INTERNATIONAL SYMPOSIUM ON RADIOPHARMACEUTICAL THERAPY HELSINKI, 18-20 NOVEMBER 2018

. 2019 Apr-Jun;18(2):205–225.

INTERNATIONAL SYMPOSIUM ON RADIOPHARMACEUTICAL THERAPY HELSINKI, 18-20 NOVEMBER 2018

PMCID: PMC6476247

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

DAY 1, SUNDAY, NOVEMBER 18, 2018: SCIENTIFIC SESSION 1: NUCLEAR CARDIOLOGY: O1 Revolution in cardiac imaging: Quantitative perfusion, inflammation and hybrid imaging

Juhani Knuuti ¹

Moderators: Juhani Knuuti, Turku, Finland and Pietro Muto, Naples, Italy

Quantification of myocardial perfusion in absolute terms has been available for two decades. Currently, the most robust technique to measure perfusion noninvasively in human heart is positron emission tomography (PET). The earlier studies have demonstrated the potential of absolute quantification of myocardial perfusion in various clinical populations.

The use of cardiac PET imaging has rapidly increased in the clinics. This is based on the evidence that has shown PET to be very accurate in detection of CAD and in assessing the severity of disease. However, mostly the assessment is based on the analysis of relative perfusion. The clinical value of quantitation has been recently demonstrated and solid evidence on the clinical value has become available.

It is well established, that a comprehensive assessment of CAD requires not only morphologic information about coronary artery stenosis location and degree but also functional information on pathophysiologic lesion severity. Only about half of the lesions classified as significant in coronary computed tomography angiography (CCTA) are linked with abnormal perfusion. Recent studies have shown that hybrid imaging combining PET or SPECT with CT or MRI improves the accuracy. Hybrid images may offer superior diagnostic information with regard to identification of the culprit vessel and therefore increase diagnostic confidence and provides complementary prognostic value.

Although assessment of myocardial viability using stand-alone systems is well established, the hybrid imaging provides clear benefits. The detected dysfunctional but viable or scar regions can be directly linked with the individual’s coronary anatomy and linked with coronary stenoses.

Currently, the position of nuclear imaging in cardiovascular research and patient care is primarily based on its capacity to image perfusion and glucose metabolism. However, the methods allow for imaging and quantification of molecular interactions and pathways with picomolar sensitivity. Thus, number of cellular processes can be studied, e.g. receptor density, enzyme activity, inflammatory processes and gene expression.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O2 Imaging innervation. Finally clinical applications?

Albert Flotats ¹

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O3 Gauging cardiac repair, regeneration and inflammation with new molecular probes

James Thackeray ¹

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O4 Novel therapies of cardiac regeneration. How imaging can help in diagnosis, targeting and monitoring?

Seppo Ylä-Herttuala ¹

SCIENTIFIC SESSION 2: NEW TRENDS IN ONCOLOGY AND PRECISION MEDICINE.

Moderators: Vivek Subbiah, Houston, TX, USA and Homer Macapinlac, Houston, TX, USA

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O5 Personalized medicine and precision oncology

Vivek Subbiah ¹

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O6 Precision oncology in rare tumors: adopting the orphans

Roman Groisberg ¹

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O7 Optimizing patient selection for phase 1 clinical trials: lessons from targeted therapy and immunotherapy drug development

Shiraj Sen ¹

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O8 Target discovery for precision oncology using large public databases

Jason Roszik ¹

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O9 Oncolytic viruses

Akseli Hemminki ¹

Oncolytic viruses have been used for treatment of cancer for more than a century, but the first products were only approved in 2004 (Latvia), 2006 (China) and 2015 (FDA, EMA). However, the finding that a major part of their anti-tumor activity is due to activation of the immune system, is a relatively recent one. Thus, currently these agents are viewed more as immunotherapy than sterile oncolytic drugs. Key to this realization was experience from human cancer patients, since laboratory models often lack the key immunological components. The central findings from our Advanced Therapy Access Program (ATAP), ongoing between 2007-2012, will be explained. 290 cancer patients were treated in an individual manner under the EU Advanced Therapy directive and its Hospital Exemption (Hemminki A, Crossing the Valley of Death with Advanced Cancer Therapy, Nomerta publishing 2015). The key trial resulting in approval of Imlygic (Amgen) in the EU and US will be summarized, in addition to subsequent developments. While robust single agent activity is seen only in a minority of patients with most oncolytic viruses, they are emerging as key ingredients of combination immunotherapy. Checkpoint inhibitors have gained much attention, including a recent Nobel prize, due to their ability to achieve lasting responses in immunologically “hot” tumors. However, they do not work in “cold” tumors. Oncolytic viruses are able to turn cold tumors hot, suggesting an attractive combination with some promisining early clinical data.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

DAY 2, MONDAY, NOVEMBER 19, 2018: O10 New Insights in Theranostics: Pre-targeted Radioimmunotherapy for Cure of Solid Human Tumors

Steven M Larson, Sarah Cheal

AJIT PADHY ORATION

Steven M. Larson, MSKCC, NY, USA

There is a major unmet need in oncology for better therapies for the common “solid” tumors of adult and childhood cancers such as colon, lung, breast, ovarian, neuroblastoma, sarcoma, and glioblastoma. Radioimmunotherapy (RIT) of human solid tumors has not achieved cures and even major responses have been few and far between.¹ A common problem for RIT has been low therapeutic index (TI), aka radiation dose to tumor/radiation dose to radiosensitive organs, such as bone marrow and kidney.¹

Since 2013, we have focused on pre-targeted radioimmunotherapy (PRIT) to improve TI in order to achieve cures of solid tumors in man. To achieve this goal, we established a collaboration with Dane Wittrup at the Massachusetts Institute of Technology (MIT) to study PRIT targeting GPA33, and with Nai Kong V. Cheung at MSK to study PRIT targeting GD2 and HER2. The PRIT was to be based on a modular bispecific anti-tumor/anti-hapten antibody format reported by the Wittrup Lab.² Building on the antibody expertise of the Cheung Laboratory, sufficient quantities of these novel recombinant forms were manufactured and validated to begin the era of PRIT testing at MSK.

We chose to develop PRIT methodology as originally proposed by Reardan, Meares, and Goodwin et al. who described a highly novel, antibody-based radiohapten capture tumor targeting approach utilizing antibodies against metal chelates.³ We were particularly impressed by the refinement of the anti-chelate antibody sequence achieved by our MIT colleagues using affinity maturation to produce a pico-molar affinity (pM) radiohapten binding antibody called C825 to bind a radiohapten, benzyl DOTA lanthanides.⁴ We refer to this approach as “DOTA-PRIT.” Useful characteristics of DOTA-PRIT include excellent post-injection contrast between tumor uptake and other tissues, as well as complete and rapid excretion of non-tumor-bound radiohapten through the kidneys, without renal retention of radioactivity.⁵,⁶

DOTA-PRIT is a three-step method in which the treatment cycle separates the anti-tumor antibody targeting from the targeting of radioactivity. First, a bifunctional antibody (bf Ab) is created in the IgG-scFv format, which has two antibody specificities on the same molecule for (a) tumor antigen binding and (b) radiohapten binding. The non-radioactive bf Ab is injected, followed by an interval of usually 24-48 hours to optimize tumor uptake on the cognate antigen. Once uptake is considered optimal, a clearing agent is administered, which selectively clears away any non-reacted antibody in blood and non-tumor tissues. The clearing agent is a high-molecular-weight dextran chelated to a non-radioactive DOTA lanthanide hapten and the dextran-bound antibody is cleared into the hepatocytes of the liver. Clearance is sufficiently rapid that within a few hours the radiohapten can be given, which is either bound within the tumor or quickly excreted through the kidneys.

At MSK, we set a high bar for DOTA-PRIT to achieve histologic “cures” of solid tumors, with minimal, totally resolving toxicity in radiosensitive target tissues at the histologic level. We next developed a definition for systemic RIT “success”; namely, a series of targeting benchmarks for the “sweet spot”—the point at which there is a balance between the essential linked features of safe and curative RIT of human tumors: tumoricidal radiation dose to tumor and non-toxic TI for target tissues. Based on tumor response and toxicity experience with other targeted radiotherapies, such as Iodine-131 treatment of thyroid cancer and Lutetium-177 and Yttrium-90 radiopeptide treatment of neuroendocrine tumors,¹ we settled on a tumor targeting goal of ~100 Gy to tumor and non-toxic TIs. Curative tumor dose >10,000 cGy; renal dose <1,500 cGy; ~7-10 TI; bone marrow dose <150 cGy; ~40-100 TI; and intestinal mucosa dose <250 cGy; 40-60 TI.¹

We began our studies of DOTA-PRIT by selecting two anti-tumor antibodies with excellent tumor antigen targeting properties based on past human experience. 3F8 binds to the ganglioside antigen GD2, common in neuroblastoma, glioma, sarcoma, and small cell lung cancer. The A33 antibody—which binds to the glycoprotein A33 antigen GPA33, a component of tight junctions—is commonly expressed in colon and small bowel cancer (~95%) and a subset of pancreatic and gastric cancers. Both antibody antigen systems have long retention in the tumor cell membrane and internalization is considered minimal. Both systems had bf Abs created, and high TIs were observed, due to excellent targeting of Lutetium-177 and Yttrium-86.

In the GD2 system, we observed 100% complete responses (CRs) of neuroblastoma xenografts with 80% histologic cures, based on total tumor radiation-absorbed doses of 3,400 cGy to tumor and “safe” TIs (Tu/B = 142; Tu/K = 23).⁸ In the A33 system, three cycles were also required for cure, with total tumor doses of ~10,000 cGy and 100% CRs and cures, with safe TIs (Tu/B = 73; Tu/K = 12) and no histologically evident toxicity in target organs.⁷ We validated SPECT/CT imaging for theranostics: The radiation-absorbed dose, determined by biodistribution studies in mice, when compared to contemporaneous non-invasive SPECT imaging, agreed to within 7%.⁷

The multistep targeting system was not thought to be useful for tumor antigen systems such as HER2, which are readily internalized from the cell membrane. HER2 is expressed in breast, ovarian, and lung cancers and in gastroesophageal junction tumors. Contrary to expectations, we discovered excellent efficacy of a three-cycle anti-HER2-DOTA-PRIT, which delivered a total radiation dose to tumor of 6,600 cGy (Tu/B = 28; Tu/K = 7), with 100% CRs, a majority of histologic cure (5/8, 62.5%), and no recurrence of microscopic residual disease (3/8) at 85 d.⁹

We have now extended the DOTA-PRIT method to enable RIT with alpha particles (α-particles). We focused development on Actinium-225 since its physical half-life of 10 d makes it well suited for DOTA-PRIT. We named this approach “proteus-DOTA” (Pr-DOTA), which contains a DOTA-chelated non-radioactive Lutetium-175 as the high-affinity “handle” or binding site cognate to the hapten binding antibody on our specialized bf Abs. A second radiometal chelate is linked by poly-ethylene glycol. Pr-DOTA radiohapten forms (e.g., Actinium-225, indium-111) that have been studied so far exhibit the same renal excretion-driven pharmacodynamics in vivo as ¹⁷⁷Lu-DOTA-PRIT.* Treatment of mice bearing human GPA33-expressing colorectal or GD2-expressing neuroblastoma xenografts with a single cycle of [²²⁵Ac]Pr-DOTA-PRIT led to significant tumor growth control, including CRs with no acute toxicity (manuscript in preparation).

SM Larson reports receiving commercial research grants from Genentech, Wilex, Telix and Regeneron; holding ownership interest/equity in Voreyda Theranostics Inc. and Elucida Oncology Inc, and holding stock in ImaginAb. SML is the inventor and owner of issued patents both currently unlicensed and licensed by MSK to Samus Therapeutics . YMABS Therapeutics, Inc. and Elucida Oncology Inc. SML is or has been consultant to Cynvec, Eli Lilly, Prescient, Advanced Innovative Partners, Gerson Lehrman, Progenics and Janssen Pharmaceuticals. All other authors have no competing interests.

