Showing papers in "Clinical and Translational Imaging in 2017"

Molecular mechanisms of hypoxia in cancer.

Abstract: Hypoxia is a condition of insufficient oxygen to support metabolism which occurs when the vascular supply is interrupted, or when a tumour outgrows its vascular supply. It is a negative prognostic factor due to its association with an aggressive tumour phenotype and therapeutic resistance. This review provides an overview of hypoxia imaging with Positron emission tomography (PET), with an emphasis on the biological relevance, mechanism of action, highlighting advantages, and limitations of the currently available hypoxia radiotracers. A comprehensive PubMed literature search was performed, identifying articles relating to biological significance and measurement of hypoxia, MRI methods, and PET imaging of hypoxia in preclinical and clinical settings, up to December 2016. A variety of approaches have been explored over the years for detecting and monitoring changes in tumour hypoxia, including regional measurements with oxygen electrodes placed under CT guidance, MRI methods that measure either oxygenation or lactate production consequent to hypoxia, different nuclear medicine approaches that utilise imaging agents the accumulation of which is inversely related to oxygen tension, and optical methods. The advantages and disadvantages of these approaches are reviewed, along with individual strategies for validating different imaging methods. PET is the preferred method for imaging tumour hypoxia due to its high specificity and sensitivity to probe physiological processes in vivo, as well as the ability to provide information about intracellular oxygenation levels. Even though hypoxia could have significant prognostic and predictive value in the clinic, the best method for hypoxia assessment has in our opinion not been realised.

Siderophores for molecular imaging applications

Abstract: This review covers publications on siderophores applied for molecular imaging applications, mainly for radionuclide-based imaging. Siderophores are low molecular weight chelators produced by bacteria and fungi to scavenge essential iron. Research on these molecules has a continuing history over the past 50 years. Many biomedical applications have been developed, most prominently the use of the siderophore desferrioxamine (DFO) to tackle iron overload related diseases. Recent research described the upregulation of siderophore production and transport systems during infection. Replacing iron in siderophores by radionuclides, the most prominent Ga-68 for PET, opens approaches for targeted imaging of infection; the proof of principle has been reported for fungal infections using 68Ga-triacetylfusarinine C (TAFC). Additionally, fluorescent siderophores and therapeutic conjugates have been described and may be translated to optical imaging and theranostic applications. Siderophores have also been applied as bifunctional chelators, initially DFO as chelator for Ga-67 and more recently for Zr-89 where it has become the standard chelator in Immuno-PET. Improved DFO constructs and bifunctional chelators based on cyclic siderophores have recently been developed for Ga-68 and Zr-89 and show promising properties for radiopharmaceutical development in PET. A huge potential from basic biomedical research on siderophores still awaits to be utilized for clinical and translational imaging.

New methodologies for the preparation of carbon-11 labeled radiopharmaceuticals.

Abstract: This short review aims to cover the more recent and promising developments of carbon-11 (11C) labeling radiochemistry and its utility in the production of novel radiopharmaceuticals, with special emphasis on methods that have the greatest potential to be translated for clinical positron emission tomography (PET) imaging. A survey of the literature was undertaken to identify articles focusing on methodological development in 11C chemistry and their use within novel radiopharmaceutical preparation. However, since 11C-labeling chemistry is such a narrow field of research, no systematic literature search was therefore feasible. The survey was further restricted to a specific timeframe (2000–2016) and articles in English. From the literature, it is clear that the majority of 11C-labeled radiopharmaceuticals prepared for clinical PET studies have been radiolabeled using the standard heteroatom methylation reaction. However, a number of methodologies have been developed in recent years, both from a technical and chemical point of view. Amongst these, two protocols may have the greatest potential to be widely adapted for the preparation of 11C-radiopharmaceuticals in a clinical setting. First, a novel method for the direct formation of 11C-labeled carbonyl groups, where organic bases are utilized as [11C]carbon dioxide-fixation agents. The second method of clinical importance is a low-pressure 11C-carbonylation technique that utilizes solvable xenon gas to effectively transfer and react [11C]carbon monoxide in a sealed reaction vessel. Both methods appear to be general and provide simple paths to 11C-labeled products. Radiochemistry is the foundation of PET imaging which relies on the administration of a radiopharmaceutical. The demand for new radiopharmaceuticals for clinical PET imaging is increasing, and 11C-radiopharmaceuticals are especially important within clinical research and drug development. This review gives a comprehensive overview of the most noteworthy 11C-labeling methods with clinical relevance to the field of PET radiochemistry.

Systematic reviews and meta-analyses of diagnostic studies: a practical guideline

Abstract: Actually, systematic reviews and meta-analyses are the cornerstone of evidence-based practice and the number of these evidence-based articles on diagnostic studies is increasing. The aim of this article is to provide a practical guideline for the researchers who intend to perform a systematic review or meta-analysis of diagnostic studies. A guideline was prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane handbook for systematic reviews of diagnostic test accuracy. Several steps needed for systematic reviews or meta-analyses of diagnostic studies are briefly discussed (i.e. formulating the question of systematic reviews, search strategy, inclusion and exclusion criteria, quality assessment of the included studies, data extraction, pooling diagnostic indices across studies, reporting heterogeneity and discussion of main findings). To publish a high-quality systematic review or meta-analysis of diagnostic test accuracy, certain methodology should be followed. Only methodologically sound systematic reviews or meta-analyses can change or support the clinical use of a diagnostic test.

