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Annual Congress of the European Association of Nuclear Medicine

October 12 – 16, 2019 Barcelona, Spain

eanm19.eanm.org

Barcelona, Spain

Visit us on.com/officialEANM

O C T O B E R 1 2 – 1 6 , 2 0 1 9 | B A R C E L O N A , S P A I N2

E A N M ’ 1 9 W O R L D L E A D I N G M E E T I N GC M E E X T E N D E D A B S T R A C T B O O K

Introduction by the Congress Chair 5

CME Sessions Overview 6

SUNDAY, OCTOBER 13, 2019

CME 1 – Dosimetry: An Educational Trip from Organ to Voxel-Based to Small Scale Dosimetry

Organ Level Dosimetry Jonathan Gear (London, United Kingdom) 9

Voxel Level Dosimetry Nicolas Chouin (Nantes, France) 10

Small Scale Dosimetry - Not so Appealing, but…It’s just Dosimetry Peter Bernhardt (Gothenburg, Sweden) 11

CME 2 – Oncology & Theranostics: NET – PRRT and More

PET/CT Imaging of PPGL in the Era of Genomic Disease Characterization (EANM/SNMMI 2019 Guidelines) David Taïeb (Marseille, France) 13

Long-Term Outcome of PRRT and Predictors of Outcome Michael Gabriel (Linz, Austria) 14

PRRT-Individualized Dosimetry vs. Fixed Dose Scheme Alexander Haug (Vienna, Austria) 15

PRRT-Treatment Sequencing and Combinations Rodney Hicks (Melbourne, Australia) 16

CME 3 – Radiation Protection + Dosimetry: Metrological Aspects on the Implementation of Dosimetry in RadionuclideTherapy

Requirements for the Dosimetry-Guided, Multi-Center Clinical Trial SELIMETRY Jonathan Wadsley (Sheffield, United Kingdom) 18

Priorities of Dosimetry in Clinical Radionuclide Therapy – The Italian Agreement between National Nuclear Medicine and Medical Physics Associations Carlo Chiesa (Milan, Italy) 19

European Initiatives to Ensure Traceable Dosimetry across Countries and Centers Michael Lassmann (Würzburg, Germany) 20

CME 4 – Radiopharmacy + Drug Development + Translational and Molecular Imaging Therapy + Oncology & Theranostics:Role of Extracellular Matrices in Cancer and Other Diseases

Extra Cellular Matrix - A Target in the Future?! Martin Behe (Villigen, Switzerland) 22

Molecular Imaging of Collagen and Oxidized Collagen in Fibrosis Peter Caravan (Charlestown, United States of America) 23

Imaging of Activated Fibroblasts in the ECM Uwe Haberkorn (Heidelberg, Germany) 24

MONDAY, OCTOBER 14, 2019

CME 5 – Oncology & Theranostics + Bone & Joint: Radionuclide Molecular Imaging in Bone Tumours and Multiple Myeloma – Pearls, Patterns & Pitfalls

Radionuclide Molecular Imaging in Primary Bone Tumours Tim van den Wyngaert (Edegem, Belgium) 26

Radionuclide Molecular Imaging of Bone Metastases Gopinath Gnanasegaran (London, United Kingdom) 27

Radionuclide Molecular Imaging in Multiple Myeloma Cristina Nanni (Bologna, Italy) 28

TABLE OF CONTENTS



CME 6 – Inflammation & Infection + Translational and Molecular Imaging Therapy + Radiopharmacy: Molecular ImagingTechnologies for Infectious Diseases

Imaging of Bacterial and Pathogen Infections, Infectious Disease Specialist’s Point of View Meta Roestenberg (Leiden, Netherlands) 30

Imaging of Bacterial and Pathogen Infections, Nuclear Medicine’s Point of View Mike Sathekge (Pretoria, South Africa) 31

Novel Approaches to Image the Pathogen, Radiopharmacy’s Point of View Clemens Decristoforo (Innsbruck, Austria) 32

CME 7 – Translational Molecular Imaging and Therapy: Imaging Immune Therapy

Imaging of Immunological Targets Wolfgang Weber (Munich, Germany) 34

Current State of Imaging in Assessment of Immunotherapy Caroline Bodet-Milin (Nantes, France) 35

Emerging Imaging Concepts in Immuno-Oncology Margret Schottelius (Garching, Germany) 36

CME 8 – Thyroid: Secondary Effects of Radioiodine Treatment

General Aspects of Radiobiology in Radioiodine Therapy Calogero D’Alessandria (Munich, Germany) 38

Deterministic Effects of Radioiodine Treatment Petar-Marko Spanjol (Geneva, Switzerland) 39

Stochastic Adverse Effects of Radioiodine Treatment Piotr Radojewski (Berlin, Germany) 40

TUESDAY, OCTOBER 15, 2019

CME 9 – Cardiovascular: Non-Invasive Imaging Strategies in Heart Failure

When and How Should I Look for Myocardial Ischemia or Viability? Fabien Hyafil (Paris, France) 42

When and How Should I Look for Cardiac Amyloidosis? Riemer Slart (Groningen, Netherlands) 43

When and How Should I Look for Cardiac Dyssynchrony? Marcus Hacker (Vienna, Austria) 44

When and How Should I Look for Cardiac Innervation? Hein Verberne (Amsterdam, Netherlands) 45

CME 10 – Neuroimagin / EAN: EANM-EAN Recommendations for the Use of Brain [18F]FDG-PET in NeurodegenerativeCognitive Impairment and Dementia

Assessing FDG-PET Diagnostic Accuracy Studies to Develop Recommendations for Clinical Use in Dementia Flavio Nobili (Genoa, Italy / EAN) 47

Clinical Utility of FDG-PET for the Differential Diagnosis Among the Main Forms of Dementia Javier Arbizu (Pamplona, Spain) 48

Clinical Utility of FDG-PET in Parkinson‘s Disease and Atypical Parkinsonism Associated with Dementia Silvia Morbelli (Genoa, Italy) 49



CME 11 – Physics + Cardiovascular: Advances in Quantitative Cardiac Imaging

Quantification in SPECT - Current State and Perspectives Mikko Hakulinen (Kuopio, Finland) 51

Quantification in PET - Current State and Perspectives Ian Armstrong (Manchester, United Kingdom) 52

Quantification in CT - Current State and Perspectives Marc Dewey (Berlin, Germany) 53

CME 12 – Paediatrics: Response Evaluation of Paediatric Sarcomas

Response of Paediatric Sarcomas – Does it Matter? Stefan Bielack (Stuttgart, Germany) 55

Radiological Response Evaluation of Paediatric Sarcomas Thekla von Kalle (Stuttgart, Germany) 56

Response Assessment in Paediatric Sarcomas – Value of Nuclear Medicine Techniques Marguerite T. Parisi (Seattle, United States of America) 57

WEDNESDAY, OCTOBER 16, 2019

CME 13 – Drug Develeopment + Radiopharmacy: Current and Future of Radiopharmaceuticals

PET Radiopharmaceuticals of Recent Years from a Radiopharmaceutical Chemist‘s Perspective Albert Windhorst (Amsterdam, Netherlands) 59

Current Value of PSMA-Targeting Ligands in Diagnostic and Therapeutic Nuclear Medicine Clemens Kratochwil (Heidelberg, Germany) 60

Established, Emerging and Future Radionuclides - Which will we use in 2030? Ulli Köster (Grenoble, France) 61

CME 14 – Bone & Joint: The Diagnosis is Complex Regional Pain Syndrome I (CRPS-I a.k.a. Reflex Sympathetic Dystrophy). Or is it? Contemporary Consensus and Controversies in Diagnosis and Management of CRPS-I Roger Atkins (Bristol, United Kingdom / IASP) 63

Role for Imaging in Diagnosis and Management of CRPS-I Frédéric Paycha (Paris, France) 64

Role for Imaging in Alternate Diagnoses Usually Confused with CRPS-I Edmond Rust (Mulhouse, France) 65

Imprint 66

E A N M ’ 1 9 W O R L D L E A D I N G M E E T I N G

5 O C T O B E R 1 3 – 1 7 , 2 0 1 9 | B A R C E L O N A , S P A I N

C M E E X T E N D E D A B S T R A C T B O O K

5

E A N M ’ 1 9C M E E X T E N D E D A B S T R A C T B O O K

W O R L D L E A D I N G M E E T I N G

B A R C E L O N A , S P A I N | O C T O B E R 1 3 – 1 7 , 2 0 1 9

On behalf of the European Association of Nuclear Medicine, it is my great pleasure and honour to cordially invite you to the 32nd Annual EANM Congress in October 2019. This year, our congress will take place in Barcelona, Spain. The city is world famous for its hospitality, its cultural attractions and its culinary highlights.

Molecular imaging is continuously expanding: it is increasingly being combined with advanced technologies such as artificial intelligence and has become a principal component of medical imaging. In the therapy field, targeted radiopharmaceuticals have been demonstrated to be effective and are increasingly used in a variety of clinical settings, often integrated with other therapeutic options. The ultimate goal is to design personalised, super-selective therapies and to identify more precise means of monitoring response to treatment in routine clinical practice.In the last three years, the status of the EANM annual meeting as the world-reference congress in nuclear medicine has been confirmed. In order to maintain the high level of excellence, the 2019 EANM Congress will build on the traditions that are highly appreciated by all attendees, with the expansion of newer features. A specific educational track, implemented with the collaboration of the European School of Multimodality Imaging and Therapy, will include up-to-date teaching sessions, enriched pitfalls seminars and Continuous Medical Education interactive sessions. In all these active learning conferences, attendees will have the possibility to enhance their knowledge of multimodality imaging. A careful evaluation procedure relating to the speakers will be implemented in order to gain feedback and ensure that future interactive sessions continue to enjoy a positive response. With similar pedagogic intent, numerous multidisciplinary joint symposia, organised by several EANM Committees in collaboration with our sister societies, will offer an integrative approach to various topics relevant to the state of the art of our discipline. All these learning sessions will not impact adversely on the predominant role of our Congress, which is to enable oral and electronic poster presentations on the latest achievements in clinical nuclear medicine, science and technology. On the

contrary, the oral sessions will be enriched. Rapid Fire sessions will draw attention to the highly rated abstracts in specific fields, with a panel of top-level presentations followed by extensive discussions; this will provide attendees with an integrated and coherent view on a wide variety of topics. Furthermore, the concept of featured oral sessions in which an invited speaker places the presentations into a broader perspective will be generalised to the other oral presentations. The now well-established tracks M2M – Molecule to Man (basic and translational science) and Do.MoRe (radionuclide therapy and dosimetry) promise to promote high-quality research through interaction between basic and translational clinical scientists and to present the latest achievements and developments in the fields of clinical molecular imaging and nuclear medicine therapy. During plenary lectures, distinguished speakers will address the state of the art and new developments in clinical and allied sciences, covering a broad range of topics with the goal of fostering the provision of the best possible care for our patients. I am particularly delighted that two young but very motivated and highly respected members of our European Nuclear Medicine community, Dr. Valentina Garibotto from Geneva, Switzerland, and Dr. Sarah Schwarzenböck from Rostock, Germany, will provide the traditional Highlights lecture.For all these reasons, I cordially invite you to EANM’19 to actively participate in our 32nd Annual Congress, to meet and interact with friends and colleagues from all over the world, to discuss science, to learn about the exciting developments in nuclear medicine, to break away from the daily routine and to enjoy everything that the city of Barcelona has to offer.

Francesco Giammarile EANM Congress Chair 2017-2019

L et te r ofINVITATIONby the Congress Chair

Francesco Giammarile EANM Congress Chair 2017-2019



SESSION OVER VIE W

Sunday, October 13

Monday, October 14

Tuesday, October 15

Wednesday, October 16

08:0

0 - 0

9:30

101CME 1

Dosimetry Committee

An Educational Trip from Organ to Voxel-Based to

Small Scale Dosimetry

601CME 5

Oncology &Theranostics + Bone &

Joint Committee

1101CME 9

Cardiovascular Committee

Non-Invasive ImagingStrategies in Heart

Failure

1601CME 13

Drug Develeopment +Radiopharmacy

Committee

08:0

0 - 0

9:30

10:0

0 - 1

1:30

1701CME 14

Bone & Joint Committee/ IASP

10:0

0 - 1

1:30

11:3

0 - 1

3:00

301CME 2

Oncology &Theranostics Committee

NET - PRRT and More

801CME 6

Inflammation &Infection +

Translational andMolecular

Imaging Therapy + Radiopharmacy

Committee

1301CME 10

NeuroimagingCommittee / EAN

EANM-EAN Recommendations for theUse of Brain 18 F-FDG-PET

in NeurodegenerativeCognitive Impairment and

Dementia11

:30

- 13:

00

14:3

0 - 1

6:00

401CME 3

Radiation Protection +Dosimetry Committee

Metrological Aspects on the Implementation

of Dosimetry inRadionuclide Therapy

901CME 7

Translational andMolecular Imaging

Therapy Committee

1401CME 11Physics +

Cardiovascular Committee

14:3

0 - 1

6:00

16:3

0 - 1

8:00

501CME 4

Radiopharmacy + Drug Development + Translational and Molecular Imaging

Therapy + Oncology & Theranostics Committee

Role of ExtracellularMatrices in Cancerand Other Diseases

1001CME 8Thyroid

Committee

1501CME 12

PaediatricsCommittee

16:3

0 - 1

8:00

Radionuclide MolecularImaging in Bone

Tumours and MultipleMyeloma - Pearls,Patterns & Pitfalls

Current and Future ofRadiopharmaceuticals

The Diagnosis isComplex Regional Pain

Syndrome I (CRPS-I a.k.a.Reflex SympatheticDystrophy). Or is it?

Molecular ImagingTechnologies for

Infectious Diseases

Advances in Quantitative Cardiac Imaging

Imaging Immune Therapy

Response Evaluation of Paediatric Sarcomas

Secondary Effects of Radioiodine Treatment

To obtain your CME/CTE credits (for single sessions as well as the congress itself ) the respective evaluations are mandatory. Deadline: October 30, 2019. After this date, or without proper evaluation, no points will be accredited.

EVALUATION.EANM.ORG

1) SCAN YOUR BADGEScan your badge at the beginning of each session when entering the room in order to acquire CME or CTE credits.

3) DOWNLOAD YOUR CERTIFICATE Once the steps above are completed, your certificate will be available within 24 hours in your vEANM area.

EANM'19 CME/CTE CERTIFICATES

W O R L D L E A D I N G M E E T I N G

ATTENTION!

Mandatory Evaluation

2) EVALUATE (Deadline - October 30, 2019)

A short evaluation has to be completed for each attended CME/CTE session until Oct 30, 2019.

Evaluation has to be done online at evaluation.eanm.org

O C T O B E R 1 3 – 1 7 , 2 0 1 9 | B A R C E L O N A , S P A I N 8


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C M E S E S S I O N 1October 13, 2019 | 08 :00 – 09:30

1An Educational Trip from Organ to

Voxel-Based to Small Scale Dosimetry

CME Session



October 13, 08:00 - 09:30

1The treatment of cancer with radiopharmaceuticals is undergoing rapid development with a number of new radiotherapeutics being introduced to the clinic over recent years. Quantitative imaging and internal dosimetry offer the potential to treat patients according to their individual biokinetics and morphological information, which may lead to better treatment optimisation and efficacy.

Methodologies for absorbed dose estimates generally use the MIRD schema. This simply states that the mean absorbed dose to any target region from any source volume is the product of the total number of radionuclide transitions and the absorbed dose delivered by emissions from a single decay, taking into account the source-target geometry. Absorbed dose factors (or S-values) for source and target organs are well tabulated by organisations such as MIRD, ICRP and RADAR for a range of anthropomorphic phantom geometries.

Calculation of the total number of radioactive decays within a source organ requires the acquisition of sequential quantitative images at times

appropriate to characterise the radiopharmaceutical biokinetics. Advances in imaging technology has allowed many of the quantitative correction methods historically only available to select research centres to be implemented in clinical routine. This has seen a recent trend towards standardised approaches and methodologies for quantitative imaging and dosimetry.

In this CME we will discuss techniques for quantitative imaging at the organ level with reference to EANM guidance documents and other related literature. Advantages of different acquisition protocols such as planar, hybrid and multi-SPECT will be presented with clinical examples of their implementation. References to organ S-value data will be given with discussion of mass scaling for more patient specific representation. Clinical examples demonstrating the application of organ level dosimetry will be given with reference to publications showing dose response and dose toxicity relationships.

Organ Level Dosimetry

References:

1. Ljungberg, M., et al., MIRD Pamphlet No. 26: Joint EANM/MIRD Guidelines for Quantitative Lu-177 SPECT Applied for Dosimetry of Radiopharmaceutical Therapy. Journal of Nuclear Medicine, 2016. 57(1): p. 151-162.

2. Lassmann, M., et al., EANM Dosimetry Committee guidance document: good practice of clinical dosimetry reporting. European Journal of Nuclear Medicine and Molecular Imaging, 2011. 38(1): p. 192-200.

3. Snyder, W.S., et al., “S,” Absorbed Dose per Unit Cumulated Activity for Selected Radionuclides and Organs, in The Society of Nuclear Medicine, Inc., O.R. Oak Ridge National Laboratory, Tennessee Editor. 1975, The Society of Nuclear Medicine, Inc.: 457 Park Ave. S,. New York, N.Y. 10016.

4. Gleisner, K.S., et al., Variations in the practice of molecular radiotherapy and implementation of dosimetry: results from a European survey. Ejnmmi Physics, 2017. 4.

5. Dewaraja, Y.K., et al., MIRD Pamphlet No. 24: Guidelines for Quantitative I-131 SPECT in Dosimetry Applications. Journal of Nuclear Medicine, 2013. 54(12): p. 2182-2188.

Jonathan Gear (London, United Kingdom)

CME Session



October 13, 08:00 - 09:30

1With the development and spread of performant SPECT/CT and PET/CT devices in nuclear medicine departments, there is a temptation to perform voxel-based dosimetry for internal radiotherapy treatments, instead of traditional organ-based dosimetry. Voxel-based dosimetry relies on the determination of the absorbed dose for each voxel of a patient image. It allows for the calculation of a Dose-Volume Histogram (DVH) within one organ or tumour, similarly to what is performed on a daily practice in external beam radiotherapy. This DVH is expected to characterize and quantify the non-uniformity of absorbed dose distribution within one volume of interest and could be used to explain the lack of tumour control, or a potential type of toxicity following the administration of a treatment in internal radiotherapy1.