SCIENTIFIC SESSION 3: RADIOEMBOLISATION AND LIVER THERAPIES

Moderators: Patrick Flamen, Brussels, Belgium and Aviral Singh, Bad Berka, Germany

Reference

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World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O11 Personalized SIRT based on predictive dosimetry, regional functional reserve measurement and molecular imaging

Patrick Flamen ¹

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O12 Re-188 Lipiodol Liver Cancer Project – an update on current status

Ajit Shinto ¹

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O13 Biologic dosimetry in SIRT

Katherine A Vallis ¹, Nadia Falzone ¹, Boon Q Lee ¹, Elliot Abbott ¹

Background: Colorectal cancer (CRC) is a common cause of cancer related deaths. Approximately half of CRC patients develop or present with hepatic metastases (mCRC). Selective internal radiation therapy (SIRT) using yttrium-90 (⁹⁰Y) radiolabelled microspheres is a therapeutic option for some patients with liver metastases. There has been an effort to incorporate dosimetry of ⁹⁰Y SIRT into the clinic, but so far without regard for the underlying radiobiologic effects of 90Y. Methods: We have determined the radiosensitivity of CRC cell lines to ⁹⁰Y exposure based on clonogenic survival data generated using an experimental setup which was purpose-built to simulate 90Y SIRT exposure. Results were compared to exposure to 6 MV X- and 137Cs γ-radiation. The α/β ratio for ⁹⁰Y was much higher than the other two modalities at ≥100 Gy due to protraction of dose delivery. This information has been applied in a dosimetric analysis of 23 mCRC patients (96 hepatic metastases) treated with SIRT. SPECT images were transformed into dose maps using an in-house MATLAB script and the direct deposition dosimetry method. The ⁹⁰Y S-value was generated by Monte Carlo simulation using the EGSnrc/EGS++ code. Baseline and follow-up CT scans were segmented to derive liver and tumour volumes. Mean, median, and D70 (minimum dose to 70% of lesion volume) values derived from dose maps were correlated to change in lesion volume and RECIST 1.1 outcome using linear and logistic regression, respectively. Results: Radiation absorbed dose correlated with lesion response (i.e. a 1 Gy increase in mean, median, and D70 dose resulted in reduction in lesion volume by 2.7%, 2.7%, and 2.3%, respectively, p < 0.02). Higher lesion doses were associated with a higher probability of RECIST response (odds ratio of 1.05, 1.05, and 1.04 for a 1 Gy increase in mean, median, and D70 doses, respectively, p < 0.2). These analyses were repeated but taking into account the radiobiological effect of 90Y and these data will be presented at ISRT. Conclusion: Higher mean, median, and D70 doses are associated with a decrease in lesion volume and an increased probability of RECIST response. The type of analysis presented here would allow sub-optimally treated liver lesions to be managed by a multi-modality approach including the addition of external beam radiotherapy.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O14 Intra-arterial PRRT of SSTR-expressing liver tumors

Aviral Singh ¹

Aim: Several studies have been published on intravenous application of peptide receptor radionuclide therapy (PRRT) in somatostatin receptor (SSTR) expressing neuroendocrine neoplasms (GEP-NEN). However, there are limited reports on intra-arterial (IA) PRRT. This study reports a single center analysis of efficacy and safety following IA-PRRT of SSTR-expressing tumors, with emphasis on hepatic tumor burden.Methods: Fifty-five patients (M 31, F 24; mean age 52 years) with tumors expressing SSTR received 77 applications of IA-PRRT using Y-90 and/or Lu-177, with a mean administered activity of 4.2 and 7.2 GBq, respectively. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier survival analysis, defined from start of PRRT and a follow-up time of at least 3 months after IA-PRRT. Subgroup analysis was performed for patients with hepatic only as well as hepatic plus extrahepatic disease. Response to therapy was performed according to the EORTC criteria with Ga-68 SSTR PET/CT. Safety analysis was performed for hematotoxicity, nephrotoxicity, and hepatotoxicity as per CTCAE (v5.0). MAG3 renogram based tubular extraction rates (TER) were calculated and assessed using scatter-plot analysis. Results: Primary tumor entities treated with IA-PRRT included GEP-NEN (n=46; 41 P-NEN, 6 SI-NEN), CUP-NEN (n=2), pheochromocytoma/paraganglioma (n=3), glomus tumor (n=2), and meningioma (n=1). For the entire cohort, median PFS and median OS were 29.9 and 70.0 months, respectively. Thirty-four (56.4%) patients died at a median follow-up of 94.6 months (range 4.0-156.2 months). Subgroup analysis revealed a median PFS of 33.4 months for patients with hepatic disease only, and 21.9 months for patients with hepatic plus extrahepatic disease; whereas, median OS was 76 months for the former and 50 months for the latter cohort of patients. For all patients, safety analysis demonstrated anemia (G1, n=31; G2, n=9; G3, n=1), leukocytopenia (G2, n=6), thrombocytopenia (G1, n=14; G3, n=1), and clinically insignificant renal dysfunction (G1, n=6; G2, n=3) after IA-PRRT. Compared to baseline, no severe liver dysfunction was observed. There was no severe deterioration of TER at end of the analysis. Conclusion: Intra-arterial PRRT of SSTR-expressing tumors is effective and prolongs median OS and PFS, particularly for patients with inoperable liver disease. It is well-tolerated and safe with a very low rate of severe hematotoxicity, and no severe nephro- or hepatotoxicity.

SCIENTIFIC SESSION 4: NEW RADIONUCLIDE THERAPIES / RADIATION HAZARDS/ SAFETY ISSUES

Moderators: Seigo Kinuya, Kanazawa, Japan and Kazuko Ohno, Kyoto, Japan

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O15 Boron neutron capture therapy and world’s first accelerator-based BNCT facility at Southern Tohoku General Hospital

Yoshihiro Takai ¹

Boron Neutron Capture Therapy (BNCT) is totally different from conventional radiotherapies and is a new approach to cancer treatment, which is capable of destroying cancer cells selectively. BNCT is a particle radiation therapy by α particles and recoiled ⁷Li nuclei produced by nuclear reaction of ¹⁰B atoms and thermal neutrons (¹⁰B(n,α)⁷Li). These particles have a very limited range in tissue of ≤ 9 µm, so all energy deposition occurs just inside a single cell. Therefore, BNCT is high LET particle radiotherapy in a cell with strong biological effect. Regarding indication for BNCT, there is a constraint due to physical property of low energy neutron. Because low energy neutrons can’t reach the deep site, shallow-seated tumors are indications for BNCT. As for epi-thermal neutrons, the deepest site of tumor should be within 6 cm from the surface of the skin. Basic research and clinical trials of BNCT have been conducted using research reactors so far. As far as we use reactors as neutron sources, BNCT never become real clinical treatment. There was increasing momentum to develop accelerator-based BNCT system around the world at the beginning of 2000’s. Kyoto University and Sumitomo Heavy Industries Ltd. succeeded to develop a new accelerator-based BNCT system as a collaborative research first in the world. Using the system, world’s first phase I clinical trial was performed at Kyoto University in 2012, and phase II trials on malignant glioma and head and neck cancer were started in 2016 at Southern TOHOKU BNCT research center (STBRC). Phase II clinical trials at STBRC have completed in 2018, and we are now preparing for an application for medical device and pharmaceutical examination of PMDA (Pharmaceuticals and Medical Devices Agency) to obtain the regulatory approval. The clinical application of BNCT at STBRC is expected to be a new option against cancer in 2020, and receive patients from around the world.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O16 What did we learn from the Fukushima accident?

Ohtsura Niwa ¹

Four months after the Fukushima Daiichi Nuclear Power Plant (F1) accident in 2011, I had a chance to give a talk in front of Fukushima residents. I talked science of radiation health effects learnt from the atomic bomb survivors. I was naturally thinking that the residents would be helped by the best science, but my lecture was a failure, since the audience expressed strong skepticism on my talk, quietly and politely. In order to find out why, I moved to Fukushima and lived there from 2012 - 2015, organizing a series of dialogue seminars to facilitate exchanges among and between residents, professionals including teachers, authorities, mass-media, and others from the local communities and from Tokyo. Twelve such seminars in three years taught me two important lessons; what people are suffering from and why the best science is of no help to them. The first question relates to the radiological situation to which local residents feel no way of coping, resulting in the loss of self-controllability of their life and even loss of dignity. The solution for this is by professionals to work with residents to take self-help actions and become free themselves from the trap. The second question relates to a gap between science and humanity, the former relies on an objective approach to reach conclusion while the latter relies on the subjective one when making a judgement. The solution is to fill the gap by using a common language to build a trust and respect between two parties.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O17 Regulatory nuclear safety aspects, Linear No-Threshold Hypothesis of risk from low-level radiation exposure

Bennett S Greenspan ¹

Lessons learned from Fukushima: maintain plant safety, have ability to withstand severe seismic events and/or flooding. Do not evacuate nearby residents without suspicion of high exposure.

Assumptions of LNT – Risk of radiation exposure extends down to zero, radiation damage is linearly related to exposure, LNT ignores evolutionary biology, LNT assumes radiation damage and therefore cancer risk is cumulative throughout life, LNT assumes dose rate does not matter, and LNT assumes a single mutation will lead to cancer.

However, LNT is wrong. No evidence to show increased risk below 100 mSv (10 rem), DNA repair is non-linear, repair processes at low dose are different than at high dose, radiation damage and associated cancer risk do not accumulate throughout life, and carcinogenesis requires multiple mutations and multiple deficiencies of defense mechanisms and immune system failure.

More evidence against LNT: Radiation hormesis is real, with substantial supportive evidence, including in atom bomb survivors, tuberculosis patients in Canada and Massachusetts who underwent fluoroscopy, nuclear power workers, and apartment dwellers in Taiwan exposed to contaminated steel.

More evidence against LNT – thresholds for carcinogenic effects. Everything else has thresholds. Low dose radiation is beneficial, high dose radiation is harmful; there must be a threshold between them. Known thresholds for deterministic effects. Evidence for thresholds for carcinogenesis: secondary cancers following radiation therapy, fluoroscopy patients, radium dial painters, nuclear power workers, nuclear shipyard workers, plutonium workers, atom bomb survivors, and people who live in high background areas, including Taiwan apartment dwellers.

Harm caused by LNT – unnecessary deaths at Fukushima, deaths and injuries from soil remediation of minimally contaminated soil, radiophobia – widespread public fear, patients refusing radiologic exams, opposition to building new nuclear power plants.

Conclusions: LNT is wrong, there is overwhelming supporting evidence. Radiation hormesis is real; there is substantial supporting evidence.

Thresholds of carcinogenic effects exist in addition to deterministic effects.

LNT should not be used for individual risk assessment.

LNT should not be used to justify avoiding clinically needed radiologic studies.

LNT should not be used for risk management.

Proposals:

1. A Unified Field Theory of low dose radiation exposure that all effects have a threshold. 2. A new model for radiation protection: A Linear Threshold Model, with a Threshold of 0.2 Gy (20 rem); exposure below 0.2 Gy (20 rem) is considered de minimis.

PANEL-discussion: Regulatory/ nuclear safety aspects

Moderators: Seigo Kinuya, Kazuko Ohno and Bennett S Greenspan

SCIENTIFIC SESSION 5: PROSTATE CANCER: PSMA RADIOLIGAND THERAPY (PRLT) – WHAT DO WE KNOW AND WHAT IS NEW? Moderator: Richard P. Baum, Bad Berka, Germany

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O18 Introduction to PRLT, Lu-177 Labeled PSMA Radioligand Therapy (PRLT) of Prostate Cancer (mCRPC): Long term Outcome of Precison Oncoloyg after 5 Years’ Experience at the Theranostics Center Bad Berka

Richard P Baum ¹, Harshad R Kulkarni ¹, Aviral Singh ¹, Thomas Langbein ¹, Christiane Schuchardt ¹, Jingjing Zhang ¹, Coline Lehmann ¹

Lu-177 PSMA Radioligand Therapy Between April 2013 and June 2018, PSMA radioligand therapy (PRLT) using Lu-177 PSMA-617 and Lu-177 DOTAGA PSMA I&T was performed in 330 patients with metastasized, castrate-resistant prostate cancer (mCRPC). Of 274 patients who received 1 to 11 PRLT cycles (total 824 courses) using 3.5 - 11.7 GBq (mean 6.7 GBq) of Lu-177 PSMA-617, any PSA decline was observed in 72% and the best response was biochemical complete remission (PSA=0.0 ng/ml). Decrease in PSA by >50% was seen in 53% of cases. Median progression-free survival (according to RECIST 1.1) was 9.8 months. Median overall survival (at 61 months follow-up) was 30.9 months (96 patients deceased). PRLT with Lu-177 DOTAGA PSMA I&T was performed in 56 mCRPC patients (Baum et al. 2016). In general, the patients tolerated Lu-177 PRLT treatment very well with no severe acute or long-term side effects (observation period 64 months). G3-4 hematological toxicity was observed in <5% of patients and was more frequently associated with previous chemotherapy or Ra-223 treatment. Nephrotoxicity was not observed, even if there was only a single functioning kidney present. Radiation effect on salivary gland function was assessed using dynamic salivary gland scintigraphy before and after PRLT. Using a standardized questionnaire, <5% of patients reported mild dryness of mouth, which was mostly reversible.

Targeted Alpha radioligand therapy (ART) The feasibility, toxicity and efficacy of targeted alpha radioligand therapy (ART) in end-stage, metastatic, treatment-resistant prostate cancer, having progressed under Lu-177 PSMA radioligand therapy, were evaluated in a pilot study in 10 patients with Bismuth-213 PSMA-617. Since February 2018, 28 patients have been treated with Actinium-225 PSMA-617 or with a combination of Lu-177 / Ac-225 PSMA (TANDEM Alpha-Beta PRLT). The results are extremely promising and will be presented in more detail.