Imaging therapy response of gastrointestinal stromal tumors (GIST) with FDG PET, CT and MRI: a systematic review

Abstract: Purpose Improvement of the therapeutic approaches in gastrointestinal stromal tumors (GIST) by the introduction of targeted therapies requires appropriate diagnostic tools, which allow sufficient assessment of therapeutic response, including differentiation of true progression from pseudoprogression due to myxoid degeneration or intratumoral hemorrhage. In this literature review the impact and limitations of different imaging modalities used in GIST therapy monitoring are discussed.

Amino acid PET and MR perfusion imaging in brain tumours

Abstract: Despite the excellent capacity of the conventional MRI to image brain tumours, problems remain in answering a number of critical diagnostic questions. To overcome these diagnostic shortcomings, PET using radiolabeled amino acids and perfusion-weighted imaging (PWI) are currently under clinical evaluation. The role of amino acid PET and PWI in different diagnostic challenges in brain tumours is controversial. Based on the literature and experience of our centres in correlative imaging with PWI and PET using O-(2-[18F]fluoroethyl)-l-tyrosine or 3,4-dihydroxy-6-[18F]-fluoro-l-phenylalanine, the current role and shortcomings of amino acid PET and PWI in different diagnostic challenges in brain tumours are reviewed. Literature searches were performed on PubMed, and additional literature was retrieved from the reference lists of identified articles. In particular, all studies in which amino acid PET was directly compared with PWI were included. PWI is more readily available, but requires substantial expertise and is more sensitive to artifacts than amino acid PET. At initial diagnosis, PWI and amino acid PET can help to define a site for biopsy but amino acid PET appears to be more powerful to define the tumor extent. Both methods are helpful to differentiate progression or recurrence from unspecific posttherapeutic changes. Assessment of therapeutic efficacy can be achieved especially with amino acid PET, while the data with PWI are sparse. Both PWI and amino acid PET add valuable diagnostic information to the conventional MRI in the assessment of patients with brain tumours, but further studies are necessary to explore the complementary nature of these two methods.

Hybrid intraoperative imaging techniques in radioguided surgery: present clinical applications and future outlook

Abstract: This review aims to summarise the hybrid modality radioguidance techniques currently in clinical use and development, and to discuss possible future avenues of research. Due to the novelty of these approaches, evidence of their clinical relevance does not yet exist. The purpose of this review is to inform nuclear medicine practitioners of current cutting edge research in radioguided surgery which may enter standard clinical practice within the next 5–10 years. Hybrid imaging is of growing importance to nuclear medicine diagnostics, but it is only with recent advances in technology that hybrid modalities are being investigated for use during radioguided surgery. These modalities aim to overcome some of the difficulties of surgical imaging while maintaining many benefits, or providing entirely new information unavailable to surgeons with traditional radioguidance. A literature review was carried out using online reference databases (Scopus, PubMed). Review articles obtained using this technique were citation mined to obtain further references. In total, 2367 papers were returned, with 425 suitable for further assessment. 60 papers directly related to hybrid intraoperative imaging in radioguided surgery are reported on. Of these papers, 25 described the clinical use of hybrid imaging, 22 described the development of new hybrid probes and tracers, and 13 described the development of hybrid technologies for future clinical use. Hybrid gamma–NIR fluorescence was found to be the most common clinical technique, with 35 papers associated with these modalities. Other hybrid combinations include gamma–bright field imaging, gamma–ultrasound imaging, gamma–β imaging and β–OCT imaging. The combination of preoperative and intraoperative images is also discussed. Hybrid imaging offers new possibilities for assisting clinicians and surgeons in localising the site of uptake in procedures such as in sentinel node detection.

Clinical PET/MRI in neurooncology: opportunities and challenges from a single-institution perspective

Abstract: Magnetic resonance imaging (MRI) plays a key role in neurooncology, i.e., for diagnosis, treatment evaluation and detection of recurrence. However, standard MRI cannot always separate malignant tissue from other pathologies or treatment-induced changes. Advanced MRI techniques such as diffusion-weighted imaging, perfusion imaging and spectroscopy show promising results in discriminating malignant from benign lesions. Further, supplemental imaging with amino acid positron emission tomography (PET) has been shown to increase accuracy significantly and is used routinely at an increasing number of sites. Several centers are now implementing hybrid PET/MRI systems allowing for multiparametric imaging, combining conventional MRI with advanced MRI and amino acid PET imaging. Neurooncology is an obvious focus area for PET/MR imaging. Based on the literature and our experience from more than 300 PET/MRI examinations of brain tumors with 18F-fluoro-ethyl-tyrosine, the clinical use of PET/MRI in adult and pediatric neurooncology is critically reviewed. Although the results are increasingly promising, the added value and range of indications for multiparametric imaging with PET/MRI are yet to be established. Robust solutions to overcome the number of issues when using a PET/MRI scanner are being developed, which is promising for a more routine use in the future. In a clinical setting, a PET/MRI scan may increase accuracy in discriminating recurrence from treatment changes, although sequential same-day imaging on separate systems will often constitute a reliable and cost-effective alternative. Pediatric patients who require general anesthesia will benefit the most from simultaneous PET and MR imaging.

