22 marzo 2017
Introduction to nuclear medicine ad molecular imaging in oncology
Medicina Nucleare, Seconda Università di Napoli
Vincenzo Cuccurullo, Roberto Vignapiano, Giuseppe Danilo Di Stasio, Francescosaverio Caserta, Andrea Ciarmiello
Nuclear Medicine Unit, Department of Clinical and Experimental Internistic F.Magrassi, A.Lanzara’
Seconda Università di Napoli, Napoli, Italy
The management of cancer requires an interdisciplinary approach in which items related to diagnosis and treatment must intervene in the early diagnostic phase, staging, follow-up and monitoring of oncologic patients. In this context, nuclear-medicine (NM), based on original pathophysiological premises which define the best feasibility in humans of a molecular imaging, produce diagnostic data more strictly connected with prognosis and therapy. Allowing morph-structural images a better anatomical and loco-regional evaluation, an implemented information is obtained when NM machines (PET or SPECT) may be associated in a single gantry with CT or MRI , in the so called hybrid devices (PET/CT, SPECT/CT, PET/MRI), that have revolutionized diagnostic imaging. At the present, a major role in oncology is connected with PET/CT using 18F- Fluoro-deoxyglucose (FDG), which is by now a pivotal diagnostic tool either in the pre-therapeutic and post-therapeutic evaluation, thanks to the growing evidence of a favorable cost/effectiveness respect to alternative procedures.scarica PDF
Currently the management of cancer requires an interdisciplinary approach in which items related to diagnosis and treatment must intervene
in the early diagnostic phase but also in staging, follow-up and monitoring. A close integration between radiologist , pathologist, nuclear physician and specialists involved in the therapeutic strategy, such as oncologist, surgeon, and radiotherapist, is mandatory to individuate the most cost/effective diagnostic/therapeutic tree.
In this context, the nuclear-medicine approach is original and unique, being characterized by a pathophysiological essence having the
ability to express information only achievable in a living being; in this way , diagnostic data are more strictly connected with a prognostic content, having also the capability to give useful data in connection with therapy. This constitutes a great difference in opposition to the standard morph-structural imaging, which does not detect differences between living or dead; as consequence, a lower capability to fill the clinical information with a supplementary content than that exclusively diagnostic is achievable.
Nevertheless, allowing the morph-structural image a better anatomical and loco-regional evaluation, an implemented information is obtained when both forms of imaging are involved in a unique approach, as it happens in hybrid devices, that have recently revolutionized diagnostic imaging.
Hybrid systems are characterized by the concomitant presence in the same gantry of a component acquiring morph-structural data, together with an associated device allowing nuclear medicine (NM) imaging. The unit for morph-structural imaging is typically a Computed Tomograph (CT), having been more recently utilized also Magnetic Resonance (MR) scanners.
With respect to the NM component, or a Positron Emission Tomograph (PET), providing images obtained after the administration of radiotracers labelled with positron emitters, or a Single Photon Emission Computed Tomograph (SPECT), producing images when using gamma
emitters may be included in the gantry.
The final result given by hybrid systems is not only the sum of individual contributions produced by both approaches, when separated.
Multiple advantages are achievable when the capability to acquire almost simultaneously functional and morph-structural information is present in the same machine. At first, a higher diagnostic accuracy in terms of specificity and sensitivity may be obtained, as result of a better localization and interpretation of functional images inside the well defined anatomic context provided by CT. Moreover, the morph-structural information can reveal alterations undetectable by NM, increasing sensitivity and also providing a more specific characterization respect to the one obtained by radionuclide procedures alone.
The hybrid imaging has also additional advantages, allowing to evaluate and implement diagnostic and therapeutic strategies respect to those feasible with separate tools. Typical examples are the improvement obtained by PET/CT respect to a CT standalone in making a biopsy or in defining a radiotherapeutic (RT) target.
While CT doesn’t allow the discrimination in a heterogeneous tumour mass between the malignant part respect to necrotic and/or fibrotic areas, PET and SPECT have typically the ability to characterize only the viable component, being absent a radiotracer’s uptake in the absence of cells. Nevertheless, a PET (or a SPECT) standalone doesn’t allow to perform a biopsy, failing anatomical landmarks mandatory to precisely localize the lesion to be biopsied.