Conclusions PSMA Radioligand Therapy with Lu-177-PSMA has been performed since April 2013 in 330 patients. PRLT of mCRPC is feasible, safe (especially no nephrotoxicity as noted without renal protection) and effective with appropriate selection and follow-up of patients by Ga-68 PSMA PET/CT applying the concept of Theranostics (Baum et al. 2015, Kulkarni et al. 2018).

Targeted alpha radioligand therapy using Ac-225 PSMA or TANDEM-ART appears to be extremely promising for Precision Oncology of end-stage metastatic treatment-resistant prostate cancer, progressing after castration, newer hormonal agents, chemotherapy as well as after progression under Lu-177 PRLT.

Randomized clinical trials have now started to confirm the results of this extremely promising new concept of molecular targeted radiotherapy.

Reference

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World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O19 Dosimetry following Lu-177 PSMA radioligand therapy and an insight into novel radionuclides for theranostics of prostate cancer

Aviral Singh ¹

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O20 Dosimetry in Radioligand Therapy of Metastasized Prostate Cancer Using Lu-177 PSMA I&T and Lu-177 PSMA 617

C Schuchardt ¹, A Singh ¹, HR Kulkarni ¹, T Langbein ¹, C Lehmann ¹, RP Baum ¹

Aim: The prostate-specific membrane antigen (PSMA) is significantly over expressed in prostate cancer cells compared to normal prostate tissue. The aim of our study was to determine the kinetics and dosimetry in patients undergoing PSMA radioligand therapy (PRLT) of progressive metastatic prostate cancer using Lu-177 labeled PSMA I&T and PSMA-617.

Methods: 147 patients were included in the analysis. 51 patients received 3.4 - 7.6GBq Lu-177 PSMA I&T, 96 patients were treated with 4.9 - 8GBq Lu-177 PSMA-617. The time-dependent biodistribution was determined by post-therapy SPECT/CT and whole-body scintigraphy. Dosimetric calculations were performed using OLINDA. To analyze the kinetics, median values of the following parameters were used: effective half-life and uptake represented by percentage of injected activity (%IA), which were calculated using the fit of the time-dependent activity curve to an exponential function.

Results: A higher uptake of Lu-177 PSMA-617 was found for whole-body as well as parotid and lacrimal glands. The renal uptake was higher for PSMA I&T. Despite the longer half-life of PSMA-617 in kidneys and parotid glands, the renal dose was slightly higher for PSMA I&T; and the dose to parotid glands was comparable for both PSMA ligands.

All metastases demonstrated a higher initial uptake for therapy using PSMA I&T followed by a faster wash out at later time points, which was confirmed by a longer half-life of PSMA-617. The longest half-life was determined for bone lesions when using PSMA-617, whereas the highest tumor dose was estimated for lymph node metastases in case of PSMA-617.

Conclusions: PRLT of progressive metastasized prostate cancer using Lu-177 PSMA I&T and Lu-177 PSMA-617 is safe due to the fast clearance from systemic circulation with predominant renal elimination, resulting in low mean absorbed doses delivered to the whole body and moderate dose to the kidneys. Amongst organs with physiological uptake, the highest absorbed dose was observed in the lacrimal and parotid glands, which was not associated with any adverse significant clinical symptoms. The results revealed a large inter-patient variability of the dosimetry parameters, which leads to the conclusion that individual patient dosimetry is important to realize the concept of personalized radioligand therapy.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O21 PSMA targeting and therapy trials in Australia

Andrew M Scott ¹

The use of PSMA targeted agents for imaging and therapy of cancer has been extensively studied in Australia for many years, in single site and multi-centre retrospective and prospective clinical trials.

There are currently over 20 sites in Australia which perform ⁶⁸Ga-PSMA PET studies for diagnosis of locoregional or distant metastatic prostate cancer. There are a number of multi-centre clinical trials exploring the ability of ⁶⁸Ga-PSMA to accurately stage prostate cancer. The PROPS study is an international, multi-centre, prospective trial comparing ¹⁸F-FCH PET, multi-parametric MRI and ⁶⁸Ga-PSMA PET in patients with high-risk features and biochemical failure after radical prostatectomy for prostate cancer. A total of 91 patients were recruited into this study. Recurrent prostate cancer was detected in 28% of pts with pelvic MRI, 32% with ¹⁸F-FCH PET and 42% with ⁶⁸Ga-PSMA, and management change was seen in 23% of pts with pelvic MRI, 46% with ¹⁸F-FCH PET, and ⁶⁸Ga-PSMA PET altered management in an additional 23% of pts. A separate multi-centre prospective study of 431 pts undergoing ⁶⁸Ga-PSMA PET found there to be a change in management plan in 51% of pts (J Nucl Med 2018; 59:82-88). A current prospective, randomised trial of ⁶⁸Ga-68 PSMA PET (proPSMA study) is exploring the ability of PSMA PET to impact on the staging of patients with high risk prostate cancer prior to curative intent surgery or radiotherapy. A total of 300 pts have been recruited to this trial, where ⁶⁸Ga-PSMA is being compared to conventional imaging (CT + bone scan), to establish diagnostic accuracy, management impact, and prognostic ability.

Prospective clinical trials of ¹⁷⁷Lu-PSMA in patients with metastatic castrate-resistant prostate cancer are also being conducted. A recent single-site (Peter MacCallum) study of ¹⁷⁷Lu-PSMA (LuPSMA study) in 43 pts with metastatic castration-resistant prostate cancer showed objective response in nodal or visceral disease was seen in 82% of pts with measurable disease, and reduction in pain scores (Lancet Oncol 2018; 19(6):825-833). A prospective, randomised, multi-centre, Phase 2 trial of ¹⁷⁷Lu-PSMA vs carbazitaxel is currently recruiting pts, aiming to compare the safety and activity of ¹⁷⁷Lu-PSMA vs carbazitaxel in 200 pts with metastatic castration-resistant prostate cancer. These studies aim to generate evidence supporting ¹⁷⁷Lu-PSMA in metastatic prostate cancer patients for regulatory approval.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O22 Ac-225- and Bi-213- PSMA-617 radioligand therapy in patients with castration resistant prostate cancer

Mike Sathekge ¹

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O23 [¹⁸F]AIF-PSMA-HBED-CC and ¹⁷⁷Lu-PSMA-617 as a potential theragnostic tandem and comparison with 68Ga-PSMA-HBED-CC in high-risk prostate cancer patients at initial staging

A novel tracer: [18F]AIF-PSMA-HBED-CC (18F-ALF-PSMA-11), was produced in our Centre, with suitable radiochemical purity for clinical purposes. The aim of the study was to compare the biodistribution of 18F-ALF-PSMA-11 and 177Lu-PSMA-617 at first cycle of therapy in two patients with metastatic prostate cancer. Additionally, we compared image quality and detection performance of 18F-ALF-PSMA-11 and 68Ga-PSMA-11 in a sample of high-risk prostate cancer patients at initial staging. We analysed two patients who underwent 18F-ALF-PSMA-11 PET/CT. After two weeks they were treated with 6.0 GBq of 177Lu-PSMA-617. Post-therapy SPECT/CT images were performed after 48 hours. We also enrolled 28 patients (median age: 63 years) imaged with both 68Ga-PSMA-11 and 18F-ALF-PSMA-11 PET/CT within a time window of 1-2 weeks, 60 minutes after the i.v. administration of 2.0 and 4.0 MBq/kg, respectively. All patients had high-risk prostate cancer. We measured the SUVmax in all abnormal foci and the SUVmax ratio (SR) in all coincident lesions, defined as SUVmax lesion/SUVmax background. The uptake in lesions and normal organs was very similar for 18F-ALF-PSMA-11 and 177Lu-PSMA-617 in both patients. 18F-ALF-PSMA-11 and 68Ga-PSMA-11 PET/CT demonstrated abnormal findings in 26 and 25 patients (93% and 89%), respectively. Images of 18F-ALF-PSMA-11 were of high visual quality. Moreover, 11/28 patients (39%) had evidence of metastatic disease. For concordant lesions (n=79), we did not find a significantly different SR for both tracers. 18F-ALF-PSMA-11 and 177Lu-PSMA-617 seem to be a potential theragnostic tandem. Besides, 18F-ALF-PSMA-11 PET/CT is a promising imaging technique for the evaluation of prostate cancer patients at initial staging.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

DAY 3, TUESDAY, NOVEMBER 20, 2018: SCIENTIFIC SESSION 6: THYROID CANCER – QUO VADIS?

Mark Tulchinsky ¹

Debating Controversies in Radioiodine Imaging and Therapy of Thyroid Cancer

World Association of Radiopharmaceutical and Molecular Therapy Proclamation

WHEREAS, Theragnostics (Theranostics) is a technique of sequential application of an identical or a biosimilar diagnostic followed by a therapeutic radiopharmaceuticals; and

WHEREAS, the diagnostic radiopharmaceutical, or a biosimilar radiopharmaceutical, is administered for the purpose of qualitative and/or quantitative diagnostic study of its avidity to the diseased tissue or organ, as well as to determine extent and the nature of the disease (e.g. tumor staging, cause of hyperthyroidism, etc.); and

WHEREAS, an adequate avidity of a said diagnostic radiopharmaceutical would represent the formative principle that shall inform the decisions involved in establishing the goals and conditions of the subsequent identical or biosimilar radiopharmaceutical therapy; and

WHEREAS, other clinical, biochemical and imaging information should be considered contributory to the therapeutic goal definition and therapy planning; and

WHEREAS, radioactive iodide is the first and the most enduring theragnostic radiopharmaceutical;

NOW, THEREFORE, the World Association of Radiopharmaceutical and Molecular Therapy, does hereby proclaims March 31^st, 1941 as

The Birthday of Theragnostics (Theranostics) throughout the world to encourage all people to become familiar with the benefits offered by this lifesaving therapeutic modality that is expanding to offer relief from increasing numbers of diseases and health conditions;

FURHTERMORE, the World Association of Radiopharmaceutical and Molecular Therapy, does hereby proclaims March 31^st as

The World Theragnostics (Theranostics) Day throughout the world to celebrate the lives made better by this therapeutic modality and to commemorate Dr. Saul Hertz who conceived of using the first theragnostic agent, radioactive iodide, and personally led its development from the research laboratory to the initial clinical trial on his brave patients who volunteered to undergo the experimental therapy.

IN TESTIMONY WHEREOF, we have hereunto set our hands at the 2018 International Symposium on Radiopharmaceutical Therapy held in the City of Helsinki the twentieth day of November in the year 2018.

Professor Irene Virgolini, The President of WARMTH Professor Kalevi Kairemo, The President of ISRT-2018 Professor Mark Tulchinsky, The Session Organizer

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O24 Introduction-thyroid cancer management

Mark Tulchinsky ¹

Thyroglobulin-Optimized Neck Ultrasound in Post Radioactive Iodine Therapy Surveillance for Recurrence of Differentiated Thyroid Cancer, Presenting Author: Mark Tulchinsky,Section of Nuclear Medicine, Department of Radiology, Penn State Health, Hershey, PA, USA; Corresponding Author: Alfredo Campennì, Nuclear Medicine Unit, Department of Biomedical and Dental Sciences and Morpho-Functional Imaging, University of Messina, Messina, Italy.

Paper Summary: We report on retrospective analysis of 230 patients with differentiated thyroid cancer (DTC) after radioactive iodine treatment (RAIT) who were regularly followed from January 2011 to December 2013 with clinical examination, basal and stimulated thyroglobulin (Tg) panel, neck ultrasound (NUS) and diagnostic radioactive iodine whole body scintigraphy (RAI-WBS), as well as other diagnostic procedures, as needed. The patients were selected based on normal anti-thyroglobulin antibody levels in order to assure bona fide thyroglobulin (Tg) results.

A total of 805 NUS were performed. There were 599 true-negative, 54 true-positive, 125 false-positive, and 27 false-negative. Hence, surveillance NUS had 66.6% sensitivity, 82.7% specificity, 30.2% positive and 95.7% negative predictive value. The false-positive NUS occurred in total of 41 patients (29 and 12 were classified as low and high risk based on 2006 European Consensus, respectively). In all of the false-positive results the Tg was < 1 µg/L at either on-replacement baseline and/or stimulated. None of the patients in true-positive or false-negative groups had Tg < 1 µg/L.

Conclusion: In post-RAIT surveillance, combination of positive NUS with bona fide Tg of < 1 µg/L is most likely a false-positive result. Consequently, NUS is not useful in DTC surveillance when Tg < 1 µg/L.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O25 Total vs. subtotal thyroidectomy. East, West, what´s the best?

Ilya V Sleptsov ¹

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O26 Dosimetric approach of thyroid cancer

Henry Bom ¹

The ideal protocol of radioactive iodine (RAI) therapy of differentiated thyroid cancer is to administer RAI the lowest possible dose which gives a lethal dose of radiation to all remnant thyroid tissue while minimizing possible side effects. The optimum individualized therapy can be done only by dosimetric approaches which include bone marrow (BM) and lesion-based dosimetry. BM dose can be calculated by two compartments, blood and whole body, which can be measured by serial blood sampling and whole body counting, respectively. The maximum tolerated dose to BM is considered as 2 Gy. The lesion dose (LD) can be measured by RAI clearance from the thyroid remnant or metastatic lesions. The threshold doses are considered as 300 Gy and 80 Gy, respectively. Small dose of I-131 and recently a positron emitter I-124 can be used to measure LD.

