ISSN (Print): 1874-4710
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Volume 14, 4 Issues, 2021
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Evidence has grown for a causal role of inflammation underlying a wide range of cardiovascular pathology, including atherosclerosis
and ischemic heart disease [1-3]. The inflammatory response represents an integral reaction to tissue injury necessary
for adequate repair or replacement of damaged cells . And yet, excessive inflammation can contribute to worsening tissue
damage and adverse outcomes [5, 6], potentially contributing to plaque rupture, myocardial infarction, and post-infarction
left ventricular remodeling. As such, modulating the inflammatory response in patients with heart disease may represent an
effective therapeutic strategy to reduce the future risk of cardiovascular events [1, 2, 7]. The myriad pathophysiological mechanisms
of inflammation lend themselves to a number of potential molecular (and possibly theranostic) targets, which may be
effectively probed using molecular imaging [8, 9].
To date, positron emission tomography (PET) using 18F-fluorodeoxyglucose (FDG) remains the most well-established molecular
imaging technique for visualization of inflammation in vivo. The high glucometabolic rate of infiltrating leukocytes
allows for sensitive detection of active inflammation using this radiotracer. However, heterogeneous glucose metabolism in the
normal heart can cause an unfavorable lesion-to-background ratio and requires special attention . Several strategies exist to
suppress this physiologic myocardial uptake of glucose by leveraging alternative mechanisms responsible for glucose uptake
within the myocardium. Following dietary intake of carbohydrates, glucose typically enters cardiac myocytes via the glucose
transporter GLUT4. In contrast, glucose enters activated inflammatory cells via the overexpressed glucose transporters GLUT1
and GLUT3 . As such, patient dietary preparations suppressing GLUT4 in normal myocardial cells can substantially increase
the accuracy of 18F-FDG PET/CT. Despite this, residual FDG uptake in normal myocardial tissue may still hamper accurate
interpretation of results . Hence, alternative tracers with greater specificity for inflammatory targets are needed in cardiovascular
Beyond glucose metabolism, novel radiotracers targeting pathways involving leukocyte recruitment to sites of inflammation
may provide additional insight into cardiovascular pathology [13, 14]. Following an initial insult, granulocytes and patrolling
monocytes are recruited from bone marrow to enter damaged tissue and isolate the affected region, thus initiating a localized
inflammatory response . During this process, different granulocyte subpopulations are characterized by a different timecourse
in their expression. Proinflammatory, M1-like macrophages are recruited early, followed by the expression of reparative,
M2-like macrophages . While the former subtype is responsible for the production of proinflammatory molecules, including
cytokines and proteases, the latter facilitates the secretion of factors stimulating angiogenesis and extracellular matrix reorganization,
which are responsible for the promotion of fibrosis, as occurs in the post-infarction myocardial scar .
Preclinical research has explored a number of potential imaging targets expressed by proinflammatory and reparative macrophages.
Promising preliminary reports have been published focusing on radiocompounds targeting amino acid metabolism
(e.g., 11C-Methionine ), chemokine receptors (e.g., CXCR4 receptor with 68Ga-Pentixafor ), somatostatin receptors
(e.g., 68Ga-DOTATATE ), mitochondrial translocator protein (e.g., 11C-PK11195 ) and integrin activity (e.g., 18FGalacto-
RGD ). While not currently utilized in routine clinical practice, translation of these approaches to clinical settings
remains of great interest, and future investigations within prospective, randomized trials leveraging comparison with histopathologic
data are needed .
To date, attempts to yield clinically prognostic data using molecular imaging have focused on two areas: (1) the identification
of vulnerable coronary atherosclerotic plaques prone to rupture [24, 25] and (2) the assessment of post-infarction inflammatory
alterations within the myocardium responsible for ventricular remodeling. While molecular imaging of atherosclerosis
can provide important mechanistic information on the composition and biological activity of these plaques, its value beyond
existing biomarkers has not yet been proven in the clinical management of patients with coronary artery disease [26, 27]. This
is also the case with imaging of post-infarction inflammatory alterations of the myocardium for therapeutic monitoring following
myocardial infarction .
