanner with shorter imaging time, less artifacts, and a faster and easier acquisition workflow.31 This could be a future improvement in a PET/MRI workflow, but it must be tested in a clinical trial first, and currently, it is not available on any commercial PET/ MRI system. Another significant improvement in simultaneous PET/MRI is the use of PET detector systems with time-of-flight capabilities (TOF).9 According to a recent publication,32,33 TOFPET/MRI reduces artifacts, particularly in patients showing metallic artifacts due to implants. This was shown to increase clinical reader confidence. TOF-PET could reduce the study time in patients with metal implants, considering that with adequate PET image quality, it is not necessary to add additional MR pulse sequences to work around such artifacts that show prominently in non-TOF-PET/MRI.

Current Literature on Workflow So far, there are only a few publications available on workflow and protocol optimization. Here, we discuss the main articles so far published on specific tumor entities. In general, the protocols published use first the PET data acquisition time to acquire basic MRI in each bed position. Dixon sequences for AC and anatomical localization are

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Figure 3 An 82-year-old patient with a right-sided parotid gland adenoid cystic carcinoma. Coronal images of PET (A), PET/ CT (B), ce T1w (C), and PET/MRI (D). A better conspicuity of postcontrast T1w demonstrating perineural spread along V3 component of trigeminal nerve through the foramen ovale (arrow) can be noted, it is partially also seen on PET.

usually acquired quickly and in a time comparable to PET/CT. The remaining additional or advanced MR sequences are often done after the PET scan.34 In such MRI-based (and biased) protocols, the PET/MRI scanner is predominantly used as a MR rather than a PET/MRI scanner, whereas the PET scanner idles. Efficient use of a hybrid PET/MRI must use combined protocols defined based on the clinical need and indication.4 Martinez-Möller et al29 suggested how oncologic diseases and target organs should be evaluated in such scenarios. However, in their approach they also suggested lengthy protocols with many MR sequences for full diagnostic workup, which—as discussed earlier—often lead to redundant information already available on the PET images. Other articles also suggest lengthy MR protocols with or without an organfocused approach.35-37 The idea of an anatomically focused approach based on the tumor staging requirement and the pattern of tumor spread seems to be more fruitful in PET/MRI.

For instance, in prostate cancer, the efforts should focus on local staging or recurrence and evaluation of pelvic and retroperitoneal lymph node stations and the axial skeleton instead of investing costly imaging time in dynamic contrastenhanced imaging of the abdomen, WB contrast-enhanced MR or even respiratory-gated pulmonary sequences. The use of DWI in PET/MRI protocols is being discussed controversially. Some publications showed value of DWI in staging or restaging lung, head and neck, gynecologic, and colorectal cancer as well as lymphoma.10,34,37-40 However, WB DWI is time consuming, and it has been documented that information obtained from DWI is partly redundant to PET imaging, for example, in head and neck cancers, not adding significant diagnostic value.41 Overall, it is currently unclear in which indications DWI should be used in the context of PET/ MRI. There might be role during follow-up examinations, where radionuclide uptake is decreased and diagnostic

