Cancer begins as a localized disease based on unrestrained cell replication. Cells reproduce; that is the basis of life. Healthy cellular reproduction is in equilibrium with cellular death and decay. When there is an error in the cells’ DNA which causes the cells to reproduce too quickly, unrestrained reproduction results in the growth of a tumor, which may or may not be cancerous. Some tumors are benign: they remain localized to one area, generally do not increase in size beyond a certain point, and can easily be removed if needed, though they often don’t warrant such treatment. (Moles are one example of such a benign tumor.) Other tumors, however, may be malignant, and are considered cancerous. Cancerous cells are able to progress through the circulatory and lymphatic systems, leading to metastasis to other parts of the body. The cancer then interferes with other cells and essential biological functions, resulting in serious illness or death. 3
requirements of PET/MRI including protocols and tracers, the potential of integrated localized breast PET/MRI exams, and possible applications of whole body PET/MRI in breast cancer patients. Currently, PET/MRI can be performed on sequential and integrated PET/MRI scanners but, as not all practices can access these dedicated machines, several studies look at PET and MRI exams that are performed separately on separate scanners within a short time frame. This practice likely provides similar clinical data, although exact co-localization for iso-voxel analysis, currently performed only in research, is not possible. In PET/MRI, the MRI sequences are flexible and can be customized according to the aim of the exam. The most commonly used radiotracer is 18 F-FDG, however, tracers that image hypoxia and drug targets such as estrogen receptors and HER2 are in development and may increase the utility of PET/MR. For dedicated breast PET/MRI, a potential advantage over standard breast MRI alone may be the
Hausmann et al. , for example, found a higher lesion de- tection rate in a study comparing TOF and non-TOF 18 F- choline in PET/CT in 32 prostate cancer patients with biochemical recurrence. The gain in lesion detection due to TOF in PET/CT is attributed to several factors, whereas an improved signal to noise ratio and contrast to noise ratio is considered to play an important role [35, 60], especially in small lesions [57, 61, 62]. It is obvious that these factors are also relevant for PET/MRI, while the correction of SUV underestimation induced by MRAC plays an additional important role. Our measurements suggest that SUV underestimation does not only affect bone tissue but also lesion in the proximity of bones, leading to a negative correlation between relative difference in lymph node activity and distance to osseous structures, as shown in Fig. 3. An additional factor that could have influenced lesion detection is reduced scatter correction artifacts around the bladder and the liver/kidney in TOF, as previously described by Minamimoto et al.  in PET/MR. Our results additionally showed a higher interreader agreement for lymph node and bone metastasis on TOF compared to non-TOF.
This study was approved by the institutional review board, and written informed consent was obtained from all pa- tients. This study was performed under an Investigational New Drug approval from the Food and Drug Administra- tion as part of a trial prospectively evaluating the accuracy of 68 Ga-PSMA-11 for the detection of prostate cancer (NCT02611882). Inclusion in the trial required a PSA doubling time of less than 12 months, and these patients have been reported as part of a change in management analysis . Fifty-five consecutive patients who under- went 68 Ga-PSMA-11 PET/MRI for BCR from March 2016 to September 2016 were evaluated. All of the patients were previously reported in a study evaluating how 68 Ga- PSMA-11 PET changed management in patients with BCR . This prior study surveyed the referring clini- cians to determine the effect that the imaging results would have on patient management but did not compare
Disclosures: Sasan Partovi and Chiara Gaeta—RELATED: a grant from Philips Health- care in support of this study.* Andres Kohan—RELATED: under a research fellowship partially funded by Philips Healthcare. Jose Luis Vercher-Conejero— RELATED: a State of Ohio Frontier Grant, which funded the PET/MRI system*; some studies were partially funded as part of a research agreement between Philips Healthcare and Case Western Reserve University. Christian Rubbert—RELATED: fellowship funded under a joint research agreement of University Hospitals Case Medical Center, Case Western Reserve University, and Philips Healthcare. Mark D. Schluchter—RELATED: per an agreement with Dr Faulhaber, work for biostatistical analyses conducted by biostatisticians on this article, who are members of the Case Comprehensive Cancer Center Biostatistics Shared Resource, was reimbursed in part via a chargeback mech- anism used by the Shared Resource. Peter Faulhaber—RELATED: a grant* and travel support, both in support of the study and paid by Philips Healthcare. *Money paid to the institution.