Indeed, the radiotracer’s uptake is the major determinant in directing the needle to the malignant part of the tumour, but this action may allow an optimal result only when using a hybrid machine. A similar advantage may be found in defining the tumour target in RT, in which PET/CT allows a more precise delineation of the malignant component of the neoplastic mass. More in general, although both information allowed by the two component of the hybrid machine are important in defining a correct diagnosis , the major contribution is generally given by PET or SPECT, being the “radiotracer” the most effective instrument in obtaining a whole body information, based on a functional and/or molecular alteration, i.e. to produce a molecular imaging.
When a label detectable from outside is bound to the molecule of interest in that peculiar process, it becomes possible to “trace” its in vivo distribution; in this way a molecular alteration into the body may be individuated through a detector placed outside of the organism itself. Labelled molecules may therefore act as “tracers” of a molecular process, when detectable from outside.
This constitutes the basis of molecular imaging, which may be performed with all the most important techniques, even if with some limitations. For example, a molecular imaging can be obtained with CT using a molecule conjugated to a iodine atom, at the base of CT contrast media; with MRI, using paramagnetic molecules; with US using micro-bubbles. In addition, it can be realized a highly accurate imaging by optical techniques, which are based on the addition as label of fluorescent substances emitting light radiation.
Finally, the molecular imaging can be obtained through the application to the molecule of a radioactive label, as it happens in NM. For studying a particular biological process, to avoid alteration of the system to be studied and/or toxic effects, it is necessary to use a very small quantity of tracing molecules, in a much smaller number than the native ones. This condition can be exclusively realized with the administration of ponderal quantities of the labelled tracers in the order of picomoles or nanomoles.
At present this eventuality may be only realized with optical imaging (OI) or NM, being necessary a higher quantity, in the order of micromoles or millimoles, when using contrast media for CT or MRI, therefore usable in the study of a very limited number of molecular processes; at the opposite , most complex events of biology up to proteomics and genomics may be better studied with OI, which is the best technique in defining molecular mechanisms in their most evolved processes; very effective and reliable for these purposes in the large majority of cases are also radionuclide procedures.
In summary, molecular imaging is only occasionally feasible by CT and MRI, having the latter more potential in this direction compared to CT, which objectively seems devoid of a capacity of molecular imaging. In this direction, MRI is addressing on a path that allows the investigation of molecular processes, but is still in research rather than in clinical application.
In producing molecular imaging NM presents a major advantage in opposition to OI. If it’s true that the latter is superior in the imaging at genomics and proteomics level, conversely it may perform an analysis only on superficial layers, as in experimental models or, in humans, on skin, eye or mucosa, when using endoscopic techniques.
This may be useful, especially in dermatology, in the endoscopic evaluation of the digestive system or as intra-surgical procedure, but it is evident that OI will never give an in vivo information on the presence and characterization, for example, of liver metastases in their three-dimensional complexity.
In fact, in the restaging of a person operated for well differentiated thyroid cancer, a whole body scan with radioactive iodine may allow diagnosis of metastasis or recurrence; individuate a favourable prognosis , being the uptake only possible in still differentiated lesions; define a rationale recruitment of the patient for a radionuclide therapy , because in this patient is possible to administer 131I at significantly higher doses for an effective and well tolerated therapeutic action.
Actually it can be attributed to this uptake also a strictly genomic meaning. In fact, the tumour’s concentration of radioactive iodine (131I, 123I or 124I) individuate the expression of the iodine symporter’s gene also in metastatic cells
Nevertheless, if tailored medicine is the new paradigm better characterizing the patient, it is not yet widely diffuse in the clinical practice.
Therefore at the present in oncology a traditional approach is still more frequently applied. In the present scenario, a diagnostic imaging is required initially to detect a lesion and to determine its malignant potential. Furthermore, information defining position, relations with nerves, vessels, surrounding organs, on dimensions and structural characteristics of the lesion is crucial either to give a differential diagnosis and to define a therapeutic strategy.