Theoretically, voxel-based dosimetry is very similar to organ-based dosimetry and can be derived following the MIRD formalism, as described in the MIRD Pamphlet 172. The only major difference is the size of the sources and targets to be considered. The MIRD formalism states that the mean absorbed dose to any target region from any source volume is the product of the total number of radionuclide transitions (i.e. the cumulated activity) and the absorbed dose delivered by emissions from a single decay, considering the source-target geometry (i.e. the S-value). Dosimetry is thus a two-part problem.

In practice, the limited size of the sources is a major issue for the determination of cumulated activity

within voxels. The size of voxels is indeed smaller than the spatial resolution of imaging devices, especially when SPECT/CT is involved (spatial resolution > 10 mm). This leads to general inaccuracy for the calculations of DVH. In addition, the calculation of DVH is also very sensitive to the methods used for PET or SPECT reconstruction, the quality of compensation methods, the noise present on the images, the internal organ motion and respiration, to cite only a few…3 Another issue is that one must derive the time-activity curve within each voxel in order to estimate the cumulated activity. Activities at different time-points following the radiopharmaceutical injection are usually obtained from a series of images. Registration of the sequential images should be thus carried out to get the time-activity curve for each voxel4. Here again, large variations on the DVH are expected according to the registration method that is used.

Concerning the determination of S-values, the use of Monte Carlo codes allows for an accurate determination of absorbed dose even at the scale of voxel. Numerous databases have been calculated for different size of voxels and radionuclides2,5 and they are available for clinicians.

In this CME we will present the general scheme for voxel-based dosimetry and discuss the influence of different issues and quantitative imaging methods on the accuracy of the derived DVH in this context.

Voxel Level Dosimetry

References:

1. d’Abadie, P., Hesse, M., Jamar, F., Lhommel, R. & Walrand, S. 90Y TOF-PET based EUD reunifies patient survival prediction in resin and glass microspheres radioembolization of HCC tumours. Phys. Med. Biol. 63, 245010 (2018).

2. 2Bolch, W. E. et al. MIRD pamphlet No. 17: the dosimetry of nonuniform activity distributions--radionuclide S values at the voxel level. Medical Internal Radiation Dose Committee. J. Nucl. Med. 40, 11S-36S (1999).

3. 3Cheng, L., Hobbs, R. F., Segars, P. W., Sgouros, G. & Frey, E. C. Improved dose-volume histogram estimates for radiopharmaceutical therapy by optimizing quantitative SPECT reconstruction parameters. Phys. Med. Biol. 58, 3631–3647 (2013).

4. Sarrut, D., Halty, A., Badel, J.-N., Ferrer, L. & Bardiès, M. Voxel-based multimodel fitting method for modeling time activity curves in SPECT images. Med. Phys. 44, 6280–6288 (2017).

5. Lanconelli, N. et al. A free database of radionuclide voxel S values for the dosimetry of nonuniform activity distributions. Phys. Med. Biol. 57, 517–533 (2012).

Nicolas Chouin (Nantes, France)

CME Session



October 13, 08:00 - 09:30

1Small-scale dosimetry aims to estimate the absorbed dose distribution at dimensions beyond the resolution of nuclear medicine imaging techniques. With planar gamma camera imaging, the determination of activity concentration and absorbed doses is limited to organs or tumors. With SPECT images higher accuracy in organ and tumor dosimetry can be obtained, and even voxel-based dosimetry is possible to perform. Nevertheless, the activity concentrations in a voxel might be highly non-uniform distributed. The activity concentration can vary within tissue structures, such as the kidney nephrons subunits, the glomeruli, and proximal- and distal tubule, or within cellular compartments as the cell membrane, cytoplasm or cell nucleus.

The absorbed dose distribution for a non-uniform voxel activity distribution depends on the radionuclide’s emission profile and the distance between the target and source, e.g. the absorbed dose to glomeruli from a radionuclide accumulation in proximal tubule.

The range for the emitted particles varies widely. Auger electrons can have an extreme short range

just a a few nm. The range of alpha particles is around 40-100 um, while the range of conversion and beta particles is from a few µm to a maximal range of 11 mm for the beta particles emitted from 90Y. The beta particles emitted from 90Y might cause a uniform absorbed dose distribution within a voxel. However, the activity concentration quantification of this radionuclide is challenging with nuclear medicine image techniques. Consequently, for 90Y-microspheres simulation models of the activity distribution in liver tissue have been developed, aiming to describe the absorbed dose distribution after radioembolization. Other tissue models for calculation of the absorbed dose distribution to different subunits involves e.g. a nephron model and a bone marrow model. At the cellular level models for calculating the mean absorbed dose to cell nucleus, cytoplasm and the cell membrane have been constructed for different cellular configurations.

In this CME session we will describe the importance of small-scale dosimetry for different radiopharmaceuticals and describe the benefit and limitation of available models

Small Scale Dosimetry - Not so Appealing, but…It’s just Dosimetry

References:

1. Uusijarvi H, Chouin N, Bernhardt P, Ferrer L, Bardies M, Forssell-Aronsson E. Comparison of electron dose-point kernels in water generated by the Monte Carlo codes, PENELOPE, GEANT4, MCNPX, and ETRAN. Cancer biotherapy & radiopharmaceuticals. 2009;24(4):461-7

2. Goddu SM, Rao DV, Howell RW. Multicellular dosimetry for micrometastases: dependence of self-dose versus cross-dose to cell nuclei on type and energy of radiation and subcellular distribution of radionuclides. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 1994;35(3):521-30.

3. Hogberg J, Rizell M, Hultborn R, Svensson J, Henrikson O, Molne J, et al. Simulation Model of Microsphere Distribution for Selective Internal Radiation Therapy Agrees With Observations. International journal of radiation oncology, biology, physics. 2016;96(2):414-21.

4. Hobbs RF, Song H, Huso DL, Sundel MH, Sgouros G. A nephron-based model of the kidneys for macro-to-micro alpha-particle dosimetry. Phys Med Biol. 2012;57(13):4403-24.

5. Hobbs RF, Song H, Watchman CJ, Bolch WE, Aksnes AK, Ramdahl T, et al. A bone marrow toxicity model for (2)(2)(3)Ra alpha-emitter radiopharmaceutical therapy. Phys Med Biol. 2012;57(10):3207-22.

6. Hobbs RF, Song H, Watchman CJ, Bolch WE, Aksnes AK, Ramdahl T, et al. A bone marrow toxicity model for (2)(2)(3)Ra alpha-emitter radiopharmaceutical therapy. Phys Med Biol. 2012;57(10):3207-22.

Peter Bernhardt (Gothenburg, Sweden)




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C M E S E S S I O N 2October 13, 2019 | 11 :30 - 13:00

2NET – PRRT and More

CME Session



October 13, 11:30 - 13:00

2

PET/CT Imaging of Paraganglioma/Pheochromocytoma in the Era of Genomic Disease Characterization of (EANM/SNMMI 2019 Guidelines)

David Taïeb (Marseille, France)

Pheochromocytoma and paraganglioma (PGGL) are the most frequent inheritable neuroendocrine tumors. Genomic characterization has profoundly helped to gain a more comprehensive pathogenic picture of PPGLs with description of 3 main subgroups associated with activation of specific signaling pathways. Nuclear medicine has also emerged at the forefront of tools in the evaluation of PPGL with the use of various radiopharmaceuticals. Beyond their ability to detect and localize disease, these imaging approaches can guide also therapy. In the recent years, the excellent results obtained with gallium-68(68Ga)-labelled somatostatin receptor analogs (SSAs) have simplified the imaging approach to PPGL patients

68Ga-DOTA-SSAs PET/CT can be recommended for diagnosis, staging, and follow-up of head and neck PGL, metastatic PPGL and those associated with succinate dehydrogenase (also called SDHx) mutations. 68Ga-DOTA-SSA seems to have limited sensitivity in HIF2A-related paraganglioma. In the kinase signaling group (NF1, RET, MAX, TMEM127), 18F-FDOPA is probably the best radiopharmaceutical due to its high tumor uptake together with a limited uptake in the remaining adrenal gland. For sporadic pheochromocytoma, [123I]MIBG, [18F]DOPA or 68Ga-DOTA-SSA can be used to confirm the diagnosis1-11. These recommandations have been approved by the EANM/SNMMI societies.

References

1. Kroiss A, Putzer D, Frech A, et al. A retrospective comparison between 68Ga-DOTA-TOC PET/CT and 18F-DOPA PET/CT in patients with extra-adrenal paraganglioma. European Journal of Nuclear Medicine and Molecular Imaging. 2013;40(12):1800-1808.

2. Archier A, Varoquaux A, Garrigue P, et al. Prospective comparison of (68)Ga-DOTATATE and (18)F-FDOPA PET/CT in patients with various pheochromocytomas and paragangliomas with emphasis on sporadic cases. Eur J Nucl Med Mol Imaging. 2016;43(7):1248-1257.

3. Janssen I, Blanchet EM, Adams K, et al. Superiority of [68Ga]-DOTATATE PET/CT to Other Functional Imaging Modalities in the Localization of SDHB-Associated Metastatic Pheochromocytoma and Paraganglioma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2015;21(17):3888-3895.

4. Janssen I, Chen CC, Taieb D, et al. 68Ga-DOTATATE PET/CT in the Localization of Head and Neck Paragangliomas Compared with Other Functional Imaging Modalities and CT/MRI. J Nucl Med. 2016;57(2):186-191.

5. Janssen I, Chen CC, Zhuang Z, et al. Functional Imaging Signature of Patients Presenting with Polycythemia/Paraganglioma Syndromes. J Nucl Med. 2017;58(8):1236-1242.

6. Taieb D, Jha A, Guerin C, et al. 18F-FDOPA PET/CT imaging of MAX-related pheochromocytoma. J Clin Endocrinol Metab. 2018;103(4):1574-1582.

7. Jha A, Ling A, Millo C, et al. Superiority of (68)Ga-DOTATATE over (18)F-FDG and anatomic imaging in the detection of succinate dehydrogenase mutation (SDHx )-related pheochromocytoma and paraganglioma in the pediatric population. Eur J Nucl Med Mol Imaging. 2018;45(5):787-797.

8. Gild ML, Naik N, Hoang J, et al. Role of DOTATATE-PET/CT in preoperative assessment of phaeochromocytoma and paragangliomas. Clin Endocrinol (Oxf ). 2018. doi: 10.1111/cen.13737

9. Kong G, Schenberg T, Yates CJ, et al. The role of 68Ga-DOTA-Octreotate (GaTate) PET/CT in follow-up of SDH-associated pheochromocytoma and paraganglioma (PPGL). J Clin Endocrinol Metab. 2019. doi: 10.1210/jc.2019-00018.

10. Kan Y, Zhang S, Wang W, Liu J, Yang J, Wang Z. (68)Ga-somatostatin receptor analogs and (18)F-FDG PET/CT in the localization of metastatic pheochromocytomas and paragangliomas with germline mutations: a meta-analysis. Acta Radiol. 2018: 59(12):1466-1474.

11. Han S, Suh CH, Woo S, Kim YJ, Lee JJ. Performance of (68)Ga-DOTA-Conjugated Somatostatin Receptor Targeting Peptide PET in Detection of Pheochromocytoma and Paraganglioma: A Systematic Review and Meta-Analysis. J Nucl Med. 2019:60(3):369-376.

CME Session



October 13, 11:30 - 13:00

2

Long-Term Outcome of PRRT and Predictors of Outcome

Michael Gabriel (Linz, Austria)

Radionuclide peptide therapy (PRRT) has established as a cornerstone in the treatment of patients with a non-operable or metastatic neuroendocrine tumor. This systemic therapy approach is based on the overexpression of somatostatin receptors (SSTR) in tumor lesions. Accordingly, the assessment of SSTRs using 68Gallium-labelled somatostatin analogs, e.g. 68Ga-DOTA-TOC-PET / CT, is a prerequisite for this therapy. Only in the case of intensive tracer accomulation this therapy can be considered, mainly suffering from G1/G2 tumors. In addition the metabolic tracer, 18F-FDG PET / CT, has also turned out to be of clinical relevance (1). Investigations suggest that patients who show increased 18FDG uptake at initial diagnosis or during the course of therapy a prognostically worse outcome can be expected, which favours the switch of the therapy regime.

But not only the metabolic activity of lesions is relevant, higher Ki-67 values had a negative outcome on both progression free survival (PFS) and overall survival (OS), as well as higher chromogranin-A (CgA) levels and previous chemotherapy (2). Tumor grading and lesion size also seem to have a significant influence on the outcome of the treatment as indicated by several retrospective studies. Accordingly, the outcome seems to be better in the surgically pretreated patients, which favours the concept of tumor reduction reduction prior to initiating systemic radionuclide peptide therapy (3).

But also the complementary concept of pretreatment by means of radionuclide peptide

therapy in the sense of a neoadjuvant therapy concept can be promising in terms of resectable or potentially resectable pancreatic neuroendocrine tumors (4).

In general, long-term results show high efficacy of this treatment, which can be carried out repeatedly and showing good tolerability (5). The treatment response of the initial PRRT application is has been found to be a good predictor for the long-term outcome, meaning response or even stabilization of the tumor disease after the first cycle of PRRT a long-term tumor control can be expected in the majority of these patients. This also includes the repeated PRRT application if recurrent disease intermediately occurs. Apart from tumor-related factors, the gender also seems to have an impact with more favourable outcome of the female gender. Whether this is due to a better therapy response or represents a tumor-specific property requires further investigation.

Although kidney function is regularly impaired without the need of hemodialysis, the quality of life is still high in many patients over many years and the associated disease-morbidity is also moderate (5). In general, PRRT is very encouraging in terms of long-term outcome. Thirty-two percent (14/44 patients) of the patients with metastatic or inoperable disease are still alive more than 12 years after the beginning of radionuclide therapy. Possible predictors for favourable outcome are initial response to PRRT, number of affected sites and female gender (5).

References:

1. Nilica B, Waitz D, Stevanovic V, et al. Direct comparison of (68)Ga-DOTA-TOC and (18)F-FDG PET-CT in the follow-up of patients with neuroendocrine tumour treated with the first full peptide receptor radionuclide therapy cycle.Eur J Nucl Med Mol Imaging 2016;43:1585-1592.

2. Aalbersberg EA, Huizing DM, Walraven I, et al. Parameters to predict progression free and overall survival after peptide receptor radionuclide therapy: a multivariate analysis in 782 patients. J Nucl Med 2019. In press.

3. Kaemmerer D, Twrzik M, Kulkarni, et al. Prior Resection of the primary tumor prolongs survival after peptide receptor radionuclide therapy of advanced neuroendocrine neoplasms. Ann Surg. 2019. In press.

4. Partelli S, Bertani E, Bartolomei M, et al. Peptide receptor radionuclide therapy as neoadjuvant therapy for resectable or potentially resectable pancreatic neuroendocrine neoplasms. Surgery 2018;163:761-767.

5. Gabriel M, Nilica B, Kaiser B, Virgolini IJ. Twelve-year follow-up after peptide receptor radionuclide therapy. J Nucl Med 2019;60:524-529.

CME Session



October 13, 11:30 - 13:00

2

PRRT-Individualized Dosimetry vs. Fixed Dose Scheme

Alexander Haug (Vienna, Austria)

Great efforts have been made in the recent past in order to improve dosimetry in radionuclide therapy. These efforts have been translated into clinical routine, subsequently with the need for costly scintigraphic measurements in order to measure absorbed doses. In order to justify these efforts the impact of dosimetry on radionuclide therapy has to be evaluated carefully. Some radionuclide therapies, such as treatment with radioiodine, have at least in part already incorporated dosimetry 1. On the other hand, dosimetry is widely performed in PRRT of neuroendocrine tumors and treatment of metastatic prostate cancer with 177Lu-PSMA. Results of dosimetry do rarely impact these treatments as thresholds for dose limiting organs are lacking and no dose-response relationship has been established. The limited clinical value of dosimetry might challenge the efforts needed to perform the necessary measurements. Looking at large industry-sponsored pivotal trials, approved treatment schemes are rather based on classical dose escalation studies, as well-known from non-radioactive drugs. Xofigo serves as an example for this strategy 2.

Another strategy is based more on available empirical data. Lutathera might serve as an suited example

3, 177Lu-PSMA-617 (the VISION trial is currently recruituing) a as another.

In these cases, the regimen is based on extensive experience from retrospective data, the efficacy of which is demonstrated in prospective trails, and modified only in the case of relevant side effects, mainly hematotoxicity. Dosimetry plays no relevant role here.

There is no question that dosimetry provides an excellent opportunity for personalized treatment strategies. So far, this potential is far from being exploited. For the future importance of dosimetry, it will therefore be of utmost importance to demonstrate reliable thresholds for organs at risk and dose-response relationships, as is customary in radiotherapy. If this does not happen in the near future, more and more fixed therapy regimens and classic dose escalation studies will come to the fore and represent the future standard.

References

1. Maxon HR, Thomas SR, Hertzberg VS, et al. Relation between effective radiation dose and outcome of radioiodine therapy for thyroid cancer. N Engl J Med. 1983;309(16):937-941.

2. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.

3. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 Trial of (177)Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. 2017;376(2):125-135.

CME Session



October 13, 11:30 - 13:00

2

PRRT-Treatment Sequencing and Combinations

Rodney Hicks (Melbourne, Australia)

Within the guidelines of many specialist societies, including those of the European Neuroendocrine Tumour Society, peptide receptor radionuclide therapy (PRRT) has long been an option for treatment of advanced neuroendocrine neoplasia (NEN), albeit generally only after the failure of almost all other available treatments. The NETTER-1 trial (1) further validated an existing evidence base for its utility in low-grade (Ki-67 <21%) NEN (2). With increasing experience with PRRT demonstrating its effectiveness, safety and general improvement in quality of life, questions arise as to when PRRT should be introduced into the treatment pathway and if the indication for PRRT should expand beyond G1-2 disease. Preliminary experience has indicated that PRRT can be effective and safe in treatment-naïve patients when used as a neoadjuvant therapy prior to surgery (3) and also in the context of G3 NEN in patients in whom chemotherapy has failed or is contraindicated (4). Based on existing trial evidence, the significantly higher objective response rates, longer progression free and overall survival and a more favorable side-effect profile of PRRT compared to the targeted agents everolimus and sunitinib and low response rates to chemotherapy could make a case for using PRRT as the preferred second-line treatment after failure of somatostatin analogue (SSA) therapy to control symptoms or disease progression. While this strategy currently lacks head-to-head comparison, current randomized control trials of PRRRT versus everolimus and PRRT versus capecitabine/temozolamide

(CAPTEM) chemotherapy are underway. A challenge in moving the use of PRRT into the treatment paradigm of G3 NEN is the risk of dedifferentiation in some or all disease sites with accompanying loss of somatostatin receptor (SSTR) expression. Selection of patients for PRRT thus requires careful phenotyping of disease with pretreatment comparison of SSTR and FDG PET/CT (5). In the situation that all sites of disease have high SSTR expression, PRRT could be considered an option. In our experience, response rates appear to be somewhat higher than with lower-grade tumours, possibly reflecting the higher radiosensitivity of actively cycling cells. The combination of PRRT with radiosensizing chemotherapy, particularly with agents that themselves have efficacy in higher grade NEN, may both enhance efficacy and prevent or delay outgrowth of cells with lower radiation exposure, which is particularly relevant to microscopic disease deposits. Other emerging options for combination therapies including use of DNA-repair modifying drugs and immunotherapy agents. Early phase clinical trials of these approaches are planned with the primary end-point being establishment of their safety. Together, these innovations have the potential to move PRRT earlier in the management of NEN and also to broaden the spectrum of patients who could benefit from this treatment. Combined with personalized PRRT regimens, further improvement in patient outcomes can be anticipated.