The absorbed dose to thyroid bed remnants and to whole body measured by RAI whole body scan based dosimetry usually shows a wide range. It is associated with the absorbed dose rate to thyroid bed remnants, the cumulated activity and the maximum RAI uptake in thyroid bed remnants, higher risk clinical findings such as extrathyroidal extension and higher AJCC class as well as serum thyroglobulin level. The ablation is usually very successful despite the wide range of absorbed dose to the thyroid be remnant and whole body. Patients treated by rhTSH show faster clearance of RAI than thyroid hormone withdrawal group. Usually dosimetry-based approach gives higher doses to patients and results in higher remission rates but also higher side effects including transient cytopenia after RAIT.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O27 Management of I¹³¹ refractory thyroid cancer : a multimodality approach

Partha S Choudhury ¹

Differentiated Thyroid Cancer (DTC) is best treated with the use of initial thyroidectomy followed by radio-iodine therapy (RAI). In a metastatic setting RAI can also be effectively used for treatment when the sodium iodide symporter (NIS) are intact leading to cure in a significant number of patients. NIS is found to be expressed more in differentiated thyroid cancer tissue and is usually negative in poorly differentiated tissues like in oxyphilic change and anaplastic transformation. GLUT -1 expression was more observed in NIS negative cases and vice versa leading to the concept of personalized treatment by the theranostic approach. NIS expression may also be helpful in predicting response and enhance patient management. The aggressive variety of thyroid cancers generally over express other receptors like GLUT, GLUT1, hexokinase 1 or HIF-1^α with or without NIS. RAI refractory DTC is best imaged by Positron Emission Tomography-Computed Tomography (PET-CT) either with ¹⁸F FDG or more recently with ⁶⁸Ga labelled DOTA compounds. RAI refractory DTC needs a multimodality approach of treatment depending on the site and volume of disease or whether there are NIS expression at some sites or such expression is totally absent. Therefore the treatment can be local or systemic or a combination of both. Many genetic alterations have been seen in the molecular pathogenesis of DTC, most commonly RET/PTC translocations and BRAFV600E point mutations in PTC and RAS point mutations in FTC & poorly DTC. Elevated expression of vascular endothelial growth factor (VGEF) and its receptors (VGEFR) may play a role in thyroid carcinoma. Studies of the tumor biology of DTC has led to the development of targeted therapies based on the theranostic concepts. Currently based on the findings of multicentre, randomized, double blind placebo controlled phase III studies, two agents, Sorafenib and Lenvatinib has been approved in US and Europe for the treatment of this group of thyroid cancer. The DECISION & SELECT trials showed that Sorafenib & Lenvatinib has significant benefit in terms of progression free survival over placebo. Patients of RAI refractory disease a negative RAI scan and a positive FDG PET-CT scan are the candidates for this treatment and FDG PET can also be used for objective response evaluation by PERCIST. So far these drugs have shown promising results in terms of disease control , regression or stable disease. It must be however remembered that these agents are associated with side effects most commonly being hand / foot skin reactions, rash, fatigue, mucositis, hypertension diarrhoea, ECG changes and weight loss. The severity of the symptoms of side effects and the potential benefit needs to be critically evaluated before starting this form of treatment.

PTC with BRAF mutations are associated with significantly reduced expression of genes involved in the metabolism of iodine, including genes for NIS, Tg & thyroperoxidase (TPO). On the other hand BRAF mutated tumors exhibit higher GLUT-1 receptors levels. These play an important part in the tumor dedifferentiation reducing efficacy of RAI . Another treatment option which has been recently proposed for RAI refractory thyroid cancer is peptide receptor radionuclide therapy (PRRT) based on the theranostic concept. PRRT is a unique way of targeting somatostatin receptors over expression on tumor cells in many cancer including thyroid. At this point of time and with the available literature PRRT shows variable results in the form of partial remission or stable disease in approx. 50% of the treated patients. However the currently available results cannot be treated as sufficient evidence for recommending this form of treatment in iodine refractory DTC. Further long term studies will be needed before PRRT can be established as an option in the treatment of RAI refractory metastatic DTC. In this presentation the investigational and therapeutic approach in a patient of RAI refractory DTC will be discussed.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O28 Prevalence of Genetic Duet and its influence on the prognosis of Differentiated Papillary Thyroid Carcinoma

Sanjana Ballal ¹, Sandeep Mathur# ¹, Sunil Shakya ¹, C S Bal ¹

Objective: The primary objective of the study was to investigate the prevalence of BRAFV600E and TERT promoter mutations in papillary thyroid cancer and secondary objective was their correlation with various clinicopathologic features in Indian population. Methods: A retrospective study of 160 pathologically proven papillary thyroid cancer patients including 105 women and 55 men with a median age of 35 years (13 –77) was conducted in the department of Nuclear Medicine, AIIMS, New Delhi, India. The study period was from the year 2008 to 2016 with a mean follow-up of 32.7 months (12-101 months). Univariate and multivariate analysis was performed to determine the association of BRAFV600E and TERT promoter with clinicopathologic features. Prognostic factors affecting the event-free survival were analyzed by Kaplan-Meier curves. Results: The prevalence of BRAFV600E mutation was in 33 % (53/160) and TERT mutation in 17.5% (28/160) of patients. Both mutations (genetic duet) were co-existent in 19 (11.8%) of patients. No mutation (wild type) was detected in 98/160 (61.3%) PTC patients. Interestingly, no mutation was detected in follicular variant of PTC (0/28) compared to 40% in classic PTC. Prognosis: Compared to wild type, BRAFV600E alone or TERT alone showed significant associated with extrathyroidal extension (P=0.030), radioiodine (RAI) refractory persistent disease (P=0.0393) until end of follow-up (P=0.017). Patients with co-existing mutations were significantly associated with poorer outcome. Kaplan-Meir Graph depicts the association of wild-type versus various mutations with event-free-survival. Conclusion: Patients with co-existing BRAFV600E and TERT mutations showed the worst clinicopathologic outcomes. The detection of these mutations paves path for the early treatment of RAI refractory disease patients with alternate therapeutic options.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O29 Comments -thyroid cancer management

Raihan Hussain ¹

Frankly speaking I am here to share a few comments on Thyroid cancer management. This is not a typical scientific abstract and I would like to begin with a story. I was then a young doctor and recently joined at the Institute of Nuclear Medicine in Dhaka. One day I was busy with taking history of thyroid cancer patients. Suddenly I noticed a very senior and renowned Professor of Internal Medicine having special interest and vast knowledge on Thyroid was standing behind the patient and listening carefully. I became surprised and embarrassed and gently asked him “Sir, anything wrong?” Because I felt why he would be here and his presence was beyond my imagination. He replied, “After all these years of experience, studies and researches I have come to conclusion that I know Nothing about thyroid. More I dig in, more I get confused. So I try to explore wherever possible to learn and find the answers.”

Still now we are looking for answers. That is why we are here. Of course in Medical Sciences there will be difference of opinion. But it has to be reasonable, rational and to be supported by scientific data. Prominent speakers have highlighted the important aspects of radioiodine therapy for thyroid cancer. It is very difficult to standardized a uniform regimen because of different regulations, protocols, disease pattern, socioeconomic factors among the different countries. In Bangladesh we follow our own Guidelines of Society of Nuclear Medicine, Bangladesh to suite our own situations. It has been published in the Bangladesh Journal of Nuclear Medicine (https://www.banglajol.info/index.php/BJNM/article/viewFile/34943/23564).

There are many questions regarding dose, regimen, use of thyrogen, role of radioiodine in anaplastic or medullary carcinoma etc. There are still apathy regarding radioactive substances not only from certain patients but also from certain clinicians. We believe it is high time that we need to find out acceptable solution. During the panel discussion followed by this, I hope there would be more fruitful discussions and we all will be enlightened.

Panel discussion: Moderator Mark Tulchinsky

“Radioiodine Imaging Before, After, Both or Neither … and How?”

“Controversies in Radioiodine Side-Effects: Confusion About Salivary Damage and Secondary Malignancy”

SCIENTIFIC SESSION 7: PEPTIDE RECEPTOR/ NEW THERAPIES

Moderator: Irene Virgolini, Innsbruck, Austria

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O30 Value of FDG in NET: importance of dual tracer imaging

Margarida Rodrigues Radischat ¹

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O31 Value of Re-PRRT in NET

Anna Yordanova ¹

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O32 PRRT in G3 neuroendocrine neoplasm

Aviral Singh ¹

Aim: There are limited clinical studies on PRRT of G3 neuroendocrine neoplasms (NEN). The NORDIC NEC study reported that patients with Ki-67 <55% were less responsive to platinum-based chemotherapy. Therefore, this study analyses the long-term outcome, efficacy and safety of PRRT in patients with SSTR-expressing G3 NEN.

Methods: Sixty-nine patients received PRRT with lutetium-177 and/or yttium-90 labeled somatostatin analogs. Progression-free survival (PFS) and overall survival (OS), defined from start of PRRT, was performed using Kaplan–Meier analysis. A subgroup analysis of survival for patients with Ki-67 of ≤55% and >55%, as well as FDG-avidity on PET was also performed. Response to therapy was evaluated using RECIST 1.1 and EORTC. PRRT associated toxicity was assessed according to CTCAE v5.0.

Results: Primary tumor entities included in this study comprised of G3 pancreatic (n=46), CUP (n=11), midgut (n=6), gastric (n=3), and rectal (n=3) NEN. For the entire cohort, the median follow-up was 94.3 months, median PFS was 9.6 months and median OS was 19.9 months. In the subgroup analysis, patients with Ki-67 ≤55% (n=53) had a median PFS of 11 months and median OS of 22 months; whereas, patients with Ki-67 >55% (n=11) had a median PFS of 4 months and a median OS of 7 months. Patients with positive SSTR imaging but no FDG uptake, had a median PFS of 24 months and median OS of 42 months. In the FDG-avid group, patients with grade of 3-4 uptake had a median PFS of 7.1 months and median OS of 17.2 months. For FDG scored as 0-2, the median PFS was 24.3 months and the median OS was 41.6 months. Safety analysis showed no grade 3/4 hematotoxicity, as well as no clinically significant deterioration of renal function.

Conclusion: PRRT in G3 NEN is efficacious with promising clinical outcomes, especially in patients with Ki-67 of ≤55%, even after failure of chemotherapy. It was well tolerated without significant adverse effects. Baseline PET/CT imaging with FDG along with SSTR-analog is beneficial both for patient selection for PRRT as well as for prognosis following therapy.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O33 New peptides for PRRT in Non-NETs

Irene Virgolini ¹

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O34 Long-term side effects and quality of life, patients view

Josh Mailman ¹

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O35 A correlation between c-Fos expression and radioiodine in breast cancer cell lines

Aisyah Elliyanti ¹, VY Susilo ², S Setiyowati ², Martalena Ramli ², Johan S Masjhur ³

When ionizing radiation hits water molecules in the cell, water will be degraded to produce free radicals. Free radicals inhibit the switch from c-Fos to Fra1 in chromatin. This inhibition will lead to the failure in cells to express cyclin D1, which then followed by cell cycle arrest. The aim of this study is to investigate the correlation between c-Fos with radioiodine effect in breast cancer cell lines.

Breast cancer cell lines (MCF7 and SKBR3), and keratinocyte cell line (HaCaT) were used in this study. To induce c-Fos expression, cells were treated with epidermal growth factor (EGF) 50ng/ml, Adenosine tri-phosphate (ATP) 100µM and a combination of both. Radioiodine effect was measured by reproductive ability of the cells after which they had been treated with 74.10⁴ Becquerel/well of NaI-131. A Quantitative Real-time reverse transcriptase polymerase chain reaction (qRT-PCR) and Immunocytofluoresence were used to assess c-Fos expressions.

In this study, c-Fos expressions are found only in MCF-7 cells. A combination of ATP and EGF has a potential to induce 22.74 ±3.67 fold (p<0.05) of c-Fos mRNA. Adenosine tri-phosphate or EGF or combination of both increases c-Fos protein expression (p<0.05). Induction of EGF or a combination of ATP and EGF reduces the reproductive ability of MCF-7 and SKBR3 cells up to 100% after radioiodine treatment (p<0.05). We find an inverse correlation between c-Fos mRNA and protein expressions with radioiodine effect as follow r = - 0.90 and r = - 0.97 (p<0.05) respectively.

There is an inverse correlation between the expressions of c-Fos with the radioiodine effect. It appears that radioiodine is able to reduce the reproductive ability of breast cancer cells and open an opportunity for radioiodine to be used for breast cancer treatment. C-Fos is seen to be involved in cell death pathways by radioiodine exposure in MCF7 cells, and other genes may correspond to cell death in SKBR3 cells.