In light of this, there is no doubt that increased collaboration between scientists and clinicians with broad expertise in these
areas will be beneficial. Working together, preclinical scientists, imaging experts, and clinician-investigators may be better positioned
to provide meaningful perspectives on the design and execution of molecular imaging research in cardiovascular disease.
Novel, targeted imaging agents may facilitate the development of clinical therapies to modulate inflammation and provide
not only a surrogate indicator of therapeutic efficacy but also of appropriate targeting and timing of optimal treatment .
Common imaging and therapeutic targets may also herald a new paradigm in clinical evaluation, wherein imaging endpoints
may serve as early ancillary indicators of therapeutic benefit, harm, or futility in clinical trials.
More than ever, molecular imaging of myocardial inflammation is poised to impact the treatment of cardiovascular disease.
Experts working collaboratively across the translational spectrum can now tailor investigations to identify early inflammatory
changes in the heart, which may contribute to subsequent adverse cardiovascular outcomes. Future efforts may play a pivotal
role in the selection of appropriate heart disease patients for specific interventions and facilitate a novel approach combining
population health with personalized precision medicine.
Today, the focus on personalized medicine and translational research has increased. This situation leads to the need for the
development of new disease-specific nanoprobes. Multifunctional nanoparticles can fulfill this need with diagnostic and therapeutic
capabilities both for target-specific diagnosis and for treating a particular disease. The future of nanomedicine lies in
multifunctional nanoplatforms that combine diagnostic ability and therapeutic effects using appropriate ligands, drugs, responses
and technological devices. Co-administration of radiolabeled nanoparticles is useful in the fields of multifunctional molecular
imaging because it has several advantages based on the architecture of nanoparticles, pharmacokinetics and pharmacodynamic
properties. This has led to the development of multiple imaging systems such as PET / CT, SPECT / CT or SPECT /
MRI and PET at the same time. As a result, with the growing interest in personalized medicine and translation research, the
need to develop disease-specific nanoprobes has been focused on radionuclide labeled nanoprops that are suitable for PET
(Positron Emission Tomography) / SPECT (Single Photon Emission Tomography). On the other hand, the need for new PET
and SPECT radionuclides has increased, instead of 99mTc and 18F, which are traditionally more commonly used. The radionuclides
couples of the same element which have different decay properties that perform both imaging and therapy with the same
chemistry, have started to gain importance as they show theranostic properties. The biggest challenges are; development of
easy-to-use, high-efficiency radiolabeling strategies, increasing imaging stability, increased sensitivity to early stage sensitivity
of the disease, and optimization of pharmacokinetics in vivo. The aim of this issue is to discuss and present some experimental
results from basic to preclinical researches and review general aspects of preclinical models for theranostic approaches.
The present issue starts with an experimental work regarding a nanoprobe that combines a natural anticancer compound
called thymoquinone to glucuronide for targeting tumor cells. The thymoquinone glucuronide was conjugated to magnetic nanoparticles
to create a nanoprobe for imaging and treatment of lung cancer. Magnetic nanoparticles (MNP) was added to the
nanoprobe for therapy with magnetic hyperthermia and MRI imaging, as well as 131I for SPECT imaging and radionuclide therapy.
Preclinical works for imaging and therapy potential of nanoprobe were presented. They concluded that TQGMNP may
ultimately be used not only for diagnosis as an in vitro diagnostic kit for the diagnosis of beta-glucuronidase rich cancers but
also for the treatment of various cancers.
Teksöz et al. proposed a research article about a novel targeted radiolabeled drug delivery system. In this work Gemcitabine(
GEM) was encapsulated into polymer nanoparticles (PLGA) together with iron oxide nanoparticles, and then labeled with
99mTc. Cytotoxicity of GEM loaded SPION-PLGA were investigated on MDA-MB-231 and MCF-7 breast cancer cells. The
authors concluded that SPION-PLGA-GEM showed high uptake on MCF-7, whilst the incorporation rate was increased for
both cell lines which external magnetic field application.