References

1. Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. N Engl J Med. 2017;376(2):125-35.

2. Hicks RJ, Kwekkeboom DJ, Krenning E, Bodei L, Grozinsky-Glasberg S, Arnold R, et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Neoplasia: Peptide Receptor Radionuclide Therapy with Radiolabeled Somatostatin Analogues. Neuroendocrinology. 2017.

3. Barber TW, Hofman MS, Thomson BN, Hicks RJ. The potential for induction peptide receptor chemoradionuclide therapy to render inoperable pancreatic and duodenal neuroendocrine tumours resectable. Eur J Surg Oncol. 2012;38(1):64-71.

4. Thang SP, Lung MS, Kong G, Hofman MS, Callahan J, Michael M, et al. Peptide receptor radionuclide therapy (PRRT) in European Neuroendocrine Tumour Society (ENETS) grade 3 (G3) neuroendocrine neoplasia (NEN) - a single-institution retrospective analysis. Eur J Nucl Med Mol Imaging. 2018;45(2):262-77.

5. Hicks RJ. Use of molecular targeted agents for the diagnosis, staging and therapy of neuroendocrine malignancy. Cancer Imaging. 2010;10 Spec no A:S83-91.




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3Metrological Aspects on the Implementation

of Dosimetry in Radionuclide Therapy

CME Session



October 13, 14:30 - 16:00

3

Requirements for the Dosimetry-Guided, Multi-Centre Clinical Trial SELIMETRY

Jonathan Wadsley (Sheffield, United Kingdom)

SELIMETRY is a multicentre study, running in 8 UK centres. It is investigating the use of a MEK inhibitor, Selumetinib, to induce re-expression of the sodium iodide symporter (NIS) in iodine refractory differentiated thyroid cancer, thus potentially allowing further radioiodine (RAI) therapy. The primary endpoint of this single arm phase 2 study is progression free survival in patients who achieve an increase in iodine uptake and go on to receive RAI therapy under recombinant TSH (rhTSH) stimulation.

The collection of dosimetry data is an important exploratory aspect of the study, to investigate whether a threshold absorbed dose for response to therapy can be determined, and whether there may be scope to individualise treatment to achieve a desirable absorbed dose to target lesions.

Collection of this dosimetry data has presented a considerable challenge and has required the

development of a network of centres capable of delivering standardised dosimetry data. In this talk I will discuss some of the barriers we have encountered and overcome. These include some of the historical difficulties with dosimetry which have more recently been overcome, difficulties in securing funding and scanner time to undertake additional scans, the need to calibrate and validate SPECT/CT at each site, the need to establish a standardised and workable imaging protocol, and arrangements for the central review of images.

It is our hope that now this UK network is established we will be able to deliver further dosimetry guided trials in the rapidly growing field of molecular radiotherapy, leading to optimisation of therapy and improved patient outcomes.

References:

1. Ho AL, Grewal RK, Leboeuf R, Sherman EJ, Pfister DG, Deandreis D, et al. Selumetinib-Enhanced Radioiodine Uptake in Advanced Thyroid Cancer. New Engl J Med. 2013 Feb 14;368(7):623-32.

2. McGowan DR, Guy MJ. Time to demand dosimetry for molecular radiotherapy? Brit J Radiol. 2015 Mar;88(1047).

3. Wadsley, J., Gregory, R., Flux, G., Newbold, K., Du, Y., Moss, L., . . . Brown, S. R. (2017). SELIMETRY- A Multicentre I-131 Dosimetry Trial: A Clinical Perspective. The British Journal of Radiology.

4. Newbold, K. L., Flux, G., & Wadsley, J. (2017). Radioiodine for High Risk and Radioiodine Refractory Thyroid Cancer: Current Concepts in Management. Clinical Oncology, 29(5), 307-309.

Acknowledgments

Cancer Research UK- main trial funding

AstraZeneca- supply of Selumetinib and research funding

Sanofi-Genzyme- supply of rhTSH

CME Session



October 13, 14:30 - 16:00

3

Priorities of Dosimetry in Clinical Radionuclide Therapy – The Italian Agreement between National Nuclear Medicine and Medical Physics Associations

Chiesa Carlo (Milan, Italy), Pacilio M (Rome), Strigari L (Bologna), Stasi M (Turin), Bagni O (Latina), Maccauro M (Milan), Scopinaro (Rome), Schillaci O (Rome)

The talk presents the document signed by the Italian Associations of Nuclear Medicine and Medical Physics about the implementation of the optimization principle in nuclear medicine therapy. The European Directive EURATOM 2013/59 explicitly defines this therapy as a kind of radiotherapy. Then article 56 (“Optimization”) is converted as a need in practice of individual dosimetric evaluation before and during therapy, since non dosimetrically optimized treatments may result either in underdosing, with consequent inefficacy (particularly serious risk in oncological patients), or overdosing. In this scenario, the conventional pharmacological approach based on posology is criticized since it was determined in order to guarantee safety to all patients, but with sacrifice of efficacy for individuals with higher individual tolerance.

The first step forward is the differentiation of the analysis according to each specific therapeutic application, which is classified as standardized or non standardized depending on complexity and risk of the pathology and therapy. Non standardized therapies are directed to: pediatric or special patients, distant metastases in thyroid cancer, liver disease, neuroendocrine tumors, PSMA. These should be optimized and personalized by a therapist and by a “closely involved” medical physics expert. This level

of involvement is defined as equivalent as in external beam radiotherapy.

The absolute statement “For ALL medical exposures...” has to face present limits in feasibility and available resources. The main goal and novelty of the document is therefore, for each application, the indication about recommended versus optional dosimetry, which is not only related to the standardized/non standardized kind of therapy. This recommendation depends on a feasibility-cost-benefit argument, and is different for oncological or non oncological disease. Dosimetry is recommended for applications where dosimetry is technically feasible and reliable, and where the benefit/cost ratio is favourable, even if the therapy is standardized (thyroid benign disease). It is optional for remnant or neck nodes treatment in thyroid cancer, and for 223Ra treatment.

With the goal of increasing efficacy, and legally supported by the optimization request, therapist should have the license of going beyond the posology indications, without being in an approved trial, provided that dosimetry is performed and reference dose value are available, either in literature or as results of internal studies.

References:

1. Chiesa C, Sjogreen Gleisner K, Flux G, Gear J, Walrand S, Bacher K, Eberlein U, Visser E, Chouin N, Ljungberg M, Bardies M, Lassmann M, Strigari L, Konijnenberg MW The conflict between treatment optimization and registration of radiopharmaceuticals with fixed activity posology in oncological nuclear medicine therapy Eur J Nucl Med Mol Imaging (2017) 44:1783-1786

CME Session



October 13, 14:30 - 16:00

3

European Initiatives to Ensure Traceable Dosimetry across Countries and Centers

Michael Lassmann (Würzburg, Germany)

There is evidence that molecular radiotherapy (MRT) are more effective if treatments were planned on the basis of individual normal tissue and target tissue dosimetry (1). Two previous international projects involving metrology institutes demonstrated in international intercomparison exercises that it is both possible a) to reduce the uncertainties of quantitative imaging (QI) for dosimetry with SPECT/CT to less than 10% (2) and to assess consistency between sites using different calibration and segmentation methods based on traceable standards (3).

Until mid-2019, the EU-EMPIR project, MRTDosimetry (http://mrtdosimetry-empir.eu/) continued the development of practical procedures for implementation of routine patient dosimetry in MRT, in close collaboration with the leading metrology institutes in Europe. Some of the results of the project are:

• Reassessment of the Y-90 positron branching ratio;

• Development of a protocol for calibration of SPECT-CT based QI systems;

• Development of radioactive test sources and 3D-printed quasi-anthropomorphic phantoms for validation of QI systems and absorbed dose measurements;

• Development of a protocol for commissioning an absorbed dose measurement system;

As a follow-up of this project, test images are made available on an open-access database that can be used for commissioning dosimetry systems; the images cover a range of cases, and the contained activity and dose distributions are available.

Another European project, “MEDIRAD” (http://www.medirad-project.eu/), that started 2017 develops and implements the tools necessary to establish, for the first time in a multicentre setting, the range of absorbed doses delivered to healthy organs to patients undergoing thyroid ablation. The technical part of the project comprises standardization of QI as well as centralized dosimetry reading.

Overall these projects will contribute to further standardization of MRT dosimetry in Europe.

References:

1. Strigari L, Konijnenberg M, Chiesa C, et al. The evidence base for the use of internal dosimetry in the clinical practice of molecular radiotherapy. Eur J Nucl Med Mol Imaging. 2014;41:1976-1988.

2. Zimmerman BE, Grosev D, Buvat I, et al. Multi-centre evaluation of accuracy and reproducibility of planar and SPECT image quantification: An IAEA phantom study. Z Med Phys. 2017;27:98-112.

3. Wevrett J, Fenwick A, Scuffham J, et al. Inter-comparison of quantitative imaging of lutetium-177 (177Lu) in European hospitals. EJNMMI Physics. 2018;5:17.




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4Role of Extracellular Matrices in

Cancer and other Diseases

CME Session



October 13, 16:30 - 18:00

4

Extra Cellular Matrix - A Target in the Future?!

Martin Behe (Villigen, Switzerland)

The extracellular matrix (ECM) is highly specialized and dynamic scaffold, which keeps the cell in its three-dimensional location [1]. It is distributed through the whole body and consists of about 300 different proteins like collagen, fibronectin or proteoglycans or glycoproteins beside ECM-modifying enzymes, ECM-binding growth factors, and other ECM-associated proteins [2]. The ECM strongly interacts with the cells and regulates diverse functions like including proliferation, migration and differentiation [3]. The role of ECM in different diseases was highly underestimated in past. The research on this topic increased in last decades dramatically and revealed the high importance of the ECM in different diseases.

Abnormal regulation of ECM is involved in many diseases like fibrotic diseases, chronic inflammatory diseases (e.g. arthritis) or cancer. In cancer this results in increased stiffness, more dense cross linking or higher cellularity. It becomes more and more evident that they plays an important if not crucial role in the

development of different diseases like cancers (e.g. pre-metastatic niches or angiogenesis). The ECM is changed in pathological compared to healthy tissues related to density of structure proteins, structural changes in structure proteins, expression of enzymes, signaling etc [3]. Therefore, these pathological specific changes are ideal for specific targeting. Different successful attempts were made in the field of radiopharmacy (e.g. integrin targeting with RGD structures, MMP targeting, VEGF or the extra domain B of fibronectin) [4]. Different possible targets in pathological tissues will be discussed and the targeting of changes in the three-dimensional structure of ECM proteins will be shown. This will be exemplified by targeting relaxed fibronectin [5]. The presentation of Peter Caravan will show the targeting of structural changes in the ECM protein collagen. Uwe Haberkorn will cover the targeting of specific cancer-associated fibroblasts which invade the ECM.

References:

1. Theocharis, A. D., Manou, D., and Karamanos, N. K. (2019) The extracellular matrix as a multitasking player in disease. The FEBS Journal.

2. Hynes, R. O., and Naba, A. (2012) Overview of the Matrisome—An Inventory of Extracellular Matrix Constituents and Functions. Cold Spring Harbor Perspectives in Biology 4.

3. Bonnans, C., Chou, J., and Werb, Z. (2014) Remodelling the extracellular matrix in development and disease. Nature Reviews Molecular Cell Biology 15, 786.

4. Sikkandhar, M. G., Nedumaran, A. M., Ravichandar, R., Singh, S., Santhakumar, I., Goh, Z. C., Mishra, S., Archunan, G., Gulyás, B., and Padmanabhan, P. (2017) Theranostic Probes for Targeting Tumor Microenvironment: An Overview. International Journal of Molecular Sciences 18, 1036.

5. Arnoldini, S., Moscaroli, A., Chabria, M., Hilbert, M., Hertig, S., Schibli, R., Béhé, M., and Vogel, V. (2017) Novel peptide probes to assess the tensional state of fibronectin fibers in cancer. Nature Communications 8, 1793.

CME Session



October 13, 16:30 - 18:00

4

Molecular Imaging of Collagen and Oxidized Collagen in Fibrosis

Peter Caravan (Charlestown, United States of America)

Fibrosis, the progressive accumulation of connective tissue that occurs in response to injury, causes irreparable organ damage and may result in organ failure. In some tissues, e. g. liver, fibrosis increases cancer risk, and many cancers themselves have a fibrotic component. Noninvasive methods to detect and stage fibrosis, and to monitor treatment response, are lacking or are suited only to very advanced disease. Furthermore, there are no good noninvasive clinical tools to distinguish mature scar tissue from active fibrogenesis.1

A hallmark of fibrosis is increased deposition of extracellular matrix, a chief component of which is type I collagen. We have developed molecular probes based on a type I collagen specific peptide labeled with either positron emission tomography (PET) or magnetic resonance imaging (MRI) reporters. In different animal models, these probes have been

shown to detect early onset of organ fibrosis, to accurately stage disease progression, and also to monitor therapeutic interventions.2-6 One of these probes, 68Ga-CBP8, has recently been deployed to image collagen in patients with idiopathic pulmonary fibrosis.7

During the active disease process, lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) enzymes are upregulated and oxidize lysine side chains on collagen and other matrix proteins to the allysine amino acid which then undergoes various crosslinking reactions. This oxidized form of collagen is primarily present during fibrogenesis and thus makes a useful marker of active disease. In stable scar LOX activity is low and oxidized collagen has been converted into stable crosslinked collagen. We are developing MRI and PET probes that target oxidized collagen and have shown that these can be useful reporters of fibrogenesis.8,9

References:

1. Montesi SB, Désogère P, Fuchs BC, Caravan P. Molecular Imaging of Fibrosis: Recent Advances and Future Directions. JCI. 2019;129(1):24-33.

2. Désogère P, Tapias LF, Hariri LP, Rotile NJ, Rietz TA, Probst CK, Blasi F, Day H, Mino-Kenudson M, Weinreb P, Violette SM, Fuchs BC, Tager AM, Lanuti M, Caravan P. Type I collagen–targeted PET probe for pulmonary fibrosis detection and staging in preclinical models. Sci. Transl. Med. 2017 Apr 5;9(384).

3. Farrar CT, Gale EM, Kennan R, Ramsay I, Masia R, Arora G, Looby K, Wei L, Bunzel MM, Zhang C, Zhu Y, Akiyama T, Klimas M, Pinto S, Diyabalanage H, Tanabe KK, Humblet V, Fuchs BC, Caravan P. CM-101: type I collagen targeted MR probe for detection of liver fibrosis. Radiology 2018;287(2):581-589.

4. Polasek M, Yang Y, Schühle DT, Yaseen MA, Kim YR, Sung YS, Guimaraes AR, Caravan P. Molecular MR imaging of fibrosis in a mouse model of pancreatic cancer. Sci Reports. 2017 Aug 14;7(1):8114.

5. Murphy AP, Greally E, O’Hogain D, Blamire A, Caravan P, Straub V. Noninvasive quantification of fibrosis in skeletal and cardiac muscle in mdx mice using EP3533 enhanced magnetic resonance imaging. Magn Reson Med. 2019;81(4):2728-2735.

6. Zhu B, Wei L, Rotile N, Day H, Rietz T, Farrar CT, Lauwers GY, Tanabe KK, Rosen BR, Fuchs BC, Caravan P. Combined MR elastography and collagen molecular MR imaging accurately stage liver fibrosis in a rat model. Hepatology. 2017;65:1015-1025.

7. Montesi SB, Izquierdo-Garcia D, Desogere P, Abston E, Liang LL, Digumarthy S, Seethamraju R, Lanuti M, Caravan P, Catana C. Type I Collagen-Targeted PET Imaging in Idiopathic Pulmonary Fibrosis: First-in-Human Studies. Am J Resp Crit Care Med. 2019.

8. Chen HH, Waghorn PA, Wei L, Tapias LF, Schühle DT, Rotile NJ, Jones CM, Looby RJ, Zhao G, Elliott JM, Probst CK, Mino-Kenudson M, Lauwers GY, Tager AM, Tanabe KK, Lanuti M, Fuchs BC, Caravan P. Molecular imaging of oxidized collagen quantifies pulmonary and hepatic fibrogenesis. JCI Insight. 2017 Jun 2;2(11). pii: 91506.

9. Wahsner J, Désogère P, Abston E, Graham-O’Regan KA, Wang J, Rotile NJ, Schirmer MD, Ferreira DS, Sui J, Fuchs BC, Lanuti M, Caravan P. 68Ga-NODAGA-indole, an allysine-reactive positron emission to-mography probe for molecular imaging of pulmonary fibrogenesis. J Am Chem Soc. 2019;141(14):5593-5596.

CME Session



October 13, 16:30 - 18:00

4

Imaging of Activated Fibroblasts in the ECM

Uwe Haberkorn (Heidelberg, Germany)

Technological advances in molecular biology and biotechnology are increasingly used for the development of new tumor targeting tracers. In oncology, major progress has recently been achieved with peptidic and small molecule compounds. This relies on the identification and validation of new target structures in close conjunction with the application of new techniques for the development of new biocompatible molecules. These are based on either rational design or highthroughput methods such as phage and ribosome display. Their further evaluation and optimization consists in the characterization of

the structure-function relationships and subsequent improvement with respect to binding, internalization and biodistribution of corresponding analogues. The concept will be shown for the fibroblast activation protein (FAP). FAP is expressed in activated fibroblasts, but not in quiescent fibroblasts, giving the opportunity to use this membrane-anchored enzyme as a target for radionuclide-based approaches for diagnosis and treatment of tumors and for the diagnosis of non-malignant disease associated with a remodelling of the extracellular matrix.

References:

1. Giesel F, Kratochwil C, Lindner T et al .FAPI-PET/CT: biodistribution and preliminary dosimetry estimate of two DOTA-containing FAP-targeting agents in patients with various cancers. J Nucl Med 2019;60:386-392.