Numerous therapeutic modalities are available for early or advanced PCa. Various options including local to systemic treatments can be used in a multitude of clinical scenarios. Furthermore, beyond the efficacy of each treatment modality, toxicities and costs play important roles in therapeutic deci- sions and adequate management of PCa, creating a demand for precise assessment of therapeutic benefits. In this setting, imaging can provide helpful information about residual disease extension, the degree/depth of response, biological heterogeneity/behavior of neoplasia, disease progression and even side effects (49). Therefore, assessing therapeutic responses in PCa is a complex issue, since each stage of disease has very specific features and requires different approaches. Localized disease can be treated with surgery or radiotherapy and followed by active surveillance with comparable outcomes (50). Advanced disease encompasses a large spectrum of tumoral phenotypes and clinical condi- tions, varying from favorable oligometastatic (29) presenta- tions to disseminated metastatic disease; each situation requires different treatments, such as hormones, radiation or chemo- therapy. However, both localized and advanced prostatic disease are under the influence of androgen receptor (AR) signaling, which is a crucial driving pathway for growth and proliferation of PCa cells and the main target for ADT (51). An important condition is metastatic castration resistant PCa (mCRPC), which is characterized by persistent AR stimulation independent of ADT (52) and is frequently associated with disseminated disease and a poor prognosis (53). In mCRPC, an important characteristic that favors imaging is that serum PSA, a consolidated surrogated marker of disease progression, can be dissociated from real burden of metastatic disease (49).
We designed the DCE-MRI protocol used in this study with consideration for its direct clinical ap- plicability. Gd-DTPA is a clinically approved CA which is widely used to quantitatively evaluate tu- mor vascular permeability preclinically and clinically and has a short plasma half-life (<12 minutes in murine models). Since iRGD was shown to improve the uptake of small molecule doxorubicin , we hypothesized that it would also increase the uptake of Gd-DTPA. Pre- and posttreatment DCE-MRI scans were obtained in the same animal to account for the tumor response variability between subjects; a critical factor for patient studies. This variablity also motivated the need to treat the same tumor with all three different conditions. A key assumption made here is that PAF and iRGD have short acting time windows (<12 hours). We believe that this was reasonable based on previous reports showing that both PAF and iRGD have high activity within 3 hours of adminis- tration [267, 49]. Other classes of small molecule vasoactive agents also have short time windows of action (<3 hours) . Furthermore, the plasma half-life of iRGD in mice is less than 10 min- utes (private communication, A.R.), suggesting that very little, if any, peptide will be in circulation more than 12 hours post administration. The fact that baseline DCE-MRI parameters for different treatments, which were obtained on separate days, did not differ significantly from each other also supported this assumption. Baseline scans were also obtained to account for intrasubject variabilty of DCE-MRI parameters over time, since this may change relatively quickly (~days) during the natural progression of preclinical tumor models .
Objectives The purpose of this study was to evaluate if positron emission tomography (PET)/magnetic resonance imaging (MRI) with just one gradient echo sequence using the body coil is diagnostically sufficient compared with a standard, low-dose non-contrast-enhanced PET/computed tomography (CT) concerning overall diagnostic accuracy, lesion detectability, size and conspicuity evaluation. Methods and materials Sixty-three patients (mean age 58 years, range 19–86 years; 23 women, 40 men) referred for either staging or restaging/follow-up of various malignant tumours (malignant melanoma, lung cancer, breast cancer, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma, CUP, gynaecology tumours, pleural mesothelioma, oesophageal cancer, colorectal cancer, stomach cancer) were prospectively included. Imaging was conducted using a tri-modality PET/CT-MR set-up (full ring, time-of-flight Discovery PET/CT 690, 3 T Discovery MR 750, both GE Healthcare, Waukesha, WI). All patients were positioned on a dedicated PET/CT- and MR-compatible examination table, allowing for patient transport from the MR system to the PET/CT without patient movement. In accordance with RECIST 1.1 criteria, measurements of the maximum lesion diameters on CT and MR images were obtained. In lymph nodes, the short axis was
likely to be cost-effective. The capital cost of PET/MRI devices are comparable to PET/CT and MRI systems purchased separately and therefore, to ensure cost- effectiveness, PET/MRI workflows need to minimise the amount of time when either component is idle. Where PET/MRI replaces PET/CT and MRI performed separately, streamlining of clerical, radiographer and nursing work related to imaging investigation of pa- tients with residual or recurrent cancer into a single imaging episode may defray some of these costs. On the other hand, potential improvements in cost-effectiveness can be anticipated. The therapeutic impact study of Catalano et al. found the commonest change in man- agement when PET/MRI was used for patient with re- sidual or recurrent disease was avoidance of biopsy . Further management changes of potential health economic importance include avoiding the cost and morbidity of futile local treatments that would have been inappropriately selected due to under-estimation of disease extent by current technology, earlier identification of limited or disseminated disease allowing timely instiga- tion of local therapy or salvage therapy respectively, and avoidance of futile chemotherapy in the presence of ad- vanced disease of an extent under-estimated by current technology. Future studies are also needed to address these aspects of PET/MRI deployment.