Current status of the development of PET radiotracers for imaging alpha synuclein aggregates in Lewy bodies and Lewy neurites

Abstract: This review provides an account of the current status of the development of PET radiotracers for imaging aggregated alpha synuclein (α-syn) in Lewy bodies and Lewy neurites. This includes a description of the various strategies used in the development of an α-syn PET probe and the technological hurdles which have limited progress in this area of research. A survey of the literature describing small molecule-based probes that bind to α-syn and have served as lead compounds for PET radiotracer development was conducted. This literature review includes a description of various radiolabeled probes having a modest affinity for α-syn which have been published within the past 5 years. Although different chemical entities have been described as having a moderate affinity for α-syn, their in vitro binding affinities for α-syn and selectivities for α-syn versus beta amyloid (Aβ) and tau fibrils are not ideal for serving as lead compounds for PET radiotracer development. Structure–activity relationship (SAR) studies have generated radiolabeled probes capable of binding to α-syn, but selectivity versus Aβ and tau remains a problem. The development of an optimal PET probe for imaging aggregated α-syn in Lewy bodies and Lewy neurites remains as a high priority in the field pf PET radiotracer development, since it would improve the diagnosis of PD and provide a biomarker for disease progression. An α-syn PET radiotracer would also be useful in the evaluation of the efficacy of therapeutic strategies aimed at reducing levels of α-syn in the CNS. Although much progress has been made in recent years, the development of a PET radiotracer for imaging α-syn aggregates represents an unmet need in field of translational PET imaging.

Hypoxia in cervical cancer: from biology to imaging

Abstract: Hypoxia imaging may improve identification of cervical cancer patients at risk of treatment failure and be utilized in treatment planning and monitoring, but its clinical potential is far from fully realized. Here, we briefly describe the biology of hypoxia in cervix tumors of relevance for imaging, and evaluate positron emission tomography (PET) and magnetic resonance imaging (MRI) techniques that have shown promise for assessing hypoxia in a clinical setting. We further discuss emerging imaging approaches, and how imaging can play a role in future treatment strategies to target hypoxia. We performed a PubMed literature search, using keywords related to imaging and hypoxia in cervical cancer, with a particular emphasis on studies correlating imaging with other hypoxia measures and treatment outcome. Only a few and rather small studies have utilized PET with tracers specific for hypoxia, and no firm conclusions regarding preferred tracer or clinical potential can be drawn so far. Most studies address indirect hypoxia imaging with dynamic contrast-enhanced techniques. Strong evidences for a role of these techniques in hypoxia imaging have been presented. Pre-treatment images have shown significant association to outcome in several studies, and images acquired during fractionated radiotherapy may further improve risk stratification. Multiparametric MRI and multimodality PET/MRI enable combined imaging of factors of relevance for tumor hypoxia and warrant further investigation. Several imaging approaches have shown promise for hypoxia imaging in cervical cancer. Evaluation in large clinical trials is required to decide upon the optimal modality and approach.

Standardization of 123I-meta-iodobenzylguanidine myocardial sympathetic activity imaging: phantom calibration and clinical applications

Abstract: Purpose Myocardial sympathetic imaging with 123I-meta-iodobenzylguanidine (123I-mIBG) has gained clinical momentum. Although the need for standardization of 123I-mIBG myocardial uptake has been recognized, the availability of practical clinical standardization approaches is limited. The need for standardization includes the heart-to-mediastinum ratio (HMR) and washout rate with planar imaging, and myocardial defect scoring with single-photon emission computed tomography (SPECT).

Molecular imaging and fusion targeted biopsy of the prostate

Abstract: Purpose This paper provides a review on molecular imaging with positron emission tomography (PET) and magnetic resonance imaging (MRI) for prostate cancer detection and its applications in fusion targeted biopsy of the prostate.

Prevalence and clinical significance of focal incidental 18F-FDG uptake in different organs: an evidence-based summary

Abstract: Several meta-analyses and systematic reviews have reported data about the prevalence and the malignancy risk of focal incidental uptake detected by 18F-FDG PET (FIU). This review aims to summarize the published evidence-based data about the most common sites, prevalence and malignancy risk of FIU, to derive schematic estimates in this setting. A comprehensive computer literature search of meta-analyses or systematic reviews regarding FIU and published in PubMed/MEDLINE and/or Cochrane library database through June 2017 was carried out. Twelve articles were discussed in our summary and different organs were evaluated. The pooled prevalence of FIU ranged, respectively, from 1.6 to 3.6% for colon–rectum, from 1 to 2.46% for thyroid, being 0.4% for breast, 1.8% for prostate and 0.6% for parotid. Despite that, the pooled risk of malignancy considering histology as reference standard was quite high in all organs evaluated in the summary, except for parotid gland. In fact, it ranged from 61.5 to 76% for FIU in the colon–rectum (including both premalignant and malignant lesions), from 33.2 to 37% for FIU in the thyroid gland, and it was 60 and 62%, respectively, for breast and prostate FIU. For parotid FIU pathologically proven the pooled risk of malignancy was only 20.4%. Our summary showed that the most frequent sites of FIUs are colon and thyroid according to literature data. The risk of malignancy is quite high for FIU in colon-rectum, thyroid, breast and prostate especially when histologically analyzed. Beyond the localization, when FIU are detected further investigation is warranted.

Somatostatin receptor PET/MRI for the evaluation of neuroendocrine tumors

Abstract: With the introduction of simultaneous PET/MRI scanners, concurrent acquisition of PET and MRI data is feasible, allowing for improved patient convenience and decreased radiation dose. Although PET/MRI has been used in many settings, not all cancers benefit from the combined modality. With the availability of somatostatin receptor-targeted PET tracers such as 68Ga-DOTA-TOC and 68Ga-DOTA-TATE, imaging of NET patients has refocused on targeted imaging, particularly with the development of peptide receptor radiotherapy. Nonetheless, there are many patients who continue to benefit from dedicated MR imaging, such as those with liver-predominant disease. In these patients, SSR PET/MRI is an important option for optimal imaging. Both diffusion-weighted imaging and hepatobiliary phase imaging provide improved lesion detection compared to conventional MRI and CT, and the results can effect therapeutic decisions. Additionally, the use of motion correction techniques can be used to leverage the additional PET data acquired in dedicated liver PET/MRI to remove respiratory artifacts.

