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ABSTRACT
Year : 2016  |  Volume : 15  |  Issue : 4  |  Page : 3-39

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How to cite this article:
. Abstracts. World J Nucl Med 2016;15, Suppl S1:3-39

How to cite this URL:
. Abstracts. World J Nucl Med [serial online] 2016 [cited 2021 Jan 25];15, Suppl S1:3-39. Available from: http://www.wjnm.org/text.asp?2016/15/4/3/193853

Lu-177-Herceptin: A Potential Radioimmunoconjugate for Treatment of HER2 Metastatic Breast Cancer

Theragnostics and Personalized Radionuclide Therapy

Priya Bhusari, Jaya Shukla, Rakhee Vatsa, Gurpreet Singh, Bhagwant Rai Mittal

Department of Nuclear Medicine and PET, PGIMER, Chandigarh, India

Introduction: Her2/neu expressing breast cancers are the most aggressive type of breast cancers. It is associated with worst prognosis. The treatment of widespread metastatic disease is still a challenge despite the advancement in technology. From the past few decades radiolabeled antibodies have emerged as promising targets for targeted treatment of widespread metastatic disease. Trastuzumab is a FDA approved monoclonal antibody used routinely in clinic in combination with other chemotherapy drugs for treatment of Her2 breast cancer. This study was aimed at evaluating the targeting ability of radioimmunoconjugate, Lu-177-Trastuzumab in patients with metastatic HER2 breast cancer disease as a palliative treatment option in these patients.

Methodology: Lu-177-Trastuzumab was developed in-house in hospital radiopharmacy lab. Trastuzumab was radiolabeled with Lu-177 by indirect means using DOTA as the bifunctional chelator. The immunoconjugate DOTA-trastuzumab was characterized using electrophoresis (structural integrity assessment) MALDI-TOF (for calculation of number of chelated molecules) and immunohistochemistry (for binding to HER breast tissue). The radioimmunoconjugate Lu-177-DOTA-Trastuzumab underwent various quality control procedures for determining the radiochemical purity, stability, pyrogenecity and binding to HER2 protein in an in-vitro radiimmunoassay. After obtaining clearance from the institute ethics committee, patients with HER metastatic breast cancer (n = 5) and HER2 negative disease (n = 2) were enrolled in the preliminary study. Low dose of Lu-177-trastuzumab (10 mCi) was administered by slow intravenous injection to the patients for imaging purpose to evaluate the specific targeting ability of the developed radioimmunoconjugate. Planar and SPECT/CT imaging was performed at day 5/7 post administration of the radioimmunoconjugate.

Results: Imaging using Lu-177-trastuzumab demonstrated promising results. The radioimmunoconjugate showed localization in primary and metastatic lesions specifically in histopathology proven HER2 positive patients. Due to low resolution of planar imaging and low abundance of 208 keV gamma photons of Lu-177, not all metastatic sites could be observed on planar gamma camera images. However, SPECT/CT imaging showed localization of the radioimmunoconjugate at the metastatic sites. No tracer uptake could be observed on planar as well as SPECT/CT imaging of the HER2 negative patients. Besides localization at the diseased sites, the radioimmunoconjugate got localized in the liver for upto 7 days of observation. High blood pool retention of the radioimmunoconjugate for upto 4 days post administration indicated imaging to be performed at day 5/7 post administration. The results were promising in terms of specific targeting of the radioimmunoconjugate. However, dosimetry studies need attention before therapeutic doses are decided for liver is indicated as the critical organ.

Conclusion: Lu-177-trastuzumab can be developed with good radiolabeling yield in a hospital radiopharmacy. The radioimmunoconjugate may be a potential treatment option for palliative treatment of HER2 positive metastatic breast cancer patients.



Development of a New Drug Carrier for Radiopharmaceuticals Based on Diethylene Triamine Pentaacetic Acid-functionalized Nanoporous MCM-41 Silica for Theranostics Applications

Theragnostics and Personalized Radionuclide Therapy

Seyed Yousef Fazaeli Hoseini Nezhad

Nuclear Science and Technology Research Institute, Tehran, Iran

Background: Mesoporous silica, MCM-41, functionalized with diethylene triamine pentaacetic acid (DTPA) and 3-aminopropyltrimethoxysilane as an interface ligand, was investigated as a potential drug delivery system for radionuclides. The outstanding properties of Gallium-67 complexes, such as noninvasively detection of tumors, inflammation, and both acute and chronic infection, proposed that these compounds might potentially be good candidates as test drugs for drug delivery systems.

Methods: In this work, 67 Ga radionuclide was grafted on DTPA-functionalized MCM-41 with direct method of modification, and the compounds were characterized by paper chromatography, Fourier transform infrared spectroscopy, low-angle X-ray diffraction, and CHN and TGA/DTA analyses.

Results: The specific activity of the final compound was found to be 3 Ci/g. The biological evaluations of the grafted complex, [ 67 Ga][email protected], were done in fibrosarcoma tumor-bearing Sprague-Dawley rats.

Conclusion: DTPA-functionalized MCM-41 was found to be a good host for diagnostic radionuclides, with the ability to form complex with DTPA. Considering the accumulation of the tracer in tumor, fast wash-out from normal tissues, appropriate half-life 67 Ga, and less imposed radiation doses to patients (compare to non-targeted radiopharmaceutical), [ 67 Ga][email protected] can be a suitable radiopharmaceutical for imaging purposes.

Synthesis, Radiolabeling, and Preliminary Biological Evaluation of Bis-(2-methyl 8-Hydroxyquinoline)-Copper-64 Complex as a Potential Theranostic Agent

Theragnostics and Personalized Radionuclide Therapy

Seyed Yousef Fazaeli Hoseini Nezhad

Nuclear Science and Technology Research Institute, Tehran, Iran

Background: In this study, radiolabeled complex, bis-(2-methyl 8-hydroxyquinoline)-copper-64, was synthesized with the ability of generalization of synthetic route to its other pharmaceutical derivatives.

Methods: Quality control experiments, biodistribution, and nuclear imaging studies of the radiolabeled complex were done.

Results: The results showed that the biodistributions of the radiolabeled complexes of 8-hydroxyquinoline are adjustable due to the type and position of substitutes in the ligand (methyl in position of 2 in this study).

Conclusion: This study revealed the fact that use of this compound in brain and lung diseases as target organs is possible and useful.

68 Ga-labeled Magnetic Nanosheets of Graphene Oxide: A New Theranostic Agent

Theragnostics and Personalized Radionuclide Therapy

Seyed Yousef Fazaeli Hoseini Nezhad, Shahzad Feizi

Nuclear Science and Technology Research Institute, Tehran, Iran

Background: Magnetite-graphene oxide (MGO) hybrid nanoflakes were investigated as a potential drug delivery system, using ( 68 Ga)-GaCl3.

Methods: Gallium-68 was labeled on magnetic nanosheets of graphene oxide with direct method of modification and the composite was characterized by paper chromatography, Fourier transform infrared spectroscopy, low angle X-ray diffraction, CHN and TGA/DTA analyses, and atomic force microscopy. The biological evaluations of the labeled nanocomposite were done in normal Sprague-Dawley rats.

Results: [ 68 Ga][email protected] was found to be a good host for theranostic radiopharmaceuticals. The results showed that grafting of Fe 3 O 4 nanoparticles on nanocomposite reduced the unwanted liver and spleen uptakes and increased the ratio of kidney/liver uptake from 0.037 to 1.07, leading to the fast removal of radioactivity and less imposed radiation to patients. The high level of hydrogen bonding caused by the presence of functional groups is responsible for this fact.

Conclusion: Considering the accumulation of the tracer in vital organs of rat (especially brain), theranostic properties of iron oxide, fast wash-out, short half-life Gallium-68, and less imposed radiation doses to patients, this nanocomposite can be a suitable candidate for imaging applications, positron emission tomography studies, and future therapeutic procedures.

Gallium-68/67-radiolabeled Radachlorin Complexes: Novel Theranostic Agents Based on Positron Emission Tomography and Photodynamic Therapy

Theragnostics and Personalized Radionuclide Therapy

Seyed Yousef Fazaeli Hoseini Nezhad

Nuclear Science and Technology Research Institute, Tehran, Iran

Background: Malignant diseases will be the major cause of mortality and morbidity in the next decades according to the WHO reports, especially in developing countries and despite introduction of various therapeutic modalities in the field and the development of new theranostic methods including radiation therapy, photodynamic therapy, as well as their combinations, are of great importance in the oncology field. Developing radiolabeled tetrahydropyrrole complexes for ultimate dual-purpose imaging as well as dual-therapeutic modalities was of our interests.

Methods: 67 Ga- and 68 Ga-labeled radachlorin were prepared followed by stability tests, partition coefficient determination, as well as biodistribution studies in wild-type and tumorous rodents, using scarification and positron emission tomography, planar and single photon emission computed tomography imaging.