İnci et al. focused on a hypoxia marker Pimonidazole (PIM) as a candidate biomarker of cancer aggressiveness. For this
purpose, PIM was derivatived as PIM-TOS to be able to be radioiodinated. They concluded that in light of the radioiodination
studies carried out in current study, further experimental studies should be performed for developing novel hypoxia probes,
including theranostics approaches.
To achieve successful results in rapidly accelerating personalized treatment research of today, the first step is to conduct
appropriate preclinical studies.
Regarding preclinical studies, Korkmaz and Üstün reviewed experimental tumor and validated methods to examine the
pathogenesis of cancer, the onset of the neoplastic process and progression. The development of animal models for breast cancer
research has been the last century. Imaging methods used in breast cancer are used for tumor localization, quantification of
tumor mass, imaging of genes and proteins, evaluation of tumor microenvironment, evaluation of tumor cell proliferation and
metabolism and treatment response evaluation. Since human breast cancer is a heterogeneous group of diseases in terms of genetics
and phenotype; it is not possible for a single model to adequately address all aspects of breast cancer biology. Considering
that each model has advantages and disadvantages compared to each other, the most suitable model should be chosen in
order to verify the thesis of the study.
Soyluoglu and Altun reviewed general aspects of preclinical models for theranostic research and present examples from the
literature reviewed to detect diseased cells by using targeted molecules using disease-specific biological pathways and then
destroy them by cellular irradiation without damaging other tissues. Diagnostic tests guide the use of specific therapeutic agents
by demonstrating the presence of the receptor/molecule on the target tissue. Because the therapeutic agent is administered to
patients who have a positive diagnostic test, the efficacy of treatment in these patients is largely guaranteed. As therapeutic efficacy
can be predicted by therapeutic agents, it is also possible to monitor the response to treatment. Many diagnostic and therapeutic
procedures in nuclear medicine are classified as theranostic. 131I treatment and scintigraphy is the best example of
theranostic application. Likewise, 177Lu/90Y octreotate for neuroendocrine tumors, 177Lu PSMA for metastatic or treatmentresistant
prostate cancer, 90Y SIRT for metastatic liver cancer, and 223Ra for bone metastasis of prostate cancer are widely used.
Also nanoparticles are one of the most rapidly developing subjects of theranostics. Diagnostic and therapeutic agents that show fluorescent, ultrasonic, magnetic, radioactive, contrast, pharmacological drug or antibody properties are loaded into the
nanoparticle to provide theranostic use.
68Ga is an ideal research and hospital-based PET radioisotope. The uptake mechanism of Gallium citrate is a combination of
specific and non-specific processes, for example, vasodilatation, increased vascular permeability, plasma transferrin binding
and lactoferrin and siderophores. Ugur and Gültekin have focused on the experimental work on the synthesis of 68Ga-citrate and
preclinical imaging studies with rabbits.
Lung cancer is considered the most common malignancy in males and females and it is associated with a poor prognosis.
Five-year survival in patients affected by lung cancer varies from 4-17% based on stage and regional differences . The introduction
of alternative treatment strategies, such as high-dose stereotactic body radiation therapy , targeted therapies  and
immunotherapy has had a profound impact on the management and survival of patients with lung cancer. Moreover, imaging
modalities, both anatomical and functional, have changed the prediction and the assessment of response to therapy .
In the present monothematic issue, we have discussed the current role of radiological and nuclear medicine techniques. In
the first manuscript by Panunzio et al. , the utility of radiological images for the staging of lung cancer has been discussed.
Farsad et al.  completed the assessment of the staging of this neoplasm by using 18F-Fluorodeoxyglucose (FDG) positron
emission tomography (PET)/computed tomography (CT). Moreover, Castello et al.  and Evangelista et al.  analysed the
ability of FDG PET/CT in predicting the response to systemic and immunotherapies, respectively. Filice et al.  described the
impact of FDG PET/CT in radiotherapy planning for the treatment of lung tumor and Crivellari et al.  discussed the implementation
of respiratory gating for the improvement of the diagnostic performance.