Nevertheless, most of the information achievable when using PET/CT is due to FDG or to radiotracers beyond FDG, essential either in oncology and in many non oncologic diseases. For example, in a DOTA-PET scan (using somatostatin analogues labelled with 68Ga, targeting somatostatin receptors hyper-expressed in neuroendocrine tumors), NM has the major role in detecting pathological areas distributed trough the body, in diagnosing a neuroendocrine tumour, in staging or re-staging, having the possibility to individuate primary tumour, recurrence and metastases; furthermore, a DOTA-PET positivity express a prognostic value, as the concentration is linked to the presence of a differentiated tumour, being this prerogative lost in dedifferentiation.
Such information is also useful to decide a therapeutic approach since patients positives at DOTA-PET may be recruited for a metabolic therapy with somatostatin analogues labelled with high doses of β- radionuclides; in this way, as it happens since decades in patients with thyroid carcinoma using radioiodine, by identifying the pathological concentration of the tracer in the diagnostic phase , it is possible to predict a priori a therapeutic efficacy in that individual patient, on the basis of the presence of an effective theranostic model.
However, it remains the need to configure this accumulation in a morph-structural context for a correct surgical or radiotherapeutic approach, and/or for increase diagnostic accuracy. This is information is only obtainable thanks to the relevant and mandatory contribution allowed by CT.
The most important advantages for MRI, and therefore for PET/MRI, could be found in the pelvis, especially in the post therapeutic evaluation, in the head and neck region, in brain demyelinating diseases, in diagnosis of breast cancer.
Thanks to the absence of ionizing radiations, MRI is also advantageous in terms of dosimetry, issue highly important for certain groups of patients such as in paediatrics. For this reason, a greater cost-benefit ratio and therefore a clinical appropriateness could be obtained in many pathological conditions as in the evaluation of inflammatory diseases.
Furthermore, PET/MRI may provide original functional information trough a series of procedures constituting the so called functional MRI (fMRI) and/or MR spectroscopy (MRS). The obtainable data are not a NM’s surrogate but an useful and original supplementary information particularly important in the analysis of
neurological correlations , linked to the ability in assessing the nerve bundles, and in defining not only the structural alteration but also changes in vascular perfusion or in cell density, as possible expression of issues related to malignancy and neo-angiogenesis. Therefore, it is possible to define PET/MRI as the opening of a third eye vision in imaging, as the standard morph-structural information by MRI and the pathophysiological PET information may be enriched by functional data achievable with the same MR scanner.
In this context, it could be expected that significant investment by Industries in the next years could further increase the wide spread distribution of hybrid systems although they will not completely replace the traditional machines, such as CT and MRI scanners, which will certainly remain highly diffuse, because of a wide utilization also as standalone devices.
Conversely , already at the present are no more sold PET systems standalone, while is increasing the relative percentage of SPECT/CT devices respect to traditional machines for gamma emitters. It is not easy to foresee a wider diffusion of PET/MRI and eventually of SPECT/ MRI scanners, which will probably find a market only if a more favourable economic condition will justify their advantages respect to the cheaper hybrid machines including CT
This is more difficult with radiolabelled glucose , showing a too fast metabolism to allow a standardized scan in humans.
Being the detection’s capability of a radiotracer determined by the lesion to background ratio , it is important to remember that glucose and FDG have a physiological high concentration in the brain; therefore, because of the unfavourable ratio, FDG is not reliable in detecting cerebral metastases and a diagnostic CT or MRI brain study is requested in the neoplastic population with a high prevalence of secondary cerebral lesions.
Favourable conditions in fasting subjects occur in the rest of the body, thanks to the absence of a significant physiological concentration, with exceptions due to the FDG excretion trough the kidneys, determining high concentration in the bladder, critical when evaluating, as example, a patient with a prostate cancer.
The great importance of FDG in oncology is linked to the fact that, as demonstrated by Warburg, glucose concentrate more where there’s an increased anaerobic glycolysis, and therefore especially in malignant tumours. Similar to glucose is the behaviour of FDG. Furthermore , in the context of a neoplastic transformation, it has been evidenced that glucose transporters expression is increased and so tumour cells have a higher glucose uptake than normal cells growing at the same rate. But it is important to remember that also benign conditions, in particular inflammatory diseases, may have an increased FDG uptake due to increased flow and metabolism, as it happens in acute disease, or to the prevalence of anaerobic glycolysis , as it may occur in chronic inflammation.