Results: The complexes were stable in final formulation and human serum at least for 24 h. At the pH 7, the log P = −1.14 and high accumulation in target organs was observed.

Conclusion: The tracer assumed to be an interesting tumor imaging agent due to similar metabolism to radachlorin molecule and the method can be developed for other therapeutic-radiolabeled complexes.

Synthesis of the Radiolabeled Complex, Tris-(2-methyl 8-hydroxyquinoline)-Gallium-67, as a Potential Nuclear Imaging Agent

Theragnostics and Personalized Radionuclide Therapy

Seyed Yousef Fazaeli Hoseini Nezhad

Nuclear Science and Technology Research Institute, Tehran, Iran

Background: Due to the interesting pharmacological properties of radiolabeled metal oxine derivatives such as cell internalization, tumor avidity, and antiproteosome activity, tris-(2-methyl 8-hydroxyquinoline)-Gallium-67 ( 67 Ga-HMQ) was developed in this work.

Methods: 67 Ga-HMQ was prepared using ( 67 Ga)-GaCl3 and HMQ for 60 min at 100°C (radiochemical purity: >99% instant thin-layer chromatography, >99% high-performance liquid chromatography, specific activity: 13-14 GBq/mmol).

Results: Stability of the complex was checked in final formulation and human serum for 48 h. The biodistribution of the labeled compound in vital organs of wild-type rats was studied using scarification studies and single photon emission computed tomography up to 24 h.

Conclusion: A detailed comparative pharmacokinetic study for 67 Ga cation and 67 Ga-HMQ up to 24 h shows distinguished properties of this complex. The complex is mostly washed out from the circulation through kidneys and has the specific uptake in the brain and chest.

Stability and Efficacy of a Therapeutic Dose of Lu-Dotatate Prepared at a Remote Centralized Radiopharmacy: The Initial Clinical Results (Work in progress)

Theragnostics and Personalized Radionuclide Therapy

Masha Maharaj, Nisaar Ahmed Korowlay 1 , Otto Knoesen 2

Umhlanga Molecular Imaging and Therapy, 1 Department of Medical Imaging and Clinical Oncology, Stellenbosch University and Tygerberg Hospital, 2 NTP Radioisotopes SOC Ltd., South Africa

Background: Lu-Dotatate therapy has established its role in the management of patients with inoperable or metastasized neuroendocrine tumors. To the best of our knowledge, the clinical stability of Lu-Dotatate therapy doses prepared at a centralized radiopharmacy and transported to a remote therapy center has never been analyzed or reported.

Aim and Objectives: To assess the stability in using Lu-Dotatate prepared from a centralized radiopharmacy then transported to a remote therapy center. This may create therapy opportunities for many remote centers in different countries with no direct access to onsite production.

Methods: The current radiopharmacy, NTP Radioisotopes, is situated in Pelindaba, 634.5 km (approximately 394 miles) from the therapy center (Umhlanga, Kwazulu-Natal). Pelindaba receives Lu-177 on a Wednesday morning (from ITG in Germany) and labels it with Dotatate using protocols obtained from two sources in Germany. The protocols are adapted to suit our conditions and the product is then suitably stabilized. This process is usually completed by 9 h. Standard doses of 7400 MBq are prepared. The doses are then taken by NTP Logistics to the airport (OR Tambo International Airport) for clearance for the scheduled flight (duration of flight 1 h). In Durban (King Shaka International Airport), NTP logistics wait on site for the labeled product to be cleared and it is taken directly to the practice for administration. We analyzed 19 therapies to determine the stability of the product from preparation to injection. The following were used for analysis: Biodistribution of posttherapy imaging versus diagnostic scan lesion uptake and clinical therapeutic response. Injection, therapy, and imaging protocols were standardized.

Results: The mean time from production to injection was 4.93 h (±1.07 standard deviation). The mode was 4.5 h. The longest time between preparation and injection was 7.33 h. The interim clinical evaluation of six patients who received Lu-Dotatate therapy: 16% complete response, 33% partial response, 50% stable disease.

Conclusion: Our center experience with Lu-Dotatate received from a central radiopharmacy suggests that the labeled compound remains stable both in vivo and in vitro with good target delivery and effective clinical outcomes.

Efficacy of Lu-177-DOTA-TATE Therapy for Neuroendocrine Tumors: Our Institutional Experience

Theragnostics and Personalized Radionuclide Therapy

Roni George Manjaly,

Indirani Muthukrishnan, Shilpa Kalal, Jaykanth Amalachandran, Avani Jain, Abhishek Khare, Shelley Simon


Apollo Hospitals, Chennai, Tamil Nadu, India

Introduction: Peptide receptor radionuclide therapy (PRRNT) employing radiolabelled somatostatin analog peptides, particularly 177 lutetium-labeled DOTA coupled Tyr3-Octreotate ( 177 Lu-DOTA-TATE), is an established therapeutic modality for the treatment of patients suffering from a wide variety of inoperable/metastatic neuroendocrine tumors (NETs) overexpressing somatostatin receptors (SSTRs). PRRNT with 177 Lu-DOTA-TATE achieves targeted therapy against NET with high specificity for SSTR Type 2 receptors, which is overexpressed in most of the NETs.

Materials and Methods: In a total of 19 therapies for eight patients (age range 47-60 years), four were males and four were females. Six of these patients had gastroenteropancreatic NETs with nodal, hepatic, and skeletal metastases; among them, one had NET in the head of pancreas. In the other two patients, one had medullary carcinoma of thyroid with hepatic, adrenal, pulmonary, and skeletal metastases and another female patient was suffering from bilateral carotid body tumor. All patients had NET proven by histopathology with Ki-67 index <20% and WHO Grade 1 or 2 with intense uptake on Ga-68-DOTA-TATE positron emission tomography/computed tomography or Tc-99m-HYNIC-TOC scan. All patients were given consecutive 177 Lu-DOTA-TATE therapies (120-150 mCi) at an interval of 8 weeks for a maximum of four cycles.

Results: After two cycles of therapy, two of the patients had good subjective response with remission of symptoms and decrease in chromogranin levels. Three patients had completed four cycles of therapy; out of them, one patient had a partial response with a stable chromogranin value and the other two patient's disease remained stable with complete remission of symptoms and good quality of life. In one of those patients, there was a mild increment in the level of chromogranin during the last therapy. Remaining three patients who completed one cycle each, two patients are planned and scheduled for the next dose, and one patient expired due to extensive disease.

Conclusion: Evidence from our initial clinical experience indicates that patients with NET and high SSTR expression receiving 177 Lu-DOTA-TATE treatment show significantly higher subjective responses compared to other available treatment modalities such as somatostatin analogs, leading to improved quality of life and longer survival.

Fludeoxyglucose and 68 Ga-somatostatin Receptors Positron Emission Tomography in the Follow-up of Patients Treated by Peptide Receptor Radionuclide Therapy: Where we are Today

Theragnostics and Personalized Radionuclide Therapy

Bernhard Nilica,

Margarida Rodrigues-Radischat, Irene Virgolini


Department for Nuclear Medicine, Medical University Innsbruck, Innsbruck, Austria

Purpose: To determine the value of 68 Ga-DOTA-TOC and 18 F-fludeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) for initial and follow-up evaluation of patients with neuroendocrine tumor (NET) treated with peptide receptor radionuclide therapy (PRRT).

Methods: We evaluated 66 patients who had histologically proven NET and underwent both PRRT and three combined 68 Ga-DOTA-TOC and 18 F-FDG PET/CT studies. 68 Ga-DOTA-TOC PET/CT was performed before PRRT, 3 months after completion of PRRT, and after a further 6-9 months. 18 F-FDG PET/CT was done within 2 months of 68 Ga-DOTA-TOC PET/CT. Follow-up ranged from 11.8 to 80.0 months (mean 34.5 months).

Results: All patients were 68 Ga-DOTA-TOC PET-positive initially and at follow-up after the first full PRRT cycle. Overall, 62 of the 198 18 F-FDG PET studies (31%) were true positive in 38 of the 66 patients (58%). Of the 66 patients, 28 (5 Grade 1, 23 Grade 2) were 18 F-FDG-negative initially and during follow-up (Group 1), 24 (5 Grade 1, 13 Grade 2, 6 Grade 3) were 18 F-FDG-positive initially and during follow-up (Group 2), nine patients (2 Grade 1, 6 Grade 2, 1 Grade 3) were 18 F-FDG negative initially but 18 F-FDG-positive during follow-up (Group 3), and five patients (all Grade 2) were 18 F-FDG-positive initially but 18 F-FDG-negative during follow-up (Group 4). 18 F-FDG PET showed more and/or larger metastases than 68 Ga-DOTA-TOC PET in five patients of Group 2 and four patients of Group 3, all with progressive disease. In three patients with progressive disease who died during follow-up, tumor maximum standardized uptake value increased by 41%-82% from the first to the last follow-up investigation.