2. Kratochwil C, Flechsig P, Lindner T et al. FAPI-PET/CT: Mean intensity of tracer-uptake (SUV) in 28 different kinds of cancer. J Nucl Med. 2019 Jun;60 (6):801-805. doi: 10.2967/jnumed.119.227967. Epub 2019 Apr 6.

3. Lindner T, Loktev A, Altmann A et al. Development of quinoline based theranostic ligands for the targeting of fibroblast activation protein. J Nucl Med 2018;59:1415-1422.

4. Lo A, Wang LCS, Scholler J, et al. Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells. Cancer Res; 2015;75: 2800–10.

5. Loktev A, Lindner T, Mier W et al. A new method for tumor imaging by targeting cancer associated fibroblasts. J Nucl Med 2018;59:1423-1429.

6. Loktev A, Lindner T, Burger EM, et al. Development of novel FAP-targeted radiotracers with improved tumor retention. J Nucl Med 2019 Mar 8. pii: jnumed.118.224469. doi: 10.2967/jnumed.118.224469




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Radionuclide Molecular Imaging in Bone Tumours and Multiple Myeloma –

Pearls, Patterns & Pitfalls

5

CME Session



October 14, 08:00 - 09:30

5

Radionuclide Molecular Imaging in Primary Bone Tumours

Tim Van den Wyngaert (Edegem, Belgium)

Subsequent advances in the understanding of tumor biology, and molecular and cytogenetic characterization have contributed to improved outcomes for patients with primary bone tumours. The role of radionuclide imaging in the diagnosis and management of these patients is supported by multiple international treatment guidelines, including those of the European Society for Medical Oncology (ESMO), and the European Reference Network on Paediatric Cancer (PaedCAN), but areas of uncertainty and opportunities for improvement remain. The focus in this CME lecture will be on osteosarcoma, chondrosarcoma, and Ewing’s sarcoma family of tumors (ESFT) which collectively account for most cases of primary malignant bone tumors and have been best studied with respect to the role of radionuclide imaging. In osteosarcoma, the disease stage at diagnosis remains one of the most important prognostic factors, with 5-year survival often below 20% when metastatic disease is present. Therefore, after locoregional imaging with X-ray and MRI, whole-body staging techniques such as 99mTc-labeled bisphosphonate bone scintigraphy with SPECT/CT, FDG-PET/CT, and NaF-PET/CT have an important role to play in this setting, with the first two modalities included in multiple guidelines. In patients receiving neo-adjuvant chemotherapy, the value of tumor necrosis as response marker is well-established, and clinical data has demonstrated the surrogacy of FDG-PET/CT with histologic response. Similarly, the increasing interest in metabolically active

tumor volume (MATV) as prognostic marker may further improve the prognostic value of radionuclide imaging techniques such as FDG-PET/CT. In Ewing sarcoma family of tumors (ESFT), the use of FDG-PET/CT for primary staging is recommended and superior to the use of 99mTc-labeled bisphosphonate bone scintigraphy. Unfortunately, data on the value of NaF-PET/CT in this setting are still lacking. For assessing response to treatment or detection of disease recurrence, numerous studies have demonstrated that FDG-PET/CT is a reliable tool in this disease. Chondrosarcoma is less common than osteosarcoma but more frequent than ESFT. While the broad overlap in FDG uptake between benign cartilage tumors and low-grade chondrosarcomas hamper the use of FDG-PET/CT as diagnostic tool, this technique can successfully be used in the staging and detection of recurrence of these malignancies. Also, recent data suggest that FDG-PET/CT can play a role to assess sarcomatous transformation in known benign chondroid neoplasms. However, important differences between the mentioned tracers and modalities exist with respect to interpretation, prognostic value, and common pitfalls, such as the detection of amongst others small pulmonary metastases or occult bone marrow disease exist. Finally, some candidate novel tracers with potential value in the diagnosis and management of primary malignant bone tumors have recently been reported and will be reviewed.

References:

1. Sigal IR, Sebro R. Preclinical PET tracers for the evaluation of sarcomas: understanding tumor biology. Am J Nucl Med Mol Imaging. 2018;8(6):428-40.

2. Behzadi AH, Raza SI, Carrino JA, Kosmas C, Gholamrezanezhad A, Basques K, et al. Applications of PET/CT and PET/MR Imaging in Primary Bone Malignancies. PET Clin. 2018;13(4):623-34.

3. Harrison DJ, Parisi MT, Shulkin BL. The Role of (18)F-FDG-PET/CT in Pediatric Sarcoma. Semin Nucl Med. 2017;47(3):229-41.

4. Costelloe CM, Chuang HH, Daw NC. PET/CT of Osteosarcoma and Ewing Sarcoma. Semin Roentgenol. 2017;52(4):255-68.

CME Session



October 14, 08:00 - 09:30

5

Radionuclide Molecular Imaging of Bone Metastases

Gopinath Gnanasegaran (London, United Kingdom)

Our understanding of the molecular mechanisms of skeletal metastases is expanding, and multimodality imaging plays an increasing and important role in diagnosing and treatment of bone metastases. There have been significant developments in both radiotracers and imaging techniques, which have improved our capability in the evaluation of skeletal metastases. Secondly, there has been increasing interest in the use of PET tracers in the investigation of skeletal disease, especially in the diagnosis and treatment response assessment of bone metastases. There are several specific (99mTc-MDP and 18F-NaF) and non-specific (18F-FDG, 68Ga-DOTA, 68Ga/18F-PSMA, 11C/18F-choline etc) SPECT & PET tracers to detect skeletal metastases with variable sensitivity and specificity. The conventional whole-body bone scan has relatively reduced specificity, and several studies have shown the addition of SPECT/CT reduces the rate of indeterminate lesions when compared to planar whole body or SPECT alone. 18F-FDG PET-CT detects both skeletal and soft tissue metastases and has high sensitivity for lytic metastases and variable or

limited sensitivity for sclerotic metastases. Compared to 99mTc-bone scintigraphy, 18F-NaF PET/CT bone imaging provides superior image quality and shown to be significantly more accurate in detecting bone metastases. 18F-NaF PET-CT has higher sensitivity than 18F-choline PET-CT for detection of bone metastases in prostate cancer patients. 18F-choline PET/CT identifies early bone marrow involvement and has shown to be useful in the early detection of metastatic bone disease and therapy monitoring. However, it is reported to be inconsistent in densely sclerotic bone lesions especially after therapy. 68Ga-PSMA has been reported to have higher sensitivity in bone and soft tissue disease detection. In general, PET-CT imaging for assessment of skeletal disease is for selective or high-risk cancer patients. In general, clinical decision to use of PET Tracers or PET/CT warrants cost-effectiveness analysis and high level of evidence. Definite, diagnostic algorithms may be useful for appropriate use in the era of limited funding and reimbursement. The advantages, limitations, and pitfalls of SPECT and PET tracers will be discussed.

References:1. Even-Sapir E, et al (2006) The detection of bone metastases in patients with high-risk prostate cancer: 99mTc-MDP Planar bone scintigraphy,

single- and multi-field-of-view SPECT, 18F-fluoride PET, and 18F-fluoride PET/CT. J Nucl Med 47:287–297

2. Beheshti M,et al (2008) Detection of bone metastases in patients with prostate cancer by 18F fluoro- choline and 18F fluoride PET-CT: a comparative study. Eur J Nucl Med Mol Imaging 35:1766–1774

3. Shen G, et al (2014) Comparison of choline-PET/ CT, MRI, SPECT, and bone scintigraphy in the diagnosis of bone metastases in patients with prostate cancer: a meta-analysis. Skeletal Radiol 43:1503–1513

4. Beheshti M, et al (2010) The use of F-18 choline PET in the assessment of bone metastases in prostate cancer: correlation with morphological changes on CT. Mol Imaging Biol 12:98–107

5. Poulsen MH, et al (2014) Spine metastases in prostate cancer: comparison of technetium-99m- MDP whole-body bone scintigraphy, [(18) F] choline positron emission tomography (PET)/computed tomography (CT) and [(18) F]NaF PET/CT. BJU Int 114:818–823

CME Session



October 14, 08:00 - 09:30

5

Radionuclide Molecular Imaging in Multiple Myeloma

Cristina Nanni (Bologna, Italy)

FDG PET/CT is recommended by the International Myeloma Working Group (IMWG) as the actual “gold standard” method for evaluating and monitoring response to therapy as it provides useful indexes to further stratify patients with different treatment outcome. However, Multiple Myeloma (MM) is a complex disease to interpret just on imaging as it may present as diffuse bone marrow infiltration, focal lesions, extramedullary lesions, fractures, and para medullary disease. In MM, interpretation related issues exist in comparison to other cancers, and most prevalent problems include:

1. A significant percentage of patients are affected by MM related anemia that results in a substantial increase in bone marrow (BM) tracer uptake causing a hot background in bone

2. The amount of FDG uptake is variable, and therefore, a baseline study is useful for reference, but seldom performed in many centers.

3. Early PET-positive MM lesions may not correspond to an osteolytic area and may be challenging to characterize and report them

on scans especially when they are small in size

4. The low spatial resolution of PET imaging does not allow “salt and pepper” BM infiltration to be accurately detected

5. Recent fractures may appear falsely positive

6. Bone metallic implants may cause significant artifacts on CT and PET images and may be a site of infection results in non-specific FDG uptake

7. Therapy response criteria are not well defined

8. Increased and diffuse BM uptake might be a sign of disease or as well as expression of anemia or GF administration

9. Mild focal FDG uptake in osteolytic lesions or high uptake in focal lesions may not be easily detectable because of a hot bone marrow

This presentation will provide knowledge on the most common patterns of MM presentation, advantages and limitations of hybrid imaging in particular on FDG PET/CT but not only.

References:

1. Interpretation criteria for FDG PET/CT in multiple myeloma (IMPeTUs): final results. IMPeTUs (Italian myeloma criteria for PET USe). Nanni C, Versari A, Chauvie S et al. Eur J Nucl Med Mol Imaging. 2018 ;45(5):712-719.

2. Toward a GEP-based PET in myeloma. Zamagni E, Cavo M. Blood. 2017l 6;130(1):2-3.

3. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Moreau P, San Miguel J, Sonneveld Pet al ; ESMO Guidelines Committee. Ann Oncol. 2017 1;28(suppl_4):iv52-iv61.

4. Role of 18F-FDG PET/CT in the diagnosis and management of multiple myeloma and other plasma cell disorders: a consensus statement by the International Myeloma Working Group. Cavo M, Terpos E, Nanni C, et al . Lancet Oncol. 2017;18(4):e206-e217.

5. Prospective Evaluation of Magnetic Resonance Imaging and [18F]Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography at Diagnosis and Before Maintenance Therapy in Symptomatic Patients With Multiple Myeloma Included in the IFM/DFCI 2009 Trial: Results of the IMAJEM Study.

6. Moreau P, Attal M, Caillot D, et al . J Clin Oncol. 2017 Sep 1;35(25):2911-2918.

7. State of the art imaging of multiple myeloma: comparative review of FDG PET/CT imaging in various clinical settings. Mesguich C, Fardanesh R, Tanenbaum L, et al L. Eur J Radiol. 2014 Dec;83(12):2203-2223

8. Interim PET analysis in first line therapy of multiple myeloma: Prognostic value of ΔSUVmax in the FDG-avid patients of the IMAJEM study. Bailly C, Carlier T, Jamet B, et al. Clin Cancer Res. 2018 Aug 1




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Molecular Imaging Technologies for Infectious Diseases

6

CME Session



October 14, 11:30 - 13:00

6

Imaging of Bacterial and Pathogen Infections, Infectious Disease Specialist’s Point of View

Meta Roestenberg (Leiden, Netherlands)

Parasitic diseases such as malaria, schistosomiasis and hookworm are responsible for a vast burden of disease affecting around 580 million people worldwide [1]. Effective vaccines for these diseases would be extremely cost-effective public health measures. Unfortunately, rising costs, declining success rates and the poor market has hampered the development of anti-parasitic vaccines. To date only one human anti-parasitic vaccine has been licensed.

To accelerate vaccine development, we have developed experimental human models to test the efficacy of vaccines and study human immune responses [2]. In these controlled human infection (CHI) trials, healthy volunteers are deliberately exposed to a pathogen to test vaccines or provide mechanistic insight into host-pathogen interaction. Using CHI trials, we discovered that repeated exposure to the first stages of the infection can induce protective immunity in the human host. Interestingly, malaria, schistosomes and hookworm parasites all enter the

body through the skin, where they encounter a wide variety of immune cells equipped to detect invading pathogens. In order to escape immune attack and establish infection, the parasites must interact with skin immune cells and navigate swiftly through the natural skin barrier. Because at this stage the parasites are still small in number and vulnerable to immune attack, the skin site may represent the achilles’ heel of parasitic disease, where both priming and effector mechanisms of immunity can occur.

Because very little is known about the migratory mechanisms of skin-penetrating parasites and their molecular targets, we set out to develop tracers which enabled us to visualize the migratory paths of malaria sporozoites, Schistosoma mansoni cercariae and Necator americanus L3 hookworm larvae. The studies will be presented, their translational potential highlighted and future imaging opportunities in this neglected disease area will be discussed.

References:

1. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017 Lancet 2018; 392: 1789–858

2. Roestenberg M et al. Experimental infection of human volunteers. Lancet Infectious Diseases, Lancet Infect Dis. 2018 Jun 8. pii: S1473-3099(18)30177-4.

CME Session



October 14, 11:30 - 13:00

6

Imaging of Bacterial and Pathogen Infections, Nuclear Medicine’s Point of View

Mike Sathekge (Pretoria, South Africa)

Nuclear medicine has demonstrated significant success in infection and inflammation imaging. Its lack of specificity in differentiating sterile inflammation from infection however represent a significant limitation. An unmet need therefore remains in the clinical differentiation of inflammation from infection. Bacterial-specific imaging is a viable attempt to cater for this need, and efforts in this regard must be encouraged especially in view of the significant morbidity and mortality burden that infections continue to cause.

Although most of the reported bacteria-specific tracers are in preclinical stages, some are rapidly moving to the clinical setting with promising results. The current studies have increased our understanding of the natural history of bacterial infection. Hence, the focus of its application is shifting from mere diagnosis

of infection to prognostication, where response to treatment can be predicted, resistant strains identified, response assessed, and at-risk patients identified and targeted for prevention.

Further, bacterial-specific imaging via SPECT/CT or PET/CT or PET/MRI will pave the way for greater clinical reliability in the localization of infection.

Despite the prospects, there also remain challenges in the development of bacterial imaging including identifying probes that have sensitivity for broader range of microbes rather than species specific probes.

A major challenge for selection of the best bacteria-specific imaging tracers is still an ongoing therefore this presentation summarizes the spectrum of potential applications and the efforts made to achieve this goal.

References:

1. Auletta S, Varani M, Horvat R, Galli F, Signore A, Hess S. PET Radiopharmaceuticals for Specific Bacteria Imaging: A Systematic Review. J Clin Med. 2019 Feb 6;8(2). pii: E197. doi: 10.3390/jcm8020197.

2. Lawal I, Zeevaart J, Ebenhan T, Ankrah A, Vorster M, Kruger HG, Govender T, Sathekge M. Metabolic Imaging of Infection. J Nucl Med. 2017 Nov;58(11):1727-1732. doi: 10.2967/jnumed.117.191635

3. Ordonez AA, Jain SK. Pathogen-Specific Bacterial Imaging in Nuclear Medicine. Semin Nucl Med. 2018 Mar;48(2):182-194. doi: 10.1053/j.semnuclmed.2017.11.003

CME Session



October 14, 11:30 - 13:00

6

Novel Approaches to Image the Pathogen,Radiopharmacy’s Point of View

Clemens Decristoforo (Innsbruck, Austria)

Despite the success of antibiotics, infections in hospitals are on the rise and current routine diagnostics (positive cultures, serology and morphologic imaging (CT, MR)) have major limitations. Nuclear Medicine plays an important role applying well-established methods involving radiolabeled leucocytes and increasingly FDG and PET. These are based on indirect detection, i.e. secondary effects of infections, thereby impairing in particular specificity. However, molecular imaging has the potential of direct imaging the invading pathogen leading to specific detection and localization of the invading pathogen. This CME reviews the most promising preclinical developments for direct imaging of bacterial and fungal infections [1,2] focusing on PET and multimodality approaches.

Direct imaging of the pathogen can only be achieved by a aiming at a target that is not expressed on mammalian cells. Initial attempts focused on radiolabelling of antimicrobial agents, including antibiotics and antimicrobial peptides interacting through their cationic domains with the anionic surface of microorganisms. More recently, two approaches have been very successful in a preclinical setting [2]: Targeting “surface markers” or metabolic processes specific for the pathogen. Immuno-PET using Cu-64 labelled antibodies has been reported to detect bacterial and fungal infections with excellent

specificity, but suffer from the slow pharmacokinetics of antibody constructs. A great variety of metabolic tracers have recently entered the field of metabolic PET imaging of infection. These include F-18 labelled carbohydrates, comparable to FDG, but with specificity for the pathogen, such as 2-Deoxy-2-[18F]-fluoro-d-sorbitol (FDS), di- and polysaccharides such as 6-[18F]-fluoromaltose and 6”-[18F]-fluoromaltotriose and substrates for the folic acid pathway, in particular m-[18F]-fluoro-PABA with promising specificity and sensitivity. Imaging the iron metabolism by targeting siderophore transporters [3], which are upregulated during infection, is another promising approach. Siderophores can be radiolabeled with Ga-68 by replacing ferric iron and by selecting appropriate candidates, such as [68Ga]-TAFC, high specificity for e.g. fungal infection could be achieved. Also optical or hybrid imaging agents have been reported for some of these targets with promising results in animal models.

Overall there has been impressive development of specific molecular infection imaging agents for PET. Careful consideration of the clinical needs for infection imaging may define the most appropriate candidates for clinical translation within prospective trials.

References:

1. Lawal I, Zeevaart J, et al. Metabolic Imaging of Infection. J Nucl Med. 2017 Nov;58(11):1727-1732

2. Welling, M. M., Hensbergen, A. W., et al (2019) An update on radiotracer development for molecular imaging of bacterial infections. Clin. Transl. Imag. 7, 105– 124

3. Petrik M, Zhai C, et al. Siderophores for molecular imaging applications. Clin Transl Imaging. 2017;5(1):15-27




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Imaging Immune Therapy

7

CME Session



October 14, 14:30 - 16:00

7

Imaging of Immunological TargetsWolfgang Weber (Munich, Germany)

Immunotherapy is now an established form of therapy for several solid tumors, including melanoma, non-small cell lung cancer, bladder cancer and others. This success is mostly based on antibodies targeting immune checkpoints that inhibit the immune response to the tumor cells. These antibodies directed against PD1, PDL-1 and CTLA-4 have shown dramatic and durable responses in patients with advanced tumors. In addition, therapy with engineered T cells (CAR-T cells) has been successful for treatment of certain relapsed leukemias. However, only about 20-30% patients achieve a durable response to monotherapy with a checkpoint inhibitor antibody. Side effects, such as autoimmune inflammation, are relatively common and can be life-threatening. Combination therapies have demonstrated higher response rates, but also cause substantially more side effects. CAR-T cell therapy has so far not shown efficacy for the treatment of solid malignancies.