Similarly, Spadafora et al.  introduced the concept of a segmental PET acquisition for the evaluation of solitary lung
nodules, particularly in patients with a low likelihood of distant metastases.
Finally, Telo et al.  and Briganti et al.  reported some data about the future of molecular imaging in lung cancer by
suggesting new alternative radiopharmaceuticals for PET and single photon emission tomography (SPET) imaging.
Melanoma is the most biologically aggressive tumor of the skin, responsible of the majority of deaths due to skin cancer .
In the last few decades, clinicians improved dramatically their ability to recognize melanoma in its early phase but, still, about
20% of the patients die due to disease progression [2-4].
In the context of advanced disease, the introduction of new target therapies and immunotherapy allowed a substantial improvement
of the prognosis of patients with metastases. Ten years ago, the average overall survival of stage 4 melanoma patients
was only 6 months. Today, the average overall survival reached 2 years, with several patients achieving the status of
long-term survivors .
Due to these dramatic changes in life expectation of advanced melanoma patients, management protocols and follow-up
procedures changed consequently. Before the era of target and immune-therapies, there was basically no need to perform aggressive
imaging procedures to monitor disease-free patients. In other words, early diagnosis of disease recurrence was not sufficient
to improve patient survival. In contrast, with the introduction of the new treatments of advanced disease, the early recognition
of metastatic disease became definitely important in order to start, as soon as possible, the proper treatment and to efficiently
prolong survival. This is why imaging of disease-free patients became strictly relevant.
In this hot topic issue on the developing role of nuclear medicine in melanoma, the value of diagnostic imaging is presented
to individuate fields of actual application and perspectives. Being the main indications connected with staging and restaging,
we will also discuss here the possible role in better defining diagnosis and prognostic stratification of the primary lesion, and in
the early evaluation of therapeutic response.
As reported above, melanoma is an aggressive tumour, historically with poor prognosis and high mortality, although recent
advances in chemotherapy and immunotherapy regimes granted improved survival.
At the first diagnosis, to define therapeutic strategies, the most important prognostic factors are the vertical growth of the
tumour (pathologic Breslow index) and the invasion of the dermis. To acquire information on these issues, a contribution by
diagnostic imaging may be given by Ultrasounds. In particular, as described by Reginelli et al. , High Frequency Ultrasonography
(HFUS) may allow a reliable in vivo evaluation of the superficial cutaneous layer, with a spatial resolution in the order
of microns. The preliminary experience presented by the authors suggests the possibility that HFUS could be already included
as support to traditional diagnostic methods in patients diagnosed with a nodular melanoma. In particular, HFUS may reliably
determine the lateral margins and therefore the thickness of the lesion.
Together with a prognostic stratification of the primary tumor, the preoperative evaluation of the presence of secondary lesions
is essential for establishing an optimal therapeutic approach and for improving the survival rate. Over primary tumor delineation,
an accurate lymph-nodal staging, mainly based on a sentinel-node evaluation using nuclear medicine procedures, is
mandatory. In their contribution, N. Quartuccio et al.  described the current clinical impact, also discussing the possible improvement
at staging associated either with SPECT/CT and using new emerging radiotracers, such as Tc99m-Tilmanocept.
18F-Fluorodeoxyglucose (FDG) PET/CT has been for many years suggested as a reliable and effective tool to complete the
staging of patients affected by melanoma, with an advanced disease status. In their paper, R. Laudicella et al.  evaluated the
increased contribution achievable using new PET/CT facilities and acquisition protocols. In particular, higher spatial resolution
realizable with full digital PET/CT scanners, improving diagnostic accuracy either in the detection of lymph node and or distant
metastases and a better definition of tumor relapse have been demonstrated. The Clinical Value of PET/CT at Staging and the potential role of new radiotracers are reported by S. Annunziata et al. .