It should be pointed out that probably, in presence of absolute quantitative models normalized for number of cells, of a sufficient spatial resolution and in absence of artefacts, a good discrimination between benign and malignant lesions concentrating FDG could be obtained.
By the way malignant tumours showing an absent or low uptake, similar to that observed in FDG positive benign diseases, have to be considered as neoplasm with a favourable prognosis. This behaviour can be explained by many issues, as the slow growing rate and the absence of anarchic neo-angiogenesis, determining low or absent anaerobic glycolysis.
Therefore, being the FDG concentration mainly determined by the dedifferentiation phenomenon, well differentiated and/or slow-growing tumours, such as well-differentiated thyroid carcinoma , neuroendocrine tumours, and prostate cancer have a low capability to concentrate FDG. In parallel, increasing the FDG’s uptake
with malignancy, this radiotracer can also give a prognostic information: in a population with the same histological classification, a higher FDG’s uptake indicates a more malignant tumour.
With respect to false positive results, it must be underlined that, if it is true that falsepositives are a problem in patients with cancer, determining possible mistakes in differential diagnosis, conversely FDG can become an helpful radiotracer when used in the study of some benign conditions. As example, PET-FDG is very useful in patients with fever of unknown origin (FUO); moreover, FDG is extremely important in the characterization of inflammatory diseases such as osteomyelitis or in the definition of activity in chronic diseases, such as Chron’s disease and sarcoidosis: in these populations only FDG positive patients must undergo therapy.
PET-FDG cannot be considered as unique determinant in the differential diagnosis of malignancy; although it may play a role in the overall diagnostic balance of some peculiar conditions, such as suspicion of lymphoma or as second line procedure in differentiating solitary pulmonary nodules. PET-FDG may be also used in detecting the primary tumour in presence of metastases of unknown origin.
In fact , although false negative results may be seen in presence of micro-metastases, lymph nodes of normal size showing high FDG uptake are very probably malignant. At the opposite, enlarged lymph nodes without FDG’s concentration are almost surely benign. Furthermore, trough a whole body analysis, PET-FDG may
augment detection of distant metastases, but a the level of the brain, in which a MRI or a CT diagnostic study may individuate a higher number of lesions.
relapse, false positive results may be seen due to inflammation or to a post-therapeutic active rearrangement, more frequently observed in earlier controls, within the first six months after the intervention. 36 A higher accuracy may be obtained thanks to the incremental contribution of CT or MRI, preferably with contrast media
Very important is also the role of FDG-PET in guiding a biopsy, to activate a more or less aggressive therapeutic approach on the basis of intensity and extension of the FDG’s uptake, in defining the target for radiotherapy. As example , using the semi-quantitative method called SUV (inaccurate and improper technique for a rigorous diagnosis, but certainly useful to establish the grade of uptake and in evaluating the same subject in follow up), it may result that a patient with a lymphoma with a high SUV has to be treated with a more aggressive therapy than a patient who has a lymphoma with a lower value, treatable with a less toxic approach.
It has also been already mentioned the importance of PET-FDG in the biological definition of the target in radiotherapy either for the better definition of the viable malignant component respect to necrosis and fibrosis, and/ or for the improved diagnostic accuracy, which allows to exclude, as example, a lymph node
involvement in enlarged lymph nodes w/o uptake.
Furthermore, PET-FDG may help to follow the effectiveness of radiotherapy on the tumour itself during the treatment
dedifferentiated metastases concentrating FDG but not iodine.
The NOPR study has also demonstrated the importance of a basal scan in patients which will probably perform PET-FDG in follow up, and the possible role of a pre-therapeutic scan in defining therapeutic strategies on the basis of intensity and extent of the FDG’s uptake.
On the basis of these premises, in patients highly suspicious for cancer, a new terminology has been proposed , which express major changes respect to a standard approach.
In particular, diagnosis and staging, traditionally individuated as separated steps, are considered together in the term “initial pre-intervention strategies”. In this context, PET-FDG may acquire relevance more than for the possibility to perform a differential diagnosis, for its contribution in staging, prognostic stratification and definition of therapeutic plans.
Similarly, the term “subsequent treatment strategies” include together “treatment monitoring and restaging/detection of recurrence”.