Workflow in simultaneous PET/MRI evaluation therefore has to be based more on the MR component. Additionally, with the advent of multiband DWI, which can significantly accelerate acquisition times, adding DWI might be less time consuming and therefore could to be integrated into a PET/MRI protocol to better advantage. Again, only very few (and small) publications report efficient protocols for lung cancer. At first glance, it might not appear useful to stage lung cancer with PET/MRI (based on the inferior image quality in MRI). However, new concepts have to be developed. Usually patients get their diagnosis of lung cancer based on a CT of the chest, and therefore, when they come for overall staging (including staging brain metastases with MR, which according to the National Comprehensive Cancer Network guidelines should be done at stage1B and higher), the local anatomy around the tumor has already been imaged and clarified. However, to complete the staging, N and M stages have to still be defined. In this setting, initial PET/MRI studies have shown promising results. In a study only including 11 patients, Kohan et al42 have demonstrated very similar accuracy for lymph node staging in patients with lung cancer by comparing PET/MRI with just one T1w AC sequence vs PET/CT. This actually highlights the importance of the PET component in N staging in lung cancer when compared with the morphologic imaging component (MR or CT), which is well known from a large body of PET/CT literature. Similar information was also obtained in a recent article describing 22 patients,43 where PET/MRI showed no difference in staging accuracy in patients with lung cancer when compared with that using PET/CT. A much longer protocol with six additional MR lung sequences was being used. No information was provided concerning the redundant information of these additional sequences. A short protocol published by Schwenzer et al44 showed comparable diagnostic and staging accuracy between contrast-enhanced PET/CT and PET/MRI in patients with lung carcinoma, using just two pulse sequences in addition to the Dixon AC sequence. This seems to be a useful approach. In a recent study presented by our group, 32 patients with NSCLC were analyzed concerning staging with PET/CT when compared with PET/MRI.45 Here, the T, the N, and the M staging were not statistically significant different. The interesting concept in this study was the limited PET/MRI protocol using just two WB sequences and one dedicated, respiratorygated T2w sequence in the chest. This approach was also used in a prior study by us.23 The protocol used can be run in 15-20 minutes; thereby, almost matching the imaging time in PET/ CT (Fig. 4). There are also only very few studies focusing on M staging in PET/MRI. Making use of the advantage of MRI, which has a better diagnostic accuracy than that of CT in common metastatic sites such as the brain and the liver, efforts in improving protocols in such areas is important. Fusion studies of PET/CT and MRI evaluating colorectal liver metastases have shown a significantly better accuracy of PET-MRI and CT,46 but no information was provided concerning the workflow, and no further discussion evaluating the sequences used was given. Another study specifically on liver metastases in 55 patients found that a simple PET/

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Figure 4 Schematic whole-body basic PET/MRI data acquisition. Simultaneous acquisition of PET data while MR pulse sequences are acquired, without contrast media injection, similar to basic unenhanced PET/CT. MR sequences of each body compartment can be acquired during the corresponding bed position. (Color version of figure is available online.)

MRI protocol with just T1w and T2w sequences already equals the diagnostic accuracy of contrast-enhanced PET/CT. When additionally using MR contrast media, diagnostic accuracy increases even further. Those data again show that PET/MRI protocols have to be adapted to the hybrid nature of PET/MRI, where the PET component already provides significant diagnostic information that should not be repeated by MR data acquisition. One large study with more than 100 patients evaluated the overall diagnostic accuracy of a limited, non–contrastenhanced PET/MRI protocol, again using just two WB sequences and one dedicated, respiratory-gated T2w sequence in the chest or upper abdominal region. Here again, the overall diagnostic accuracy was comparable to that of PET/CT.23 As discussed earlier, a useful concept one might think about is the integration of a “rule-out brain metastases” protocol into a PET/MRI examination. This makes sense because many

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focused on research rather than on clinical imaging. This may change with the increasing use of the new amyloid-t or tautracers for imaging Alzheimer disease and other neurodegenerative disorders.47 Other general applications of PET/MRI are musculoskeletal applications and pediatric imaging. Especially the latter seems to be appealing because it opens the door for dose reduction in children or for closer follow-up studies, while not increasing radiation dose when compared with the current imaging standard. However, especially in the pediatric patient population, wisely chosen protocols are important to keep imaging times as short as possible. The last area is hybrid imaging in cardiology, which eventually also may develop some relevant clinical applications in hybrid imaging with PET/MRI.48 The next section discusses these five main potential applications focusing on workflow considerations.

Oncology (WB Imaging)

Figure 5 Schematic whole-body advanced PET/MRI data acquisition. When compared with the basic protocol, the added respiratorytriggered T2 propeller of the upper abdomen can be noted. First acquired the unenhanced MR sequences simultaneously to PET and afterward enhanced brain protocol or liver-enhanced sequence or both (red rectangle). (Color version of figure is available online.)

tumors metastasize to the brain frequently and PET/CT is not suitable to exclude brain metastases with adequate sensitivity. In such a protocol using three dedicated brain sequences including contrast enhancement after the acquisition of WB PET/MRI, brain metastases can be excluded for sure. If needed, the same contrast media injection can be used for a quick whole (or partial)-body MR survey with contrast as well. In this way, a complete workup including the brain can be done in a clinically acceptable imaging time of 30-40 minutes using a PET/MRI (Fig. 5).