SCIENTIFIC SESSION 8: NEW ALPHA- THERAPIES

Moderators: Oyvind Bruland, Oslo, Norway and Roy Larsen, Oslo, Norway

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O36 Predicting the future of Alpha: clinical indications and radioisotopes of choice?

Jean-François Chatal ¹

The clinical interest in alpha-emitting radionuclides for therapy stems from the highly cytotoxic effect of alpha particles due to their high linear energy transfer (LET) and an irradiation path length of less than 100 µm. This is in comparison with lower-energy electrons of β-emitting radioisotopes with a path length of a few mm, resulting in higher radiation exposure to normal tissue and (in theory) less effective tumour cell killing effect. As such, it is postulated that alpha therapy is more efficient and less toxic than conventional therapy using β-emitting radionuclides. In an era of evidence-based medicine, this advantage has yet to be fully demonstrated in meaningful clinical trials, however a number of early-stage clinical studies demonstrate tantalizing results.

Given the radio-physical characteristics of alpha-emitters, the most likely clinical application is the treatment of microscopic disease, benifiting of the very short path length of alpha particles. However, clinical efficacy has also been demonstrated in advanced metastatic disease, for example in metastatic prostate cancer, likely due to accessible and well-perfused boney lesions. Route of administration may also matter for alpha therapy and in addition to systemic administration, intracavitary routes such as intrathecal or intravesical delivery may also be attractive. For example, BCG-resistant bladder cancer could be an attractive medical application for alpha-therapy where lesions would be rapidly accessible to intravesical instillation and the irradiation profile of alpha particles would be a good fit with the typically superficial extent of disease.

At present, less than ten alpha-emitting nuclides are serious contenders for routine clinical use, with really only four in active clinical evaluation. Each radionuclide has significant advantages and disadvantages. Arguably,²²⁵Ac is the front-runner with a half-life of approximately 10 days, supportive of centralized production. Actinium can also be used with conventional conjugation chemistry, similar to that of ¹⁷⁷Lu and ⁶⁸Ga, and therefore is potentially able to be “theranostic”. However, production is non-trivial, with three different routes, each with their own limitations including technically difficult production conditions, limited material access, contamination with other radionuclides and significant waste management issues. Additionally, very little work has been done on the potential health impact and dosimetry of daughter nuclides, a potentially clinically significant issue.²¹³Bi is available as a decay product from an ²²⁵Ac generator and also has straightforward conjugation chemistry. However, the half-life is short and it suffers from the same availability issues as actinium. In contrast,²¹¹At is easily produced using mid-energy cyclotrons or linear accelerators, and has an appealing decay profile. Astatine chemistry is generally similarly to ¹²³I or ¹²⁴I, and therefore also potentially supportive of “theranostic” strategies. However astatine’s half-life of 7.2 hours presents a significant commercial challenge in that networks of production facilities would be required to deliver meaningful scale-up. Finally,²¹²Bi (half-life 60.55 minutes) is available from a ²²⁴Ra generator (half-life of 3.6 days), in turn derived from ²³²Th. The concept is to use ²¹²Pb which decays to ²¹² Bi as an “in vivo generator” with a beneficial half-life of 10.64 h. However, controlling this radiation modality is difficult and current availability is limited.

On the balance of characteristics, we postulate that the battle for alpha therapy supremacy will be between ²²⁵Ac and ²¹¹At. Both have strengths and weaknesses but for the right clinical applications, both could be commercially scaled with significant benefit for patients.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O37 Radiometabolic therapy with ²²³Ra-dichloride: the European Institute of Oncology experience

Chiara Maria Grana ¹, Colandrea M ¹, Baio SM ¹, Fracassi SL ¹, Gilardi L ¹, Travaini LL ¹, Rocca PA ¹, Cossu Rocca M ¹, Verri E ¹

Introduction: 223Ra-dichloride is a consolidated and approved treatment for bone metastases from castration resistant prostate cancer (mCRPC). Its chemical affinity with calcium and the high dose delivered, make Ra-223 dichloride a relevant radiopharmaceutical for targeting areas of increased bone turnover.Aim: To present an update of the IEO experience with 223Ra-dichloride in the treatment of patients with mCRPCMethods:The treatment was proposed to twenty progressive and symptomatic patients with multiple bone metastases without involvement of any other organ (median age 68 yrs, medium PSA 109 ng/mL); at present 11 pts completed the treatment receiving 223Ra-dichloride 50-55 kBq/kg i.v./28 days for 6 cycles.2 pts are in treatment; 3 pts were enrolled but did not started due to rapid progression of disease; 3 pts interrupted the therapy as other diseases occurred and 1 pts for rapid PD. Pretreatment evaluation was performed with CT scan and bone scan. Two patients were also evaluated with Choline-PET. Patients have been evaluated at every cycle with complete blood chemistry and pain scale and QoL evaluations. A multidisciplinary team followed patients during both screening and treatment period. Results: So far our patients received 84 cycles of 223Ra-dichloride.No problems in vial manipulation, dose preparation, administration and radiation protection issues occurred. Therapy was well tolerated in all patients and none presented acute side effects. No cycles were delayed due to blood toxicity. Eleven patients have already completed therapy: transient G1 anemia and G1 thrombocytopenia were the most common side-effects; no significant long-term hematologic toxicity. Most of patients had bone pain relief and reduced pain drugs intake, also during the treatment. Only one patient experienced significative flare effect. No patient presented anorexia; only one case of diarrhea was observed during the first 4 cycles.Biomarker responses are under evaluation. So far, bone scan was performed in 8 pts and showed a stable disease in 4 pts; a decrease in number and intensities of uptakes in 3 pts; bone scan progression was present in 1 pt.CT or MRI showed a PD in 4 pt; stable disease in 3 pts and was doubtful in 1 pts.Conclusion: our experience shows the feasibility of radiometabolic therapy with 223Radium-dichloride in patients with mCRPC in a multidisciplinary team. Palliative effect allows decreasing pain drugs consume with a mild toxicity profile. We are planning to give an update in terms of PFS and OS during the Congress.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O38 Ra-223 in osteosarcoma –Ph I-trial

Vivek Subbiah ¹

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O39 Ra-224 labelled biodegradable carbonate microparticles (Radspherin^R) to combate microscopical residual peritoneal carcinomatosis

T Bønsdorff ¹, E Napoli ¹, I S Jorstad ¹, S Westrøm ¹, Ø S Bruland ², R H Larsen ³

Radium-224 (²²⁴Ra) labelled calcium carbonate (CaCO₃) microparticles have been developed with the intent to treat micrometastases located in the abdominal cavity by intra peritoneal (IP) administration following cytoreductive surgery. The microparticles act as carriers for the α-emitter ²²⁴Ra. This novel α- therapy has a short range of action in tissue and is designed to confine the radiation exposure to the IP cavity, treating both serosal linings of the peritoneal surfaces and liquid volumes. The main function of the microparticle component of ²²⁴Ra-CaCO₃ is to retain the radionuclides in the peritoneal cavity. The particles themselves are too big to escape from the peritoneum, while free ²²⁴Ra and daughter radionuclides to some extent will leak and distribute to extraperitoneal tissues. Due to the bone-seeking property of ²²⁴Ra, the level of release of ²²⁴Ra from the radiolabelled particles in vivo can be determined by measurement of the skeletal uptake of ²²⁴Ra. Here we compare data from an in vitro model of the in vivo retention of radionuclides across the peritoneum with biodistribution data from femur of mice. The effect of varying the microparticle amount on ²²⁴Ra retention has been examined. Release and retention properties of ²²⁴Ra and ²¹²Pb from the microparticles were evaluated in relation to product stability. Furthermore, the therapeutic efficacy of IP injected ²²⁴Ra-microparticles was examined both in an aggressive ascites presenting murine xenograft and in an immunocompetent mouse model of ovarian cancer. Phase 1 clinical studies are planned.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

O40 “Dual-alpha” - an expanding technology for development of targeted alpha therapies

Asta Juzeniene ¹, Vilde Yuli Stenberg ², Øyvind Sverre Bruland ^3,⁴, Roy Hartvig Larsen ^1,^2,⁵

Metastases in bones, lymph nodes and lungs are common challenges among oncology patients (e.g. breast cancer, prostate cancer, osteosarcoma) and are the primary cause of death. Efficacious new treatment options are sorely needed. Alpha-particle emitting radionuclides being highly cytotoxic may fulfil this critical need. We present a novel technology with potentially broad therapeutic applications for cancer micrometastases by means of dual targeted alpha particle radiation. The treatment involves administration of a bone-seeking, alpha-particle emitting radionuclide ²²⁴Ra and its daughter radionuclide ²¹²Pb solution containing chelator-labelled new and existing molecular ligands and tumour-associated monoclonal antibodies (mAb) as carriers for the daughter radionuclide (patents US9433690 B1 and EP 3 061 464 A1). Pb-212 is a source of highly cytotoxic alpha particles via its decay to ²¹²Bi daughter.

Epidermal growth-factor receptor (EGFR) is overexpressed in cancers of colon (25–77%), breast (14–91%), prostate (40–80%), osteosarcoma (50-90%) and ovary (35–70%). For this reason EGFR is an attractive candidate for “Dual-alpha” targeted therapy. Cetuximab is a chimeric mAb targeting EGFR. The potential of cetuximab chelated by TCMC as a vehicle for the delivery of ²¹²Pb was investigated both in vitro and in vivo. The effectiveness of ²²⁴Ra-solution with chelator-labelled cetuximab was investigated against LNCaP spheroids, which is an in vitro model for micrometastatic cancer. Ra-224-solution with cetuximab effectively stopped growth of LNCaP spheroids relative to the equivalent dose of ²²⁴Ra-solution alone. The anti-cancer effect of ²²⁴Ra-solution with cetuximab was also investigated in athymic mice with MDA-MB-231-Luc breast cancer metastasis. “Dual-alpha” extended survival (57 days) compared to the control group (35 days).

TP-3 mAb recognizes an antigen expressed on the surface of osteosarcoma cells. Spheroid models of osteosarcoma were used to evaluate feasibility of using “dual-alpha” to target micrometastatic clusters. Our preliminary results show that the cytotoxic effect of ²²⁴Ra-solution with mAb TP-3 was significantly higher than that of ²²⁴Ra alone.

The bone-seeking EDTMP (ethylenediamine tetra(methylene phosphonic acid)) added to ²²⁴Ra solution also targets the daughter radionuclide ²¹²Pb to bones. We demonstrate that a single dose of ²²⁴Ra-solution with EDTMP prolongs survival time and lowers incidence of paralysis and bone metastases in nude mice with breast cancer micrometastases. Ra-224 solution containing EDTMP-chelated ²¹²Pb is a promising candidate for the treatment of cancer patients with bone metastases.

The preliminary studies provide conceptual and strong evidence that dual alpha ²²⁴Ra-solution with bone or tumour-targeted delivery of ²¹²Pb has potential to inhibit cancer metastases without significant toxicity.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

SCIENTIFIC SESSION 9: FUTURE ASPECTS OF COLLABORATION OF WARMTH, IAEA AND WFNMB – ROUND TABLE DISCUSSION: P1 The quantitative analysis of post-selective internal radiation therapy (SIRT)⁹⁰Y microspheres PET/CT in hepatocellular carcinoma in comparison with ^99mTc-labelled macroaggregated albumin (MAA) planar and SPECT/CT

Ngoc Ha Le ¹, Mai HS ¹, Nguyen DK ¹

⁹⁰Y microspheres are recommended for intra-arterial treatment of hepatocellular carcinoma. Before treatment,^99mTc-labelled macroaggregated albumin (MAA) is injected intra-arterially to simulate the treatment and ⁹⁰Y PET/CT imaging is performed to evaluate post-treatment. The aim of the study is to assess the correlation between the pretreatment 99mTc-MAA planar and SPECT/CT with post-treatment ⁹⁰Y PET/CT images. Methods: Twenty patients with the intermediate and advanced stage HCC were reviewed in this study.^99mTc-MAA was injected intra-arterially before treatment, planar scintigraphy and SPECT/CT were done after 60 minutes. Post-injection of ⁹⁰Y microspheres (SIRTEX, Australia), the patients underwent post-treatment 90Y PET/CT within six hours. Tumor to normal ratios (T/N ratios) and liver lung shunting fraction (LSF) on ^99mTc-MAA planar, SPECT/CT and ⁹⁰Y PET/CT images were analyzed and correlated using Spearman rank correlation test. Results: In 20 patients, the distribution of microspheres was more consistently demonstrated between 99mTc-MAA SPECT/CT and ⁹⁰Y PET/CT images than when compared with planar imaging. A strong correlation was observed between T/N on ^99mTc-MAA SPECT/CT before treatment and T/N on ⁹⁰Y PET/CT images after treatment (rho value=0.738 p<0.001). The correlation of LSF on ⁹⁰Y PET/CT and ^99mTc-MAA SPECT/CT (rho=0.471, p=0.05) was higher than the correlation between PET/CT and planar imaging (rho=0.178, p>0,05). Conclusions: The ^99mTc-MAA SPECT/CT showed the better distribution and correlation with ⁹⁰Y PET/CT than planar imaging. Furthermore,⁹⁰Y PET/CT could be a powerful evaluation tool which should be included routinely in the post-therapeutic protocol.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