Conclusion: In NET patients, the presence of 18 F-FDG-positive tumors correlates strongly with a higher risk of progression. Initially, patients with 18 F-FDG-negative NET may show 18 F-FDG-positive tumors during follow-up. Further, patients with Grade 1 and Grade 2 NETs may have 18 F-FDG-positive tumors. Therefore, 18 F-FDG PET/CT is a complementary tool to 68 Ga-DOTA-TOC PET/CT with clinical relevance for molecular investigation.

Role of Single Photon Emission Computed Tomography-Computed Tomography with 99m Tc-Tektrotyd in the Management of Neuroendocrine Tumors

Theragnostics and Personalized Radionuclide Therapy

Sonya Sergieva, Bozhil Robev 1 , Albena Fakirov 2 , Milena Dimcheva, Radka Hristiskova 2

Department of Nuclear Medicine, Sofia Cancer Center, 1 UH "St. Ivan Rilsky", 2 Department of Pathology, Military Medical Academy, Sofia, Bulgaria

Introduction: The incidence of carcinoid is characterized with a consistent trend growth and due to the improved diagnosis of these tumors in recent years. The clinical presentation of the neuroendocrine tumors (NETs) may vary depending on the site of tumor origin. About 72% of NETs arise in gastrointestinal tract and 25% are bronchopulmonary in origin. Very often, these tumors are locally advanced with distant metastases, inoperable at the moment of diagnosis. The latest development in the imaging of NETs is the fusion of anatomical and functional single photon emission computed tomography/computed tomography (SPECT-CT) or positron emission tomography-CT (PET-CT) modalities with radiolabeled somatostatin analogs.

Purpose: The aim of this study was to evaluate clinical utility of SPECT-CT scintigraphy with 99m Tc-tektrotyd in the management of these patients (pts).

Materials and Methods: One hundred and eight pts (68 males; 40 females) with various NETs were studied: (a) 64 were with gastroenteropancreatic NETs, (b) 25 with pulmonary carcinoids, (c) eight with medullary thyroid carcinoma (MTC) (d) six with other NETs, and (e) five with metastatic lesions from tumor with unknown primary origin (UPO). One hundred and seventy-two examinations including SPECT-CT studies of the neck and chest and/or abdomen were performed 2-4 h postintravenous injection of 740 MBq (mean dosage) 99m Tc-HYNIC-TOC (Tektrotyd, Polatom). SPECT-CT gamma camera Symbia T2, Siemens, was used. Pts were studied after 4 weeks of withdrawal of Sandostatin LAR 4 if applicable and emptying gastrointestinal stromal tumor before somatostatin-receptor scintigraphy (SRS).

Results: In five pts with UPO, primary tumors were established as follows: MTC in 2 pts; mesenterial NET in 1 pt, and pancreatic NET in 2 pts, proven after biopsy and surgery. For exact N- and M-staging, SRS was performed in 91 pts: 41 of them were with locoregional lymphadenopathy; 37 pts were with distant liver, bone, and/or pulmonary metastatic lesions overexpressing somatostatin receptors. In 55 pts, SPECT-CT studies were used to evaluate effect of complex therapy. Functional imaging results were compared to biochemical evaluation of tumors that secret markers - chromogranin A (CgA)/calcitonin: (1) Complete therapeutic response - in 4 pts: Disappearance of all target lesions was observed and normalization of tumor marker level - CgA/calcitonin. (2) Partial response - in 22 pts: ≥30% decrease in the sum of the longest diameters of two target lesions compared with baseline or disappearance of >50% of hot spots. (3) Stable disease - in 18 pts: Persistence of one or more lesions and decreasing level of tumor marker level above the normal limits - CgA. (4) Progressive disease - in 11 pts: Appearance of one or more new lesions and/or unequivocal progression of existing lesions. Progression of the disease was observed in five cases with pulmonary and colorectal carcinoid but liver metastases were false negative. In all of these pts, scheme of therapy was changed. In 3 pts, the presence of a malignant tumor was not collaborated by biochemical findings - level of CgA was <100 ng/ml (normal range 1-100 ng/ml). High tracer uptake was obtained in eight benign tumors - two suprarenal adenomas, five thyroid adenoma, and one benign ovary cyst. Intensive physiological uptake was shown in the both breasts of two young women (<35 years) due to fibrocystic alteration, in 2 pts with accessory spleen and in the pancreatic duct.

Conclusion: Main indications for SPECT-CT SRS with clinical role to perform optimal individual treatment in pts with NETs are as follows: (a) Diagnosis of primary NETs: (1) Limited role only in selected cases: To depict the most appropriate tumor lesion for correct biopsy. (2) To image primary tumor in cases with metastatic lesions from tumor with UPO. (3) To assess somatostatin receptor expression in order to predict an individual response to therapy and thus could effectively influence the management of individuals with NETs. (b) Staging and follow-up of NETs pts: (1) For pretreatment - correct N- and M-staging of NETs. (2) For monitoring of treatment response - complete, partial, stable, or progressive disease. (3) For differential diagnosis of pathological lesions from physiological uptake, especially in the regions below the diaphragm. (4) For early determination of recurrence in cases with clinical and biochemical indices for the presence and extent of NETs. (5) For precise topography of metastatic foci in patients with disease extension. (6) In patients with negative SRS, PET-CT studies should be performed.

Novel Noniodinated Radiopaque Microbeads that can be Labeled with 188 Rhenium, for Transarterial Radioembolization of Liver Tumors

Theragnostics and Personalized Radionuclide Therapy

Vijay Harish Somasundaram,

Anusha Ashokan, Nazar Puthukudiyil Kader, Unni Ayalur Kodakara Kochugovindan, Shanmugasundaram Palaniswamy, Shantikumar Nair, Manzoor Koyakutty


Amrita Institute of Medical Sciences and Research Centre, Amrita Center for Nanosciences and Molecular Medicine, Ernakulam, Kerala, India

Background: Advent of microbeads has allowed for more targeted embolization and hence more predictable outcomes. In routine embolization procedures, once the iodinated contrast agents used for delivery of the microbeads wash-out, location of microbeads is unknown. We have developed and characterized biocompatible ceramic microbeads with inherent X-ray attenuation properties that can also be radiolabeled onsite using 188 rhenium. Characteristics and potential application of these microbeads have been demonstrated in vitro and in vivo (animal models).

Materials and Methods: Ceramic microbeads were prepared using electrospraying technique. GE 8-slice computed tomography scanner was used to optimize X-ray attenuation offered by the microbeads in vitro and in vivo. Biocompatibility was tested in vitro in peripheral blood mononuclear cells (PBMCs), in vivo in Sprague-Dawley (SD) rats and New Zealand White (NZW) rabbits. Radiolabeling of microbeads with 99m technetium was optimized using Capintec gamma counter. Embolizing potential of microbeads and their degradation was studied in healthy rabbit models under GE OEC-9800 C-arm.

Results: Ceramic microbeads of three size ranges: 200-300 μm, 300-500 μm, and 500-800 μm prepared, which had uniform X-ray attenuation on imaging. Material was nontoxic to PBMCs at concentration ≈250 μm/ml and was well tolerated by SD rats and NZW rabbits at dose ≈50 mg/kg. ≈1.2 g of microbeads required to bind 100 mCi of 99m technetium. Microbeads could be visualized during and after embolization procedure in vivo (confirmed with histopathological evaluation).

Conclusion: The biocompatible ceramic microbeads allow better intraprocedural monitoring and postprocedural follow-up of transarterial embolization. Microbeads have the potential to be radiolabeled onsite using generator-produced 188 rhenium (since it has the same chemical properties as 99m technetium) for radioembolization, thus significantly reducing the cost of transarterial radioembolization and will allow for more patient-specific titration of the radionuclide dose.

RGD: Biomarker for Angiogenesis as a Potential Theranostic Radiopharmaceutical

Theragnostics and Personalized Radionuclide Therapy

Rakhee Vatsa, Priya Bhusari, Sunil Kumar, Gurpreet Singh, Sudipta Chakraborty 1 , Ashutosh Dash 1 , Devinder Kumar Dhawan 2 , Jaya Shukla, Bhagwant Rai Mittal

Postgraduate Institute of Medical Education and Research, 2 Panjab University, Chandigarh, 1 BARC, India

Background: Integrin is one of the various biomarkers predominantly overexpressed on the tumor cells as compared to normal endothelial cells. Out of the 24 integrins known, integrin αvβ3 is identified to regulate angiogenesis more strongly, the hallmark of tumor growth and metastasis. Radiolabeled RGD tripeptide, an antagonist of integrin αvβ3, can be used for imaging tumors with high angiogenesis. In the present study, Ga-68- and Lu-177-labeled RGDs were prepared in-house and clinical efficacy was assessed in breast and lung carcinoma patients.