Adopting this new paradigm, PET/CT with FDG could acquire a fundamental importance in the most cancers, with some notable exceptions such as in prostate cancer, breast cancer and melanoma. These exclusions are justified for prostate, by the low sensitivity of FDG in this neoplasm; respect to breast cancer and melanoma, a different choice has to be adopted in patients early diagnosed, being Mammography/Echography/FNAB, and sentinel node techniques, more cost/effectives and accurate respect to PET-FDG. In prostate cancer different approaches, including MRI and eventually radiotracers beyond FDG have to be preferred.
In these conditions, i.e. in tumours as GIST and when biological therapies are used, and more in general in the large majority of tumours also when using a traditional chemo and/or radiotherapy, FDG may indicate a therapeutic response earlier than CT. For these reasons, PET-FDG may be already suggested as first line diagnostic method to identify patients undergoing biological therapies, having capability to reliably separate responders versus non responders. In this way, a huge gain for the health system may be obtained, individually identifying patients who can benefit from a high-cost treatment.
The better capability to earlier individuate responders respect to CT may play a major role also in monitoring tumour response in the large majority of patients with cancer submitted to chemo or radiotherapy. In this way, trough an evaluation performed few days or weeks after the intervention, the decision to continue or not a therapeutic strategy may be better and earlier defined with enormous advantages for the patient, also in terms of a reduction in toxicity.
Unfortunately, PET-FDG is not a perfect method in evaluating tumour response: if it is true that we can reliably and rapidly discriminate responders from non-responders, it is also true that it is not always possible to understand whether there will be a full therapeutic efficacy.
In other words, an early decrease of the FDG’s uptake cannot predict certainly a complete therapeutic response, in particular in polyclonal neoplasm in which a clone could continue to grow despite the radiotracer’s reduction seen at the first evaluation.
Nevertheless, for its advantages respect to radiological methods, which are however more standardized and continue to be more widely utilized, PET-FDG is now slowly entering in protocols, having already acquired a primary role in some tumours.
Currently, a routine worldwide application is already present in lymphomas, in which PETFDG is also utilized as interim procedure to define the correct therapeutic strategy in individual patients. It has to be pointed out that the favourable situation in lymphoma is either due to the type of neoplasm and to a very close and interactive international collaboration between some of the major experts in the field, which allowed the definition of well organized and standardized protocols, fully shared by all the participants to the multicenter trials.
Therefore, reliable data have been acquired in a large population, using identical procedures and therapeutic strategies. Interesting results begin to appear in myeloma, while it is more difficult to obtain homogeneous data in solid tumours. To facilitate a diffusion of PET-FDG in the evaluation of solid tumour response, R. Wahl has proposed the PET Response Criteria in Solid Tumors (PERCIST), as alternative to RECIST; this method is based on a semi-quantitative analysis of the variation in FDG’s uptake calculated in the most relevant lesions present in solid tumours. Relatively to the quantitative system applied, the chosen method has been the standardized uptake value (SUV). This method, although partially inaccurate, still remains the most easily and rationally usable in a strategy of standardization.
Obviously it would be ideal to have absolutely quantitative methods, but these approaches are still far from the clinic. It has however to be pointed out that, although its limitations, the SUV measurement allows a lower intra and inter-observer variability respect to the RECIST method, more affected by a subjective evaluation. Nevertheless , although its advantages respect to the alternative radiological method, PERCIST is not yet widely adopted in defining tumour response in patients with solid neoplasm.
For a wider diffusion, based on validated extensive data, well organized and standardized multicenter trials, as for lymphoma, are mandatory to demonstrate an evidence based efficacy. In this way, the already perceived impression of its superiority respect to RECIST in earlier distinguish responders from non responders,
could support a wider and more consolidated diffusion in many neoplasms.
As previously mentioned, when using PERCIST, it must be realized a series of successivecontrols because an early response is not synonymous of a total response; therefore a more extensive clinical research has to acquire many other data to better define the most effective and rationale utilization. At present interesting
data start to be published on the application of PET-FDG in the evaluation of therapies in tumours, such as those of breast, lung, colorectal and oesophagus. It is hoped that further data will rapidly give to oncologists a relevant tool able to more reliably and earlier define therapeutic strategies, changing drugs when it is realized a lack of effectiveness.