18F-FDG PET for diagnosing painful arthroplasty/prosthetic joint infection

Abstract: Up to now, there were some studies about the role of 18F-FDG PET or PET/CT in the diagnosis of prosthetic joint infection after arthroplasty with different values of sensitivity and specificity. The purpose of this study was to systematically review the published data regarding the diagnostic performance of positron emission tomography (PET) or PET/computed tomography (PET/CT) in prosthetic infection after arthroplasty. A comprehensive computer literature search of studies published regarding PET or PET/CT in patients suspicious of prosthetic infection was performed. Pooled sensitivity, specificity and area under the receiver operating characteristic (ROC) curve of PET or PET/CT in patients suspicious of prosthetic infection on a per prosthesis-based analysis were calculated. Sixteen studies comprising 1101 prosthesis with suspicious of prosthetic infection after arthroplasty were included in this meta-analysis. The pooled sensitivity of PET or PET/CT in detecting prosthetic infection was 87% [95% confidence interval (CI) 83–90%] on a per prosthesis-based analysis. The pooled specificity of PET or PET/CT in detecting prosthetic infection was 87% (95% CI 85–89%) on a per prosthesis-based analysis. The area under the ROC curve was 0.94 on a per prosthesis-based analysis. 18F-FDG PET or PET/CT demonstrated high sensitivity and specificity in subjects suspicious of prosthetic infection. However, various degrees of uptake in the asymptomatic patients are very common. Physicians should recognize these characteristics, and then 18F-FDG PET or PET/CT can act as an effective method in the diagnosis of prosthetic infection.

Hypoxia 18 F-FAZA PET/CT imaging in lung cancer and high-grade glioma: open issues in clinical application

Abstract: Hypoxia can influence response to chemo and radiotherapy in different tumours, including non-small cell lung cancer (NSCLC) and high-grade gliomas (HGG). PET/CT can non-invasively investigate hypoxia and 18F-FAZA seems to be the most promising radiotracer. However, there are still controversial issues related to image analysis and data interpretation hampering the effective possibility to translate the use of this imaging modality in clinical applications. The aim of the present pictorial review is to provide insights and answers on the open issues related to the potential clinical applicability of 18F-FAZA PET/CT for hypoxia delineation. From Pubmed and Scopus databases, a literature research has been performed with the following research filters for both NSCLC and HGG: (1) time frame: last 10 years; (2) language: English; (3) species: human. Applied searching keywords were “hypoxia” or “hypoxic” and “PET” and “lung cancer” for NSCLS and “hypoxia”, “PET” and “glioma” for HGG. Papers not strictly matching the imposed search filters have not been considered. The literature search led to 76 papers for NSCLC, but for the purpose of the review only 10 have been considered, after double-checking and exclusion if not matching the imposed search filters. For HGG, the selected filters lead to 19 papers but only 8 have been considered for data analysis. Results on the use of 18F-FAZA PET/CT in two different settings are reported in the present pictorial essay and methodological suggestions for clinical practice are presented through the description of addressed representative case reports. Based on literature evidence and presentation of relevant clinical case reports, issues related to 18F-FAZA PET/CT in clinical settings have been addressed, providing possible solutions that may help the reliable use of this imaging method in clinical practice.

Fifty shades of meningioma: challenges and perspectives of different PET molecular probes

Abstract: tissue only. Nevertheless, increased uptake of 18F/11Ccholine has been observed in meningiomas of patients who were examined during staging or restaging of prostate cancer [3, 4]. Recently, similar findings have also been reported for 64Cu/68Ga labeled prostate-specific membrane antigen (PSMA) [5–7], demonstrating a limited specificity of these tracers for prostate cancer. Moreover, meningiomas have been reported as avid of several other PET radiopharmaceuticals, such as l-3,4-dihydroxy-6-[18F]fluorophenylalanine (18F-DOPA) [8], 18F-NaF [9, 10], 18F-fluroethylthyrosine (18F-FET) [11] and 68Ga-DOTA-DPhe1,Tyr3-octreotate (68GaDOTATATE) [12, 13]. The molecular mechanisms leading to increased uptake of these tracers in meningiomas remain to be elucidated. Being a lesion with a conspicuous calcific component, the uptake of 18F-NaF is most likely to be related to the deposition of hydroxyapatite crystals in the intralesional calcifications. The moderate rise of lipogenesis associated with the increased production of cellular walls and the higher rate of protein synthesis could induce the uptake of radiolabeled choline and that of amino acid tracers, such as 11C-methionine [14], 18F-FET [11] and 18F-DOPA [8]. The 64Cu/68Ga PSMA uptake in meningioma could be due to the neo-vasculature of the tumor tissue [7]. Anyway, the molecular causes of the uptake of several PET radiopharmaceuticals still need to be addressed. Furthermore, the higher proliferative activity as shown by the direct relationship between Ki67 expression and tumor grade [15], could lead to greater metabolic activity of meningiomas. Generally, the very low background radioactivity of radiolabeled choline and amino acid tracers facilitates the recognition of cerebral neoplastic processes. This feature represents a major advantage for the application of these radiopharmaceuticals in neuro-oncology but their lack of specificity remains a challenge. Co-registration with Most meningiomas are classified as primitive grade I brain tumors, following the World Health Organization (WHO), and represent approximately 30% of all intracranial tumors, which are particularly frequent in the elderly. Atypical or anaplastic meningiomas, classified as grade II and III, represent a minority, likely associated with neurological symptoms. These tumors need aggressive treatment and the conundrum for clinicians and surgeons is whether treating these patients with surgery and/or radiotherapy. Furthermore, the possibility of metastatic extra-cranial spread must be taken into account [1] and in the further course of the disease the possibility of local relapse [2] which represents a challenge to nuclear medicine physicians and radiologists. In routine clinical practice, meningiomas may represent diagnostic pitfalls occurring during single photon emission computed tomography (SPECT) or positron emission tomography (PET) scans, performed for somatic tumors. Several papers describe the possibility of incidental uptake of various radiopharmaceuticals applied for the diagnostics of meningiomas. The development of hybrid imaging, especially PET/CT scanners, allowed to easily recognize meningiomas as hyperdense areas with calcifications, following CT diagnostic criteria. Despite this improvement of specificity, the report of such brain lesions still represents a diagnostic dilemma, in terms of differential diagnosis with metastatic lesions from somatic tumors or other malignant primary brain tumors. The ideal radiopharmaceutical in nuclear medicine should accumulate in the specific target