Disease Specific and Applications Currently, it is agreed in the literature that there are five major (clinical) fields for PET/MRI. The great majority of articles focus on oncologic imaging because of the great success PET/CT as robust imaging tool in these diseases. Thus, there are high expectations that PET/MRI can improve on diagnostic accuracy, at least in some specific indications. The second area with similarly high expectations is in neuroimaging. However, here the expectations are more

Currently PET/MRI in the oncologic population uses two different approaches, WB or organ-based protocols. In the latter, localized disease is present in a single organ or body compartment, meaning that a limited area has to be covered by PET/MRI. This makes the protocols easier and faster. Consequently, there is less need for special workflow planning or scan time restrictions—even lengthy MR pulse sequences would not impair workflow. Currently, such organ-based cases would represent the minority of the clinical indications. A good example is imaging of brain tumors. The WB PET/MRI approaches can in essence be designed in two ways, which we call basic and advanced. Basic Protocol The main purpose in such an approach is very similar to a standard, low-dose, and unenhanced PET/CT. It is therefore useful, for example, for follow-up studies to evaluate therapy response in known lesions. MR pulse sequences in such protocols are limited basically to WB axial T1w Dixon and coronal or axial T2w sequences (eg, short-tau inversion recovery or fast-recovery fast spin echo). These sequences can be done truly simultaneously with PET, and within a PET acquisition segment of 2-3 minutes. Options are available (and described in the literature) concerning the chest: here, for example, a respiratory-gated sequence for the chest and upper abdomen (eg, T2 PROPELLER) or navigator-based imaging for the chest can be added to the WB T2w imaging.23 Such a basic protocol has a similar imaging time compared with that of PET/ CT. Adding more MR pulse sequences (eg, with contrast media) would partly result in redundant information because the main determinants of therapy response—reduction of tracer uptake and morphologic reduction of lesion size—are adequately evaluated with such a limited protocol. As discussed earlier, a limited protocol including a respiratory-gated sequence for the chest showed the same diagnostic accuracy as that of PET/CT, even for pulmonary lesions. It has to be mentioned that this protocol detects fewer pulmonary lesions,

Workflow in simultaneous PET/MRI comprising mostly small lesions of uncertain diagnostic relevance.4 An option to improve lesion detectability is to implement simultaneous PET and MR respiratory gating. Although respiratory-gated MR pulse sequences for the whole chest might take up to 5 minutes, a simultaneously gated PET component would eradicate the typical “smearing” artifacts seen on ungated PET. However, as the acquisition would be truly simultaneous, no time penalty would be incurred. Clinical experience is currently obtained in our center, but no publications on such an approach are currently available. Experimental studies using different approaches have shown promising results.49 Advanced Protocol The term advanced refers to more complex protocols, which start with the same MR pulse sequences as the basic approach but add high resolution and contrast-enhanced acquisition in specific body compartments. This approach should therefore be used in primary staging situations, as here, the decision concerning the therapeutic approach has to be made. However, the advanced part should be confined to the patient's primary disease area or tailored to the disease-spreading pattern to avoid excessive imaging times.34 Martinez-Moller et al29 gave an extended overview of possible scenarios and their specific advanced protocols. However, those were mostly MRI protocols known from stand-alone MR not adapted to the needs of PET/MRI. 1. For head and neck cancer staging, additional T1 and T2, diffusion-weighted, and contrast-enhanced T1w images may be acquired in different planes, adding approximately 20-30 minutes to the basic protocol (35-45 minutes total study time). As an additional option, a dedicated PET acquisition can be done during the additional MRI, resulting in higher image quality. As indicated earlier, this scenario should be used for primary staging, and the situation is different for surveillance or after systemic treatment. Initial experience indicates that for therapy follow-up, just one adequately acquired, high-resolution T2w sequence might be enough for follow-up in head and neck cancer50 (Fig. 6). Although data from single modality imaging studies support the importance of DWI for such a patient population, initial data specifically on PET/CT demonstrated that DWI offers mostly redundant clinical information compared with that by PET.41,51 2. Advanced protocols for the chest are even more challenging. As previously discussed, simultaneously respiratory-gated PET/MRI acquisition should improve the accuracy for small lung lesions. Current literature explored the addition of contrast media for the lung. Rauscher et al52 showed better accuracy for small pulmonary nodules (o1.0 cm) with contrast-enhanced, T1w volume interpolated breathhold examination when compared with that using noncontrast imaging. Admittedly, not only contrast media was given, but the sequence had a higher resolution as well. Contrast-