Interesting perspectives , mainly in better defining response to radiotherapy, could be connected with radiotracers of hypoxia. But many other radiotracers could have a primary role in the near future , as those tracing neo-angiogenesis, creating opportunities in optimizing new targeted therapies, in the scenario of a tailored medicine.
This is a long, but promising and exciting process, in which it is fundamental, on one hand, to develop research and on the other, better define clinical applications, methodological standardization, quantitative analysis and so on. In this context , an essential issue is the strong and interactive relationship between the molecular imager and his/her referents, the clinicians.
It is already time for them to understand that the diagnostic information is no more sufficient alone, being more effective, for the whole understanding of the patient and of his disease, to think giving more importance to the pathophysiological than to morphostructural information in a future scenario which will be probably dominated by hybrid machines.
2. Miles K, McQueen L, Ngai S, Law P. Evidence-based medicine and clinical fluorodeoxyglucose PET/MRI in oncology. Cancer Imaging. 2015 Nov 17;15:18.
3. Fraum TJ, Fowler KJ, McConathy J. PET/MRI: Emerging Clinical Applications in Oncology. Acad Radiol. 2016 Feb;23(2):220-36.
4. Houshmand S, Boursi B, Salavati A, Simone CB, Alavi A. Applications of Fluorodeoxyglucose PET/Computed Tomography in the Assessment and Prediction of Radiation Therapy-related Complications. PET Clin. 2015 Oct;10(4):555-71.
5. Gill BS, Pai SS, McKenzie S, Beriwal S. Utility of PET for Radiotherapy Treatment Planning. PET Clin. 2015 Oct;10(4):541-54.
6. Sergieva S, Mihaylova I, Alexandrova E, Dimcheva M, Mansi L. SPECT-CT in Radiotherapy Planning, with Main Reference to Patients with Breast Cancer. Curr Radiopharm. 2015;8(1):9-18
7. Jeraj R, Bradshaw T, Simončič U. Molecular Imaging to Plan Radiotherapy and Evaluate Its Efficacy.J Nucl Med. 2015 Nov;56(11):1752-65
8. Abou DS, Pickett JE, Thorek DL. Nuclear molecular imaging with nanoparticles: radiochemistry, applications and translation. Br J Radiol. 2015 Oct;88(1054):201
9. Mansi L, Moncayo R, Cuccurullo V, Dottorini ME, Rambaldi PF. Nuclear medicine in diagnosis, staging and follow-up of thyroid cancer. Q J Nucl Med Mol Imaging. 2004;48(2):82-95.
10. Evangelista L, Farsad M, Piotto A, Pelizzo MR. 18FDOPA and 18F-FDG PET/CT, scintigraphic localization and radioguided surgery of recurrent medullary thyroid cancer: two case reports. Curr Radiopharm. 2014;7(2):133-7.
11. Kim HS, Lee KS, Ohno Y, van Beek EJ, Biederer J. PET/CT versus MRI for diagnosis, staging, and followup of lung cancer. J Magn Reson Imaging. 2015 Aug;42(2):247-60
12. Johnbeck CB, Knigge U, Kjær A. PET tracers for somatostatin receptor imaging of neuroendocrine tumors: current status and review of the literature. Future Oncol. 2014 Nov;10(14):2259-77
13. Cascini GL, Cuccurullo V, Tamburrini O, Rotondo A, Mansi L. Peptide imaging with somatostatin analogues: more than cancer probes. Curr Radiopharm. 2013 Mar;6(1):36-40.
14. Mansi L, Cuccurullo V. Diagnostic imaging in neuroendocrine tumors. J Nucl Med. 2014 Oct;55(10):1576-7.
15. Cuccurullo V, Faggiano A, Scialpi M, Cascini GL, Piunno A, Catalano O, Colao A, Mansi L. Questions and answers: what can be said by diagnostic imaging in neuroendocrine tumors? Minerva Endocrinol. 2012 Dec;37(4):367-77
16. Herzog H, Lerche C. Advances in Clinical PET/MRI Instrumentation. PET Clin. 2016 Apr;11(2):95-103
17. Jung JH, Choi Y, Im KC. PET/MRI: Technical Challenges and Recent Advances. Nucl Med Mol Imaging. 2016 Mar;50(1):3-12.