Nuclear medicine techniques in transplantation

Abstract: To evaluate the indications and perspectives of nuclear medicine techniques in transplantation. We performed a systematic review of the literature using PubMed/Medline and Google scholars, with multiple research keywords for each organ accompanying the terms “transplant”, “transplantation”, “graft”, “nuclear imaging”, “scintigraphy”, “PET” and “PET/CT”. The review considers the following organs/systems: kidney, liver, pancreas, heart, lung, bone and salivary glands, as well as a common complication, the post-transplant lymphoproliferative disorder. The references of the retrieved articles were also considered to find supplementary articles. The search was limited to English language. Preoperative workup exploration, preclinical and animal studies were not included in the review. A total of 146 original articles were considered for the review, including 118 retrospective and 28 prospective studies. The functional integrity of the renal graft is safely and reliably assessed using quantitative dynamic scintigraphy with 99mTc-DTPA or 99mTc-MAG3. 18F-FDG PET/CT is a promising method for early detection of acute rejection. The glomerular filtration rate (GFR) of potential donors should ideally be assessed using 51Cr-EDTA, and the split renal function could be quantified using 99mTc-MAG3 or 99mTc-DMSA imaging. In liver transplantation, both 99mTc-GSA and 99mTc-HIDA scintigraphies can be used for evaluating the function of transplanted liver, and 18F-FDG PET/CT increasingly appears as a powerful tool for characterising the aggressiveness of hepatocellular carcinoma and contributes to the decision of transplantation in selected patients. In heart transplants, the major indication is the evaluation of cardiac allograft vasculopathy using myocardial perfusion imaging, either with SPECT or PET. In the context of lung transplantation, perfusion scanning helps select potential donors and contributes to the postoperative follow-up, either early on for detecting primary graft dysfunction or later on in the diagnosis of chronic rejection. Bone scintigraphy and 18F-NaF PET/CT are valuable tools for assessing bone graft viability. This is particularly established in mandible grafts, but convincing data are available in other types of graft. Salivary gland transplantation is not frequently performed, but in such a clinical situation, 99mTcO4 scintigraphy is an elegant way to help select the transplant and to verify the viability of the graft. Finally, 18F-FDG PET/CT is very effective in patients with post-transplant lymphoproliferative disorder (PTLD), both at diagnosis and for evaluating the response to treatment. Nuclear medicine techniques are strongly established as valuable clinical tools in a wide variety of indications, before and after organ transplantation. Furthermore, 18F-FDG PET/CT in PTLD and radio-isotopic evaluation of the renal function in putative kidney donors are recommended in clinical algorithms proposed in international guidelines.

Molecular imaging in early diagnosis, differential diagnosis and follow-up of patients with neurodegenerative diseases

Abstract: Current disease models suggest that many neurodegenerative disorders are associated with pathological protein aggregations that start to develop in the brain long before the onset of clinical symptoms. Therefore, biomarkers allowing early and reliable characterization of neurodegenerative disease are required. Here we illustrate the potential value of neuroimaging procedures by means of selected examples. Multimodal imaging data of exemplary patients who underwent FDG, Amyloid and AV-1451-PET, FP-CIT-SPECT and MRI imaging in the routine clinical workup in our department is presented and the currently available literature on the topic of imaging in neurodegenerative diseases was reviewed. The complementary value of the applied imaging methods is demonstrated in pairs of representative cases. Depending on the clinical question, individual methods or a meaningful multimodal combination is required to achieve optimal diagnostic benefit. Imaging biomarkers have high potential for early diagnosis, differential diagnosis and follow-up of patients with neurodegenerative diseases already and will gain an even higher importance in the future, when specific pathology-targeted therapies will be evaluated in clinical trials.

The new era of cancer immunotherapy: what can molecular imaging do to help?