339 enhanced MRI has known advantages in the evaluation of the pleura and the thoracic wall. Thus, in cases with indicated infiltration of these structures (malignant pleural mesothelioma and Pancoast tumors), PET/MRI with contrast-enhanced sequences (with one additional plane, eg, axial and coronal) would theoretically have an advantage when compared with PET/CT or MRI alone.53-55 However, there are no publications available on that specific topic. The inclusion of a rule-out brain metastases protocol for lung carcinoma (see earlier) gives the advanced protocols an extra complexity that can only be managed in an acceptable imaging time if one strictly adheres to the limited underlying basic protocol. 3. The protocols for liver metastases, pancreatic tumors, gall bladder tumors, or tumors of the distal esophagus or stomach are basically the same. Again, a respiratorygated T2w sequence for the liver is needed in addition to (dynamic) contrast-enhanced sequences, partly in different planes. In addition, DWI is used on most cases in stand-alone MRI, especially for small lesions (o1.0 cm), where the sensitivity of PET is lower. Some studies advocate that DWI alone has the same sensitivity as that of contrast-enanced (ce) sequences,56,57 whereas others demonstrated that ce-MRI with gadoliniumethoxybenzyl diethylenetriamine pentaacetic acid had better accuracy than that of DWI.58 Our initial experience in PET/MRI showed overall better results with ceMRI than that with DWI,59 and thus, DWI should only be used if contrast media are contraindicated. Concerning the choice of contrast media, there is a large body of literature available showing the superiority of dinatriumgadoxetat (Primovist) in detection and characterization of liver lesions. It remains to be seen if that is still the case for liver metastases in PET/MRI, where the additional PET component adds already substantial information on the characterization of these lesions. Additionally, simultaneous respiratory gating can be used to increase PET image quality, especially for small lesions. A different scenario applies to liver tumors (hepatocellular carcinoma [HCC] and cholangiocellular carcinoma), where the (18F-FDG)-PET component frequently does not help to identify and characterize the tumor (eg, well-differentiated HCC), and the MRI would definitively be the leading imaging component. However, the differentiation of dysplastic liver nodules and early- or well-differentiated HCC is complicated even in MRI with Dinatriumgadoxetat. Combined PET/MRI with different tracers (18F-Choline and 11C-Acetate) might actually be helpful in the evaluation of these “borderline” cases.60-65 4. In pelvic oncology protocols, adding a 3D isotropic T2w image sequence of the pelvis is recommended for better anatomical assessment of disease extent, rather than high-resolution multiplanar acquisitions. Consequently, workflow is improved and time-saving is obtained.37 From such a data set, different imaging planes of the pelvis can be reconstructed, depending on the disease to be imaged (uterus, cervix, and ovaries). There are only

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Figure 6 An 83-year-old patient for restaging with recurrent melanoma resected 2 years before. Ce T1w image (A), T2w (B), ce CT (C), PET (D), PET/MRI with T2w (E), and PET/CT (F). All images show the recurrent solid lesion infiltrating the etmoidal trabeculae with corresponding PET uptake. Here, the T2w offers the same lesion detectability when compared with that using ce T1w.

case reports available in the literature concerning the integration of an adequate multiparametric protocol for prostate cancer evaluation.66-68 The advent of 68galliumlabeled ligand of the prostate-specific membrane antigen has the potential to improve prostate cancer evaluation in cases where even advanced MRI protocols fail to detect early cancer deposits.69