18. Mier W, Mier D Advantages in functional imaging of the brain. Front Hum Neurosci. 2015 May 19;9:249
19. Barthel H, Schroeter ML, Hoffmann KT, Sabri O. PET/MR in dementia and other neurodegenerative diseases. Semin Nucl Med. 2015 May;45(3):224-33.
20. Boss A, Weiger M, Wiesinger F. Future image acquisition trends for PET/MRI. Semin Nucl Med. 2015 May;45(3):201-11.
21. Tudisca C, Nasoodi A, Fraioli F. PET-MRI: clinical application of the new hybrid technology. Nucl Med Commun. 2015 Jul;36(7):666-78
22. Basu S, Hess S, Nielsen Braad PE, Olsen BB, Inglev S, Høilund-Carlsen PF. The Basic Principles of FDG-PET/CT Imaging. PET Clin. 2014 Oct;9(4):355-70,
23. Farwell MD, Pryma DA, Mankoff DA. PET/CT imaging in cancer: current applications and future directions. Cancer. 2014 Nov 15;120(22):3433-45.
24. Basu S, Kwee TC, Surti S, Akin EA, Yoo D, Alavi A. Fundamentals of PET and PET/CT imaging. Ann N Y Acad Sci. 2011 Jun;1228:1-18.
25. Kapoor V, McCook BM, Torok FS. An introduction to PET-CT imaging. Radiographics. 2004 Mar- Apr;24(2):523-43
26. Cistaro A, Cuccurullo V, Quartuccio N, Pagani M, Valentini MC, Mansi L. Role of PET and SPECT in the study of amyotrophic lateral sclerosis. Biomed Res Int. 2014;161. Apr 10.
27. Hess S, Hansson SH, Pedersen KT, Basu S, Høilund-Carlsen PF. FDG-PET/CT in Infectious and Inflammatory Diseases. PET Clin. 2014 Oct;9(4):497-519.
28. Sioka C, Assimakopoulos A, Fotopoulos A. The diagnostic role of (18)F fluorodeoxyglucose positron emission tomography in patients with fever of unknown origin. Eur J Clin Invest. 2015 Jun;45(6):601-8.
29. Langer A. A systematic review of PET and PET/CT in oncology: a way to personalize cancer treatment in a cost-effective manner? BMC Health Serv Res. 2010
30. Padma S, Sundaram PS, George S. Role of positron emission tomography computed tomography in carcinoma lung evaluation. J Cancer Res Ther. 2011
31. Høilund-Carlsen PF, Poulsen MH, Petersen H, Hess S, Lund L. FDG in Urologic Malignancies. PET Clin. 2014 Oct;9(4):457-68
32. Tabouret-Viaud C, Botsikas D, Delattre BM, Mainta I, Amzalag G, Rager O, Vinh-Hung V, Miralbell R, Ratib O. PET/MR in Breast Cancer. Semin Nucl Med. 2015 Jul;45(4):304-21
33. Karaosmanoğlu AD, Blake MA. Applications of PETCT in patients with esophageal cancer. Diagn Interv Radiol. 2012 Mar-Apr;18(2):171-82
34. Mac Manus MP. Use of PET/CT for staging and radiation therapy planning in patients with non-small cell lung cancer. Q J Nucl Med Mol Imaging. 2010
35. Maffione AM, Marzola MC, Capirci C, Colletti PM, Rubello D. Value of (18)F-FDG PET for Predicting Response to Neoadjuvant Therapy in Rectal Cancer: Systematic Review and Meta-Analysis. AJR Am J Roentgenol. 2015 Jun;204(6):1261-8.
36. Meignan M, Itti E, Gallamini A, Younes A. FDG PET/CT imaging as a biomarker in lymphoma. Eur J Nucl Med Mol Imaging. 2015 Apr;42(4):623-33.
37. Schipper RJ, Moossdorff M, Beets-Tan RG, Smidt ML, Lobbes MB. Noninvasive nodal restaging in clinically node positive breast cancer patients after neoadjuvant systemic therapy: a systematic review. Eur J Radiol. 2015 Jan;84(1):41-7.