Abstract: Homeostasis of the immune system is regulated by a complex network of signals including multiple checkpoints that prevent uncontrolled harmful immune responses and maintain self-tolerance. Cancer cells are self-derived tissues and may take advantage of these checkpoints to escape detection by the innate immune system. Blockade of these immune checkpoint pathways has shown remarkable efficacy in the treatment of many cancers, including Hodgkin lymphoma, non–small-cell lung cancer, melanoma, and others [1]. Some of these checkpoints, such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD-1), have been extensively studied as targets for more efficacious and precise cancer immunotherapy. CTLA4 counteracts the activity of the T cell co-stimulatory receptor CD28 and actively delivers inhibitory signals to the T cell, with the final downregulation of T cell activation through several mechanisms (e.g., increasing the T cell activation threshold and attenuation of clonal expansion). In addition to its expression on T cells, CTLA4 may also be expressed by many tumor types, such as nonsmall-cell lung cancer, although the biological consequences remain to be elucidated. CTLA4-targeted antibodies have shown efficacy in the treatment of many cancers, and many of these antibodies have been approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for clinical use [1]. However, despite the therapeutic benefits, antiCTLA4 treatments can also lead to severe adverse effects [1]. PD-1 has two endogenous ligands, PD-1 ligand 1 (PDL1) and PD-L2, and their inhibitory effect is accomplished through a dual mechanism of promoting apoptosis by antigen-specific T cells in lymph nodes while simultaneously reducing apoptosis for regulatory T cells (i.e., suppressor T cells). Immunotherapy strategies that interfere with the PD-1 checkpoint have shown enhanced anticancer activity in the clinical setting. In contrast to PD-1, which is primarily expressed on T cells and pro-B cells, PD-L1 is naturally expressed on several tissues, including some tumor cells, vascular endothelium, hepatocytes, mesenchymal stem cells, T and B cells, macrophages, and mast cells. In general, PD-1-targeted treatments have shown fewer adverse effects than therapy targeting the CTLA4 pathway. Besides these commonly studied targets (i.e., PD-1/PDL1 and CTLA4), there are at least a dozen immune checkpoint receptors, all of which could be potential therapeutic targets. However, most of these play a secondary role in T cell responses to tumors, such as Lag-3, T-cell immunoglobulin and Tim-3, and T-cell immunoglobulin and ITIM domain (TIGIT). Since these targets are usually co-expressed with PD-1 on exhausted T & Laura Evangelista laura.evangelista@iov.veneto.it

Biodistribution of 99mTc-MAA on SPECT/CT performed for 90Y radioembolization therapy planning: a pictorial review.

Abstract: To evaluate the frequency of 99mTc-MAA uptake in extrahepatic organs during 90Y-radioembolization therapy planning. This retrospective case series of 70 subjects who underwent 99mTc-MAA hepatic artery perfusion studies between January 2014 and July 2016 for 90Y-radioembolization therapy planning at our institution involved direct image review for all subjects, with endpoints recorded: lung shunt fraction, extrahepatic radiotracer uptake, time from MAA injection to imaging. Combined planar and SPECT/CT imaging findings in the 70 subjects demonstrated lung shunt fraction measurements of less than 10% in 53 (76%) subjects and greater than 10% in 17 (24%) subjects. All patients demonstrated renal cortical uptake, 23 (33%) demonstrated salivary gland uptake, 23 (33%) demonstrated thyroid uptake, and 32 (46%) demonstrated gastric mucosal uptake, with significant overlap between these groups. The range of elapsed times between MAA injection and initial imaging was 41–138 min, with a mean of 92 min. There was no correlation between time to imaging and the presence of extrahepatic radiotracer uptake at any site. During hepatic artery perfusion scanning for 90Y-radioembolization therapy planning, extrahepatic uptake is common, particularly in the kidney, salivary gland, thyroid and gastric mucosa, and is hypothesized to result from breakdown of 99mTc-MAA over time. Given the breakdown to smaller aggregates and ultimately pertechnetate, this should not be a contraindication to actual Y-90 microsphere therapy. Although we found no correlation between time to imaging and extrahepatic uptake, most of our injection-to-imaging times were relatively short.

Therapeutic options to overcome tumor hypoxia in radiation oncology

Abstract: Expert review summarizing the overcome tumor cell hypoxia by treatment modification in radiation oncology. An extensive literature search regarding various means of treatment modification was performed and key papers on those modifications were included in this review article. Based on the identified key papers the means to overcome hypoxia in radiation oncology were summarized in this review article, e.g., increasing levels of oxygen, combining radiotherapy with agents counteracting hypoxia, or modifying radiation treatment itself. This review summarizes the results of preclinical and clinical studies counteracting hypoxia and highlights the measures that have found their way into clinical practice.

PET/MRI in breast cancer

Abstract: This review aims to evaluate the respective values of MRI and FDG PET and their combination as a single imaging device in detection, staging, treatment selection, response evaluation, recurrence detection and restaging in breast cancer patients. A comprehensive literature search in the PubMed/MEDLINE, Embase and Scopus databases was performed including articles up to February 2016, resulting in the selection of 57 articles. The combination of PET and MRI in a single imaging device could provide synergistic diagnostic value and logistical benefit for patients. However, currently there are insufficient data to identify situations where PET/MRI would provide sufficient clinical benefit to justify its application. In addition, current generation equipment is hampered by technical challenges. Adequate acquisitions of PET and MRI require the current issues with prone position imaging and signal quantification in PET/MRI to be resolved. It is advised to perform integrated PET/MRI for primary breast tumours within the scope of clinical trials. It is expected that the technical issues of PET/MRI will be resolved, and that this promising imaging combined modality will have a significant benefit for patients with breast cancer, at least for selected subgroups.