In this setting, according to the preclinical data, new radiotracers, such as 18F-29-fluoro-29-deoxy-1-b-D-b-arabinofuranosyl-5-
ethyluracil (18F-FEAU), 64Cu-CB-TE2A-c(RGDyK) and 64Cu-diamsar-c(RGDfD), integrine-analogues, 18F-FMISO, 18Fbenzamines,
such as 18F-MEL05, 18F-5-fluoro-N-(2-(Diethylamino)ethyl)picolinamide (18F-5-FPN), 18F-CCZ01064, 68Ga-
DOTA-Pip-Nle-CycMSHhex (CCZ01048), could permit a better detection of melanoma lymph-node and distant metastases,
because of the possibility to reach a higher target to background ratio with respect to FDG. Furthermore, a wider molecular
evaluation, allowing the definition of a more precise tailored therapy, could be defined. In humans, a better characterization of
tumor proliferation with respect to FDG may be already allowed using 18F-Fluoro-thymidine (FLT). This radiopharmaceutical
could be also useful for a more precise evaluation of therapeutic response.
The consolidated clinical and prognostic value of PET/CT in the restaging process of Melanoma is presented by D. Albano
et al. , describing how the use of this approach could be important to better define therapeutic strategies.
Particularly relevant is the contribution of E. Lopci et al , concerning the evaluation of the role of PET/CT in evaluating
the response to new immune therapy agents in Melanoma. In the treatment management, new agents, the so-called immune
checkpoint inhibitors (ICI), have achieved astonishing results and improved overall survival (OS). New response criteria have
been introduced on time and are being continuously updated. Along with morphologic criteria, expressed by Response Evaluation
Criteria in Solid Tumors (RECIST), and including more recent classifications, such as immune-RECIST (iRECIST), other
response criteria have been proposed, based on metabolic parameters. In this setting, the role of FDG PET/CT for response assessment
and prediction is still in an early phase and not sufficiently robust. For now, the recommended approach is to evaluate
morphologic and metabolic changes in the patient’s clinical context. The development of more specific imaging biomarkers
could potentially allow an early response evaluation and also provide a better patients’ selection eligible to ICI treatment. The
prognostic role of restaging PET has been demonstrated in different tumours after treatment [12-15]. Nevertheless, its role to
restage patients with recurrent CM needs still to be defined.
The last contribution is presented by Sinagra et al , who described a rare clinical case of ileal melanoma where FDG
PET/CT completed correctly the staging by identifying a bone metastasis and changing therapy management.
On the basis of the papers presented in this thematic issue, we hope to contribute to the literature either by presenting and/or
reviewing consolidated procedures and supporting the possible application of new diagnostic methods, with main reference to
those utilizing nuclear medicine imaging procedures.
The present thematic “hot topic” issue in Current Radiopharmaceuticals is dedicated to the applications of molecular imaging
as major player in the diagnostic scenario of pancreatic neuroendocrine tumours (PanNETs). The therapeutic aspects using
radiopharmaceuticals have also been considered.
In the last years, we assisted to a progressive evolution of the available radionuclide imaging techniques dedicated to Pan-
NETs investigation, starting from the conventional Octreoscan© and moving forward to more sophisticated techniques such as
The possibility to provide an accurate characterization both of primary and metastatic disease is of utmost importance in the
clinical work-up of PanNETs and molecular imaging has revealed to be a cornerstone for Physicians to support the therapeutic
The present issue starts with an accurate description of physiopathological premises underlying the mechanisms of uptake
of several radiotracers that can be used, with main reference to those characterizing the presence of Somatostatin Receptors
(SSTRs), expressed by different subtypes of PanNETs. In this paper, Cuccurullo et al. begins with the explanation of the ancillary
role of 18F- Fluorodeoxyglucose (18F-FDG) . In NETs, 18F-FDG may act mainly as a negative prognostic indicator,
having capability to reveal dedifferentiated lesions in the restaging of individual patients with a critical clinical evolution. The
reason for its infrequent indication is consequently connected with the favorable biological behavior of the majority of Pan-
NETs, which are typically slow growing and express SSTRs according to their degree of differentiation. Therefore, using somatostatin
analogs (SSA) labeled with gamma or positron emitters, SSTRs can be used not only as a target for both diagnosis and
therapy, but also for a prognostic evaluation. Currently, the somatostatin theranostic model, based on diagnosis with radiotracers
and a Peptide Receptor Radionuclide Therapy (PRRT) performed with a similar molecule radiolabeled with a β- (or α,
hopefully in the future) emitter, represents one of the most successful options for the targeted therapy. Although radio-labeled
agonists usually provide efficient results, somatostatin antagonists (SS-ANTs) have been recently also proposed, being usable
for imaging and therapy. The Cuccurullo’s paper also highlights the reasons why the theranostic model based on SSTRs doesn’t
work in insulinoma, which scarcely express SSTR2 and SSTR5, wich are. the most important targets for the routinely used radiolabeled
somatostatin analogues. Therefore, in patients with a suspicious of insulinoma, different radiotracers, such as 18F
FluoroDOPA (18F-DOPA) or tracers targeting glucagon-like peptide-1 receptor, have to be preferred. However, it has to be
pointed out that, although F-DOPA showed interesting results in patients with PanNETs, its role is currently considered secondary
compared to somatostatin analogues, especially because of the lack of a theranostic model.