PET/MR Neuroimaging The workflow in PET/MRI for brain imaging poses fewer problems. One of the most interesting improvements in brain imaging is the possibility to evaluate the so-called three-eye vision, fusing metabolic or functional imaging of PET, standard morphoanatomical MRI, and functional MRI data.70 Studies in the literature have already demonstrated the feasibility of simultaneous brain scanning for these three

components. Main indications are functional assessment for vascular or neurodegenerative cognitive disturbances or both, the evaluation of foci in patients with epilepsy, and the evaluation of brain tumors (staging, therapy follow-up, and recurrence).71-73 PET/MRI of the brain is a dedicated study using just one bed position with possibly long PET acquisition times, ranging 15-60 minutes based to the indication, the used radiotracer, and the choice of a static or dynamic PET acquisition protocol. Some authors advocate dynamic scanning, which requires a shorter uptake period than that of standard 18F-FDG but longer PET acquisition times, for instance, in case of 18F-fluoro-ethyl-Ltyrosine, 30 minutes is used. Amyloid-targeting PET imaging protocols may take up to 60 minutes. In this case, brain MRI acquisition can start at the beginning of the dynamic radiotracer uptake scan and last until the PET acquisition is completed. More in-depth information on this subject is given in Barthel et al.47

Workflow in simultaneous PET/MRI

PET/MR Cardiac Imaging The same workflow considerations for one bed position apply to cardiac imaging—again, imaging occurs in only one bed position. In addition, the same potential benefits—providing better anatomical, functional, flow, perfusion, and metabolic information at the same time—are expected in cardiac imaging. A potential clinical application is myocardial viability assessment with higher resolution when compared with that using standard SPECT-myocardial perfusion imaging, and initial trials already have demonstrated an excellent correlation of ischemic myocardial segments in late gadolinium enhancement MRI and FDG-PET.74,75 Myocardial viability protocols in the literature range from 30 minutes up to 60 minutes, with just one bed position imaged. Here, it is certainly necessary to adjust protocols to the minimally necessary imaging time to avoid movement and partial-volume effects, which possibly affect, for example, coronary artery imaging.76 A very promising application of cardiac PET/MRI is quantitative myocardial perfusion imaging, which might identify preoperatively ischemic patients who could benefit from coronary revascularization. However, the advantages over standard gadolinium-enhanced MR perfusion are not entirely clinically clear yet.76 Another potential application is the evaluation and characterization of atherosclerotic plaques in peripheral vessels and potentially also in coronary vessels, which could identify unstable plaques with high risk of rupture. Although 18F-FDG can detect inflammation, more specific tracers are being tested, such as 18F-galacto-RGD and αvβ3 integrin.77 It is necessary that further preclinical studies confirm the potential value and that there is development of these new PET tracers for clinical routine application. A more comprehensive overview on PET/MRI cardiac application in research and clinical routine is given in Rischpler et al.48

Musculoskeletal Workflow considerations for musculoskeletal applications are anticipated here for single bed positions. With current knowledge, no special preparation before imaging seems to be needed. Applications in musculoskeletal imaging are mainly in oncology. Primary tumors of the bone and soft tissues do not have specific patterns of uptake to define malignancy. However, it is known that standardized uptake value measurements can partly differentiate low-grade from high-grade tumors and have a prognostic value in sarcomas.78,79 The benefits of PET/ MRI for primary soft tissue and bone tumors are the high accuracy in local staging (mainly based on the MR component) and the possibility to guide diagnostic biopsies (mainly based on the PET component), supporting correct staging and grading. Another usefulness clinical application is therapeutic response assessment, especially in soft tissue sarcomas.80 For malignant bone lesions, it is expected that PET/MRI is more robust and would provide a better anatomical delineation when compared with PET/CT. However, for this, additional dedicated sequences rather than only two basic sequences might be needed.27 Again, especially in such scenarios where small infiltrations of critical structures are important to be seen,