Methodology: Reaction conditions were optimized for radiolabeling of Ga-68-DOTA-RGD2 and Lu-177-DOTA-RGD2. Characterization was done by radio-high-performance liquid chromatography. For quality control, radio-instant thin-layer chromatography, gas chromatography, sterility, apyrogenicity tests were performed. Biodistribution was studied in normal Sprague-Dawley female rats and C57/BL6 mice-bearing melanoma at various time intervals p.i. of 100-150 μCi of Ga-68/Lu-177-DOTA-RGD2. Whole-body positron emission tomography/computed tomography (PET/CT) images (base of skull to mid-thigh) were acquired in three-dimensional mode, 45 min postintravenous injection of 3-5 mCi of Ga-68-DOTA-RGD2 in patients with lung (n = 5) and breast (n = 20) carcinoma after obtaining clearance from the Institutional Committee. Imaging was done on a dedicated hybrid PET/CT scanner.

Results: Maximum of 98% radiolabeling yield was achieved for Ga-68-DOTA-RGD2 (20 μg RGD peptide, pH 4.0, 10 min 95°C). 5 molar excess RGD peptide, pH 5.5, and 60 min incubation at 95°C resulted in 99% radiolabeling yield as revealed by characterization studies. All the quality control parameters including radionuclide and radiochemical purity >99%, endotoxins <4 EU/mL, ethanol <2500 ppm, and sterility indicated that Ga-68/Lu-177-DOTA-RGD2 formulations were suitable for intravenous administration. Blood pool activity was found to be decreased after 15 min p.i in biodistribution studies. Liver and spleen were the major organs of uptake at 60 min along with faint uptake in intestines. Kidneys were the major excretory route of both Ga-68/Lu-177-DOTA-RGD2. Good tumor to background ratio was observed at 45 min. In clinical studies, physiological uptake of radiotracer was seen in ventricles, thyroid, salivary glands, liver, and spleen with excretion through the kidneys. High radiotracer uptake was noticed in lung, breast lesions and metastatic sites in all patients.

Conclusion: RGD tripeptide, an antagonist of integrin αvβ3, was successfully radiolabeled with Ga-68 (diagnostic) and Lu-177 (therapeutic) radioisotopes with good radiolabeling yield. The high uptake in primary and metastatic lesions suggested the potential of radiolabeled RGD tripeptide as a promising theranostic agent for tumors with high neoangiogenesis. Imaging with Ga-68 RGD will also help in selection of patients having nonresectable metastatic cancers for peptide receptor radionuclide therapy using Lu-177 RGD.

Evaluation of Quality of Life after Each Cycle in Patients Treated with Peptide Receptor Radionuclide Therapy

PRRT

Ivy M. Vito, Helena Mcmeekin, Shaunak Navalkissoor

Royal Free London NHS Foundation Trust, London, UK

Background: Neuroendocrine tumor (NET)-related symptoms such as flushing and diarrheas as well as disease-related worries (DRWs) reduce quality of life in patients with NETs. Peptide receptor radionuclide therapy (PRRT) is an established treatment in NETs and has been shown to prolong survival. However, quality of life data post-PRRT is lacking.

Aim: To evaluate the symptoms prevalence, intensity, and their relation to quality of life in patients receiving PRRT.

Method: Thirty-nine patients (mean age = 63 years, range 36-79 years; 17 females and 22 males) completed four cycles of PRRT treatments (7.4 GBq of Lu-177-DOTATATE) and filled in QLQ-GINET21 questionnaires before the first session of administration and before three succeeding treatments were available for analysis. The first questionnaire was used as a baseline. QLQ-GINET21 is a disease-specific module, intended for use among patients with gut-related carcinoid in varying disease stage. The response format of the questionnaire is a 4-point Likert scale, with higher scores reflecting more severe symptoms. Categories include endocrine (ED; 3 items) symptoms, gastrointestinal (5 items) symptoms, treatment-related (TR; 3 items) symptoms, social functioning-21 (SF21; 3 items), DRWs (3 items). Responses to the questionnaire were linearly transformed to a 0-100 scale using the European Organisation for Research and Treatment of Cancer guidelines. The individual categories were analyzed, looking at the mean change in score. In addition, the global score (S) was evaluated according to the guidelines, with a mean change in score between 0 and 5 being regarded as not clinically important; a change between 5 and 10 being regarded as little subjective change, whereas a change between 10 and 20 being regarded as moderate change, and >20 being regarded as an important change.



Results: The module comprises 21 questions assessing disease symptoms, side effects of treatment, body image, DRWs, SF, communication, and sexuality. Results were analyzed according to change in overall score and change in category score. The mean scores within all categories (except TR effects) were reduced after one treatment and remained reduced before the fourth cycle of treatment [Table 1]. The biggest changes were seen in DRWs, followed by SF21 and ED. After one treatment, the global quality of life score (S) showed changes as follows: 51% showed an improvement, 28% had no change/improvement, 20% worsening of quality of life (QOL). Before the fourth cycle, 39% of patients had improvement of QOL.

Conclusion: This study demonstrates improved quality of life, reduction of symptoms, and improved emotional and social function scale in patients who have received PRRT with improvement seen as quickly as after one cycle of treatment.

The Initial Chilean Experience with 68 Ga/ 177 Lu-PSMA in Castration-resistant Prostate Cancer

Prostate Cancer: Small Molecule Radioligand Therapy

Horacio Amaral, Vasko Kramer 1 , Pamela Salman 2 , Hugo Lavados, Camilo Sandoval 2 , Jessica Ribbeck 1 , Rene Fernandez, Christian Caglevic 2 , Ivan Pinto 2

PositronMed - Arturo Lopez Perez Foundation, 1 PositronPharma, 2 Arturo Lopez Perez Foundation, Chile

Background: Several studies have confirmed that 177 Lu-PSMA-617 is a safe and effective treatment option for hormone-resistant prostate cancer patients, which have progressed after hormonotherapy and/or cytotoxic chemotherapy treatment. The aim of this work is to report our preliminary experience with prostate-specific membrane antigen (PSMA)-targeted therapy in Chile.

Methods: Ten patients with biochemical progression and refractory hormonal/chemotherapy with either bone, lymph node, or visceral metastases or combination of them received one or more doses of 5.6 GBq (150 mCi) 177 Lu-PSMA-617. All patients have a complete clinical evaluation and laboratory workup including prostate-specific antigen (PSA) blood levels and follow-up every 4 weeks. Pretreatment positron emission tomography/computed tomography (PET/CT) images with 68 Ga-PSMA were acquired and every 8 weeks as follow-up. The radiopharmaceuticals were synthesized in our laboratory according to the Good Manufacturing Practices guidelines. Single photon emission computed tomography/CT (SPECT/CT) images were acquired 24 h after 177 Lu-PSMA. All patients presented radiological diseases progression after hormonotherapy and at least one line of chemotherapy (docetaxel), enzalutamide, or/and abiraterone.

Results: Most of the patients achieved remarkable improvements in clinical and laboratory parameters, including quality of life, pain release, and decline in PSA and maximum standardized uptake values in PET/CT images. No significant side effects were observed. SPECT/CT images presented an excellent correlation with 68 Ga-PSMA PET/CT, demonstrating the validity of the theranostic concept.

Conclusion: Our initial experience with 177 Lu-PSMA-617 therapy in patients with castration-resistant prostate cancer is very encouraging and promising personalized therapy (Theranostics) in a group of patients with currently limited therapeutic options.

Lymph Node Metastases Respond Better than Osseous Metastases to Treatment with Lu-177-labeled PSMA Inhibitor in Patients with Metastatic Castration-resistant Prostate Cancer

Prostate Cancer: Small Molecule Radioligand Therapy

Harshad R. Kulkarni, Aviral Singh, Richard P. Baum

THERANOSTICS Center for Molecular Radiotherapy and Molecular Imaging (PET/CT), Germany

Background: The objective of this study was to assess the response of bone and lymph node metastases on Ga-68 prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) after PSMA-targeted radioligand therapy (PRLT).

Methods: A total of 61 skeletal and 73 lymph node metastases in 99 patients with progressive metastatic castration-resistant prostate cancer (mCRPC), who underwent PRLT using Lu-177-labeled PSMA inhibitor, were analyzed. Response after at least 2 cycles of PRLT was determined applying molecular (European Organisation for Research and Treatment of Cancer) and morphological (Response Evaluation Criteria In Solid Tumors) imaging criteria, using Ga-68-PSMA PET/CT.

Results: CT detected decrease in size of 4/61 (6.6%) skeletal metastases and 29/73 (39.7%) lymph node metastases. Molecular response (reduction in the standardized uptake value [SUV] of the target lesion on PET/CT by >25%) was observed in 32/61 (52.4%) bone lesions and 48/73 (65.7%) lymph node lesions, whereas progression (increase of SUV by >25%) was noted in 5/61 (8.2%) bone and 10/73 (13.7%) lymph node lesions. All the lesions responding on CT also revealed a significant decrease in SUV. There was a progression on CT in 10/73 (13.7%) lymph nodes, all of which showed concordant progression on PET/CT. Interestingly, there was an increase in size on the CT of two osteoblastic lesions in a patient who had a molecular and biochemical complete remission (Ga-68-PSMA PET-negative and prostate-specific antigen undetectable, respectively) after two PRLT cycles.