Positron emission tomography and magnetic resonance spectroscopy in cerebral gliomas

Abstract: Conventional MRI, the gold standard in structural brain imaging, alone has its limitations in pre-operative tumour grading, biopsy targeting, determination of accurate tumour margins prior to surgical resection/radiation therapy, detection of tumour recurrence and determination of early therapeutic response. The aim was to introduce and review two of the recently most discussed adjunct modalities for molecular imaging in glioma: PET and MRS, and the combination of both. A PubMed search with a combination of the terms “MRS”, “glioma” and “glioblastoma”, “brain tumour”, “positron emission” and “PET” was carried out. These results were complemented with a search of the authors’ own files. Preclinical in vitro studies as well as animal studies were excluded. Published single modality data show that 1H-MRS and PET perform similarly in answering clinical questions, which cannot be adequately answered by conventional MR imaging alone. Original articles including patients with gliomas and combining the PET and MRS modalities within the same study were scarce and resulted in 17 research papers. These articles especially point to a spatial correlation between 1H-MRS metabolic ratios and amino acid uptake and a positive relationship with histologically proven cell proliferation markers, indicating diagnostic improvement in the differentiation between glioma and benign lesions, in the delineation of brain tumours and in the differentiation between treatment-related changes and tumour progression. PET and 1H-MRS have shown their value in the non-invasive diagnosis of gliomas delivering metabolic tumour information in addition to pure structural information from conventional MRI or CT alone. The very few studies, which were conducted evaluating 1H-MRS and PET in combination, indicate a diagnostic benefit from a combined imaging approach in glioma and encourage more systematic investigation—ideally carried out in multicentric settings, in experienced neuroimaging centres (with access to integrated PET/MRI scanners), using standardized imaging- and analysis protocols.

Dose optimization: a review of CT imaging for PET attenuation correction

Abstract: Review limitations and benefits of various options for CT-based attenuation correction for PET/CT studies With the combination of PET and CT, came the combination of patient radiation dose from the two imaging modalities Modern advances in CT technology provide opportunities to design CT acquisitions for attenuation correction allowing for the optimization of the attenuation correction acquisition for specific clinical purposes We reviewed published literature, accepted practices, and the authors’ experience, to identify and classify various tailored approaches for CT attenuation correction of PET emission data ImageWisely recommends three broad categories for dose optimization of attenuation correction in PET/CT imaging: (1) attenuation correction at diagnostic CT quality (PET/CTD); (2) attenuation correction for anatomic localization only of PET images (PET/CTAL); and (3) for PET attenuation correction only (PET/CTAC) The advantages, disadvantages, and dosimetry for each approach are considered Modern dose reduction techniques allow some CTAL and CTAC exams to have a sufficient image quality for anatomic localization at radiation dose levels equivalent to the previous radionuclide attenuation correction method with [68-Ge/68-Ga] transmission sources Thus, the major justifications for combining diagnostic quality CTD with PET would be to provide excellent anatomic image correlation in the cases, where subtle functional or lesion uptake requires greater localization refinement, and to reduce patient dose by removing the CTAC or CTAL exam in conjunction with a separate diagnostic CT in lieu of a single CTD exam The choice of method depends on a variety of factors, including institutional and physician preference and experience, and technology availability

Clinical applications of PET using C-11/F-18-choline in brain tumours: a systematic review

Abstract: The purpose of this study is to conduct a systematic review of the published data about the current indications in clinical practice for the use of positron emission tomography (PET) or PET/computed tomography (PET/CT) using either Carbon-11 (11C) or Fluorine-18 (18F) choline tracer in brain tumours. A comprehensive literature search of PubMed until April 30, 2016 with the Mesh terms: ‘‘positron emission tomography’’, ‘‘choline’’, and ‘‘brain neoplasm’’ was first performed. On a second step, the references of the retrieved articles were also screened, adding any relevant publications about the subject. A total of 15 articles corresponding to 453 patients with brain lesions (mostly gliomas) were included for the analysis, successfully imaging brain tumours for the following indications: diagnosis and tumour characterisation; biopsy guide; treatment planning; differential diagnosis of recurrence or radiation necrosis; and therapy response assessment and prognosis. In addition, other brain lesions have been imaged by PET choline, such as meningiomas and metastasis. PET or PET/CT with radiolabelled choline must be considered as an emerging procedure for the evaluation of brain tumours. Since choline has a low physiological uptake, it provides precise images with a very good tumour-to-background ratio, especially in lesions with disruption of the blood–brain barrier. Even though the small population and heterogeneity of analyzed studies precluded performing a meta-analysis, the exposed results in this review support the use of choline in the aforementioned indications based on its availability, but larger studies are needed to better validate its use.

The current and evolving role of FDG–PET/CT in personalized iodine-131 therapy of differentiated thyroid cancer

Abstract: Several approaches have been recommended for the selection of patients with differentiated thyroid cancer amenable for postoperative radioiodine remnant ablation or repeated radioiodine treatment, though with inadequate results. 2-[18F]-fluoro-2-deoxy-d-glucose positron emission tomography is gaining consideration for predicting disease-free or survival of differentiated thyroid carcinoma patients, in particular in the peri-or post-surgery setting and for the detection of recurrence in patients with elevated or rising thyroglobulin without evidence of disease on neck ultrasound or iodine scintigraphy. This paper aims to review the role of FDG–PET/CT in tailoring iodine-131 empiric therapy for radioiodine remnant ablation and the detection of recurrence in patients with elevated thyroglobulin and negative iodine-123 scan. A literature search up to May 2017 of MEDLINE® and SCOPUS® with the Mesh terms: “PET/CT”, “iodine-131 therapy”, “differentiated thyroid cancer” and “prognosis” was performed. Thereafter, papers dealing with radioiodine remnant ablation and empiric therapy were selected. Ninety papers were retrieved from the initial search and 19 considered for the review. The percentage of positive FDG–PET/CT performed at radioiodine remnant ablation or shortly after ranged from 17 to 69%, with highest values in high- and intermediate-to-high risk patients. The response rate to radioiodine remnant ablation and survival were consistently higher in negative FDG–PET/CT patients. Besides, FDG–PET/CT imaging was found to be a very accurate diagnostic tool for the detection of recurrence in patients with elevated thyroglobulin and negative iodine-123 scan, discriminating patients needing further empirical iodine-131 therapy from those who could benefit from alternative approaches. Although a meta-analysis was not possible due to the heterogeneity and the small population samples of the studies retrieved, the results of the present review support the use of FDG–PET/CT in tailoring iodine-131 therapy when used close to radioiodine remnant ablation and in patients amenable to iodine-131 empiric therapy.