P2 Establishment of incident reporting programme and lesson learnt in unsealed radionuclide therapy

Noreen Marwat ¹

Introduction: Radionuclide therapy is an important part of nuclear medicine department. There are always few risks associated to this that it may seriously harm the patient in case of a wrongly performed treatment or it can cause an exposure to general public or staff if not well briefed. Establishing an Incident learning programme in Nuclear Medicine department and to successfully implement it. Benefit of this programme is to make it a trust worthy practice and dedicate a team which document, analayze and extract lesson learnt for future practices from this incident reporting programme.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

P3 Practices across Pakistan how medical emergency is handled in case of patients who has undergone unsealed radionuclide therapy

Noreen Marwat ¹

This paper highlights the practices and procedures that are being adopted by different Nuclear Medicine Centres across Pakistan when they come across Medical Emergency in case of Patients who has taken Radionuclide therapy. who are the people they report to, how the manage Medical Emergency. what improvement and suggestion can be incorporated. How well they are prepared if a Patient who is being administered Radionuclide for therapy purpose and Patient dies with Radioactivity still present within the Patient.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

P4 ¹⁷⁷Lutetium-Prostate-specific Membrane Antigen Radionuclide Treatment of Lymph Node Metastatic Prostate Cancer with PSA Recurrence: A Cohort Study

Finn Edler von Eyben* ^a, Aviral Singh* ^b, Jingjing Zhang ^b, Karin Nipsch ^b, Danielle Meyrick ^c, Nat Lenzo ^d, Kalevi Kairemo ^e, Timo Joensuu ^e, Irene Virgolini ^f, Cigdem Soydal ^g, Harshad R Kulkarni# ^b, Richard P Baum# ^b

Context:¹⁷⁷Lutetium [¹⁷⁷Lu]-prostate specific membrane antigen radionuclide treatment (LuPSMA) is mainly used as an investigational, but safe and effective treatment of patients with end stage prostate cancer.

Objectives: The study aimed to analyze how patients with lymph node metastases (LNM) responded to LuPSMA treatment.

Methods: The study is a multicenter single-arm open labelled cohort study. The patients had PSA recurrence. On pretreatment⁶⁸Ga-PSMA PET/CT scans, 35 patients had LNM and ten had LNM and 1 or 2 bone metastases. LuPSMA was given in cycles at 8 weeks intervals with median 6 GBq per cycle.

Results: Six centers enrolled consecutively 45 patients between December 11, 2013, and October 17, 2017. Pretreatment prostate specific antigen (PSA) was median 18 µg/l (interquartile range (IQR): 3.3-39). LuPSMA was given with median 3 cycles and a cumulative¹⁷⁷Lu activity of median 14.5 GBq (IQR: 12.2-19.7). Best PSA response was median 91% (IQR: 70-99). The centers followed the patients until June 20, or September 20, 2018. PSA progression-free survival was median 12 mo. LuPSMA gave mild and transitory adverse effects.

Conclusions: LuPSMA was an effective and safe treatment of patients with predominant LNM. The finding is a caveat to a present recommendation that only patients with end-stage prostate cancer should be treated with LuPSMA.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

P5 Dosimetry in Molecular Radiotherapy - Bad Berka Experience

Christiane Schuchardt ¹, Richard P Baum ¹

Aim: Calculating the absorbed dose is important for the determination of risk and therapeutic benefit of internal radiation therapy. Optimal dose estimations require time-consuming and sophisticated methods, which are difficult due to practical reasons. To make dosimetry available for each of the patients, we developed a specific dosimetry procedure used in daily clinical routine.

Methods: Dosimetry is performed according to the MIRD-scheme and adapted to the special conditions at our department. The so-called “Bad Berka Dose Protocol” is a hybrid dosimetry concept using the combination of planar whole body scintigraphy and quantitative SPECT/CT imaging. The biodistribution is determined by whole-body scintigraphy and the SPECT/CT is used for activity calibration. The cumulated activity is calculated using the fit of the time-activity curve to a mono- or biexponential function. In the last step, mean absorbed organ and tumor doses are estimated using the software OLINDA 2.0. Results: We found a compromise between the calculation model (given by the MIRD-scheme) and practical conditions. It has ensured dose estimation in daily clinical routine with a reasonable effort and within acceptable time. In consequence, the dosimetry method developed for Bad Berka allows each of our patients to undergo dosimetry after therapy using Lu-177 labeled peptides. Additionally, the Bad Berka Dosimetry approach can be used for any internal radiotherapy using a gamma-emitting radionuclide.

Conclusions: The Bad Berka Dosimetry method is a practicable dosimetric approach, which can be used in daily clinical routine. It not only helps in identifying patients who would benefit most from the treatment, but also those with unfavorable dosimetry.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

P6 Web-Monitoring Tool for ¹⁷⁷Lutetium-PSMA Treatments in Prostate Cancer Patients

Kalevi Kairemo ¹, Katja Samushenkova ¹, Timo Joensuu ¹, Henri Virtanen ²

Background / Aims: Docrates Cancer Center has offered multiple targeted radiotherapies for metastatic prostate cancer. Recently, we have introduced ¹⁷⁷Lutetium-PSMA, so far we have been given more than ¹⁷⁷Lutetium 300 therapy cycles. The therapy is effective and many symptoms may be related to treatment effects. To separate side effects from treatment effects we started to monitor carefully our patients’ symptoms. A web-monitoring tool was taken into our weekly routine.

Methods: We administer the ¹⁷⁷Lu-activity in a slow 30-minute infusion 2-7 times over the course of 4-6 weeks. Normal physiologic uptake is seen in salivary glands, and parotid glands are protected with cooling compressions in order to minimize side effects. The patients fill out a web-based EORTC-30-QLQ questionnaire for the follow-up of their symptoms and possible side effects after receiving the treatment. There are 10 questions addressing common symptoms such as general well being, fatigue, xerostomia etc. We have developed these questions to evaluate severity of symptoms as well. The web-based follow-up tool gives also symptom related self-care instructions to the patients.

Results: The program sends an automatic email notifications weekly. To fill the questionnaire takes less than three minutes. Despite it being quick and easy for the patients, the obtained information is valuable, and can also be used for planning of the future treatments.

Conclusion: It has been reported that digital patient monitoring helps patients live longer and is cost effective (Denis et al. JNCI 2017;109(9):djx029). It gives important information to medical staff and helps us react quickly to alarming symptoms.

Since the ¹⁷⁷Lu treatment is still very new and experimental, this program will help us learn more about it and separate treatment effects from side effects. This enables better patient support.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

P7 Antithyroglobulin antibody as a marker of successful ablation therapy in differentiated thyroid cancer

Ayu Rosemeilia Dewi ¹, Budi D ¹, Kartamihardja AHS ¹, Hidayat B ¹, Masjhur JS ¹

The aim of this study was to determine the role of antithyroglobulin antibody (ATA) serum as a marker of successful I-131 ablation therapy in differentiated thyroid cancer (DTC) patients with low serum thyroglobulin (Tg). A retrospective study was conducted on 60 patients (10 male and 50 female) underwent total thyroidectomy continued with 2.96 to 3 GBq I-131 ablation therapy. Subjects were divided into succesful and unsuccessful groups. Pre-ablation serum Tg and ATA level (Tg1 and ATA1) and 6-12 months post-ablation (Tg2 and ATA2) were measured. The successful of ablation therapy was evaluated by diagnostic whole body scan (DxWBS) 6-12 months post-ablation. There were no significant differences in age, gender, type of histopathology, tumor size, and nodal metastasis, between the two groups. ATA2 ≤30 kIU/L were found in 23 (62.2%) subjects with successful ablation therapy, and >30 kIU/L in 16 (69.6%) subjects belongs to unsuccessful group (p=0.017). Changes between ATA1 and ATA2 level did not differ significantly in both groups (p=0.062). Tg1 <10 µg/L was found in 26 (57.8%) subjects with successful therapy (p=0.037). Multivariate analysis showed ATA2 and Tg1 as the independent factors for the success of ablation therapy (p=0.007 and 0.015). Adjusted odds ratio of post-ablation ATA was 5.379 (95% CI 1.590 to 18.203) and pre-ablation Tg was 5.822 (95% CI 1.418 to 23.902). ATA levels at 6-12 months post-ablation, by considering the pre-ablation Tg levels, is a useful marker to determine successful ablation therapy in WDTC patients with low serum Tg. Changes in serum ATA levels, although not statistically significant, can provide additional information about the course of the disease.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

P8 Importance of isolated raised thyroglobulin antibody in follow up and management of differentiated thyroid cancer

Ray Soumendranath ¹, Das Jayanta ¹

Purpose:We analyzed the impact of elevated Thyroglobuline antibody (Tg Ab) in the management of Differentiated Thyroid Cancer (DTC) patients. The importance of FDG PET was evaluated.

Methods:536 DTC patients were treated with I-131 in 3 years and evaluated after 6 months with whole body I-131 scan(WBS), Thyroglobuline(Tg) and Tg Ab with USG. Treatment records were retrospectively analyzed.

Results:Tg Ab was elevated in 21 patients .I-131 scan was negative in 6 and showed abnormal uptake in 15 patients. 4 had multifocal disease. 7 had extrathyroidal extension and 5 had lymph node metastasis. USG showed 3 residual thyroid and 6 lymphnodal disease .Post therapy WBS was normal in 5 patients. FDG PET-CT was performed in 6 patients of whom 4 were positive. Two of these four patients with positive PET scan were treated with empirical I-131 therapy and one patient received Sorafinib. Conclusion: Elevated serum Tg Ab is an important parameter like Tg. It checks the reliability of Tg value and if elevated, should be supplemented with investigations like USG or FDG PET as in case of TENIS syndrome.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

P9 Contribution of manual fusion in thyroid cancer whole body study with I-131. Case Report

Mariela Agolti ¹, Solari L ¹, Aruga C ¹

Background: Differentiated Thyroid carcinoma is increasing pathology. The correct stadification is very important to make the correct treatment; there is evidence that the use of hybrid equipment allows changes in treatment in up to 31 % of the patients. We have the dedicated SPECT Camara Gamma. Methods: We have used diagnosis CT in two of our patients manually fused with I-131 SPECT to improve the diagnostic accuracy. Both patients had received 100 mCi of I-131 for treatment and the whole body scan and SPECT were done eighth days after the dose. We made some metallic markers (needles) with 0,001 mCi of I-131 SPECT of 64 images of 20 second per frame in a Camara gamma Alfa nuclear with one head. We did a neck and superior thorax tomography with the same markers and proceed to do manual fusion with Horos® Results: In one patient we found in an I-131 whole body imaging three uptake focus in the neck. We could see two of theme were thyroid residual tissue but one of the hypermetabolic focus was co-registered with a cervical node, which in CT wasn’t adenomegaly, but with this method we concluded that it uptake I-131, so it had differentiated thyroid tissue (metastasis). The other patient was a female with focal uptake in the left lung and in the fused image it was a lung nodular metastasis. Conclusion:Manual fusion is a very useful methodology for Nuclear Medicine Centers with dedicated equipment for the etiological diagnostic of focal I-131 uptake.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

P10 Contribution of manual fusion in thyroid cancer whole body study with I-131

Mariela Agolti ¹, Aruga C ¹, Solari L ¹

Background: Differentiated Thyroid carcinoma is increasing pathology. The correct stadification is very important to make the correct treatment; There is evidence that the use of hybrid equipment allows changes in treatment in up to 31% of the patients. We have the dedicated SPECT Camera Gamma. Methods: We have used CT diagnosis in two of our patients manually fused with I-131 SPECT to improve the diagnostic accuracy. Both patients had received 100 mCi of I-131 for treatment and the whole body scan and SPECT were done eighth days after the dose. We made some metallic markers (needles) with 0,001 mCi of I-131 SPECT of 64 images of 20 second per frame in a Camera gamma Alfa nuclear with one head. We did a neck and upper thorax tomography with the same markers and proceeded to do manual fusion with Horos® Results: In one patient we found in to I-131 whole-body imaging three uptake focus in the neck. We could see two of the subject’s thyroid residual tissue but one of the hypermetabolic focus was co-registered with a cervical node, which CT was not adenomegaly, but with this method, we concluded that it was uptake I-131, so it had differentiated thyroid tissue (metastasis). The other patient was focal in the left lung and in the fused image it was a lung nodular metastasis. Conclusion: Manual fusion is a very useful methodology for Nuclear Medicine Centers with dedicated equipment for the etiological diagnostic of focal I-131 uptake.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

P11 First ex-vivo experience with β- radiation and radioguided surgery technique in meningioma and neuroendocrine patients