Conclusion: Ga-68-PSMA PET/CT detects response at an earlier stage than CT (i.e., molecular response precedes morphological changes). It is also superior in response to assessment of skeletal metastases compared to CT alone, in which the actual size of the osteoblastic metastases is difficult to measure and change in size difficult to appreciate. The paradoxical increase in size of the osteoblastic lesions in a patient with complete remission was most probably due to osteosclerosis after therapy. Lymph node metastases of mCRPC respond better than bone metastases to PRLT. This may be explained by a higher and more uniform absorbed radiation dose by lymph node metastases as compared to bone lesions, probably due to attenuation of radiation in bone lesions due to the normal surrounding bone tissue. In addition, the biological differences in radiation sensitivity must be considered.

PSMA Radioligand Therapy using Lu-177-PSMA I&T and Lu-177-PSMA-617: Intra-individual Comparison of Kinetics and Dosimetry

Prostate Cancer: Small Molecule Radioligand Therapy

Christiane Schuchardt, Harshad R. Kulkarni, Stefan Wiessalla, Mostafa Shahinfar, Aviral Singh, Richard P. Baum

THERANOSTICS Center for Molecular Radiotherapy and Molecular Imaging (PET/CT), Zentralklinik Bad Berka GmbH, Germany

Aim: PSMA radioligand therapy (PRLT) using Lu-177-labeled PSMA ligands is a promising therapy option for metastatic castration-resistant prostate cancer (mCRPC). The objective of our study was the intra-individual comparison of the kinetics and mean absorbed dose in organs and tumor lesions in PRLT using Lu-177-PSMA I&T and Lu-177-PSMA-617.

Methods: Four patients (P1-P4) suffering from mCRPC were enrolled (intense PSMA expression was verified before therapy using Ga-68-PSMA positron emission tomography/computed tomography [CT]). Three patients (P1-P3) initially received Lu-177-PSMA I&T (P1-P3: 5, 6, 5.4 GBq, respectively), in the following cycle PSMA-617 (each 6.4 GBq). P4 was treated using 6 GBq Lu-177-PSMA-617 in the first cycle, followed by 7.4 GBq Lu-177-PSMA I&T in the next cycle. The kinetics was determined by means of planar whole-body scintigraphies plus single photon emission computed tomography/CT acquisitions, and dose estimations were performed according to the MIRD scheme (OLINDA/EXM). For intra-individual comparison, the following parameters were analyzed: Effective half-life, uptake, and mean absorbed dose.

Results: P1: PSMA-617 showed a higher uptake, longer half-life, and a higher mean absorbed dose for all normal organs. In contrast, the bone lesion analyzed demonstrated a higher uptake, longer half-life, and higher tumor dose when using PSMA I&T for therapy. P2: The half-life of PSMA-617 was longer in normal organs; the uptake as well as dose of both ligands in kidneys and parotid glands was comparable, but the dose to parotid glands was higher for PSMA I&T. In contrast to P1, a longer half-life, higher uptake, and therefore, a higher tumor dose were found for a bone lesion in case of PSMA-617. P3: PSMA I&T demonstrated a longer half-life, a higher uptake, and a higher dose to normal organs and the bone metastasis. P4: PSMA-617 revealed higher uptake, and dose, as well as a longer half-life for whole body and parotid glands. The renal parameters were comparable. A higher uptake and a longer half-life were also found for the lymph node metastasis using PSMA-617.

Conclusions: These first comparative investigations demonstrate the different kinetics of Lu-177-PSMA I&T and Lu-177-PSMA-617. PSMA-617 demonstrated a higher uptake in normal organs. Due to the different biodistribution and mean absorbed dose to normal organs and tumor lesions, individual dosimetry should be performed.

PSMA Radioligand Therapy of Metastatic Prostate Cancer Using

Lu-177-PSMA I&T and Lu-177-PSMA-617: Comparison of Biodistribution and Dosimetry


Prostate Cancer: Small Molecule Radioligand Therapy

Christiane Schuchardt, Harshad Kulkarni, Stefan Wiessalla, Mostafa Shahinfar, Aviral Singh, Richard P. Baum

THERANOSTICS Center for Molecular Radiotherapy and Molecular Imaging (PET/CT), Zentralklinik Bad Berka GmbH, Germany

Aim: Prostate-specific membrane antigen (PSMA) is significantly overexpressed by prostate cancer cells as 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 metastatic castration-resistant prostate cancer (mCRPC) using Lu-177-labeled PSMA I&T and PSMA-617.

Methods: Fifty-six patients with progressive mCRPC (aged 71 ± 8 years) were included in the analysis. High PSMA expression was verified before treatment by Ga-6-PSMA positron emission tomography/computed tomography (CT). Thirty-seven patients received 3.4-7.6 GBq Lu-177-PSMA I&T and 19 patients were treated with 4.9-8 GBq Lu-177-PSMA-617. The time-dependent whole-body, organ, and tumor activities were determined based on conjugated planar whole-body scintigraphies and single photon emission computed tomography/CT acquisitions. Dosimetric calculations (MIRD scheme) were performed using OLINDA/EXM software. To analyze the kinetics, we used the following parameters (median values): Effective half-life (hours) and uptake (fraction of injected activity), which were calculated using the fit of the time-dependent activity curve to a mono- or bi-exponential function.

Results: Relatively, intense uptake in the metastases as well as a significant uptake in the kidneys, as well as the parotid and lacrimal glands, was observed in all patients.

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 higher for PSMA I&T (PSMA I&T 0.95 Gy/GBq, PSMA-617 0.78 Gy/GBq); the dose to parotid glands was comparable for both PSMA ligands (1.1 Gy/GBq). Bone and lymph node metastases were analyzed separately. All tumor lesions demonstrated a higher initial uptake for therapy using PSMA I&T, followed by a faster washout 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 (PSMA-617 71 h, PSMA I&T 44 h), but the highest tumor dose to lymph node metastases was delivered by PSMA I&T (PSMA I&T 8 Gy/GBq, PSMA-617 6 Gy/GBq). No clinically relevant renal or salivary gland toxicity was observed in any of the patients.

Conclusions: These results demonstrate the different kinetics of both PSMA ligands in mCRPC patients. There is a large inter-patient variability of the dosimetric parameters, underlining the importance of individual patient dosimetry of personalized radioligand therapy.

Role of Copper-64 Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography in Theranostics of Prostate Cancer

Prostate Cancer: Small Molecule Radioligand Therapy

Aviral Singh, Harshad R. Kulkarni, Richard P. Baum

Theranostics Center for Molecular Radiotherapy and Molecular Imaging, ENETS Center of Excellence, Zentralklinik Bad Berka, Germany

Objectives: Copper-64 ( 64 Cu) is suitable for in vivo positron emission tomography (PET) imaging. The physical properties of 64Cu include its longer half-life (T1/2 = 12.7 h) and low-energy positrons (Eβ+ max = 0.65 MeV [17.9%]; Eβ max = 0.57 MeV [39%]). Prostate-specific membrane antigen (PSMA) is particularly overexpressed in undifferentiated prostate cancer. We report the results of molecular imaging with 64 Cu-PSMA PET/computed tomography (CT) in patients with suspected recurrent prostate cancer.

Methods: Nine prostate cancer patients (age: mean = 72.1 years, range = 60-80 years) with elevated prostate-specific antigen (PSA) and suspicion of recurrent disease after conventional treatments were referred by their respective urologists to our center for restaging. Following acquisition of informed consent, a mean activity of 251 MBq of 64 Cu was administered to these patients. Whole-body PET/CT (Biograph mCT Flow 64) was performed. Late images, up to 17 h p.i., were acquired in three patients. Qualitative analysis (visual assessment) and quantitative analysis (recording of maximum standardized uptake value) were performed for each study by two experienced nuclear medicine physicians. For restaging of disease, comparison was made with previous and concurrent imaging.

Results: Previous prostatectomy had been performed in 7/9 (77.7%) patients. Visual analysis demonstrated uptake in the prostate bed, suggestive of local recurrent disease in 2/9 (22.2%) patients. Pathological tracer uptake was detected in lymph nodes in 5/9 (55.5%) and skeletal (bone/bone marrow) lesions in 4/9 (44.4%) patients, suggestive of metastases. There was no pathological tracer uptake seen in 2/9 (22.2%) patients. Consequently, three patients had stable disease despite PSA increase. Progressive disease was observed in 4/9 (44.4%) patients, of which three were recommended 177 Lu-PSMA radioligand therapy (PRLT) and one was rescheduled for restaging in 6 months. No adverse effects were observed in any patient, following administration of 64 Cu-labeled PSMA.