Thus, despite the success of immunotherapy there are several open research questions and clinical problems, for example, the selection of patients for immunotherapy, the duration of immunotherapy and a rational combination of immunotherapy with other drugs. There is also an urgent need to prevent immune related complications. It is challenging to address these issues in animal models of cancer or

by analyzing tissue samples. Therefore, there is a clear need for imaging targets of immunotherapy non-invasively in patients.

By radiolabeling approved therapeutic antibodies with 89Zirconium or other long-lived positron emitters their accumulation in the tumor and normal organs can be studied non-invasively over time. In addition, preclinical and initial clinical studies have shown that tumor uptake of radiolabeled antibodies correlates with the expression levels immune checkpoints, such as PD-L1. In addition, preclinical studies have shown the feasibility of imaging the distribution of CAR T cells by reporter gene imaging. These new imaging tool hold great promise to achieve a better understanding of the time course and duration of immune responses as well as mechanisms of resistance to immunotherapy. However, challenges of imaging with radiolabeled antibodies include the long time between injection and imaging (about 7 days) as well as the high radiation exposure which is several-fold higher than for studies with 18F-labeled radiotracers. For broader clinical application, it will therefore be necessary to develop smaller ligands for immunological targets that allow for earlier imaging. Radiolabeled antibody fragments, other smaller proteins, such as adnectins as well as peptides are currently in clinical development.

References:

1. Ehlerding et al. Molecular Imaging of Immunotherapy Targets in Cancer. J Nucl Med. 2016 Oct;57(10):1487-1492

2. Niemeijer et al.. Whole body PD-1 and PD-L1 positron emission tomography in patients with non-small-cell lung cancer. Nat Commun. 2018 Nov7;9(1):4664.

3. Bensch et al. (89)Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer. Nat Med. 2018 Dec;24(12):1852-1858.

4. Paz-Ares et al. KEYNOTE-407 Investigators. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med. 2018 Nov 22;379(21):2040-2051.

5. Wolchok et al. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017 Oct 5;377(14):1345-1356.

CME Session



October 14, 14:30 - 16:00

7

Current State of Imaging in Assessment of Immunotherapy

Caroline Bodet-Milin (Nantes, France)

Cancer immunotherapies were recently introduced in clinical practice as an effective treatment option for a variety of advanced cancers. These immunotherapies include non-specific immune molecules like cytokines (i.e. interferon), T cell therapy (i.e. TILs, CAR) and immune check points inhibitors. The most commonly used are the immune checkpoints inhibitors (i.e. anti PD1 /PDL1 or CTLA-4) for solid tumors and more recently T CAR cells for hematological malignancies [1-2].

Unlike conventional treatments that have a direct effect on tumor cells, immunotherapies act indirectly on these latter. By activating host immunity, they generate immune-related effects responsible for the tumor response but also eventually for the tumor size progression or induced-toxicity.

The conventional imaging criteria usually recommended for therapeutic evaluation of solid tumors (RECIST) have shown their limits for the evaluation of response to immunotherapy, leading to the creation of new criteria (irRC, iRECIST...) whose

relevance is sometimes limited, particularly in terms of detection and monitoring of adverse events related to the immune system [3-5].

The use of FDG-PET for monitoring treatment efficacy and side effects of immunotherapy has always been questioned. The potential difficulty for FDG-PET lies in the differentiation of responders from non-responders because of a potential increase in FDG uptake caused by the infiltration of the tumor by immune cells (pseudo-progression). While several PET interpretation criteria have already been proposed for therapeutic evaluation of immunotherapies in solid and hematological tumors (PERCIST, PERCIMT, PERCRIT, LYRIC…), a standardization and validation work remains to be done by prospective studies [6-7].

In a near future, the use of specific PET tracers, allowing direct visualization of therapeutic targets for immunotherapies (immuno-PET), will certainly represent the best opportunity to select patients for these expensive treatments and to monitor therapeutic efficacy [8].

References:

1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012 Mar 22; 12(4):252-64.

2. Zhang H, Chen J. Current status and future directions of cancer immunotherapy. J Cancer. 2018 Apr 19;9(10):1773-1781.

3. Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé C, Maio M, Binder M, Bohnsack O, Nichol G, Humphrey R, Hodi FS. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria.. Clin Cancer Res. 2009 Dec 1; 15(23):7412-20.

4. Hodi FS, Hwu WJ, Kefford R, Weber JS, Daud A, Hamid O, et al. Evaluation of immune-related response criteria and RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab. J Clin Oncol. 2016;34:1510–1517

5. Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017;18:e143–e152.

6. Nicolas Aide, Rodney J. Hicks, Christophe Le Tourneau, Stéphanie Lheureux, Stefano Fanti, and Egesta Lopci. FDG PET/CT for assessing tumour response to immunotherapy. Report on the EANM symposium on immune modulation and recent review of the literature.. Eur J Nucl Med Mol Imaging. 2019; 46(1): 238–250.

7. Cheson BD, Ansell S, Schwartz L, et al Refinement of the Lugano classification response criteria for lymphoma in the era of immunomodulatory therapy. Blood.2016;128:2489–2496

8. Bensch F, van der Veen EL, Lub-de Hooge MN, Jorritsma-Smit A, Boellaard R, Kok tIC et al. (89)Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer. Nat Med. 2018 Dec;24(12):1852-1858.

CME Session



October 14, 14:30 - 16:00

7

Emerging Imaging Concepts in Immuno-Oncology

Margret Schottelius (Garching, Germany)

Cancer immunotherapy, i.e. the concept of enhancing tumor-specific immunity via e.g. adoptive T-cell transfer, immune checkpoint inhibition or other interventions, has evolved as a very powerful therapeutic approach in clinical oncology and has moved forward at a tremendous pace during the last years. Also driven by the limited predictability of therapy response vs non-response and the need for improved patient selection, these developments are accompanied by intense preclinical research, striving to provide a more and more detailed and accurate insight into the highly complex and interwoven mutual relationships between the tumor, the cells of the tumor microenvironment (TME) and the immune system [1].

Given the complexity of this interplay, its individual kinetics, the multitude of distinct cell types contributing to or preventing efficient therapy and the resulting sheer abundance of molecular biomarkers present on tumor cells and cells of the TME, the identification and selection of clinically relevant targets for molecular imaging represents a true challenge. Consequently, the clinically established and newly emerging molecular imaging concepts in the context of immuno-oncology cover a very broad scope, including:

• in vivo quantification of the expression of the therapeutic target (PD-1/PD-L1/CTLA-4) [2],

• pre- and post-therapeutic assessment of the tumor immune status by quantitative imaging of specific immune cell populations (CD8+ T cells, CD4+ T cells, neutrophils, NK cells) [3],

• quantification of pro-tumorigenic immune cell infiltrates (e.g. M2 macrophages)

• imaging of specific pro-tumorigenic cells of the TME, e.g. FAP+ CAFs [4],

• quantification of chemokine receptor expression (e.g. CXCR4) by tumor cells [5], cells of the TME and tumor infiltrating immune cells,

• detection of immunosuppressive pathways upregulated by tumor cells (e.g. IDO-1)

• visualization of T-cell homing and expansion by ex vivo cell labeling before adoptive T-cell transfer or by reporter gene-targeted imaging of genetically engineered T-cells, and

• assessment of the T-cell activation status by targeting specific activation markers.

It will be the objective of this contribution to provide a comprehensive overview over these highly diverse molecular imaging approaches, to highlight radiopharmaceutical developments beyond antibody-based probes, and to weigh the potential of the respective targeting strategy to yield patient-specific, therapy-decisive and predictive information.

References:

1. M. Binnewies, E.W. Roberts, K. Kersten et al., Nature Med. 2018, 24:541-550.

2. K. Broos, Q. Lecocq, G. Raes et al., Theranostics. 2018, 8(13):3559-3570.

3. J.W. Soo, R. Tavaré, L.M. Mahakian et al., Clin. Cancer Res. 2018, 24(20):4976-4987.

4. F.L. Giesel, C. Kratochwil T. Lindner et al., J. Nucl. Med. 2019, 60(3):386-392.

5. M. Kircher, P. Herhaus, M. Schottelius et al., Ann. Nucl. Med. 2018, 32(8):503-511




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Secondary Effects of Radioiodine Treatment

8

CME Session



October 14, 16:30 - 18:00

8

General Aspects of Radiobiology in Radioiodine Therapy

Calogero D’Alessandria (Munich, Germany)

Differentiated thyroid carcinoma (DTC) is the most frequent primary endocrine-related malignancy. The majority of cases are papillary and follicular thyroid cancers, which have an excellent 10-year overall survival, exceeding 90%. In most cases, treatment for DTC consists of a total or near-total thyroidectomy, followed by the administration of radioactive iodine (I-131) for remnant ablation and to effectively treat any iodine-avid locoregional and distant metastases. As DTC has favorable outcome and its incidence - and consequently the use of radioiodine treatment (RIT) - is increasing worldwide, concerns have raised about the possible adverse effects of ionizing radiation due to I-131 therapy. Especially, the use of RIT for remnant ablation in low-risk patients is still a debated question. Salivary and lacrimal gland dysfunctions are reported as “common intermediate-term adverse effects” of I-131 therapy. Second primary malignancies (SPM), like rare acute radiation pneumonitis and fibrosis and neutropenia, low platelet count and anemia, as well as (transient) abnormalities in gonadal function

and female reproductive outcomes are reported as “long-term adverse effects”. Ionizing radiation not only destroys the malignant iodine-avid cells, but also can induce damages to healthy tissues and cells. As an example, DNA damage in blood lymphocytes can be induced by protracted, nearly homogeneous whole-body irradiation involving all organs, including the blood, due to b-particles emitted from circulating 131I and from penetrating g-radiation originating from activity dispersed throughout the body. These complications mainly affect the patients’ quality of life but can even be life threatening. Insight into the prevalence and risk factors of adverse effects of I-131 therapy is essential to develop optimal DTC treatment strategies. In this context, the identification and validation of new biomarkers, whose expression is restricted only to thyroid malignant nodules and absent in normal thyroid tissue, might help in patient management, reduction of unnecessary thyroid surgery and development of alternative radiotherapy approaches.

References:

1. Siegel, R.L., Miller, K.D., and Jemal, A. 2018. Cancer statistics, 2018. CA Cancer J Clin 68:7-30.

2. Clement SC et al. Intermediate and long-term adverse effects of radioiodine therapy for differentiated thyroid carcinoma--a systematic review. Cancer Treat Rev. 2015 Dec;41(10):925-34.

3. Eberlein U et al. DNA Damage in Peripheral Blood Lymphocytes of Thyroid Cancer Patients After Radioiodine Therapy. J Nucl Med. 2016 Feb;57(2):173-9.

4. De Rose F et al. Galectin-3 targeting in thyroid orthotopic tumors opens new ways to characterize thyroid cancer. J Nucl Med. 2018 Oct 25. pii: jnumed.118.219105.

5. D’Alessandria C et al. Noninvasive In Vivo Imaging and Biologic Characterization of Thyroid Tumors by ImmunoPET Targeting of Galectin-3. Cancer Res. 2016 Jun 15;76(12):3583-92.

CME Session



October 14, 16:30 - 18:00

8

Deterministic Effects of Radioiodine Treatment

Petar-Marko Spanjol (Geneva, Switzerland)

Radioiodine (RAI) treatment exists already nearly eight decades and is used worldwide. It is mostly used in the treatment of differentiated thyroid cancer and hyperthyroidism. Radioiodine proofed that its treatment is very efficient (1, 2). However, beside the great efficacy of radioiodine, this treatment may have unwanted effects on non-target tissue. This can occur in other organs by having the Sodium-Iodide Symporter, in the elimination pathway or through blood supply.

Radiation may provoke two different effects on the cell, cell damage a stochastic effect or cell death, the deterministic effect. The deterministic effect is characterized by a threshold below which an adverse event does not occur. However, once the threshold has been exceeded, the severity of an adverse event increases with the dose. The deterministic effect comprises very heterogeneous group of adverse events in various organs, for example.

Salivary gland cells express Sodium-Iodide-

Symporters and this characteristic makes it to a co-target in any radioiodine treatment. At high activities as used in the treatment of differentiated thyroid cancer one study showed that one year after treatment, up to 42.9% of all patients suffered from xerostomia (3). Xerostomia may lead to reduced dental health as reported by some authors (4).

Parathyroid glands due to their proximity to thyroid tissue may receive significant radiation. The character of the adverse event may vary from hypo- to hyperparathyroidism (5).

The distribution of radioiodine with the blood, may cause a radiation dose to bone marrow, where it may lead to reduction of blood cell count below the normal range (6) or even to aplasia.

This presentation will show the latest findings, a variety of reported deterministic toxicities, their risk profile, possible preventive actions and models for treatment aftercare.

References:

1. Durante C, Haddy N, Baudin E, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid

carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab 2006;91:2892-9.

2. Franklyn JA, Daykin J, Drolc Z, Farmer M, Sheppard MC. Long-term follow-up of treatment of thyrotoxicosis by three different methods. Clin Endocrinol (Oxf ) 1991;34:71-6.

3. Alexander C, Bader JB, Schaefer A, Finke C, Kirsch CM. Intermediate and long-term side effects of high-dose radioiodine therapy for thyroid carcinoma. J Nucl Med 1998;39:1551-4.

4. Walter MA, Turtschi CP, Schindler C, Minnig P, Muller-Brand J, Muller B. The dental safety profile of high-dose radioiodine therapy for thyroid cancer: long-term results of a longitudinal cohort study. J Nucl Med 2007;48:1620-5.

5. Colaco SM, Si M, Reiff E, Clark OH. Hyperparathyroidism after radioactive iodine therapy. Am J Surg 2007;194:323-7

6. Molinaro E, Leboeuf R, Shue B, et al. Mild decreases in white blood cell and platelet counts are present one year after radioactive iodine remnant ablation. Thyroid 2009;19:1035-41.

CME Session



October 14, 16:30 - 18:00

8

Stochastic Adverse Effects of Radioiodine Treatment

Piotr Radojewski (Berlin, Germany)

Radioiodine has been used since the 1940s to treat hyperthyroidism and thyroid cancer. After several decades of use, it is considered safe, even for use in women of childbearing age and in older children. However, due to the excellent survival of patients with well-differentiated thyroid cancer and hypothyroidism, some patients may experience potential long-term adverse effects of radiation.

Most adverse effects of radiation exposure may be grouped in two categories: deterministic and stochastic effects. The stochastic effects describe adverse events in which the probability of occurrence (but not their severity) is a function of the dose without a threshold value. That probability differs dependent on the organs or tissues. This group comprises mostly cancer and heritable effects. Although an accurate risk estimation is difficult, dose-rate effectiveness factors have been used for approximation. Thereby, risk factors of about 5.5 per Sievert for cancer and 0.2 per Sievert for heritable effects after exposure to radiation at low dose rate have been indicated (1).

In most hypothyroidism-related clinical studies, radioiodine has not been associated with an increased

risk of cancer. For example in a large thyrotoxicosis therapy study with long follow-up, no increase in the overall risk of death from cancer was reported (2). Smaller studies reported a slight increase in the risk of thyroid and colon cancer (3) and increased risk of stomach, kidney, and breast cancer after radioiodine treatment for hyperthyroidism (4).

In studies on radioiodine treatment for thyroid cancer a significantly increased risk of second primary malignancy has been reported (5). Some authors even postulate significantly higher incidence than previously assumed (6). In the case of heritable diseases the clinical evidence is scarce. Experimental observations however show convincingly that such risks is relevant and should be taken into consideration in the radiation protection.

The aims of this presentation are to 1) enable an understanding of the concept of stochastic adverse events of radiation, to 2) provide an overview of the available evidence for risk of stochastic effects after radioiodine treatment, to 3) discuss the consequences for the follow-up after radioiodine treatment.

References:

1. ICRP, 2007. The 2007 Recommendations of the International Commission on Radiological Protection. ICRP Publication 103. Ann. ICRP 37 (2-4).

2. Ron et al. E, et al. Cancer mortality following treatment for adult hyperthyroidism. JAMA 1998;280: 347-55.

3. Franklyn JA et al. Cancer incidence and mortality after radioiodine treatment for hyperthyroidism: a population-based cohort study. Lancet 1999; 353:2111-5.

4. Metso S et al. Increased cancer incidence after radioiodine treatment for hyperthyroidism. Cancer 2007;109:1972-9. [Erratum, Cancer 2007;110:1875.]

5. Mayumi E et al. Incidence of Second Malignancy in Patients with Papillary Thyroid Cancer from Surveillance, Epidemiology, and End Results . J Thyroid Res. 2018; 2018: 8765369.

6. Lu CH et al. Second primary malignancies following thyroid cancer: a population-based study in Taiwan. Eur J Endocrinol 2013;169:577-85.




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Non-Invasive Imaging Strategiesin Heart Failure

9

CME Session



October 15, 08:00 - 09:30

9

When and How Should I Look for Myocardial Ischemia or Viability?

Fabien Hyafil (Paris, France)

Learning objectives:

• To learn how to identify and quantify the extent of myocardial ischemia and viability using nuclear imaging approaches.

• To understand how the identification of myocardial ischemia and viability in patients with ischemic cardiomyopathy can provide additional prognostic information and help guide indications for coronary revascularization.

Summary: The optimal management strategy of patients with ischemic cardiomyopathy remains largely discussed. Small observational studies have reported superior survival in patients with hibernating myocardium following coronary revascularization compared with medical therapy and worsened survival after coronary revascularization in absence of hibernating myocardium (1–4). Meta-analyses (1,3,5) have confirmed these findings, but these studies have been limited by underuse of cardioprotective

medication and inadequate adjustment for baseline risk (6). The only prospective trial to randomize patients with LV dysfunction to a strategy integrating viability imaging with FDG-PET vs. standard care failed to demonstrate improved outcome (7). In the non-randomized Surgical Treatment of Ischemic Heart Failure (STICH) viability sub-study, the presence of myocardial viability did not identify patients with a survival benefit from coronary artery bypass grafting (CABG) compared with aggressive medical therapy alone (8). Nevertheless, multiple other factors than viability such as ischemia, scar and LV remodeling play a role in the potential benefits of coronary revascularization in ischemic cardiomyopathy. Strategies evaluating globally the extent of hibernating and ischemic myocardium might improve the identification of patients who benefit the most from revascularization versus medical therapy.