Chiara Maria Grana ¹, Faccini R ¹, Colandrea M ¹, Schiariti M ¹, Solfaroli Camillocci E ¹, Collamati F ¹, Morganti S ¹, Bertani E ¹, Pisa E ¹, Cremonesi M ¹, Papi S ¹

Introduction: Radioguided surgery (RGS) is a technique aimed at assisting the surgeon to reach a complete resection of the neoplastic lesion, while minimizing the amount of healthy tissue to be removed. RGS with beta- radioisotopes, as ⁹⁰Y, is a novelty under investigation: one of the main advantages is its capability to detect small lesions after the injection of low activities. This novel approach allows to develop a new probe which, detecting electrons and operating with low background, provides a clearer delineation of the margins of lesions with low radiation exposition for surgeons Aim: To explore the applicability of this new technique and to overcome the limits of gamma-RGS, extending the applicability of RGS in different tumors. Materials and Methods: We started evaluating tumors highly expressing somatostatin receptors (SSR), where we can study the uptake of ⁹⁰Y-DOTATOC, first in meningioma and then in neuroendocrine tumors. These studies started from PET images with ⁶⁸Ga-DOTATOC and, assuming that the biodistribution of the tracer did not change when labeled with ⁹⁰Y, with a simulation program (FLUKA) estimated the signal rate on the probe. So far, 4 pts with meningioma and 3 pts with bowel neuroendocrine tumor (NET), received ⁶⁸Ga-DOTATOC/PET, two weeks prior to surgery in order to know the uptake in the lesions. Twenty-four hours before surgery, the patients were injected with a median activity of 4.5 mCi (we started with 8 mCi in the first patient and we decreased to 2.5 mCi in the last meningioma patient); the NET pts received 5 mCi of ⁹⁰Y-DOTATOC. Before surgery the probe was placed in proximity to the skin of the patient to estimate the background. Results: Surgery was performed as clinical indicated in meningioma and NET pt. Tumors and the around tissues were sectioned in different samples and the probe was put in contact with each sample to measure its activity: all the samples identified by the probe as malignant were actually of tumor tissue, as histologically routine detected in meningioma. Data about NET pts are still in evaluation and results will be provided during the congress. Conclusions: These first ex-vivo RGS tests showed that through this probe we could discriminate very strongly between tumor and nearby healthy tissues by the administration of low activities of ⁹⁰Y-DOTATOC. We are planning to enroll new NET patients, as it is well known that a complete surgery could better the prognosis of this disease, and to further improve the probe.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

P12 Lutetium-labelled DOTA-TOC and radionuclide therapy (PRRT) in China: First Experience

Feng Wang ¹, Yao X ¹, Zang C ¹, Zang S ¹

Background: Treatment with lutetium-labelled Peptide receptors radionuclide therapy (PRRT) is a promising treatment strategy for patients with inoperable or metastatic neuroendocrine tumors (NETs). The aim of this study is to evaluate the outcome of PRRT and main adverse effects in China. METHODS: Twenty five Patients with advanced unresectable progressive differentiated NETs and five patients with Pheochromacytoma/ Paraganglioma (PHEO/PGL) were consecutively enrolled in this prospective study from Aug 2016 to Sep 2017. All patients showed multiple ⁶⁸Ga-DOTA-NOC avid lesions, and received 80-190mCi (143±25mCi)¹⁷⁷Lu-DOTA-TOC at 12 weeks interval, amino acid protection protocols were routinely performed before and after administration. Totally, 52 cycles were performed in 30 patients, tumor response were evaluated with RECIST or PERCIST criteria.¹⁷⁷Lu-DOTA-TOC SPECT/CT and wholebody scan was performed p at 3 day post-therapy. RESULTS: No significant adverse effects such as nephrotoxicity and acute bone marrow depression were observed in this study. However, transient mild hematological toxicity and acratia appeared in some patients, abdominal pains which associated with heavy tumor burden were also observed. Out of 30 patients, 11 patients had partial response, 13 patients had stable disease, 5 patients progressed. Three patients were dead, 1 died of intestinal obstruction and acute kidney failure, 1 with massive hemorrhage of gastrointestinal tract, the third with cachexia and multiple organ failure. PRRT showed better outcomes in PHEO/PGL, catecholamine and serum CGA was significantly decreased, symptoms were gradually released. CONCLUSIONS: This Chinese study on PRRT resulted in SD or PR in GEP-NET, which showed significant symptom release and tumor marker reduction, whereas, transient and mild adverse effects were observed but tolerable. Due to small scale population, large scale multi-center studies are needed in the future.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

P13 Developing neuropeptide Y (NPY) nanoconstructs as potential theranostic agents

Irfan Ullah Khan ¹, Shahid A ¹, Iram F ¹, Iqbal MS ¹

Background: The over-expression of neuropeptide Y1-receptors in human breast cancer leads to a potential application of selective neuropeptide Y (NPY) Y1-receptor ligands as a new generation of agents for cancer diagnosis and therapy. NPY-derived Y1-receptor ligands, e.g.,^99mTc(core)3+-(NαHis-ac)-labeled-[Phe7,Pro34]NPY have been previously developed and investigated in vitro and in vivo. The preclinical and first clinical data by using these NPY derivatives in human breast cancer patients produced very promising results with remarkable peptide uptake in metastases spread in other organs, originating from the tumor. These novel findings clearly indicate that the overexpression of the Y1 receptor in human breast cancers offers a unique possibility for tumor targeting by using NPY-derived Y1-receptor ligands. These excellent results prompted us to develop peptide-based gold and silver nanoparticles, thus ultimately, resulting highly specific radiolabeled nanoconstructs decorated with DOTA-NPY molecules to act as ‘nanotheranostics’. Methods: For this purpose, we produced highly stable gold and silver nanoparticles (NPs) using arabinoxylan (AX) from ispaghula (Plantagoovata) seed husk. The NPs were synthesized by stirring a mixture of AX and HAuCl4•H2O or AgNO3, separately, below 100?C for less than an hour, where AX worked as the reducing and the stabilizing agent. The synthesized NPs were characterized by various analytical techniques, and coupled with DOTA-NPY Y1-specific derivatives, thus resulting in “nanoconstructs”. The peptides were labeled with Gallium-69 to test the binding affinity with the Y1/Y2 receptors. In vivo uptake of radiolabeled ¹⁹⁸Au-labeled nanoconstructs was studied in various organs of normal rabbits after regular time intervals.

Results: The particle size was (for silver: 5-20 nm and gold: 8-30 nm) found to be dependent on pH, temperature, reaction time and concentrations of AX and the metal salts used. The biodistribution data showed a slower uptake with a significantly higher retention time, thus leading to sufficient renal excretion to allow absorption of the labeled compound into the tumor, with ultimately fast body clearance to avoid unspecific peptide accumulation. These potential features of NPY nanoconstructs make them strong candidates for theranostic applications after radiolabeling with ⁶⁸Ga for PET imaging studies and radionuclide therapy after labeling with beta or alpha-emitting radionuclides (study in progress). Summary: This approach might be further extended to a tumor-specific targeting by using NPY derivatives for carrier of chemotherapeutic agents and might not be limited to breast cancer, because Y-receptor expression has been identified in other tumors, such as neuroblastoma, glioblastoma, ovarian adenocarcinoma, gastrointenstinal stromal tumor, nephroblastomas, renal cell carcinoma, and pheochromocytoma, thus ultimately, used as a future tool for Peptide Receptor Radionuclide Therapy (PRRNT).

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

P14 Clinical case of benefit due to deviation in Ra-223 treatment schedule

Tatiana Kochetova ¹, Valeriy Krylov ¹

Ra-223 dichloride is new effective drug which can influence on survival. It is the unique seeking radiopharmaceutical which effectiveness was proven in evidence based trials. But some questions remain unclear. In the population of castration resistant cancer patients 6 cycles of Ra-223 with 4-week intervals can prolong survival. The influence of deviations in the treatment schedule on the outcome is not investigated. In our clinical case, the best response observed in patient who had two unexpected treatment interruptions 56-year-old man suffered from poor differentiated (Gleason 8) prostate cancer with bone metastases since the 10.2012. Standard androgen deprivation therapy was effective till 02.2014, then he became castration resistant. As he refused from chemotherapy and nuclear therapy wasn’t available his treatment consisted of Eligard 22.5 mg/3 months and Zoledronic acid. By the start of Ra-223 treatment he had wide spread mild symptomatic bone metastases in all parts of the skeleton. Anemia (101 g/l) and thrombocytopenia (100x109/l) appeared due to bone marrow involvement. PSA and ALP levels were extremely high: more than 4 000 ng/ml and 2900 U/l respectively. After two cycles PSA level dropped down to 70 ng/dl and ALP level to 878. Due to technical problems, the interval between the second and the third cycle was 5,5 months. Unexpectedly, the Ra-223 still worked: PSA and ALP levels decrease continued. At the time of restart PSA was 0.01 ng/ml and ALP level was a little bit higher than normal range – 139 U/l. After the withdrawal treatment continued in a normal schedule. At the end of the treatment the patient had only minimal signs of disease on bone scan, he was asymptomatic with no biochemical signs of disease about 1.5 year. Two of the three patients also experienced the interruption in treatment. One of them demonstrated clear signs of progression after the 1st and the 2nd cycles, during the drug withdraw he also progressed. He demonstrated very good response after adding of Abiraterone acetate. In the third case, after two cycles of Ra-223 the patient became stable and remained stable during the interruption and following treatment cycles. Three months after the end of therapy he failed into progression again. This data suggests that in some cases treatment schedule may be individual, depended on clinical situation and response for the therapy. Restart of the therapy is possible and effective.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

P15 Personalized molecular imaging with bone scintigraphy, NaF-PET, and FDG-PET for evaluation of osteosarcoma response to Radium-223

Vivek Subbiah ¹, Eric M Rohren ², Gregory C Ravizzini ³, Arvind Rao ⁴, Homer A Macapinlac ⁵, Kalevi Kairemo ⁶

BACKGROUND: Evaluation of osteoblastic metastases in osteosarcoma by conventional CT and MRI is challenging. We investigated the role of different imaging modalities in a phase I clinical trial of radium 223 (²²³RaCl₂) in the treatment of patients (N=18) with high-risk relapsed bone-forming osteosarcoma (NCT01833520).

HYPOTHESIS: Do the different imaging modalities give additional information.

METHODS: Patients received 1–6 cycles of ²²³RaCl₂, and cumulative doses varied from 6.84 MBq to 57.81 MBq. Molecular imaging with technetium (Tc)- 99m phosphonate scintigraphy, 2-F-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) or sodium fluoride-18 (NaF) PET was used to characterize the disease. All 18 patients had multiple lesions diagnosed with one of the imaging techniques. Bone scintigraphy and FDG-PET studies could be compared in 10 patients at two time points and in two patients before ²²³RaCl₂ administration. Bone scintigraphy and NaF-PET could be compared in 10 patients at two time points, in two patients at three time points and in one patient before ²²³RaCl₂ administration. Lesion number, lesion volume, and total lesion volume were analyzed via FDG-PET and NaF-PET studies. We also developed methods to analyze lung volume and skeletal volume to compare disease behavior using different PET tracers.

RESULTS: Of the 18 patients, 17 had bone lesions that were visible in at least one of the imaging studies. In four of the seven patients with multiple skeletal lesions (>5), FDG-PET and NaF-PET studies could be compared. In these four patients, the sclerotic bone volume and pathologic NaF and FDG volumes varied widely. The skeletal tumor locations varied in our patient population: two patients had skull lesions, seven patients had lesions in the extremities, 10 patients had pelvic bone tumors, 12 patients had lesions in the spine, and nine patients had lesions in the ribs. The FDG-PET and NaF-PET studies could be compared in all four patients who had multiple lung lesions (>5). In these patients, the lung volume, calcified lung nodules, and pathologic NaF and FDG volumes varied substantially. One patient had brain metastases at baseline, and the other developed brain metastases during the study. Most of the patients (14/18) had soft-tissue metastases, and at least some of the metastases were calcified in all 14 patients. In two patients, the soft-tissue lesions could be identified as lymph nodes. One patient had a liver metastasis. In most of the patients, the soft-tissue lesions were extensions of bone tumors. Overall response was seen in only one patient, but 4 patients experienced mixed responses, in which the bone lesion decreased in intensity, and the surrounding soft tissues increased in intensity. Lung tumors, which were rarely calcified, seldom responded to ²²³RaCl₂ treatment.

Our results indicate that personalized molecular imaging with NaF-PET is an essential part of osteosarcoma staging and NaF PET and FDG PET are complementary to each other in osteosarcoma.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

P16 Treatment response evaluation in soft-tissue osteosarcoma metastases using fluoride-18 (¹⁸F)-PET/CT radiomics analysis for ²²³Ra-therapy

Kalevi Kairemo ¹, Arvind Rao ¹, Home Macapinlac ¹, Vivek Subbiah ¹

Background: Bone forming osteosarcoma metastases are common in extra-osseous sites especially when metastastic in the lungs. Since bone forming tumors do not shrink in response to therapy, intra-tumoral and inter-tumoral changes are challenging to evaluate using conventional imaging modalities. Sodium fluoride-18 (Na ¹⁸F)-PET/CT better characterizes bone forming metastases than FDG-PET CT scan.