Several technical factors influence the quantitative measurements in clinical PET/ MRI data, but could be neglected in this study by using a phantom with CT-based AC for both systems. For clinical scans at the Siemens PET/MRI system, AC is based on segmentation of tissue, providing predefined attenuation coefficients for soft tissue, fat, lung tissue, and air, and bone is included by co-registration with a bone atlas. This can cause quantification and registrations errors, influencing the PET images [44, 45]. In addition, the flexible body surface coils are not accounted for in clinical AC PET im- ages and may lead to a regionally dependent bias . Furthermore, respiratory motion can lead to PET image blurring, artifacts, and tracer uptake quantification errors in general , but this affects both PET/MRI and PET/CT data, and motion correction methods are improving [47 – 50]. A review study by Spick et al.  summarized 46 stud- ies (including 2340 patients) and found that the PET/MRI and PET/CT provide com- parable diagnostic information for most types of cancer despite both technical and operational issues.
Yttrium-90 ( 90 Y) radioembolization involves the intra-arterial delivery of radioactive microspheres to primary or metastatic disease in the liver. 90 Y decays primarily with β − emission (mean 0.937 MeV, 64.2 h half-life, 2.5 mm mean soft tissue pene- tration, 11 mm max tissue penetration) , allowing for high amount of radiation dose within a well-confined region. The current commercially available micro- spheres, TheraSpheres (glass microspheres; BTG, London, UK) and SIR-Spheres (resin microspheres; Sirtex Medical, Sydney, Australia), were first approved in the USA by the Food and Drug Administration in 1999 and 2002 and received the European CE mark in 2005 and 2002, respectively [2, 3]. Since then, 90 Y micro- sphere radioembolization has continued to grow as a third-line therapy for patients with some clinical trials into using this technology as a first-line therapy concur- rent with FOLFOX-based chemotherapy . While the use of 90 Y microspheres to treat cancer in the liver has been utilized for over 50 years , the treatment plan- ning protocol from pre-treatment imaging to prescription activity calculation is not well optimized. Standard protocol does not allow for assessing the actual distribu- tion of the microspheres or for predicting the effectiveness of treatment or possible toxicity events without waiting for follow-up imaging studies at least 30 days after treatment . Patients who undergo 90 Y radioembolization typically have poor prognoses and earlier assessment of therapy immediately after injection could guide optimization of therapy.
Earlier, it was believed that the information from MRI image can be used for defining the region of interest in PET data (Evans et al. 1988). However, Atlases are used to map certain regions that can be registered to the subject ’ s organ. Also, the atlases of human body are employed for determining the bio-distribution of tumours and metastases. The multimodal atlas can be acquired from a 3D slicer module for simple evaluation of the available image. This module has been validated with a publicly available soft tissue sarcoma information from the CancerImaging Archive (Rackerseder et al. 2017). Beyond this visualisation technique, retrospective analysis of structural and metabolic neuro-imaging can be performed using the free access software such as MRIcron, BrainSuite, BioImageSuite, ImageJ, FSL, Amide and MeVIS Lab. Usually, BrainSuite is used for stripping off the skull and creating the binary cerebral volume mask, hence, it will be processed with FSL FAST software. Also, the co-registration techniques can be achieved using BrainImageSuite. In recent time, Yuankai Zhu et al. evaluated the glucose metabolism in epileptic paediatric patients with the visual assessment and Statistical Parametric Mapping (SPM) (Fig. 11) (Zhu et al. 2017). While SPM is designed to perform segmentation of brain tissues consisting of Grey Matter (GM), White Matter (WM) and Cerebrospinal Fluid, the FSL and Brainsuite can segment sub-cortical structures also. Also, the performance of FSL was influenced by image noise and intensity non-homogenity (Kazemi and Noorizadeh 2014). Also, PMOD (version 3.5, PMOD Technologies, Zurich, Switzerland) was used in parametric images of Dopamine receptors (D 1 R) distribution volume ratio (DVR) and binding potential (BP ND ) of the PET data from
Prostate cancer is the second most prevalent cancer in men, with an estimated 1.1 million new cases diagnosed worldwide in 2012. 120 Excluding non-melanoma skin cancer, this represents a staggering 15% of all male cancer cases. 120 Despite recent improvements in the diagnosis and staging of this carcinoma, the World Health Organization predicted about 7% of all deaths from cancer to be due to PCa in the year 2012. 120 The introduction of the mpMRI exam utilizing functional magnetic resonance imaging, PET/MRI multimodality imaging and the development of novel PET/CT probes for imaging prostate cancer (e.g. 64 Cu-CB-TE2A-AR06) have all aided in the identification and localization of cancerous tumours. 15 In addition, these advancements have enabled clinicians to find treatment programs best suited to patients’ diagnoses. However, in spite of these successes and achievements, several problems still remain: the ability to detect recurrent prostate cancer after radical prostatectomy, limited tumour detection in the c- zone of the prostate gland (which is not accessible by conventional diagnostic techniques such as the DRE exam) and most importantly of all, efficiently distinguishing between BPH and PCa.