Conclusions: The results of this study demonstrate that Cu-64-PSMA PET/CT has potential for prostate cancer staging, restaging, and 177 Lu-PSMA radioligand therapy planning. High-resolution PET images can be obtained using 64 Cu-PSMA. Late imaging, up to 17 h p.i., is possible due to the longer half-life of 64 Cu as compared to 68 Ga. 64 Cu can be produced centrally and distributed to distant centers without a cyclotron or where 68 Ga-generator facilities are not available. 64 Cu was found safe for clinical use. Future application as a theranostics "matched pair" is possible, utilizing the therapeutic properties of the beta-emitting 67 Cu, in combination with the diagnostic properties of 64 Cu. Further clinical studies directly comparing other radiopharmaceuticals, such as 68 Ga- or 18 F-choline, are warranted to establish the specific role of 64 Cu-PSMA PET/CT in theranostics of prostate cancer.

177 Lu-PSMA-617 Radioligand Therapy of Metastatic Castration-resistant Prostate Cancer: Update on the Bad Berka Experience

Prostate Cancer: Small Molecule Radioligand Therapy

Ariral Singh, Harshad R. Kulkarni, Christiane Schuchardt, Karin Niepsch, Richard P. Baum

Theranostics Center for Molecular Radiotherapy and Molecular Imaging, Zentralklinik Bad Berka, Germany

Objectives: The objective of this study was to reanalyze the safety, efficacy, and dosimetry data of 177 Lu-PSMA-617 radioligand therapy (PRLT) in a larger number of patients with progressive metastatic castration-resistant prostate cancer (mCRPC), who have exhausted other methods of possible conventional therapies.

Methods: Fifty-three patients were diagnosed with progressive mCRPC on 68 Ga-PSMA-HBED-CC ( 68 Ga-PSMA) positron emission tomography/computed tomography (PET/CT). These patients were treated with a total of 137 cycles (1: n = 10; 2: n = 15; 3: n = 18; 4: n = 7; 5: n = 3) of PRLT using 177 Lu-PSMA-617 between April 2015 and May 2016 according to our previously published protocol. The median administered activity of 177 Lu per cycle was 6.04 GBq. Safety of PRLT using 177 Lu-PSMA was analyzed according to the following parameters: (a) clinical assessment - monitoring side effects, such as xerostomia, nausea, vomiting, constipation, and disease-related pain, (b) assessment of hematological status before and after PRLT - complete blood counts (hemoglobin, leukocytes, thrombocytes), and (c) assessment of renal function before and after PRLT - biochemical analysis (urea, creatinine, estimated glomerular filtration rate [eGFR]), and tubuloexcretory function (TER) using MAG3-renogram. Efficacy was evaluated according to the following parameters: (a) clinical response: Change in pain score using visual analog scale (VAS), (b) biochemical response: Change in serum prostate-specific antigen (PSA) levels, and (c) disease control rate (DCR) was calculated using molecular response to therapy on 68 Ga-PSMA PET/CT. Dosimetry using the MIRD scheme was performed in 19 patients.

Results: Regarding safety of therapy, 177 Lu-PRLT was well tolerated in most patients. Mild reversible xerostomia was observed in five patients. Nausea (n = 0), emitus (n = 1), and constipation (n = 2) were observed in patients receiving opioid analgesia for disease-related pain and were not directly related to PRLT. Temporary increase in bone pain up to 36 h was observed in three patients with skeletal metastases, and this was attributed to flare phenomenon. Post-PRLT, grade G1, G2, and G3 anemia was observed in one patient each. Grade G2 (n = 2) and G4 (n = 1) leukocytopenia and G1 (n = 2) and G4 (n = 1) thrombocytopenia were also observed. Predisposing risk factors for higher grade (>G2) or preexisting hematotoxicity were associated with previous chemotherapy, 223 Ra-chloride therapy, or extensive skeletal metastases. There was no evidence of clinically significant nephrotoxicity, and the mean serum urea and creatinine, eGFR, and MAG3-renogam-based TER remained within the acceptable normal limits, following PRLT. Regarding efficacy of PRLT, improvement in pain scores (VAS) was observed in all patients having disease related pain before the commencement of PRLT. Biochemically, PSA decline was observed in 42/53 (79%) of patients, with the best PSA response of PSA decline from 66.31 to 0 ng/ml. Molecular response evaluation using 68 Ga-PSMA PET/CT was performed in 26 patients who were followed up for 3-12 (mean = 6) months after 2-4 cycles of PRLT. DCR was 69%, with 18/26 patients showing clear response (n = 3, 11%), partial response (n = 9, 35%), and stable disease (n = 6, 23%). Progressive disease was observed in 8/26 (31%) patients. Dosimetry demonstrated a median absorbed tumor dose of 5.1 mGy/MBq. The mean absorbed dose to the whole body, kidneys, parotid glands, and lacrimal glands was 0.04, 0.8, 1.1, and 9.9 MGy/MBq, respectively. At the time of this analysis, 7/53 (13%) patients were deceased (six due to progression of disease and one due to acute myocardial infarction).

Conclusion: The results of this study demonstrate that PRLT using 177 Lu-PSMA-617 appears to be safe and effective in the management of progressive mCRPC. It may potentially offer an additional survival benefit compared to the conventional therapy regimens in patients who have progression of disease after exhaustion of all such possible measures. Dosimetry and tracer kinetics were favorable and similar to that of 177 Lu-PSMA I&T. Application of the concept of Theranostics enable appropriate selection and follow-up of patients by 68 Ga-PSMA PET/CT.

Assessment of Proton Therapy and New Proposed Plasma Therapy on the View of Bragg Effect

Current and Future Therapeutic Radiopharmaceuticals

Tanvir Ahmed Biman, Md. Nahid Hossain, Anwar-Ul Azim, Ramit Azad 1

National Institute of Nuclear Medicine and Allied Sciences, Bangladesh Atomic Energy Commission, 1 American International University, Bangladesh

Objective: To introduce a new therapeutic technique, this is more safety (almost no dose regularities) and cost-effective with less biological side effects; we should analyze two types of particle radiation therapy procedures, namely, proton therapy and new proposed on the view of Bragg effect.

Background: The objective of all therapeutic procedures is to reduce the generated radicals or masses, causing for different physiological abnormalities in human body. To prevent the reproducibility of abnormal radicals and mass different energized (particle or nonparticle), therapeutic techniques are taken, i.e., make enforce into tissues, cells, and DNA level of the abnormalities in human body (cancer cell, tumor, etc.). Usually, nonparticle external radiation or particle radiation, such as proton beam, is used for treatment of various cancer, which is very costly and having some side effects. Here, we like to introduce (cost-effective and with less side effects) plasma therapy as similar form of proton therapy (particle radiation) but originated from plasma, in which electrons are heated by beam plasma discharge in mirror magnetic trap. Electrons and ions leaving the magnetic trap in beam plasma discharge may take part into the collective acceleration during the period of plasma fall off. In this process, the ions (which are called in Plasma Physics as "Plasmon") can be accelerated up to heated electrons' velocities. Keep in account that the mass ratio of electrons and ions (for proton 1840), one can assume that the "plasmons" get enough high energies from the heating system. We know that to separate "plasmons" from the heated electrons needs some electron capturing filters (such as carbon). Thus, we can get the high-energized "plasmons," which may introduce as a new technique of external beam therapy. Comparison of the newly proposed technique to the proton therapy is low costing and having the opportunity to neutralize the generated radicals in same way as proton beam therapy (with regulation of energy) and also can reach the electroneutrality of affected organ; if we consider the high mass ratio "plasmons" than proton, we can assume that the depth of Bragg peak in tissue for "plasmons" is relatively better than proton therapy with relatively low dose of radiation. The depth of the Bragg peak in tissue for proton therapy is dependent on the energy of the beam; the higher the energy, the deeper the Bragg Peak and therefore, the deeper the dose. The Bragg peak is a pronounced peak on the Bragg curve which plots the energy loss of ionizing radiation during its travel through matter. A peak occurs because the interaction cross-section increases as the charged particle's energy decreases.

Materials and Methods: Heated electrons leaving the mirror magnetic trap may participate in acceleration during plasma fall off, whereby the ions ("plasmons") accelerate up to the velocities of heated electrons, thereby reaching sufficiently high energies while the heated electrons were found 250 keV (the peak of the spectrum of X-ray quanta) at stationary process of plasma heating by beam plasma discharge. A series of experiments of electron heating by beam plasma discharge into the mirror magnetic trap was executed in "Kurchatov Institute, Moscow, Russia " on the installation of "Oratoria-10" as stationary mode and adiabatic compression of plasma. Separating heated electrons requires capturing filters such as carbon to obtain high energized "plasmons" as a basis for a new approach of external beam therapy.