Key words: dilated cardiomyopathy; myocardial ischemia; myocardial viability; coronary revascularization.

References:

1. Allman KC, Shaw LJ, Hachamovitch R, Udelson JE. Myocardial viability testing and impact of revascularization on prognosis in patients with coronary artery disease and left ventricular dysfunction: a meta-analysis. J Am Coll Cardiol. 2002;39:1151–1158.

2. Camici PG, Prasad SK, Rimoldi OE. Stunning, hibernation, and assessment of myocardial viability. Circulation. 2008;117:103–114.

3. Inaba Y, Chen JA, Bergmann SR. Quantity of viable myocardium required to improve survival with revascularization in patients with ischemic cardiomyopathy: A meta-analysis. J Nucl Cardiol. 2010;17:646–654.

4. Schinkel AF, Bax JJ, Poldermans D, Elhendy A, Ferrari R, Rahimtoola SH. Hibernating myocardium: diagnosis and patient outcomes. Curr Probl Cardiol. 2007;32:375–410.

5. Bourque JM, Hasselblad V, Velazquez EJ, Borges-Neto S, O’connor CM. Revascularization in patients with coronary artery disease, left ventricular dysfunction, and viability: a meta-analysis. Am Heart J. 2003;146:621–627.

6. Bonow RO, Holly TA. Myocardial viability testing: still viable after stich? J Nucl Cardiol. 2011;18:991–994.

7. Beanlands RS, et al; PARR-2 Investigators. F-18-fluorodeoxyglucose positron emission tomography imaging-assisted management of patients with severe left ventricular dysfunction and suspected coronary disease: a randomized, controlled trial (PARR-2). J Am Coll Cardiol. 2007;50:2002–2012.

8. Bonow RO, et al; STICH Trial Investigators. Myocardial viability and survival in ischemic left ventricular dysfunction. N Engl J Med. 2011;364:1617–1625.

CME Session



October 15, 08:00 - 09:30

9

When and How Should I Look for Cardiac Amyloidosis?

Riemer Slart (Groningen, Netherlands)


• Background information the different types of cardiac amyloidosis (CA).

• The role of non-invasive imaging in the diagnostic work-up of CA.

• Imaging protocol, scoring, and interpretation of bone scintigraphy in CA.

• Overview of novel PET imaging in CA

• New therapy approaches for managing patients with CA

Summary: Cardiac amyloidosis (CA), commonly resulting from deposition of misfolded immuno-globulin light chain (AL) or transthyretin (ATTR) protein, is an underestimated cause of heart failure. ATTR can be divided into a hereditary type (ATTRv) and a wild-type (ATTRwt). Diagnosis of CA is frequently delayed for several reasons. Clinical manifestations are varied, serum cardiac biomarker elevation is non-specific, awareness of CA is lacking, and non-invasive techniques for specific diagnosis became only more recently available.

Accurate and early diagnosis of heart failure as a result of CA has major implications on prognosis and treatment, using echo and MRI in the first line.

Molecular imaging with PET and SPECT nowadays play a critical role in the diagnosis, identification and distinction between ATTR and AL type CA.

Bone scintigraphy is an important non-invasive tool to diagnose cardiac amyloidosis due to ATTR (either ATTRv or ATTRwt). Additionally, the innervation agent 123I-MIBG accumulates in vesicles in sympathetic nerve endings close to myocardial cells and the reduced uptake and increased loss reflects myocardial cell damage caused by amyloid. More specific PET-imaging tracers in amyloidosis selectively bind to β-amyloid plaques, such as 11C–Pittsburgh compound-B (11C-PiB), 18F–florbetaben, and 18F–florbetapir and are useful for the detection of AL and ATTR CA.

Current and new treatments are targeted at reducing the production or stabilisation of the precursor protein or aiming at promoting amyloid removal and thereby aim to stop or slow down further accumulation of CA. Molecular imaging holds promise to visualize regression of CA under these new treatment regimens.

Key word: cardiac amyloidosis, new PET tracers, novel therapy

References:

1. Maurer MS, et al. Addressing common questions encountered in the diagnosis and management of cardiac amyloidosis. Circulation. 2017;135:1357–77.

2. Mohammed SF, et al. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail. 2014;2:113–22.

3. Slart RHJA, et al. Time for new imaging and therapeutic approaches in cardiac amyloidosis. Eur J Nucl Med Mol Imaging. 2019 Apr 23.

4. Slart RHJA, et al. Imaging cardiac innervation in amyloidosis. J Nucl Cardiol. 2019;26(1):174–87.

5. Kim YJ, et al. Cardiac amyloidosis imaging with amyloid positron emission tomography: a systematic review and meta-analysis. J Nucl Cardiol. 2018.

6. Glaudemans AW, et al. Bone scintigraphy with (99m)technetium-hydroxymethylene diphosphonate allows early diagnosis of cardiac involvement in patients with transthyretin-derived systemic amyloidosis. Amyloid. 2014;21:35–44.

7. Solomon SD, et al. Effects of Patisiran, an RNA interference therapeutic, on cardiac parameters in patients with hereditary transthyretin-mediated amyloidosis. Circulation. 2019;139:431–43.

8. Benson MD, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med. 2018;379:22–31.

CME Session



October 15, 08:00 - 09:30

9

When and How Should I Look for Cardiac Dyssynchrony ?

Marcus Hacker (Vienna; Austria)


• To learn how to identify and measure LV dyssynchrony in patients with dilated cardiomyopathy.

• To understand how the evaluation of LV dyssynchrony can help assess the prognosis of patients and guide indications for resynchronization treatments.

Summary: Coronary artery disease (CAD) is one of the leading causes of morbidity and mortality in western countries. At advanced stages of disease, the processes of remodeling of the myocardium can lead to progressive heart failure and left ventricular (LV) dysfunction. A number of physiological parameters, including ejection fraction, viability, QRS duration and perfusion defects have been reported to identify patients at high risk of subsequent cardiac events and therapies. Medication or treatments such as revascularization or resynchronization aim to reverse the process of remodeling of the LV, but the reasons for treatment decisions are not always clear.

In this context, gated single-photon emission CT (SPECT) myocardial perfusion imaging (MPI) has emerged as an established and widely available technique for measuring within a single setting LV perfusion and functional parameters with low inter- and intra-observer variability [1, 2, 3]. Furthermore, gated SPECT MPI allows phase analysis of the LV motion based on the Fourier function histogram, in which the parameters bandwidth and standard deviation have been characterized as valid markers of LV mechanical dyssynchrony (LVMD) [3]. LVMD has been shown to predict response to cardiac resynchronization therapy (CRT) in patients with advanced heart failure [4, 5]. In addition to mediating treatment outcome in CRT patients, LVMD has also been identified as an independent risk factor for predicting cardiac events during long-term follow-up in an unselected patient population with suspected or known CAD with incremental prognostic value to LV ejection fraction [6, 7].

Key word: Dilated cardiomyopathy; LV dyssynchrony; Nuclear cardiology.

References:

1. Chen J, Boogers MJ, Bax JJ, Soman P, Garcia EV. The use of nuclear imaging for cardiac resynchronization therapy. Curr Cardiol Rep. 2010;12(2):185–91.

2. Trimble MA, Velazquez EJ, Adams GL, Honeycutt EF, Pagnanelli RA, Barnhart HX, et al. Repeatability and reproducibility of phase analysis of gated single-photon emission computed tomography myocardial perfusion imaging used to quantify cardiac dyssynchrony. Nucl Med Commun. 2008;29(4):374–81.

3. Henneman MM, Chen J, Dibbets-Schneider P, Stokkel MP, Bleeker GB, Ypenburg C, et al. Can LV dyssynchrony as assessed with phase analysis on gated myocardial perfusion SPECT predict response to CRT? J Nucl Med. 2007;48(7):1104–11.

4. Bax JJ, Bleeker GB, Marwick TH, Molhoek SG, Boersma E, Steendijk P, et al. Left ventricular dyssynchrony predicts response and prognosis after cardiac resynchronization therapy. J Am Coll Cardiol. 2004;44(9):1834–40.

5. Boogers MM, Van Kriekinge SD, Henneman MM, Ypenburg C, Van Bommel RJ, Boersma E, et al. Quantitative gated SPECT-derived phase analysis on gated myocardial perfusion SPECT detects left ventricular dyssynchrony and predicts response to cardiac resynchronization therapy. J Nucl Med. 2009;50(5):718–25.

6. Pazhenkottil AP, Buechel RR, Husmann L, Nkoulou RN, Wolfrum M, Ghadri JR, et al. Long-term prognostic value of left ventricular dyssynchrony assessment by phase analysis from myocardial perfusion imaging. Heart. 2011;97(1):33–7.

7. Uebleis, C., Hellweger, S., Laubender, R.P. et al. Eur J Nucl Med Mol Imaging (2012) 39: 1561.

CME Session



October 15, 08:00 - 09:30

9

When and How Should I Look for Cardiac Innervation ?

Hein Verberne (Amsterdam, Netherlands)


• Review how sympathetic cardiac innervation can be approached with 123-I-MIBG SPECT imaging

• Discuss how the assessment of cardiac innervation with 123-I-MIBG SPECT imaging in patients with chronic heart failure (CHF) can provide additional prognostic information and might help guide indications for implantable cardiac defibrillators (ICD).

Summary: The incidence of CHF has increased over the last decades (1). Current guidelines recommend ICD implantation to prevent sudden cardiac death (SCD) in patients with left ventricular ejection fraction (LVEF) < 35% and NYHA class II or III under optimal medical therapy. While initial trials showed that ICDs are effective in reducing SCD in CHF patients (2), recent studies suggest that several ICD recipients experience inappropriate shocks and ICD-associated infectious complication (3,4). This suggests that current ICD selection criteria in CHF patients, largely guided by LVEF values, are suboptimal.

Cardiac sympathetic activity plays an important role in the pathogenesis and prognosis of CHF with impaired LVEF. Beta-adrenergic receptor stimulation by increased synaptic norepinephrine levels helps to compensate for impaired myocardial function, but long-term NE excess has detrimental effects on myocardial structure and gives rise to a downregulation and decrease in the sensitivity of post-synaptic β-adrenergic receptor and, consequently, poor outcome (5). Cardiac sympathetic activity can non-invasively be assessed with meta-iodobenzylguanidine (123I-mIBG) using both planar and SPECT techniques (6). 123I-mIBG is a radiolabeled NE analogue and accumulates in the presynaptic myocardial sympathetic nerve endings. Quantified myocardial 123I-mIBG parameters have proved to be of prognostic value in CHF (7, 8, 9). Patients with impaired myocardial 123I-mIBG parameters had a worse prognosis compared with those with relatively preserved parameters.

Key words: dilated cardiomyopathy; cardiac innervation; MIBG; SPECT; prognosis.

References:

1. Yancy CW, et al. 2013 ACCF/AHA Guideline for the Management of Heart Failure. J Am Coll Cardiol. 2013;62:e147–239.

2. Borne RT, et al. Temporal trends in patient characteristics and outcomes among Medicare beneficiaries undergoing primary prevention implantable cardioverter-defibrillator placement in the United States, 2006-2010. Circulation. 2014;130:845–53.

3. Daubert JP, et al. Inappropriate implantable cardioverter-defibrillator shocks in MADIT II: frequency, mechanisms, predictors, and survival impact. J Am Col Cardiol. 2008;51:1357–65.

4. Moss AJ, et al. Long-term clinical course of patients after termination of ventricular tachyarrhythmia by an implanted defibrillator. Circulation. 2004;110:3760–5.

5. Hattori N, Schwaiger M. Metaiodobenzylguanidine scintigraphy of the heart: what have we learnt clinically? Eur J Nucl Med. 2000;27:1–6.

6. Wieland DM, et al. Radiolabeled Adrenergic Neuron-Blocking Agents: Adrenomedullary Imaging with [131I] Iodobenzylguanidine. J Nucl Med. 1980;21:349–53.

7. Jacobson AF, et al. Myocardial iodine-123 meta-iodobenzylguanidine imaging and cardiac events in heart failure. Results of the prospective ADMIRE-HF study. J Am Coll Cardiol. 2010;55:2212–21.

8. Boogers MJ, et al. Cardiac Sympathetic Denervation Assessed With 123-Iodine Metaiodobenzylguanidine Imaging Predicts Ventricular Arrhythmias in Implantable Cardioverter-Defibrillator Patients. J Am Coll Cardiol. 2010;55:2769–77.

9. Verberne HJ, et al. Prognostic value of myocardial 123I-metaiodobenzylguanidine (MIBG) parameters in patients with heart failure: a systematic review. Eur Heart J. 2008;29:1147–59.




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C M E S E S S I O N 1 0October 15, 2019 | 11 :30 - 13:00

EANM-EAN Recommendations for the Use of Brain [18F]FDG-PET in Neurodegenerative

Cognitive Impairment and Dementia

10

CME Session



October 15, 11:30 - 13:00

10

Assessing FDG-PET Diagnostic Accuracy Studies to Develop Recommendations for Clinical Use in Dementia

Flavio Nobili (Genoa, Italy) / EAN

Background: FDG-PET is included in the diagnostic criteria of several neurodegenerative conditions, although it lacks pathological specificity, because the topographic pattern of hypometabolism is often useful to guide the clinician reasoning. However, despite its widespread but patchwork clinical use, shared recommendations are sparse and poorly structured.

Methods: A panel of seven experts appointed by the EANM and by the European Academy of Neurology defined 21 PICO (i.e., Patient, Intervention, Comparison, and Outcome) questions on diagnostic issues (20 PICOs) and on semi-automated analysis to assist visual reading (1 PICO). Literature was searched for by another panel of facilitators who assessed the quality of the studies. Literature was interrogated using common database, such as Pubmed and Embase, and concerned full and original papers in English, thus excluding reviews and redundant publications. Papers were selected if they included at least 30 patients for the commonest pathologies, at least 5 cases for rare conditions, while there was no limited number of cases for papers with pathologic confirmation. All the usual measures of efficacy were assessed, such as sensitivity, specificity, accuracy, and so forth. The results of this analysis was then transferred to the experts who analyzed the output and voted for/against the use of FDG-PET, thus based both on published evidence and their own expertise, using the Delphi method.

Results (1): To November 2015, only 58 out of the 1435 selected papers were consistent with selection criteria. After one to four rounds during

which each expert had access to the justified, anonymized answers of the other experts, the panel agreed on recommending clinical use of FDG-PET for 14 PICOs. They include the support of FDG-PET to i) the diagnosis of mild cognitive impairment due to Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTLD) or dementia with Lewy bodies (DLB); ii) the diagnosis of atypical AD and pseudodementia; iii) differentiate between AD and DLB, FTLD, or vascular dementia, between DLB and FTLD, and between Parkinson’s disease (PD) and progressive supranuclear palsy. Also, they voted the utility of FDG-PET for iv) suggesting underlying pathophysiology in corticobasal syndrome and primary progressive aphasia, and v) to track cortical dysfunction in PD. Panelists also recommended the use of semi-automated assessment to assist –not to replace- visual reading of nuclear physicians. Panelists did not support the clinical use of FDG-PET for preclinical stages of neurodegenerative disorders, including subjective cognitive impairment and the pre-symptomatic stages of genetic AD, for amyotrophic lateral sclerosis (ALS) and Huntington disease (HD) diagnoses, and ALS or HD-related cognitive decline.

Conclusions: Despite the limited formal evidence, panelists deemed FDG-PET useful in the early and differential diagnosis of the main neurodegenerative disorders, and semiautomated assessment helpful to assist visual reading. These decisions are proposed as interim recommendations whereas further prospective studies with robust design and either sufficient clinical follow-up or pathological confirmation, are encouraged (1,2).

References: 1. Nobili F, et al; EANM-EAN Task Force for the Prescription of FDG-PET for Dementing Neurodegenerative Disorders. Eur J Neurol. 2018;25:1201-

1217.

2. Several Authors. Eur J Nucl Med Mol Imaging. Topical issue 2018;45:1467-1566.

CME Session



October 15, 11:30 - 13:00

10

Clinical Utility of FDG-PET for the Differential Diagnosis Among the Main Forms of Dementia

Javier Arbizu (Pamplona, Spain)

Despite the current lack of effective treatments that reverse or stop the course of cognitive impairment due to neurodegenerative dementias, available treatments provide greater benefits in mild compared to moderate dementia. In addition, the early knowledge of an accurate diagnosis has an additional value to positively modify risk factors aggravating the effects of neurodegenerative conditions (e.g. cardiovascular), and to perform rest of life planning.

The results of neuroimaging studies in dementia have impacted clinical practice and resulted in recommendations for new Alzheimer’s Disease criteria (1), Dementia with Lewy bodies (2), Frontotemporal dementia (behavioural variant and primary progressive aphasias) (3, 4), and most recently Progressive supranuclear palsy (5), among other neurodegenerative diseases. Among the radiotracers available for the evaluation of neurodegenerative conditions associated with dementia, 18F-FDG is the most available worldwide and the radiotracer with

the largest experience accounted in clinical practice.

Metabolic imaging using FDG-PET more strictly mirror severity and topography of neurodegeneration, and consequently may better guide the differential diagnosis in patients with mixed pathological features, especially when the final diagnosis is still unclear even after Amyoid PET or CSF analysis.

In this CME session, the use of FDG-PET for diagnosing and differentiating the main forms of dementing neurodegenerative disorders—namely Alzheimer’s disease (AD) both in its typical memory-onset presentation and atypical presentations; frontotemporal lobar degeneration; dementia with Lewy bodies; vascular dementia; and pseudodementia will be assessed and the Consensus recommendations of the European Association of Nuclear Medicine (EANM) and the European Academy of Neurology (EAN) Task Force for the Prescription of FDG-PET for Dementing Neurodegenerative Disorders reviewed.

References:

1. McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & Dementia 2011; 7: 263–9.

2. McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies. Neurology 2017; 89: 88–100.

3. Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus J, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011;134:2456-77.

4. Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology 2011; 76: 1006–14.

5. Höglinger GU, Respondek G, Stamelou M, et al. Clinical diagnosis of progressive supranuclear palsy: The movement disorder society criteria. Movement Disorders 2017; 32: 853–64.

6. Nestor PJ, Altomare D, Festari C, Drzezga A, Rivolta J, Walker Z, et al. Clinical utility of FDG-PET for the differential diagnosis among the main forms of dementia. Eur J Nucl Med Mol Imaging. 2018;45:1509-25.