Starting from the classification and physiopathology of PanNETs, the paper by Briganti et al. deeply analyse the currently
available gamma-emitters for SSTRs evaluation . A detailed comparison of the diagnostic performance of the available tracers
and of hybrid machines compared to the traditional stand-alone tools is also included. In this paper, it is reported that 111Inpentetreotide
(Octreoscan©), successfully applied in well-differentiated (G1-G2) tumors, has lost its primary position because of
the better diagnostic accuracy of 68Ga DOTA-Peptides PET/CT, maintaining an ancillary role in PanNETs. Briganti et al. also
discuss preliminary data obtained with 99mTc-EDDA/HYNIC-TOC (Tektrotyd©), labeled with 99mTc, having more favorable
energy characteristics compared to 111Indium, radiolabeling Octreoscan©. To better identify a possible clinical role for Tektrotyd
©, in terms of cost/effectiveness, its pharmacokinetics and pharmacodynamics have been compared with respect to those of
Octreoscan© and PET DOTA-peptides.
The paper by Carollo et al. is focused on radiochemical issues, providing deep insights of the molecular imaging techniques
that can be applied in this setting, including a discussion on the comparison between the different radiotracers; the therapeutic
implications that might rise from a precise definition of disease extension and metabolic characterization are also evaluated .
This paper shows an overview of the radiopharmaceuticals that have been used so far in the imaging of PanNETs with insights
on the potential of new radiopharmaceuticals currently under clinical evaluation.
The implications for therapy of SSTRs imaging are fundamental for PanNETs patients work-up . The expression of
SSTRs is a pre-requisite for the success of PRRT, which has been tackled by Alsadik et al. in the current issue . The authors used a comprehensive literature search strategy of all studies published in English that can be found on SCOPUS and PubMed.
The results of PRRT, using 177Lutetium or 90Yttrium- DOTA- conjugated peptides in p-NETs, individuated either as a standalone
entity or as subgroup within the wider category of Gastro-entero-pancreatic neuroendocrine tumours (GEP NETs), have
been evaluated. This meta-analysis confirms that PRRT is a well-tolerated and effective treatment option for non-operable
and/or metastatic PanNETs. A strong support on a wider diffusion could be achieved from larger randomized controlled trials,
comparing PRRT with other treatment modalities.
The radiological aspects regarding the theranostic of PanNETs should not be underestimated neither be allocated on a second
level in comparison to molecular imaging. For this reason, this issue also includes an outline on the available conventional
radiological techniques that are currently used in PanNETs work-up . In the presence of a primary role of nuclear medicine,
either for a whole body analysis or for a molecular characterization, an extensive conventional radiological imaging is however
requested, remaining the foundation for the initial diagnosis and staging of these tumors.