Results: At the late 90`s a series of experiments were executed on the installation "Oratoria 10" at "Kurchatov Institute" to generate high-energized X-ray quanta: Two types (hydrogen and argon) of working gases were used and the optimal discharge parameters for hydrogen (for X-ray quanta from hydrogen with energy 230-250 keV) in stationary mode were like that; magnetic field 330 Oe, pressure of working gas 8.5 × 10−5 Torr, energy of the beam 3 keV, beam current 0.75 A. On the other hand, the optimal discharge parameters for argon (for X-ray quanta from argon with energy 380-400 keV) in stationary mode were like that; magnetic field 600 Oe, pressure of working gas was achieved as 8.5 × 10−5 Torr, energy of the beam was 3 keV, beam current was up to 0.75 A. In the process of collective acceleration of particles, "plasmons" could be heated about ~2000 times of X-ray quanta with respective discharge parameters for each working gas. To evaluate the biological effect which is required to introduce this new therapy technique for various cancer treatments. We assume to get the distinctly deeper Bragg peak in tissue than any other particle radiation therapy such as proton therapy.

Conclusion: The new therapeutic technique is proposed on the base of experimental works executed at "Kurchatov Institute" on the installation of "Oratoria-10." Hence, to introduce the mentioned technique, we have to realize a series of experiments with the analog installation.

Production and Therapeutic Application of Iodine-131 in Nuclear Medicine of Bangladesh: Present Status and Future Plan

Current and Future Therapeutic Radiopharmaceuticals

Mohammad Anwar-Ul Azim, Mizanul Hasan, Raihan Hossain, Israque Hossain Ansari, Faria Nasreen, Nahid Hossain, Tanvir Ahmed Biman, Simoon Salekin

National Institute of Nuclear Medicine and Allied Sciences, Bangladesh Atomic Energy Commission, Dhaka, Bangladesh

Background: Radionuclide therapy has the advantages of systemic administration as well as selective irradiation of tissues. Various radionuclides have been discovered or developed for therapeutic purposes since the first use of radium in the early 1900s. At present, iodine-131 labeled with sodium iodide (NaI) in capsule or liquid form is the most commonly used therapeutic radionuclide in the nuclear medicine (NM) of Bangladesh. The treatment is widely known as radioactive iodine (RAI) therapy, which uses I-131 to treat thyroid-related diseases such as Graves' disease, solitary hyperfunctioning nodule, and toxic multinodular goiter. RAI may also benefit patients with subclinical hyperthyroidism.

Production Methods: Radioisotope Production Division (RIPD) of Bangladesh Atomic Energy Commission (BAEC) produces I-131 by irradiating natural tellurium dioxide (containing 33.4% of Te-130) target in the 3 MW TRIGA Mark-II Research Reactor (BTRR). Te-130 captures neutron to produce Te-131, which transforms into I-131 by beta emission. The irradiated tellurium dioxide is cooled down for 2 days and then heated at about 730°C. Iodine-131 is released and transferred by air stream into a trap filled with Na 2 CO 3 /NaHCO 3 buffer or 10 mM NaOH solution. More than 99% of iodine is absorbed as NaI at pH 7-9. To produce I-131 capsules locally, a plant has been installed at RIPD in 2001. The facility can be used for the production of both diagnostic and therapeutic capsules. I-131 capsules are prepared by absorbing a solution of carrier-free 131 I-NaI into inert filler. Inert filling material of the capsules is the mixture of dry Na 2 HPO 4 , ascorbic acid, and Na 2 S 2 O 3 powder in 10:1:1 ratio.

Results: With the present production facility, RIPD can produce 370 GBq of I-131 solution per batch, whereas the country's present weekly demand is ~850 mCi and present weekly demand of I-131 capsule is 56 GBq (~1.5 ci). Among the 20 NM facilities of Bangladesh, 14 Institutes of Nuclear Medicine and Allied Sciences (INMAS) and 1 National INMAS (NINMAS) run under the Bioscience division of BAEC. In all the NM facilities of Bangladesh, BTRR produced I-131 is used for both diagnostic and therapeutic purposes, such as diagnostic studies of thyroid disorders, therapeutic application for treatment of thyrotoxicosis, and thyroid cancer. NINMAS, situated at Bangabandhu Sheikh Mujib Medical University, Dhaka, is by far the largest NM facility in the country. From 2005 to June 2016, NINMAS has served a total of 3398 new toxic patients and 3843 new carcinoma thyroid patients with the 131 I-NaI solutions and 131 I-NaI capsule, respectively.

Conclusion: At present, I-131 is the only radionuclide being used for therapy in Bangladesh. The production facility of Lu-177 by irradiating Lu-176 in the research reactor and Y-90 from Sr-90/Y-90 generator is in the final stage to be installed, with the assistance of International Atomic Energy Agency TC project (BGD/6/022). Inclusion of Lu-177 and Y-90 and their labeled compounds for radionuclide therapy for bone pain palliation of cancer patients will definitely expand the therapeutic NM services in Bangladesh.

Radionuclidic Dye Analogs for Cancer Targeting

Current and Future Therapeutic Radiopharmaceuticals

Daya Hazra, Padmamalika Hazra 1

Innovative Cancer Therapy and Research Foundation, S. N. Medical College, 1 St. Johns College, Agra, Uttar Pradesh, India

Background: Despite advances in radiolabeled antibody therapy (even with alpha nuclides which can kill by single cell traverses), modeling shows that the fraction of cell kill does not reach 100% because not all cancer cells express the target antigen (Roger Howell: Treatment Planning at the Cellular level is required to sterilise Disseminated Tumour Cells: Presentation at the SNMMI annual meeting San Diego, June 14, 2016). Using a cocktail of antibodies against different surface targets may increase cell kill, but this is logistically difficult and expensive and may still not achieve 100% kill because of the lognormal distribution of antigen targets and the phenomenon of antigenic modulation. An attractive option is the use of agents which stain nuclei such as propidium iodide or toluidine blue, coupled with radionuclides, to supplement radiolabeled antibodies. This communication briefly reviews current knowledge and proposes a rational strategy.

Methods: Literature review shows that the concept of selective dyes dates back to Paul Ehrlich's doctoral dissertation on Beitrδge zur Theorie und Praxis der histologischen Fδrbung, 1878, the forerunner of his magic bullet concept which culminated in the Salvarsan triumph against syphilis. Dyes can be classified as the propidium type basic dyes targeting nuclear DNA/RNA and acidic dyes targeting basic cytoplasm. For cancer therapy as opposed to mere diagnosis, one needs "nucleophilic" (histological rather than the chemical sense of the term) dyes which can enter living cells and target their nuclei, i.e., supravital type staining, such as toluidine blue rather than propidium iodide type dyes which stain dead cells. Oropharyngeal cancers, many of them related to tobacco, are a major problem in North India, especially Mainpuri district of the Agra region. Toluidine blue has already been used in the visual diagnosis of oral cancers, somewhat analogous to the Papanicolaou technique for diagnosing cancer cervix and their value for both screening and case finding has been critically reviewed (Lingen et al., 2007: Oral Oncology, doi:10.1016/j.oraloncology.2007.06.011). High sensitivities have been reported, especially for multiple primaries frequently encountered ("field cancerization"). Serologically, they exhibit a very high titer of therapeutic plasma system (TPS) antigen, and therefore, radiolabeled anti-TPS antibody M3 can be used for imaging and perhaps in the future radiobioconjugate therapy after surgery. Radiolabeled toluidine blue thus appears to be an attractive adjunctive therapy to achieve 100% cell kill combined with radioimmunotherapy. Chemically, toluidine blue is a basic thiazine metachromatic dye with high affinity for acidic tissue components, thiazines, which contain 4 carbon, one nitrogen, and one sulfur atoms. Toluidine blue has the molecular weight 270, with the formula C 15 H 16 N 3 S+. Radiolabeling this for imaging and/or therapy is therefore proposed. Apart from cancer cell suspensions, the radiolabeled agent can be tested against lignin in plant sections before use in experimental animal tumors.

Results and Conclusion: A strategy for using radiolabelled dyes to enhance cancer cell kill is proposed, which can be evaluated against cancer cell suspensions, pari passu, with anti-cytokeratin radioimmunotherapy.

Radioimmunoliposomes Targeting Cancer Stem Cells in Mesothelioma

Current and Future Therapeutic Radiopharmaceuticals

Jiang He, Jae Sam Lee, Tao Huang, Anna B. Banizs

University of Virginia, VA, USA

Background: Malignant mesothelioma (MM) is a lethal tumor originating in the mesothelium with high chemotherapeutic resistance. Cancer stem cells (CSCs) persist in tumors and are critical targets responsible for tumor resistance and recurrence. The objective is to isolate CSCs and test 177 Lu-labeled immunoliposomes ( 177 Lu-ILs) for therapeutic effect.

Methods: MM CSCs were sorted based on CD26/24 expression level and their functional significances were established by small interference RNA. CSC potential of MMs was evaluated for drug resistance, cell invasion, and cell growth rate in vitro. MM cells were incubated with 18 F-fludeoxyglucose to evaluate metabolism in CSCs. Approximately 90 nm ILs were radiolabeled with 177 Lu through diethylene triamine pentaacetic acid conjugated on the liposome lipid. Therapeutic effects of 177 Lu-ILs were evaluated in vitro through proliferation and apoptotic assays.