38. Treglia G, Sadeghi R, Giovanella L, Cafarotti S, Filosso P, Lococo F. Is (18)F-FDG PET useful in predicting the WHO grade of malignancy in thymic epithelial tumors? A meta-analysis. Lung Cancer. 2014 Oct;86(1):5-13
39. Marcus C, Whitworth PW, Surasi DS, Pai SI, Subramaniam RM. PET/CT in the management of thyroid cancers. AJR Am J Roentgenol. 2014 Jun;202(6):1316- 29.
40. Pak K, Cheon GJ, Nam HY, Kim SJ, Kang KW, Chung JK, Kim EE, Lee DS. Prognostic value of metabolic tumor volume and total lesion glycolysis in head and neck cancer: a systematic review and meta-analysis. J Nucl Med. 2014 Jun;55(6):884-90
41. Kwee RM, Marcus C, Sheikhbahaei S, Subramaniam RM. PET with Fluorodeoxyglucose F 18/Computed Tomography in the Clinical Management and Patient Outcomes of Esophageal Cancer. PET Clin. 2015 Apr;10(2):197-205.
42. Lee ST, Scott AM. The Current Role of PET/CT in Radiotherapy Planning. Curr Radiopharm. 2015;8(1):38-44.
43. Dimitrakopoulou-Strauss A. PET-based molecular imaging in personalized oncology: potential of the assessment of therapeutic outcome. Future Oncol.
44. Sheikhbahaei S, Ahn SJ, Moriarty E, Kang H, Fakhry C, Subramaniam RM. Intratherapy or Posttherapy FDG PET or FDG PET/CT for Patients With Head and Neck Cancer: A Systematic Review and Metaanalysis of Prognostic Studies. AJR Am J Roentgenol. 2015 Nov;205(5):1102-13.
45. Salvatori M, Biondi B, Rufini V. Imaging in endocrinology: 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography
in differentiated thyroid carcinoma: clinical indications and controversies in diagnosis and follow-up. Eur J Endocrinol. 2015 Sep;173(3):R115-30.
46. Lindsay MJ, Siegel BA, Tunis SR, Hillner BE, Shields AF, Carey BP, Coleman RE. The National Oncologic PET Registry: expanded medicare coverage for PET under coverage with evidence development. AJR Am J Roentgenol. 2007 Apr;188(4):1109-13.
47. Tunis S, Whicher D. The National Oncologic PET Registry: lessons learned for coverage with evidence development. J Am Coll Radiol. 2009 May;6(5):360-5.
48. Hillner BE, Siegel BA, Hanna L, Duan F, Shields AF, Coleman RE. Impact of 18F-fluoride PET in patients with known prostate cancer: initial results from the National Oncologic PET Registry. J Nucl Med. 2014 Apr;55(4):574-81.
49. Wu P, Zhang Y, Sun Y, Shi X, Li F, Zhu Z. Clinical applications of 18F-FDG PET/CT in monitoring anti-cancer therapies. Curr Pharm Biotechnol. 2013;14(7):658-68.
50. Teng FF, Meng X, Sun XD, Yu JM. New strategy for monitoring targeted therapy: molecular imaging. Int J Nanomedicine. 2013;8:3703-13
51. Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: Evolving Considerations for PET response criteria in solid tumors. J Nucl Med. 2009 May;50 Suppl 1:122S-50S
52. Hyun O J, Luber BS, Leal JP, Wang H, Bolejack V, Schuetze SM, Schwartz LH, Helman LJ, Reinke D, Baker LH, Wahl RL. Response to Early Treatment Evaluated with 18F-FDG PET and PERCIST 1.0 Predicts Survival in Patients with Ewing Sarcoma Family of Tumors Treated with a Monoclonal Antibody to the Insulinlike Growth Factor 1 Receptor. J Nucl Med. 2016 May;57(5):735-40
53. O JH, Lodge MA, Wahl RL. Practical PERCIST: A Simplified Guide to PET Response Criteria in Solid Tumors 1.0. Radiology. 2016 Feb 24:142043.
54. Soderlund AT, Chaal J, Tjio G, Totman JJ, Conti M, Townsend DW. Beyond 18F-FDG: Characterization of PET/CT and PET/MR Scanners for a Comprehensive Set of Positron Emitters of Growing Application- -18F, 11C, 89Zr, 124I, 68Ga, and 90Y. J Nucl Med. 2015 Aug;56(8):1285-91