In terms of technological advances, a significant improvement has been obtained with the advent of new hybrid machines
that could potentially improve the management of these patients . Hybrid PET/MRI systems are currently available in few
Centres world-wide, providing excellent results derived from the combination of PET with MRI, which is better for soft tissue
characterization and for reducing radiation exposure compared to CT . Furthermore, Diffusion-Weighted Imaging (DWI) is
an invaluable tool to depict small liver lesions undetectable by PET or CT; a further improvement allowed by MR in detecting
small hepatic metastases may be achieved combining 3-Tesla and DWI together with the administration of liver specific contrast
media. Hence, the best candidates to be imaged with SSTR PET/MRI are patients selected for hepatic de-bulking or having
liver predominant disease. in the perspective by Mapelli and Picchio, the capability of PET/MRI to better evaluate tumor
response to treatment difficult to be analyzed using traditional RECIST criteria is also discussed. The better evaluation of anatomic
changes and enhancement characteristics allowed by MRI may significantly implement SSTR PET, defining a more reliable
procedure to be used in place of CT and MRI alone or of PET/CT. In this context, SSTR-RADS Version 1.0 response criteria
have been recently introduced as a promising alternative and valuable tool for response assessment in NETs . To better
define the clinical role of PET/MRI in patients with p-NETs, it has to be pointed out that at present, this tool doesn’t show,
using a standard approach, the same diagnostic accuracy in detecting small lung lesions with respect to PET/CT. Therefore, in
presence of a negative or dubious pattern at pulmonary level, a chest CT scan would be recommended additionally to PET/MRI
[9, 10]. Moreover, MRI has a lower sensitivity in identifying hypersclerotic bone lesions compared to other imaging modalities
and SUV quantification with attenuation correction is still suboptimal . At present, these limitations, although scarcely significant
for a clinical utilization in PanNETs, have to be taken in account, looking forward to technological improvements, allowing
to obtain similar accuracies as for PET/CT
Based on the contents reported in the present issue, it can be concluded that in patients with PanNETs, a protean disease often
presenting with liver metastases, many topics have to be considered to understand the role of molecular imaging in the different
At first diagnosis, it is mandatory to detect primary tumour, more frequently identified using radiological techniques, and to
define whole body diffusion and molecular characterization. In the latter field, nuclear medicine techniques are determinant.
Being the major role actually played by PET/CT with 68Ga-DOTA peptides, the use of Octreoscan© is considered to be a second
choice, while the clinical position of Tektrotyd© is still to be fully defined. In patients with insulinoma, waiting for radiopharmaceuticals
having a better diagnostic accuracy, 18F-DOPA has to be preferred compared to radiolabeled somatostatin analogues.
Interesting perspectives seem to be related to a wider evaluation of innovative radiotracers, including GLP-1 Receptor
Peptides, as exendin, GRP receptor ligands, as bombesin agonists and antagonists, and gastrin/cholecystokinin analogs, as
minigastrin. Nevertheless, further studies, also better evaluating radiochemistry and pharmacokinetics, are needed before their
possible clinical application. Similarly, new approaches capable to early predict the efficacy of anti-angiogenesis treatments
could be defined through a research based on radiolabeled new drugs, such as bevacizumab. Conversely, it is currently too early
to predict the clinical impact of a technological revolution associated with fully digital PET scanners or with the use of alternative
radionuclides, with main reference to Cu-64.
This means that in the near future, the primacy of somatotastatin analogues labelled with 68Ga will remain unquestionable
in the general evaluation of PanNETs, also because of the theranostic model associated with PRRT. Regarding innovative radiopharmaceuticals,
neither radiolabeled somatostatin antagonists nor 11C-5-hydroxy-tryptophan (HTP), negatively affected by
the labelling with the short life radionuclide C-11, may actually cover a clinical role. Conversely, 18F-FDG may find a clinical
utility in restaging patients in whom a dedifferentiation is suspected, in order to better define therapeutic strategies.