341 excessive acquisition times should be avoided. Staging and therapy response assessment are also potential applications of PET/MRI in systemic diseases that affect bony structures, such as multiple myeloma, lymphoma, and melanoma, but currently, there are no studies evaluating its potential benefit. Despite the known FDG avidity for inflammatory activity, there are no data to support PET/MRI as a possible imaging method, for example, in arthropathies (psoriasis, rheumatoid arthritis, gout, and ankylosing spondylitis).80

Pediatric The main added value that comes with PET/MRI in this population is the possibility to reduce radiation exposure, with an estimated saving of 80% of radiation when compared with that using PET/CT.81 However, in the study cited here, the dose reduction was calculated based on the fact a PET/CT examination was obviated, because PET/MRI delivered a diagnostic result, and the standard workup of PET/CT and an additional MRI were no longer needed. No direct comparison of dosing between PET/MRI and PET/CT was made. As in adults, the main application in pediatric imaging is oncology and in some brain applications. Again, only a few articles are available with an oncologic pediatric patient population.81-83 Comparable results of PET/MRI and PET/CT were shown. The additional information given by the MR component resulted in an overall slightly improved accuracy on a per patient basis. However, rather lengthy protocols including WB multiplanar T2w and DWI were used, resulting in an acquisition time of approximately 60 minutes. Such acquisition times can certainly be reduced, which would make this imaging modality even more appealing for the pediatric population. There is no report of the effect of sedation in such groups, which is another important issue to be aware of regarding workflow management. One special potential benefit in oncologic patients is the differentiation between highly cellular hematopoietic and neoplastic marrow that could be assessed by the chemical shift information given by T1 Dixon sequences.80

Data Visualization, Analysis, and Reporting There are some considerations regarding PET/MRI analysis and reporting that should be pointed out. Similar to PET/CT, reading PET/MRI should be done as joint reading by physicians from both radiology and nuclear medicine or ideally by doubly trained experts. For WB MRI, generally radiologists trained for body imaging are sufficiently trained. For other indications including neuroradiology or pediatric radiology, it is necessary to call on dedicated specialists for combined reading. There is already a suggestion for an integrated training program by the American College of Radiology to prepare physicians in diagnostic radiology, nuclear medicine, and molecular imaging, which lasts for 5 years.84 This or other combined programs based on country-specific requirements are hopefully the future standard in training for hybrid imaging physicians. There is no standard strategy for PET/MRI reading,

342 and every institution currently establishes its own reading procedure. Generally, the reading process is similar to that of PET/CT. However, there are a few basic differences. Different from PET/CT, PET/MRI might have more than one PET data set as compared with PET/CT, where dual time point imaging or late imaging in clinical routine is rare. These second PET data sets are acquired, as commented previously, when a patient is scanned in the WB mode (2-3 minute per bed position) and also receives a dedicated localized PET/MRI (brain, neck, liver, prostate, etc). Although this second data set can be used for dedicated diagnosis of this body compartment, care has to be taken that always the same PET imaging time (either primarily acquired during standard WB or reconstructed from secondary localized PET/MRI) is used or available for follow-up studies. In cases with artifacts and nondiagnostic imaging areas, the nonattenuated PET image as well as the u-map has to be available to consider if enough diagnostic information is available for adequate diagnosis. Other aspects such as fusing the MR and PET images on dedicated workstations and generating maximum intensity projections are not different from that of PET/CT.

Conclusion PET/MRI systems allow simultaneous acquisition of PET and MRI information, but the currently proposed protocols in the literature are mainly biased toward MRI-only protocols. Only very few studies on optimization of protocols and workflow have been published so far. However, protocols have to be optimized to provide complementary or confirmatory information by the two modalities, but redundant information generated by multiple MR pulse sequences must be avoided. Development of new and faster MR sequences is needed, especially for lung and bone imaging, as discussed in other articles of PET/MR Part 1 and 2. PET/MRI is still more a research tool rather than a clinical imaging system, and more studies are needed to understand its potential clinical superiority when compared with that of PET/CT. To achieve this goal, defining good workflow is essential.

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