Abstract: A novel nanocarrier system was designed and developed with key components uniquely structured at the nanoscale for early cancer diagnosis and treatment. In order to per- form magnetic resonance imaging, hydrophilic superparamagnetic maghemite nanoparticles (NPs) were synthesized and coated with a lipophilic organic ligand. Next, they were entrapped into polymeric NPs made of biodegradable poly(lactic-co-glycolic acid) linked to polyethylene glycol. In addition, resulting NPs have been conjugated on their surface with a 2,2′-(7-(4-((2- aminoethyl)amino)-1-carboxy-4-oxobutyl)-1,4,7-triazonane-1,4-diyl)diacetic acid ligand for subsequent 68 Ga incorporation. A cell-based cytotoxicity assay has been employed to verify
During the last decade, tremendous progress has been made in the development of new molecularimaging probes and therapeutic agents targeting cancer [1-4]. However, cancer still remains a major fatal disease around the world. There is clearly a need to develop innovative diagnostic and therapeutic methods beyond tradition and convention. Recently, the advancement of nanotechnology has provided unprecedented opportunities for the development of nanoparticle enabled technologies for detecting and treating cancer [5-8]. For example, surface functionalized organic/inorganic nanoparticles hold the great promises for the eradication of cancer by creating the theranostic systems (therapy + multifunctional diagnosis) that enable i) early detection of the disease, ii) monitoring therapeutic response, and iii) targeted delivery of therapeutic agents, based on the “whole in one approach” [9, 10]. However, applications of these nanotechniques were limited by the potential toxicity from inorganic core and the lack of well controlled surface modification method [11, 12]. The development of well defined and biodegradable delivery systems is therefore preferred. As shown in Figure 1, phage particles are unique platforms for imaging probes or drug carriers in that 1) they could be genetically modified to display target specific ligands; 2) they can be economically and effectively produced with absolute uniformity controlled by nature; 3) they can be covalently attached to radiometal chelators while simultaneously expressing multiple copies of cancer targeting peptides; 4) they are physically well-characterized, resistant to harsh conditions, biocompatible and nonpathogenic (compared with virus based particles); 5) the genetic material inside the capsid can be removed without affecting the integrity of capsid . Such empty container is ideal for encapsulating other therapeutic reagents which can be released after reaching specific cellular sites. These factors suggest that functionalized bacteriophage particles hold great potential as novel advanced imagingagents and targeting systems for drug and DNA delivery, and will likely complement existing organic/inorganic nanoplatforms [14-17]. Although target specific radiolabeled phage particles obtained from either high throughput screen (phage display) or rational design (the expression of established affinity reagents on the phage surface) have been reported in molecularimaging of variety of diseases, most of the imaging results are still suboptimal [18, 19]. Both two-step and
In order to create targetedmolecularimagingagents (TMIAs) from the peptide targeting groups that are synthesizing, we will use makes use of the puzzle piece approach developed in our group. Puzzle pieces (also known as imaging modules) are synthesized by bonding imaging groups, such as near infrared (NIR) dyes to amino acids such as lysine, which have a reactive amine on the side chain. NIR dyes are useful in optical molecularimaging (OMI) methods including confocal fluorescence microscopy (CFM) and a variety of other in-vitro and in-vivo fluorescent imaging methods. 18
We have previously developed a folate receptor (FR)-targeted optical imaging and PDT agent, por- phyrin-GDEVDGSGK-folate (PPF, Figure 1) . PPF is composed of three modules: 1) pyropheophor- bide-α (Pyro), a near-infrared fluorescent porphyrin, 2) folate for targeted delivery of Pyro to FR-expressing cancer cells, and 3) a short peptide as a pharmacoki- netics modifying (PKM) linker. We have demon- strated, both in vitro and in vivo, that the use of three functional modules significantly improved tumor uptake efficiency, pharmacokinetics and biodistribu- tion of the porphyrin moiety itself . Here we hy- pothesize that incorporating 64 Cu into the Pyro moiety