Methods: A dose-escalation trial of ²²³RaCl₂ (50, 75, and 100 kBq ²²³RaCl₂ /kg) enrolled pts age 15y+ w advanced osteosarcma. Molecular imaging with technetium (Tc)-99m bone scan, FDG PET or sodium fluoride-18 (NaF) PET was done at baseline and at restaging. We developed a PET radiomics method for analyzing NaF, i.e. radioactive ¹⁸F^- -atom concentration in soft-tissues, approximately 1000 concentration data points for ¹⁸F^- per 1 cm³ metastatic tumor. We analysed data from the SUV intensity values, we obtained (i) the histogram of intensities, (ii) entropy value. The fractions of voxels were plotted against intensity bins.

Results: We applied this method to two lung metastases and two soft-tissue metastases, before and after two cycles of Ra-223-treatment. The metastatic tumors were 80 -120 cm ³ in size. This alpha-therapy is effective only in the close vicinity of the target cell, i.e. 4-5 cell diameter range. All these metastases demonstrated mixed type of response, where RECIST nor PERCIST type of criteria do not apply.

In these metastatic sites there were abundant conformational changes which could be considered as therapeutic changes. These can be explained e.g. by changes in entropy, kurtosis. The configuration, amount of distortion etc. can give us guidance of responding tumor parts.

Conclusion: Radiomics can inform about intra-tumoral and intertumoral heterogeneity in response of bone forming osteosarcoma to alpha particle therapy. With the help of this new PET radiomics method for ¹⁸F^- -atom concentration, this can be studied in detail, bone formation regions can be identified. Characteristic changes in entropy may be used to quantify the treatment response. Further larger validated studies are warranted.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

P17 Substantiation of an individual therapeutic dose of ¹⁵³Sm-oxabiphor for the treatment of bone metastases

Ganna Grushka ¹, Larysa Stadnyk

Background. Individualized activity allows to optimize the radionuclide bone therapy (RBT). Aim. Optimization of the intravenous dose of 153Sm-oxybiphor for limitation of the red bone marrow absorbed dose (RBMAD) up to about 2 Gy. Materials. Eleven patients with painful bone metastases received 18 courses of RBT. The average value of administered activities of 153Sm was 2630.0 ± 970.0 MBq. Using the external body radiometry after the first injection, the coefficient of retention of 153Sm in bone tissues (Kret) for all patients was determined. Using CT slices the coefficients of variability of the volume of trabecular bone of the L2-L4 vertebra (KL2-L4) for each patient were calculated. The estimation of cumulative activity in bone tissues and RBMAD and their correlation with the values of individual Kret and KL2-L4 was performed. Results. The analytical correlation for the estimation of the value of optimal specific activity (Aspec) by 153Sm for the following RBT courses was found: Aspec = DRBMAD / (1,15 × Kret × KL2-L4), where DRBMAD - the value of the limit of RBMAD - 2000 mГр; 1.15 is a constant. Conclusions. The prognostic assessment of the RBMAD in the first course of RBT allows optimize the individual activity of 153Sm for next RBT courses and prevents haematotoxicity.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

P18 Radionuclide therapy for bone pain palliation in anemic patients: role of erythropoietin

Sukanta Barai ¹, Dutta D ¹, Rastogi N ², Gambhir S ¹

Background: Low haemoglobin level is one of the common reasons of postponement/cancellation of radionuclide therapy for painful skeletal metastases. A universal adverse effect of radionuclide therapy is temporary myelosupression, moreover many these patients have pre-existing anaemia due to marrow involvement and chemotherapy.

Erythropoietin (EPO) is widely used in the management of cancer-related anaemia. Data evaluating the use of EPO in preparing patients with pre-existing grade-3 anaemia (HB: 8-6.5g/dl) for radionuclide therapy is almost nonexistent but would be important information to Nuclear Medicine physicians.

Aim of the study: To evaluate the effectiveness of EPO in stabilizing haemoglobin in patients with pre-existing grade-3 anaemia (HB: 8-6.5g/dl) according to common toxicity criteria needing radionuclide therapy for bone pain palliation.

Methods: Twenty seven patients with grade-3 anaemia (HB:8-6.5g/dl) with normal leukocyte and platelets count scheduled to receive Samarim-153-EDTMP therapy was recruited. They were treated with 40,000 I.U Erythropoietin/week/subcutaneously in single dose starting 2 weeks prior to Samarim-153-EDTMP therapy. Hemoglobin level was measured again on prior to Samarium153 therapy and at 3 week post therapy. Erythropoietin treatment was continued during the 3 weeks of post-treatment observation period.

Result: Mean age was 59.4±13.5 years. Baseline mean Hb was 7.1 ± 0.51 gram/dl. After 2 weeks of EPO therapy 26 patients attained HB >8gm/dl considered adequate for radionuclide therapy. Post therapy Hb was 8.8±0.96 gram/dl. Haemoglobin level improved further in 22(81.4%) patients, remained stable in 2(7.4%) while showed drop in 1(3.7%) patient in subsequent 3 weeks to radionuclide administration.

Conclusion: Erythropoietin at dose of 40,000 I.U /week is effective in stabilizing haemoglobin in patients with pre-existing cancer induced anaemia needing radionuclide therapy for bone pain palliation.

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

P19¹⁸F-fluoroethyltyrosine PET/CT: the European Institute of Oncology experience in brain tumors

Chiara Maria Grana ¹, Colandrea M ¹, Baio SM ¹, Fracassi SL ¹, Gilardi L ¹, Travaini LL ¹, PA Rocca ¹, S Alessi ¹, IM Milanesi ¹, EA Lamperti ¹

Introduction. Increased amino acid transport in brain tumour cells results from overexpression of the transporter systems and is related to alterations in the tumour vessels and tumour cell proliferation. Radiolabelled amino acids offer significant improvement in the diagnostic evaluation of cerebral tumours in comparison with conventional imaging, either in diagnosis or during follow-up. 18F-fluorethyltyrosine (18F-FET) PET/CT is useful for the noninvasive differentiation of tumor and non-tumoral lesions, as tumors have significantly higher uptake than non-neoplastic tissue. Aim. To present the IEO single-centre experience with 18F-FET PET/CT in glioma patients with suspected recurrence at MRI. Materials and methods: so far, nine patients (6 males, 3 females, median age 38 yrs) affected by brain tumors (2 glioblastoma, 2 anaplastic astrocytoma, 5 oligoastrocytoma-oligodendroglioma) already treated with surgery and radio-chemotherapy, presented during follow up a doubtful MRI and were evaluated with 18F-FET PET/CT in order to better define the nature of the lesions. Manually drawn regions of interest over areas of maximal FET uptake were used to calculate tumor to background ratios [TBRmax]. Moreover MR and PET images were fused using the Advantage Windows Workstation (GE Healthcare) to have precise localization of uptake regions. Results: Six out nine patients underwent 0-40 min dynamic 18F-FET PET/CT scans and 3 pts received a 20-40 min scan. TBRmax was assessed in the 20-40 min summation images in all pts, as well as in summation images from 5-20 min in 6 pts: no difference between early and late images in terms of TBRmax was found. 6 out 9 pts were diagnosed with recurrent diasease (TBRmax>1.6), 1 with suspected recurrence (TBRmax >1.52) and 2 pts with radiation necrosis (non focal uptakes). In the 6 positive pts all areas of suspected recurrence at MRI were identified as recurrence at 18F-FET PET/CT. In one pt with two MRI lesions, 18F-FET PET/CT discovered a third area of unknown pathological uptake. Whole-body scans did not showed relevant uptakes. Conclusions: 18F-FET PET/CT is feasible and gives clear information. Moreover the fusion of functional and morphological images allows a better definition of uptakes areas, and may have the potential to impact on the management of pts with glioma by timely and conclusive recognition of recurrence or radiation necrosis. We are planning to give an update about the follow up during the congress

World J Nucl Med. 2019 Apr-Jun;18(2):205–225.

P20 Pharmaceutical development of the therapeutic radiopharmaceutical based on –emitting Sm-153 in heat-sensitive carrier for brachytherapy of tumors of various locations

NM Tolbit ¹

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PERMALINK

INTERNATIONAL SYMPOSIUM ON RADIOPHARMACEUTICAL THERAPY HELSINKI, 18-20 NOVEMBER 2018

DAY 1, SUNDAY, NOVEMBER 18, 2018: SCIENTIFIC SESSION 1: NUCLEAR CARDIOLOGY: O1 Revolution in cardiac imaging: Quantitative perfusion, inflammation and hybrid imaging

Juhani Knuuti

O2 Imaging innervation. Finally clinical applications?

Albert Flotats

O3 Gauging cardiac repair, regeneration and inflammation with new molecular probes

James Thackeray

O4 Novel therapies of cardiac regeneration. How imaging can help in diagnosis, targeting and monitoring?

Seppo Ylä-Herttuala

O5 Personalized medicine and precision oncology

Vivek Subbiah

O6 Precision oncology in rare tumors: adopting the orphans

Roman Groisberg

O7 Optimizing patient selection for phase 1 clinical trials: lessons from targeted therapy and immunotherapy drug development

Shiraj Sen

O8 Target discovery for precision oncology using large public databases

Jason Roszik

O9 Oncolytic viruses

Akseli Hemminki

DAY 2, MONDAY, NOVEMBER 19, 2018: O10 New Insights in Theranostics: Pre-targeted Radioimmunotherapy for Cure of Solid Human Tumors

Steven M Larson, M.D

Sarah Cheal, Ph.D

Reference

O11 Personalized SIRT based on predictive dosimetry, regional functional reserve measurement and molecular imaging

Patrick Flamen

O12 Re-188 Lipiodol Liver Cancer Project – an update on current status

Ajit Shinto

O13 Biologic dosimetry in SIRT

Katherine A Vallis

Nadia Falzone

Boon Q Lee

Elliot Abbott

O14 Intra-arterial PRRT of SSTR-expressing liver tumors

Aviral Singh

O15 Boron neutron capture therapy and world’s first accelerator-based BNCT facility at Southern Tohoku General Hospital

Yoshihiro Takai

O16 What did we learn from the Fukushima accident?

Ohtsura Niwa

O17 Regulatory nuclear safety aspects, Linear No-Threshold Hypothesis of risk from low-level radiation exposure

Bennett S Greenspan

O18 Introduction to PRLT, Lu-177 Labeled PSMA Radioligand Therapy (PRLT) of Prostate Cancer (mCRPC): Long term Outcome of Precison Oncoloyg after 5 Years’ Experience at the Theranostics Center Bad Berka

Richard P Baum

Harshad R Kulkarni

Aviral Singh

Thomas Langbein

Christiane Schuchardt

Jingjing Zhang

Coline Lehmann

Reference

O19 Dosimetry following Lu-177 PSMA radioligand therapy and an insight into novel radionuclides for theranostics of prostate cancer

Aviral Singh

O20 Dosimetry in Radioligand Therapy of Metastasized Prostate Cancer Using Lu-177 PSMA I&T and Lu-177 PSMA 617

C Schuchardt

A Singh

HR Kulkarni

T Langbein

C Lehmann

RP Baum

O21 PSMA targeting and therapy trials in Australia

Andrew M Scott

O22 Ac-225- and Bi-213- PSMA-617 radioligand therapy in patients with castration resistant prostate cancer

Mike Sathekge

O23 [18F]AIF-PSMA-HBED-CC and 177Lu-PSMA-617 as a potential theragnostic tandem and comparison with 68Ga-PSMA-HBED-CC in high-risk prostate cancer patients at initial staging

Omar Alonso

dos Santos G

Hermida J

Rodriguez Taroco M

Silvera E

Giglio J

De Marco E

Vera L

Savio E

Balter H

Engler H Montevideo

DAY 3, TUESDAY, NOVEMBER 20, 2018: SCIENTIFIC SESSION 6: THYROID CANCER – QUO VADIS?

Mark Tulchinsky

O24 Introduction-thyroid cancer management

Mark Tulchinsky

O25 Total vs. subtotal thyroidectomy. East, West, what´s the best?

O23 [¹⁸F]AIF-PSMA-HBED-CC and ¹⁷⁷Lu-PSMA-617 as a potential theragnostic tandem and comparison with 68Ga-PSMA-HBED-CC in high-risk prostate cancer patients at initial staging

O27 Management of I¹³¹ refractory thyroid cancer : a multimodality approach

O37 Radiometabolic therapy with ²²³Ra-dichloride: the European Institute of Oncology experience

O39 Ra-224 labelled biodegradable carbonate microparticles (Radspherin^R) to combate microscopical residual peritoneal carcinomatosis

P4 ¹⁷⁷Lutetium-Prostate-specific Membrane Antigen Radionuclide Treatment of Lymph Node Metastatic Prostate Cancer with PSA Recurrence: A Cohort Study