Approaches for the discovery of novel positron emission tomography radiotracers for brain imaging

Abstract: Positron emission tomography (PET) is a widely used imaging technique with many biomedical and drug development applications. The implementation of this technology requires the availability of selective radiotracers with suitable physicochemical characteristics relevant for each target, disease process/pathology, or physiological application. The purpose of the present review was to outline a typical high-level flow scheme for the discovery of PET radiotracers and discuss a variety of methods employed in the field to prosecute the flow scheme steps. In addition, techniques will be described which may be employed to overcome obstacles encountered during the execution of a radiotracer discovery flow scheme when specific challenges are encountered. Based on our experience and a survey of the available literature we critically reviewed the manner in which laboratories execute each radiotracer discovery flow scheme step according to the ex vivo, in vitro, and in vivo resources available. We found that PET radiotracer identification requires that certain steps or scientific hurdles are met. The strategy or technology applied to answer these scientific challenges varies across laboratories as a function of access to resources. These resources may be accessed through collaboration with other scientists and laboratories. There has been an attempt by a number of research groups to define the optimal physiochemical property space for brain-penetrant PET radiotracers and to use these criteria to reduce the number of molecules further evaluated in vitro or in vivo. While these represent useful guidelines, they should not be taken as rules as none of them have demonstrated 100% accuracy in predicting success and failure of potential PET radiotracers. The advent and application of new technologies, such as protein target overexpression and viral vector administration, along with improvements in LC–MS/MS sensitivity, are expanding the ability of laboratories to initiate radiotracer discovery efforts for targets challenged by low rodent protein target expression or differences in protein sequences between rodent and human. The techniques and approaches available for the discovery of novel small molecule CNS PET radiotracers continue to evolve. As new research technologies and scientific input from a variety of disciplines are applied to the discovery effort, novel solutions are generated and expand the field of radiotracer discovery.

PET/MRI and brain tumors: focus on radiation oncology treatment planning

Abstract: In brain tumors, imaging by magnetic resonance imaging (MRI) can very accurately visualize anatomy and morphology of healthy and malignant tissue, but neither contrast-enhancing areas in T1-weighted sequences, nor hyperintensities in T2/FLAIR sequences are specific for tumor tissue, especially when considering the manifold alterations resulting from previous treatment. Imaging the biology of tumor tissue by positron emission tomography (PET), therefore, is a highly interesting approach to improve the detection of macroscopic tumor which is the prerequisite for high-precision radiotherapy treatment planning. This review will focus on the benefits of amino acid tracers (l-[methyl-11C]methionine (MET) and O-(2-[18F]fluoroethyl)-l-tyrosine (FET)) in neurooncology and their implementation in radiation oncology. Furthermore, a brief overview of the current impact of 2-deoxy-2-(18F)fluoro-d-glucose (FDG), nucleic acid analogs, hypoxia tracers, and Somatostatin receptor (SSTR) analogs on radiotherapy planning in brain tumors is provided. Among advances in multiparametric MRI, Diffusion-weighted imaging (DWI) has attracted particular attention since it can predict prognosis, as well as indicate response to treatment and has already been introduced into target volume definition for radiotherapy of various cancers (e.g., prostate and rectal cancer). Additionally, advances in MR spectroscopy (MRS) are mentioned. Finally, these findings will be discussed concerning their influence on current aspects of integrated PET/MR hybrid imaging.

PET probes for imaging pancreatic islet cells

Abstract: PET can detect very low concentrations of the probes at subpicomolar range in the target tissue with high sensitivity. The development of PET probes for imaging pancreatic islet cells depends on several key elements: the amount of target receptors in the beta cells; the target specificity and the target tissue delivery. This review summarized the latest developments of PET probes which are targeting proteins including GLP-1, VMAT2, GPR44, antigen, glucokinase and reporter genes in the beta cell for imaging pancreatic islet cells. A survey of the literature was performed to select the articles focusing on the development of PET probes for proteins targeting in the beta cell. Since PET probe development for imaging pancreatic islet cells is a narrow research field, the literature survey comprised of those articles published from 1993 when first probe C-11 DTBZ was synthesized to 2017 in English journals. In-111 SPECT probes are included for comparison study. A selection of 97 papers were identified following the literature review. The probes covered tritium-3-, carbon-11-, fluorine-18-, gallium-68-, copper-64- and indium-111 (for SPECT)-labeled radioligands. The PET imaging studies with the probes have been evaluated for in vitro, ex vivo, preclinical and clinical applications. Some issues of targeting probes have been addressed to develop ideal non-invasive PET probes for imaging pancreatic islet cells. From the literature, a number of new probes have been developed in recent years to improve their biological profile such as higher specific binding to target with lower nonspecific binding to surrounding tissue, or optimal residence time in the subjects. PET imaging modality for imaging pancreatic islet cell especially beta cell provided high resolution, high sensitivity, and accurate quantification through the biodistribution, pharmacokinetics and target binding of tracers. The demand for new PET probes for preclinical and clinical investigations is increasing. This review gives comprehensive overview of noteworthy probes which are proteins targeting in beta cell. The review provides some future research directions for this emerging field.