CME Session



October 15, 11:30 - 13:00

10

Clinical Utility of FDG-PET in Parkinson’s Disease and Atypical Parkinsonism Associated with Dementia

Silvia Morbelli (Genoa, Italy)

PD is a common degenerative disorder associated with an increased incidence of cognitive impairment and dementia. The pathology underlying this cognitive decline is variable: while in some patients it is purely Lewy body pathology, in many other it is due to mixtures of amyloid, tau and Lewy body pathology. Older age, scores from non-motor assessments, reduced dopamine transporter uptake in the caudate, deficit on smell testing, CSF amyloid β (Aβ42) to t-tau ratio, and APOE ε4 status are all known risk factors for cognitive decline in patients with newly diagnosed PD . Available studies showed that in comparison with PD patients with no cognitive impairment, patients with PD dementia (PDD) showed greater metabolic deficits in the parietal and frontal regions but that metabolic patterns in PDD patients and patients with Lewy body dementia were broadly similar. Alternative pathologies that can present with parkinsonism and cognitive decline are PSP and CBS. They can mimic PD in early stages and are particularly difficult to diagnose

in prodromal stages. In published studies, FDG PET demonstrated good sensitivity in discriminating idiopathic PD from atypical parkinsonism (range 83–86%) and a moderate sensitivity in diagnosing PSP and discriminating it from CBD and MSA (range 73–88%). In studies evaluating the role of FDG in CBS, the most frequent pattern of hypometabolism associated with CBS included asymmetrical hypometabolism of the parietal and frontal cortex, thalamus and basal ganglia. The occipital cortex and cerebellum were usually spared. The final conclusion of EAN/EANM guidelines in this clinical settings, was that despite the widespread use of FDG PET in clinical practice and extensive research, given the quality of the available studies, there is still very limited good quality evidence for the use of FDG PET. However, in the opinion of the majority of the panellists, FDG PET was defined as a clinically useful imaging biomarker for idiopathic PD and atypical parkinsonism associated with dementia.

References:

1. Nobili F, Arbizu J, Bouwman F, Drzezga A, Filippi M, Nestor P, et al. EAN-EANM recommendations for the use of brain 18F-Fluorodeoxyglucose

Positron Emission Tomography (FDG-PET) in neurodegenerative cognitive impairment and dementia: Delphi consensus. Eur J Neurol. 20181

2. Walker Z, Gandolfo F, Orini S, Garibotto V, Agosta F, Arbizu J, Bouwman F, Drzezga A, Nestor P, Boccardi M, Altomare D, Festari C, Nobili F; EANM-EAN Task Force for the recommendation of FDG PET for Dementing Neurodegenerative Disorders. Clinical utility of FDG PET in Parkinson’s disease and atypical parkinsonism associated with dementia. Eur J Nucl Med Mol Imaging. 2018 Jul;45(9):1534-45.




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Advances in Quantitative Cardiac Imaging

11

CME Session



October 15, 14:30 - 16:00

11

Quantification in SPECT - Current State and Perspectives

Mikko Hakulinen (Kuopio, Finland)

Myocardial perfusion imaging (MPI) SPECT is a widely used imaging method in current clinical practice in the diagnosis and risk assessment of patients with known or suspected coronary artery disease (CAD). MPI is based on the ability of induced stress to inflict regional heterogeneity of coronary artery blood flow in the presence of CAD. MPI SPECT is widely available and has been extensively validated. In MPI SPECT, the ratio of perfusion at stress/rest is only an approximation of myocardial flow reserve (MFR). It is based on relative distribution of radiopharmaceutical in myocardium and the best-preserved region is assumed normal. Therefore, method may be wide of the mark with three-vessel stenosis (balanced ischemia), coronary microvascular dysfunction (CMVD) or decreased vasodilator function (i.e. diffuse atherosclerosis). Absolute quantification allows

assessment of stress and rest myocardial blood flow (MBF, ml/min/g), coronary vasodilator function, i.e. coronary flow reserve (CFR = stress/rest flow), and complete assessment of coronary vascular tree including evaluation of microvascular function. Most recently, several studies have presented new methods and highlighted the importance and the potential of absolute quantification (i.e. MBF and CFR) in cardiac SPECT imaging.1,2,3 This talk will provide an overview of features and challenges in absolute quantification (standard uptake values (SUV)4, MBF, CFR) in SPECT. Moreover, a short overview to current state-of-art imaging systems and new image reconstruction methods is provided. Finally, a short summary of current and future aspects of quantitative cardiac SPECT is presented.

References:1. Sciammarella M, .... and Botvinick EH. A combined static-dynamic single-dose imaging protocol to compare quantitative dynamic SPECT with

static conventional SPECT, J Nucl Cardiol, 2019, Volume 26, Issue 3, pp 763–771

2. Slomka P, Berman DS, Germano G. Myocardial blood flow from SPECT, J Nucl Cardiol, 2017, Volume 24, Issue 1, pp 278-281

3. Shrestha U,…. and Gullberg GT. Measurement of absolute myocardial blood flow in humans using dynamic cardiac SPECT and 99mTc-tetrofosmin: Method and validation, J Nucl Cardiol, 2017, Volume 24, Issue 1, pp 268–77

4. Ljungberg M. Absolute quantitation of SPECT studies, Semin Nucl Med, 2018, Volume 48, Issue 4, pp 348–358

CME Session



October 15, 14:30 - 16:00

11

Quantification in PET - Current State and Perspectives

Ian Armstrong (Manchester, United Kingdom)

Myocardial blood flow (MBF) in PET is now a well-established technique and has been shown to offer incremental prognostic value when incorporated into Myocardial Perfusion Imaging [1]. In PET, the most common tracer used for assessment of MBF is rubidium-82. Many commercial software packages are available with a variety of options. There are also several technical factors that can influence the calculation of MBF [2].

This talk will cover a brief overview of MBF measurements using rubidium-82 and discuss the features of various software packages. I will go on to give a brief overview of the effect of some technical factors.

Finally, I will discuss the problems that are still present in processing data for MBF calculation and suggest new potential solutions that may make calculation of MBF more robust.

References:

1. 1, Muthy VL, Bateman TM, Beanlands RS, Berman DS, Borges-Neto S, Chareonthaitawee P, et al.Clinical quantification of myocardial blood flow using PET: Joint position paper of the SNMMI Cardiovascular Council and the ASNC. J Nucl Cardiol 2018;25:269–97.

2. 2, Moody JB, Lee BC, Corbett JR, Ficaro EP, Murthy VL. Precision and accuracy of clinical

3. quantification of myocardial blood flow by dynamic PET: A technical perspective. J Nucl Cardiol 2015;22:935–51.

CME Session



October 15, 14:30 - 16:00

11

Quantification in CT - Current State and Perspectives

Marc Dewey (Berlin, Germany)

Coronary CT angiography is the most accuracy noninvasive imaging tests for detecting obstructive coronary artery disease (CAD) and is equally effective in patients with different angina types1 yet was unable to quantify the functional relevance of obstructions. Recently, two methods were developed that provide the opportunity to assess coronary flow (CT-FFR) or quantify myocardial perfusion (CTP).2 This talk will

provide an overview of the advantages and drawback of these two state-of-the-art approached to quantify myocardial ischemia. Future perspectives for CTP and CT-FFR will also be provided together with gain in knowledge for clinical care possible. Finally, I will discuss the required evidence to draw comclusions about the effectiveness of quantitative cardiac CT.

References:

1. Haase R, .... and Dewey M. COME-CCT investigators. Diagnosis of obstructive coronary artery disease using computed tomography angiography in patients with stable chest pain: meta-analysis of individual patient data. BMJ. 2019;in press.

2. Kitagawa K, Erglis A and Dewey M. Chapter 19. Myocardial Perfusion and Fractional Flow Reserve. In: M. Dewey, ed. Cardiac CT. 2nd ed. Heidelberg: Springer; 2014: 303-326.




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Response Evaluation of Paediatric Sarcomas

12

CME Session



October 15, 16:30 - 18:00

12

Response of Paediatric Sarcomas – Does it Matter?

Stefan Bielack (Stuttgart, Germany)

Embryonal and alveolar rhabdomyosarcoma are the most frequent pediatric soft tissue sarcomas (STS), osteosarcoma and Ewing sarcoma the most frequent pediatric bone sarcomas. All carry a very high risk for metastatic spread, so that local treatment alone is usually not curative. Current treatment concepts often include pre- and postoperative chemotherapy, with radiotherapy reserved for selected indications. Approximately two thirds of affected patients may be cured by such approaches.

The potential prognostic importance of tumor response to preoperative chemotherapy, the best ways of measuring response, attempts towards response prediction during the disease course, and attempts to guide treatment decisions based upon response have been the focus of multiple studies. In general, response of cancer to systemic treatment is often assessed by measuring changes of tumor-size according to the RECIST criteria (Response Evaluation Criteria for Solid Tumors). While such an approach may be appropriate for soft-tissue sarcomas such as rhabdomyosarcoma, it has considerable limitations when it comes to bony lesions. This is particularly evident for osteosarcoma, where the tumor’s osteoid matrix often prevents tumor shrinkage even in cases of excellent response and even in case of extraosseous lesions. Another measure of response to preoperative chemotherapy, however, the proportion of viable tumor as assessed by histological evaluation of the resected primary, has emerged as one of the most important prognostic factors in both of the bone sarcomas. In both osteo- as well as Ewing sarcoma, good histologic responses, generally defined as <10% remaining viable tumor cells, are very closely linked to reductions of both local and systemic failure risks.

In rhabdomyosarcoma, response is often defined by imaging measures of tumor shrinkage, but the time at which this was measured and its correlation with outcomes has varied between studies. Response can also be assessed by measuring changes of metabolic parameters, but so far no gold standard upon which treatment decisions should be based has emerged.

Predicting response may be of value in guiding local therapy. Various imaging techniques have been employed at variable timepoints of preoperative treatment, but no unanimous conclusions about when to measure what with which method can be drawn. The question whether treatment decisions should be based upon the extent of tumor response is also not easily answered. Many surgeons agree that it is easier to operate tumors which have responded well, and recommendations for (perioperative) radiotherapy often also vary according to response. As for systemic treatments, a large randomized trial, EURAMOS1, failed to provide evidence that postoperative treatment modifications might improve the prognosis in case of a poor response of osteosarcomas to standard preoperative chemotherapy. In contrast, the postoperative addition of high-dose chemotherapy with autologous peripheral blood stem-cell rescue improved outcomes for patients with poorly responding Ewing sarcomas in another large randomized trial, EURO-E.W.I.N.G.99. In rhabdomyosarcoma, the practice to base treatment decisions based upon early volumetric response has been challenged by recent studies.

In summary, while response is clearly important, defining the best ways of measuring response and drawing the right conclusions regarding local and systemic treatment remains challenging.

CME Session



October 15, 16:30 - 18:00

12

Radiological Response Evaluation of Paediatric Sarcomas

Thekla von Kalle (Stuttgart, Germany)

In a child, MRI is the modality of choice to assess the primary site of a sarcoma. If performed according to current guidelines, MRI is superior to computed tomography in delineating a tumour’s soft tissue mass and intramedullary extension. It provides versatile options including diffusion weighted imaging (DWI) as well as dynamic and static assessment of contrast enhancement. These options not only allow to evaluate changes in tumour size under neo-adjuvant chemotherapy but also generate information on tumour vascularization, cell integrity and necrosis. However, predicting tumour response to pre-operative chemotherapy is probably one of the most controversial fields of imaging.

Clearly defined assessment criteria are necessary for any response evaluation. They exist for morphological changes in tumour size or volume (e.g. RECIST, WHO) and are helpful in most soft tissue sarcomas. The amount of surrounding edema may additionally serve as qualitative response criterion. However, tumour entities such as osteosarcomas or synovial sarcomas may only scarcely shrink under chemotherapy, making RECIST criteria hardly applicable.

Dynamic contrast enhanced MRI evaluates the inflow and the wash-out or accumulation of a contrast agent in a tissue over time during and after injection. The resulting time intensity curves have long been shown to correlate well to the degree of tumour angiogenesis and necrosis. They thus allow

to depict early effects of therapy and also help to discriminate tumour invasion from tumour-free bone marrow. While quantitative measurements require a procedure with a high level of standardization, semi-quantitative analyses of curve shapes provide a more practical approach with comparable results.

DWI is based on the Brownian motion of water molecules, which is restricted by structures such as cell membranes. Although restricted diffusion is not specific for malignant lesions and is also typical of normal lymphatic tissue DWI allows to distinguish tumour parts with high cell density from necrotic areas and to monitor changes in diffusivity before and after chemotherapy. In osteosarcomas, it has been shown to predict tumour response to therapy prior to surgery and complete histological work-up.

However, as technical parameters largely influence results standardized MR protocols would be required. Qualified studies on the role of diffusion weighted imaging are rare, especially in children with rhabdomyosarcomas, and larger prospective studies are yet to be performed for primary bone sarcomas. Therefore, Princess Maxima center for pediatric oncology, Utrecht NL, and COSS (Cooperative Osteosarcoma Study Group), Stuttgart D, have decided to join forces and to initiate a study group on DWI in osteosarcomas. To join the study group write to [email protected]

References:

1. Bajpaj J, Gamanagatti S, Sharma MC et al. Noninvasive imaging surrogate of angiogenesis in osteosarcoma. Pediatr Blood Caner 2010; 54: 526-31.

2. Casali PG, Abecassis N, Bauer S et al. Soft tissue and visceral sarcomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018; 29 : iv268-iv285.

3. Casali PG, Bielack S, Abecassis N et al. Bone sarcomas: ESMO-PaedCan-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018; 29: iv79-iv95.

4. Dyke JP, Panicek DM, Healey JH et al. Osteogenic and Ewing sarcomas: estimation of necrotic fraction during induction chemotherapy with dynamic contrast-enhanced MR imaging. Radiology 2003; 228: 271-8.

5. Kubo T, Furuta T, Johan MP et al. Value of diffusion-weighted imaging for evaluating chemotherapy response in osteosarcoma: A meta-analysis. Mol Clin Oncol. 2017; 7:88-92.

6. Norman G, Fayter D, Lewis-Light K et al. Mind the gap: extent of use of diffusion-weighted MRI in children with rhabdomyosarcoma. Pediatr Radiol 2015; 45: 778-81.

CME Session



October 15, 16:30 - 18:00

12

Response Assessment in Paediatric Sarcomas – Value of Nuclear Medicine Techniques

Marguerite T. Parisi (Seattle, United States of America)

The pediatric sarcomas, which encompass a variety of histologic subtypes, represent 13% of all pediatric malignancies. (1) For the most common sarcomas - osteosarcoma, Ewing sarcoma and rhabdomyosarcoma - treatment is typically multimodal incorporating intensive systemic chemotherapy, aggressive surgical resection, and radiation depending on the clinical scenario. Pediatric sarcomas most often metastasize to the lungs or to bone, thus imaging plays an important role at diagnosis and in disease staging. Sadly, those with high-risk, metastatic or recurrent disease have a dismal prognosis. (2)

In osteosarcoma, Ewing sarcoma and rhabdomyosarcoma, 18Fluorine-Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT appears to be most useful in delineating the primary tumor and in the identification of skeletal metastases with published data consistently suggesting that this modality has improved sensitivity, specificity, and diagnostic accuracy for skeletal metastases compared to bone scintigraphy. (3) In rhabdomyosarcoma, 18F-FDG PET/

CT was found to be more effective than conventional imaging in detecting lymph node, bone, and bone marrow disease. (4)

While there is a clear role for the use of 18F-FDG PET/CT in the staging of the pediatric sarcomas, its value in response assessment and in predicting outcomes is less clear. Several studies have determined that for osteogenic sarcoma, variables on 18F-FDG PET/CT including change in SUV max following neoadjuvant therapy compared to that at diagnosis may predict histologic response as well as outcome. (5,6). Unfortunately, the evidence is not as conclusive in Ewing sarcoma or rhabdomyosarcoma where the ability of this modality to predict outcomes is an area of ongoing controversy. (5,7-9) Further, there is limited literature regarding how best to incorporate 18F-FDG PET/CT in the staging, therapeutic response monitoring and in predicting outcomes in the non-rhabdomyosarcoma soft tissue sarcomas. This presentation will focus on the current literature regarding the role of imaging - and specifically 18F-FDG PET/CT – in assessing response and its use in prognostication in the pediatric sarcomas.

References:

1. Ries LAG, Smith MA, Gurney JG, et al., editors. Cancer incidence and survival among children and Adolescents: United States SEER Program 1975-1995.National Cancer Institute, SEER Program. NIH Pub.no 99-4649 Bethesda, MD, 1999.

2. Harrison DJ, Parisi MT, Shulkin BL. The role of 18F-FDG PET/CT in Pediatric Sarcoma. Semin Nucl Med 2017; 47:229-241.

3. Hurley C, McCarville MB, Shulkin BL, et al: Comparison of (18)F-FDG PET-CT and bone scintigraphy for evaluation of osseous metastases in newly diagnosed and recurrent osteosarcoma. Pediatr Blood Cancer 2016; 63(8):1381-1386.

4. Federico SM, Spunt SL, Krasin MJ, et al: Comparison of PET-CT and conventional imaging in staging pediatric rhabdomyosarcoma. Pediatr Blood Cancer 2013; 60(&):1128-1134.

5. Denecke T, Hundsdorfer P, Misch D, et al: Assessment of histological response os paediaatric sarcomas using FDG PET in comparison to morphologic volume measurement and standardized MRI parameters. Eur J Nucl Med Mol Imaging 2010; 37(10):1842-1853.

6. Hongtao I, Hui Z, Bingshun W, et al: 18F-FDG positron emission tomography for assessment of histological response to neoadjuvant chemotherapy in osteosarcoma: A meta-analysis. Surg Oncol 2012; 21(4): e165-e170.

7. Gaston LL, di Bella C, Slavin J, et al: 18F-FDG PET response to neoadjuvant therapy for Ewing sarcoma nd osteosarcoma are different. Skeletal Radiol 2011; 40(8):1007-1015.

8. Casey DL, Wexler LH, Fox JJ et al: Predicting outcome in patients with rhabdomyosarcoma: Role of [18F] fluorodeoxyglucose positron emission tomography. Int J Radiat Oncol Biol Phys 2014; 90(5):1136-1142.

9. Harrison DJ, Parisi MT, Shulkin BL, et al: 18F-2Fluoro-2deoxy-d-glucose positron emission tomography(FDG-PET) response to predict event-free survival(EFS) in intermediate risk (IR) or high-risk(HR) rhabdomyosarcoma (RMS): A report from the Soft Tissue Sarcoma Committee if the Children’s Oncology Group (COG)> Presented at 2016 ASCO Annual Meeting, Chicago Il, June3-7, 2016.