Inflammation of the pericardium can have diverse aetiologies including idiopathic, autoimmune diseases, infections, post myocardial infarction, uremia, and radiation. Pericarditis can be of acute, chronic inflammatory, or chronic fibrosing types. MRI has become an important modality in the evaluation of pericardial disease. In acute pericarditis, there is pericardial thickening, pericardial effusion (Fig. 14a), and pericardial in- flammation, which is manifested as delayed enhancement. In the chronic phase, pericardial thickening is present, but with lower amount of effusion and inflammation than acute type. In chronic fibrosing type, there is pericardial thickening with/ without calcification and features of pericardial constriction may be seen. MRI is valuable in the evaluation of pericardial constriction, since it shows features of ventricular interdepen- dence such as exaggerated septal flattening in real-time imag- ing (Movie 1), diastolic septal bounce, and abrupt cessation of diastolic filling. MRI is increasingly being used in the evalu- ation of pericardial inflammation, particularly in the context of transient pericardial constriction, which may be seen in the acute or subacute phase of pericarditis due to impaired peri- cardial distensibility. Although the standard treatment of peri- cardial constriction is aggressive pericardial stripping, in tran- sient pericardial constriction, anti-inflammatory therapy (NSAIDs, colchicine, steroids) may be beneficial . The presence of inflammation on MRI, even in the absence of clinical and serologic evidence of inflammation warrants con- tinued therapy .
technology has its own benefits and limitations that affect the 3D-printed end product. Some of the limitations are further described, for instance, there is a possibility of leftover sup- port material, which means that if a solution is filled into the phantom it might take up less space than intended. If this is measured, the volume measurement will be lower than the original volume. 18 In addition, printers have physical con- straints which may affect the phantom and lead to final differ- ences from the prototype. 34 A few articles have undertaken only qualitative comparison, which does not create reliable conclusions regarding the printer’s actual resolution. Quanti- tative comparison is more representative since the percentage difference of any desired property can be calculated. The phantom is compared against the original MRI and/or CT patient scan, or another physical, computational phantom, or even with the original dimensions of the geometrical shape that was developed using CAD software. Although quantita- tive results are directly measurable, their values in these cases often originate from medical images that have been created digitally or physically with the use of digital or physical cali- pers. Geometrical parameters, for example, thickness, vol- ume, and length, are numerical measures used to represent the accuracy of 3D-printed phantoms. However, these mea- sures may represent several millions of voxels, therefore, if there is a small error in each voxel, then the errors will accu- mulate and the whole 3D-printed phantom will have different dimensions. For instance, Craft et al. 49 developed a phantom which consisted of 11 slices and observed such discrepancies. Furthermore, Mitsouras et al. 52 scanned the printed phantom with CT and MRI and then tested its accuracy using both CT and MRI modalities. They identified that the dimensions in the two modalities were different, with the MRI demonstrat- ing much larger differences in the phantom’s dimensions compared with the CT. This is an example which shows that imaging modalities have their own limitations as well, and
was determined during a separate experiment performed on a bone sample imaged using the same MRI and CT systems. Different coil loading by the bone sample and the rat head might explain 31 P sensitivity differences between the two experiments. Another explanation for inaccurate conversion factor could be chemical differences between the bovine sample and the rat skull. The attenuation of γ -photons by the bone is mostly due to calcium (atomic number Z = 20 versus Z = 15 for phosphorus): indeed interactions between photons and mineral bone are dominated by photoelectric effect for which μ∝Z 4  so that attenuation by one Ca atom is ~3 times as high as attenuation by one P atom. Since 31 P-ZTE detects phosphorus atoms, the conversion factor determined on our bovine sample would not apply to the rat skull if the Ca/P ratio were significantly different between species or bones. A literature review on the chemical properties of mineral bone reveals that hydroxyapatite Ca 5 (PO 4 ) 3 OH is partly