Future developments will be based on a wider diffusion of more performing technologies, such as PET/MRI or digital PET,
in the clinical application of new radiopharmaceuticals and a more comprehensive multilevel integration of biologic information
pertaining to a specific tumor and single patient. This approach, possibly encompassing genomic considerations, is currently
evolving as a new entity denoted ‘precision medicine’ . In this context, together with nonspecific biomarkers, such as
chromogranin-A (CgA) and 5-hydroxyindoleacetic acid (5-HIAA), the evaluation of proliferative activity (Ki67) should be
considered. In the future, the clinical application of specific NET transcripts in whole blood could potentially conduct to an
earlier diagnosis, also providing information useful for prognostic stratification and a better definition of therapeutic strategies
. A further improvement is also required for an improved monitoring of tumor response. In PanNETs, radiological procedures
based on RECIST are unsatisfactory while newer radiological criteria are not yet consolidated; therefore, validated techniques utilizing molecular imaging, supported by the morpho-structural information allowed by CT or MRI should be implemented.
In this direction, more reliable results could be obtained through the development of new criteria, eventually including
the adoption of functional MRI, of more precise hematic biomarkers, of quantitative methods not only based on SUV.
In conclusion, a multidisciplinary approach is mandatory in clinical practice in roder to reach the best consensus on treatment
approach for each patient. In this context, together with the major role of nuclear medicine physicians and radiologists, of
oncologists, endocrinologists and surgeons, the contribution of experts in epidemiology, laboratory medicine and genomics is
advocated. Therefore, in agreement with L. Bodei, we can conclude that “a fusion product of molecular and genomic information
with tumor imaging is likely to be the quintessence of future NET diagnosis and define the progress from darkness to light”
In this special CRP issue, the production, radiochemical aspects, chelation and latest pre-clinical and clinical results are presented
for the application of 225Ac and 213Bi-based radiopharmaceuticals for Targeted Alpha Therapy (TAT).
The first block of papers discusses the production, radiochemical and chelation aspects for the production of radiopharmaceuticals
based on 225Ac and 213Bi.
In the review by A. Robertson et al. , an overview of the current supply of 225Ac/213Bi is discussed as well as alternative
production strategies to meet the current demand. Radiochemical aspects for isolating 225Ac from 229Th or from irradiated target
materials are discussed in the second part of this review. Finally, chelation aspects and challenges associated with the delivery
of alpha-emitting radionuclides to the targeting sites are described. All of these aspects are also discussed from the experiences,
capabilities and perspectives of TRIUMF.
The review by J. Engle  specifically aims to provide a broad overview of the current supply and possible additional
strategies for the production of 225Ac and 213Bi. These include discussion of the current status of 229Th, as well as alternative
production by irradiation of 226Ra with neutrons, protons and electrons and thorium with high energy protons.
In the review by J. Harvey , specific efforts pursued by the NorthStar company are reported and include the recovery of
229Th from fuel pellets, irradiation of 226-Radium with electrons and 232-Throium with high energy protons and testing of radiochemical
separation based on solid phase chromatography resins.
The next block of reviews and research articles report the results of pre-clinical and clinical studies using 225Ac and 213Bi.
In the research article by Z. Jiang et al. , in vivo animal studies using two different sources of 225Ac were evaluated. One
source was derived from the standard decay of 229Th and the second source was 225Ac extracted from proton irradiated thorium
target (containing 227Ac). Biodistribution studies of 225Ac in free form and chelated with DOTA were examined.
A research article by N. Pfankuchen et al.  provides results from the work on radiolabeling and pre-clinical evaluation of
225Ac attached to the zoledronic acid bone-seeking agent.
In the review by J. Jurcic , clinical results of using the 213Bi- and 225Ac-radiolabelled monoclonal antibody (Lintuzumab)
for therapy of acute myeloid leukemia (AML) are discussed.
In the review article by A. Morgenstern et al.  the current status of the field of TAT is given, including an overview of
the availability of the 225Ac and 225Ac/213Bi generator, as well as a broad overview of clinical trials using 225Ac and 213Bi.
The last review article discuss the importance of dosimetric and radiobiological considerations for the application of alpha
emitters by G. Sgouros et al. .
This special issue of Current Radiopharmaceuticals provides an up-to-date and useful comprehensive overview describing
the production, radiochemistry and use of both 213Bi and 225Ac and their important emerging clinical roles for therapeutic treatment
of a variety of specific cancers and chronic diseases.