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Current and Future of Radiopharmaceuticals

13

CME Session



October 16, 08:00 - 09:30

13

PET Radiopharmaceuticals of RecentYears from a Radiopharmaceutical Chemist’s Perspective

Albert Windhorst (Amsterdam, Netherlands)

Many new PET radiopharmaceuticals have been introduced in the last decade, the series of PSMA targeting tracer being the most dominant ones. However, the clinical drive for other new radiopharmaceuticals is tremendous, despite of reimbursement issues. Focus is mainly on their use in drug development and understanding of disease, so more clinical research related.

Radiopharmaceutical chemists are very active in developing new methodologies for radiolabeling of molecules, thereby pushing radiopharmaceuticals development. A selection of new radiopharmaceuticals (not targeting PSMA) and new radiopharmaceutical chemistry methodologies will be discussed critically.

Educational objectives

Learn about:

• The synthesis and radiopharmacy aspects of new radiopharmaceuticals.

• Opportunities and limitations from a radiopharmaceutical chemistry perspective.

• Explained with a few cases.

CME Session



October 16, 08:00 - 09:30

13

Current Value of PSMA-Targeting Ligands in Diagnostic and Therapeutic Nuclear Medicine

Clemens Kratochwil (Heidelberg, Germany)

In 90% of prostate cancers PSMA overexpression is sufficient for diagnostic purpose and in 75% of advanced stage patients for therapy. PSMA is an enzyme and all current small molecule PSMA-ligands are inhibitors of its catalytic domain, e.g. Glu-ureas.

123I-MIP-1072 and 123I-MIP-1095 followed by 99mTc-MIP-1404 and 99mTc-MIP-1405 were the first diagnostic ligands, suitable for SPECT imaging. Currently most clinical experience is available for PET/CT with 68Ga-labeled PSMA-11, but newer data imply that the clinical value of 18F-DCFPyl and 18F-PSMA-1007 is comparable and their production is better scalable. Various other 99mTc- or 18F-labeled ligands amended the portfolio of diagnostic tracers, but none of them demonstrated an additional clinical advantage, yet [1].

In the diagnostic setting, PSMA-PET/MR can be used to guide biopsies to the dominant intra-prostatic lesion, used to tailor low-risk patients toward active surveillance, high-risk patient toward aggressive therapy; but imaging cannot substitute biopsy. PSMA-PET/CT for primary staging of high-risk patients is still controversial. Due to low sensitivity for micro-metastases (<3 mm diameter), a negative PET-scan cannot rule out lymph-nodal disease and avoid

limited lymphadenectomy. However, high specificity in detecting metastases outside the boundaries of extended lymph-node dissection supports its use. In the setting of biochemical recurrence (30-40% of initial patients), early onset of secondary local therapy (e.g. salvage prostatectomy following radiotherapy and vice versa) or tailoring toward systemic treatment improves prognosis; PSMA-PET/CT is already considered the new gold-standard for this situation. Both PSMA-PET and -SPECT can be used for follow-up exams in advanced stage patients and phenotyping in advance of PSMA-therapy [2].

Overcoming the slow pharmacokinetics of antibodies and practical issues of 131I-labeled compounds, 177Lu-PSMA therapy is currently on the way to clinical translation. A retrospective German multicenter and a prospective Australian phase-2 trial reported good tolerability and a >50% PSA decline in 40%-57% of patients, dependent on selection criteria [3, 4]. 177Lu-PSMA is currently evaluated in an international phase-3 trial [5]. Recent academically driven work implies that 225Ac-PSMA-targeting alpha-emitter therapy could gradually improve the efficacy in comparison to 177Lu-PSMA, but additional work is needed to optimize the trade-off between anti-tumor activity and tolerability [6].

References:

1. Kratochwil C, et al. Semin Nucl Med. 2016;46:405-18.

2. Eiber M, et al. J Nucl Med. 2017;58:67S-76S.

3. Rahbar K, et al. J Nucl Med. 2017;58:85-90.

4. Hofman MS, et al. Lancet Oncol. 2018;19:825-833.

5. https://clinicaltrials.gov/ct2/show/NCT03511664

6. Kratochwil C, et al. Semin Nucl Med. 2019;49:313-325.

CME Session



October 16, 08:00 - 09:30

13

Established, Emerging and Future Radionuclides - Which will we use in 2030?

Ulli Köster (Grenoble, France)

Among the over 3000 known radioactive nuclides, there are over 100 with nuclear decay characteristics potentially suitable for nuclear medicine applications. However, the number of radionuclides in regular clinical use is much smaller. Has this subset really been selected by a rigorous optimization process or could it be that certain radionuclides with better properties for certain applications had simply been overlooked so far because they were not easily available? What effort would be required to produce such “optimum” radionuclides in the required quality and quantity and which of these could become available for regular use within the next decade?

The focus of the presentation will be on therapeutic radionuclides and their theranostic companions. First generation radionuclide therapies were mainly based on easily available “established” radionuclides such as 131I and 90Y. The development of new vectors providing improved biological targeting goes hand in hand with the demand for radionuclides that provide improved physical targeting, namely via shorter range radiation. This explains why the low-energy beta emitter 177Lu is presently becoming the “gold standard in radionuclide therapy”. However, other radionuclides emitting conversion electrons alone or in combination with low-energy betas are being discussed to further enhance the dose deposition at short sub-mm distances [1-3]. For still shorter ranges alpha emitters and Auger electron emitters are required. For a sustainable use eventually

a compromise has to be reached between optimum nuclear and chemical properties on one side and reliable production at reasonable costs on the other. This intrinsic conflict will be exemplified with the terbium quadruplet 149Tb, 152Tb, 155Tb and 161Tb [4]. All four radionuclides have been used preclinically [e.g. 5-7] and 152Tb even clinically [8]. The neutron-deficient Tb isotopes were initially produced at CERN-ISOLDE by high-energy proton induced spallation reactions combined with on-line mass separation. This is an excellent method to produce research quantities of many different radionuclides in non-carrier-added form, but complementary production methods have to be investigated to assure scalability for large scale use.

Novel therapies such as PSMA-targeting radionuclide therapies of CRPC are leading to a spectacular rise in radionuclide demand. Can the production capacity of emerging and future radionuclides follow or is there an intrinsic supply limitation or even a risk of supply interruptions as had been experienced previously even for established radionuclides? What are the bottlenecks in expanding supply of such radionuclides and which production capacities (nuclear research reactors, large cyclotrons, isotope enrichment facilities, radiochemical separation, etc.) would be required and how does this match with the existing infrastructure ?

References:

1. Uusijärvi H et al., J Nucl Med 2006; 47:807–814.

2. Hindié E et al., J Nucl Med 2016; 57:759–764. 3.

3. Falzone N et al. Theranostics 2018;8:292-303.

4. Müller C, al. J Nucl Med 2012; 53:1951–1959.

5. Müller C, al. J Nucl Med 2012; 53:1951–1959.

6. Beyer GJ et al. EJNMMI 2004;31:547–554.

7. Müller C, al. Nucl Med Biol 2014;41:e58–e65

8. Baum et al. RP Dalton Trans 2017;46:14638-14646




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The Diagnosis is Complex Regional Pain Syndrome I (CRPS-I a.k.a. Reflex Sympathetic

Dystrophy). Or is it?

14

CME Session



October 16, 10:00 - 11:30

14

Contemporary Consensus and Controversies in Diagnosis and Management of CRPS-I

Roger Atkins (Bristol, United Kingdom) / IASP

Complex regional pain syndrome of type I (CRPS-I) is a term coined by the International Association for the Study of Pain (IASP) to describe disorders characterized by spontaneous or stimulus-induced pain that is disproportionate to the inciting event and accompanied by a wide variety of autonomic and motor disturbances in highly variable combinations. The IASP proposed a new taxonomy and consensus-based diagnostic criteria (1). There is no gold standard diagnostic test for CRPS. The diagnosis entirely rests on the assessment of clinical criteria and is a diagnosis of exclusion:

1. Continuing pain which is disproportionate to any inciting event

2. Must report at least one symptom in each of the four following categories:

a) Sensory: report of hyperesthesia, b) Vasomotor: temperature asymmetry and/or skin color changes/asymmetry, c) Sudomotor/edema: edema and/or sweating changes/asymmetry, d) Motor/trophic: decreased range of motion (ROM) and/or motor dysfunction and/or trophic changes

3. Must display at least one sign in two or more of the following categories:

a) Sensory: hyperalgesia and/or allodynia, b) Vasomotor: temperature asymmetry and/or skin color changes/asymmetry, c) Sudomotor/edema: edema and/or sweating changes/asymmetry, d) Motor/trophic: decreased ROM and/or motor dysfunction and/or trophic changes

4. There must be no other diagnosis that better explains the signs and symptoms

The Budapest revised clinical criteria set achieved a specificity of 0.68 (against 0.41 for the previous IASP

criteria) while retaining the exceptional sensitivity of the previous IASP criteria (0.99). Some adaptative refinements may be set to settle the positive diagnosis of CRPS-I in an orthopedic context (2). A variety of paraclinical tests help in the exclusion of other diagnoses. Bone scintigraphy, when displaying a pattern of diffuse periarticular uptake of the affected extremity on delayed phase, is considered to be typical of CRPS-I especially during the first 6 months. MRI is not diagnostic but may be helpful to exclude other local MSK conditions.

Differential diagnosis gamut is wide: a) MSK tissue injuries, b) Nerve disorders, c) Vascular disorders, d) Inflammatory disorders, e) MSK, soft tissue, and skin infections, f ) Toxic exposure: vinca-alkaloids, heavy metals, g) Psychological somatoform disorders, including Münchhausen syndrome.

An autoimmune model for CRPS has been lately developed, in which injury facilitates the binding of pre-existing autoantibodies to target structures, thereby enhancing central sensitization.

The keystone of therapy is early recognition. The mainstay of treatment is physiotherapy and occupational therapy in order to improve active ROM and to avoid atrophy and contractures. Published randomized controlled trial provides evidence that bisphosphonates can significantly relieve pain syndrome and improve functional status in patients with early disease (< 6 months duration) and abnormal uptake on bone scintigraphy. The results of prospective studies of patients with CRPS-I after fracture suggest that many of the symptoms resolve over the course of ~ 12 months. Nonetheless, approximately 20–25% of cases become chronic.

References

1. Atkins RM. Principles of complex regional pain syndrome., https://pdfs.semanticscholar.org/8110/451df47066d4c7ab0d66ca0366004cd79c94.pdf | Website last browsed on June, 18, 2019

2. Thomson McBride AR, Barnett AJ, Livingstone JA, Atkins RM. Complex regional pain syndrome (type 1): a comparison of 2 diagnostic criteria methods. Clin J Pain. 2008 Sep;24(7):637-40. doi: 10.1097/AJP.0b013e31817591da. PubMed PMID: 18716503

CME Session



October 16, 10:00 - 11:30

14

Role for Imaging in Diagnosis and Management of CRPS-I

Frédéric Paycha (Paris, France)

Suspicion of CRPS-I in adult is a frequent indication of bone scintigraphy (BS) in everyday practice of European Nuclear Medicine departments.

BS is mainly prescribed when CRPS-I is spontaneously developing, involving a proximal joint, the clinical presentation is atypical, an arduous differential diagnosis is at stake, and medico-legal issue is to be addressed (1).

BS workflow should include 3- or 2-phase study with delayed SPECT/CT modality, at the exception of the hand if CRPS-I is indisputable on the planar scintigraphic pattern.

Semiological pattern of planar bone scan usually proves distinctive for CRPS-I of the extremities (hand, foot). For the extremities, 4 signs have been indeed itemized: 1) diffusely increased peri-articular uptake in the carpus or tarsus; 2) diffusely uptake in all small joints in the involved extremity; 3) diffusely increased uptake in adjacent diaphyses (radius and ulna, or tibia and fibula); 4) diffusely increased uptake in an adjacent large joint. Multivariate analysis identified combination of sign 1, sign 2 and increased blood pool phase as the pattern with the highest diagnostic accuracy (98.9%) (2).

Indication of bone scan is sustained for CRPS-I suspicion of the mesomelic joints (knee) in a post-traumatic or iatrogenic (meniscectomy++) setting. BS abnormalities prove highly fluctuating: 1) diffuse uptake, 2) localized uptake (femoral condyle, tibial plateau, patella), 3) pseudo-articular uptake (patello-

femoral). Such a diagnosis is exceptionally confirmed but regularly reoriented by BS.

There is a rarefaction, if not a shutdown, of indication of BS for suspicion of CRPS-I of rhizomelic joints (shoulder, hip) but a continuance of BS indication in case of unexplained persistent hip pain.

Meta-analysis of test accuracy studies in diagnosis of CRPS-I, all factors considered, showed that BS features adequate sensitivity (80%) but moderate specificity (70%) (3).

The factors that appear to be affecting the reported sensitivity and specificity values of planar BS in these studies are: 1) diagnostic criteria of CRPS-1 used in each study, 2) duration of symptoms in the study population, 3) age of patients in the study population, 4) BS interpretation criteria, 5) location of disease (4).

In this respect, in studies using Budapest criteria as reference, the sensitivity dramatically decreased (55%) while the specificity increased to a lesser extent (93%)! (5)

However, bone SPECT-CT modality plays a foremost role in reorienting towards a differential diagnosis with accuracy and inter-reader agreement significantly more prominent in comparison with planar images.

This specificity gain of bone SPECT-CT is preeminent inasmuch as most routine bone scan findings militate against a CRPS-I and often properly reorient towards an unsuspected alternative skeletal condition.

References

1. Paycha F, Salmon F, Brunot B, Houzard C. Algodystrophie et médecine nucléaire. Méd Nucl 1998; 22: 102-6.

2. Leitha, A. Staudenherz, M. Korpan, V. Fialka. Pattern recognition in five-phase BS: Diagnostic patterns of reflex sympathetic dystrophy in adults. Eur J Nucl Med Mol Imag 1996 ; 23: 256-62.

3. Ringer R, Wertli M, Bachmann LM, Buck FM, Brunner F. Concordance of qualitative BS results withpresence of clinical complex regional pain syndrome 1: Meta-analysis of test accuracy studies. Eur J Pain 2012; 16(10): 1347-56.

4. Fournier RS, Holder LE. Reflex sympathetic dystrophy: Diagnostic controversies. Semin Nucl Med 1998; 28(1): 116-23.

5. Wertli MM, Brunner F, Steurer J, Held U. Usefulness of bone scintigraphy for the diagnosis of Complex Regional Pain Syndrome 1: A systematic review and Bayesian meta-analysis. PLoS One. 2017 Mar 16;12(3): e0173688. doi: 10.1371/journal.pone.0173688. eCollection 2017

CME Session



October 16, 10:00 - 11:30

14

Role for Imaging in alternate Diagnoses Usually Confused with CRPS-I

Edmond Rust (Mulhouse, France)

In Budapest clinical diagnostic revised criteria set for complex regional pain syndrome type I (CRPS-I), the 4th criterium states “there is no other diagnosis that better explains the signs and symptoms”. This last criterion underscores the foremost need to rule out disorders mimicking CRPS-I amenable by appropriate and timely therapy but entailing irreversible damage of bone and joint if overlooked. Therefore, CRPS-I is considered to be a diagnosis by exclusion

Image acquisition and processing workflows are tailored in order to ascertain the positive diagnosis of CRPS-I as well to pick up alternative diagnoses. For hand and foot, planar blood pool and delayed spot views are mandatory. For all localizations, but the hands, excepted if a carpal lesion is suspected, a SPECT-CT delayed phase study is mandatory. A complementary blood pool SPECT-CT study is optional. Whichever localization, a whole-body planar scan must be performed. For arduous differential diagnosis or intricate conditions (e.g. CRPS-I secondary to insufficiency fracture) a post-hoc fusion of SPECT and MRI datasets whenever available through dedicated software routine is advocated to optimizing diagnostic process.

Common bone and joint conditions mimicking CRPS-I that must be vigorously searched for on bone SPECT-CT encompass a) localized disorders: disuse osteoporosis of the limb, occult stress fracture, avascular necrosis, osteoarthritis (early stage), osteomyelitis or septic arthritis, microcrystalline arthritis, peri-articular primitive bone tumors, and b) systemic disorders: monoarthritis heralding a rheumatoid arthritis or a spondyloarthropathy, metabolic osteopathies, paraneoplastic syndromes, peri-articular bone metastasis.

Moreover, almost each condition of this list may

be a triggering event for an authentic CRPS-I. Thus, it is crux to corroborate clinical signs of CRPS-I, at best with the helping of chart or picture, to bone SPECT-CT findings.

Specific differentials gamuts are to be thoroughly entertained according to joint localization.

a. CRPS-I of the shoulder: Adhesive capsulitis is definitively the diagnostic field of MRI and echography.

b. CRPS-I of the hand: Colles’ fracture, triangular fibrocartilage complex tear, distal radioulnar joint subluxation, rheumatic arthritis, osteoarthritis, avascular necrosis (lunate, scaphoid), tendonitis

c. CRPS-I of the hip: Diagnostic deconstruction of transient hip disorders stems from the pattern triptych: Transient osteoporosis, transient edema, and transient increased uptake of the hip. Matching causative conditions are: Ischemia of the femoral head, subchondral stress fracture of the femoral head, early phase of coxitis, incipient rapidly destructive hip osteoarthritis. Non- identified causes but also some quoted conditions used to be labelled as CRPS-I of the hip… (1).

d. CRPS-I of the knee: Positive diagnosis of CRPS-I is made difficult because of various clinical pictures and variable SPECT increased uptake: juxta-articular bone, pseudo-articular, diffuse.

e. CRPS-I of the foot: Specific diagnostic traps are represented by osteochondral lesions of talar dome, injury of the distal tibio-fibular syndesmosis, tarsal coalition, osteoid osteoma of the tarsus, Lyme arthritis. All these conditions must be carefully searched for on SPECT-CT exam.

Reference

1. Bruce W, Higgs RJ, Munidasa D, Hunjan JS, Van der Wall H. Acute osteochondral injuries of the hip. Clin Nucl Med 2002; 27(8): 547-9.



Publisher European Association of Nuclear MedicineSchmalzhofgasse 26, 1060 Vienna, AustriaPhone: +43 1 890 44 27 | Fax: +43 1 890 44 27 - 9Email: [email protected] | URL: www.eanm.org

Editors Barbora Trnena, EANM Executive Office

Content No responsibility is taken for the correctness of this information. Information as per date of publishing.

Layout & Design Barbora Trnena, EANM Executive Office

barcelona, spain...man (basic and translational science) and do.more (radionuclide therapy and...

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