Results: CSCs expressed significant drug resistance with upregulated proliferative and invasive activities compared to the H28 and shRNA cells (P < 0.001). Cell line-dependent decreases in cell viability were observed following treatment of ILs as well as 177 Lu-labeled control liposomes ( 177 Lu-CLs) and 177 Lu-ILs. Significant inhibition of cell proliferation was apparent in the treatment groups compared to untreated controls, and most affecting treatment was 177 Lu-ILs in CSCs (P < 0.01). Cytotoxicity to CSCs induced by 177 Lu-CLs was less significant than achieved with 177 Lu-ILs (P = 0.07).

Conclusion: 177 Lu-IL has showed effective in reducing proliferative activities and activating apoptosis of CSCs in MMs compared to each immunotherapy and radiotherapy.

Radium Dichloride Therapy of Symptomatic Bone Metastases in Patient with Castration-resistant Prostate Cancer

Current and Future Therapeutic Radiopharmaceuticals

Lucia Kaliska, Iveta Vinarcikova Miksikova, Marika Vereb 1

Institute of Nuclear and Molecular Medicine, SK, 1 Praxis für Radiologie, Nuklearmedizin und Strahlentherapie, Germany

Background: Prostate cancer is a hormonally sensitive disease that can often be controlled for long periods with androgen-deprivation therapy. Metastatic hormone-refractory prostate cancer is a challenging form of the disease to treat because cancer has spread to distant sites in the body and does not respond to treatment with standard hormonal therapy. Bone metastases often result in painful skeletal events, reduced quality of life, and reduced survival. Ra-223 represents new form of radionuclide therapy aimed to symptomatic bone metastases (requiring regular analgesic medication) in metastatic castration-resistant prostate cancer (mCRPC). This alpha emitter mimics calcium and forms complexes with the bone mineral hydroxyapatite at areas of increased bone turnover, such as bone metastases. The way of its action ensures to deliver radiation directly to bone tumors, thereby limiting the damage to the surrounding normal tissues. Our aim was to evaluate the efficacy and safety of Ra-223 therapy in men with mCRPC.

Patients and Methods: Eleven consecutive patients with mCRPC with symptomatic bone metastases (confirmed by bone scintigraphy) and no known visceral metastatic disease (proved by contrast-enhanced computed tomography) were prospectively enrolled in the study. Taking appropriate radiation safety precautions, six injections of Ra-223 (in dose of 50 kBq/kg) are intravenously administered to each patient at 4 weeks intervals. Complete blood counts are taken 1 week before each subsequent dose of Ra-223. Before initial radium-223 administration, the hemoglobin, platelet, and absolute neutrophil counts must be ≥10 g/dL, ≥100 × 109/L, and ≥1.5 × 109/L, respectively. Subsequent Ra-223 administrations require an absolute neutrophil count of ≥1 × 109/L and a platelet count of ≥50 × 109/L. Patients and caregivers are educated regarding radium-223 efficacy and safety. Urologists coordinate the administration of Ra-223 with nuclear medicine physicians while monitoring patients during and after the therapeutic course.

Results: Of 11 patients, four received all six cycles of radium-223 (recommended treatment course); follow-up bone scintigraphy confirmed good therapy response with reduction number and intensity of metastatic lesions; moderate relief of bone pain was noticed in all 4/11 patients. The treatment was discontinued in 1/11 patient due to sustained bone marrow suppression. Of 11 patients, six continued in the course of therapy. Side effects: 1/11 patient showed transitionally worsening of jaw osteonecrosis but carried on in therapy; in 6/11 patients, temporary increase in bone pain and moderate fatigue were seen; in 1/11 patient, blood transfusion before Ra-233 administration was necessary due to anemia. Of 11 patients, one had initial scintigraphic pattern of superscan, however continues in therapy without hematologic abnormalities in laboratory results. In all 11/11 patients, temporarily mild to moderate decrease in white and red blood cells and platelet counts were noticed and no interruption in therapy was necessary.

Conclusion: Ra-223 has been already approved to prolonged time to first symptomatic skeletal event by 5.8 months. According to our preliminary results, the therapy with Ra-223 in mCRPC is efficient with partial to significant reduction of tumor volume on sequential bone scintigraphy scan, partial pain palliation with ameliorated performance status. It is relatively well tolerated, without severe hematological laboratory abnormalities.

NETTER-1 Phase III in Patients with Mid-gut Neuroendocrine Tumors Treated with 177 Lu-DOTATATE: Efficacy, Safety, Quality of Life Results, and Subgroup Analysis

Current and Future Therapeutic Radiopharmaceuticals

Maribel Lopera Sierra, Jonathan Strosberg 1 , Edward Wolin 2 , Beth Chasen 3 , Matthew Kulke 4 , David Bushnell 5 ,

Martin Caplin 6 , Richard Baum 7 , Pamela Kunz 8 , Timothy Hobday 9 , Andrew Hendifar 10 , Kjell Φberg 11 , Kwekkeboom DJ 12 , Philippe Ruszniewski 13 ,

Eric Krenning 14


Maribel Lopera Sierra, Advanced Accelerator Applications Inc., 1 Moffitt Cancer Center, Tampa, FL, 2 Markey Cancer Center, University of Kentucky, Lexington, 3 University of Texas MD Anderson Cancer Center, Houston, TX, 4 Dana-Farber Cancer Institute, Boston, MA, 5 University of Iowa, Iowa City, IA, 8 Stanford University Medical Center, Stanford, 10 Cedars Sinai Medical Center, Los Angeles, CA, 9 Mayo Clinic College of Medicine, Rochester, MN, USA, 7 Zentralklinik Bad Berka, Germany, 11 University Hospital, Uppsala University, Uppsala, Sweden, 12 Erasmus Medical Center, Rotterdam, The Netherlands, 13 Hospital Beaujon, Clichy, France, 14 Erasmus Medical Center, Rotterdam, The Netherlands, 6 Royal Free Hospital, London, UK

Background: Currently, there are limited therapeutic options for patients with advanced mid-gut neuroendocrine tumors progressing on first-line somatostatin analog therapy.

Methods: NETTER-1 is the first Phase III, randomized trial evaluating 177 Lu-DOTA0-Tyr3-Octreotate (Lutathera® ) in patients with progressive, somatostatin receptor-positive mid-gut neuroendocrine tumor (NETs). A total of 230 patients were randomized to receive Lutathera 7.4 GBq every 8 weeks (×4 administrations) versus Octreotide LAR 60 mg every 4 weeks. The primary endpoint was progression-free survival (PFS) (RECIST 1.1). Secondary objectives included overall response rate, overall survival (OS), toxicity, and quality of life (QoL) based on European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-G.I.NET21 questionnaires. Subgroup analysis of PFS was performed to assess impact of potential prognostic factors.

Results: The centrally confirmed disease progressions or deaths were 23 in the Lutathera arm and 68 in the Octreotide LAR 60 mg arm. The median PFS was not reached for Lutathera and was 8.4 months with control, P < 0.0001, hazard ratio 0.21. At the time of the NDA/MAA submission, interim OS analysis (14 deaths in Lutathera group and 26 in control group; P = 0.0043) suggested an improvement in OS. Subgroup analyses for PFS confirmed consistent benefits of Lutathera irrespective of stratification and prognostic factors including tumor grade, age, gender, tumor marker levels, and levels of radiotracer uptake. Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9% of patients in Lutathera arm versus none in controls. Health-related QoL surveys indicated a moderate improvement in the global health status in the Lutathera treatment arm, demonstrating that the treatment benefit of Lutathera is not offset by a negative impact on patient QoL.

Conclusions: The Phase III NETTER-1 trial provides evidence for a clinically meaningful and statistically significant increase in PFS and suggests an OS benefit in patients with advanced mid-gut NETs treated with Lutathera. Subgroup analysis demonstrates consistent benefit across prognostic factors. The Lutathera's safety and QoL profile were found to be favorable.

Combined External and Internal Beam Radiotherapy for Inoperable Carotid Paraganglioma

Dosimetry

Vineet Pant, Ishita Barat Sen,

Sugandha Dureja, Parul Thakral


Fortis Memorial Research Institute, Gurgaon, Haryana, India

Background: Paragangliomas are tumors originating from neural crest-derived cells situated in the region of the autonomic nervous system ganglia. Surgery is the treatment of choice for both sympathetic and parasympathetic PGLs. Other types of treatment include medical agents (such as gemcitabine, cisplatin, or sunitinib) and radiotherapy (external beam radiotherapy or stereotactic surgery). Surgery and radiotherapy, however, can cause important side effects such as vascular complications and peripheral nerve damage (hypoglossal, recurrent laryngeal, glossopharyngeal, and vagus). Another treatment option is the use of peptide receptor radionuclide therapy (PRRT), including PRRT with 177 Lu-DOTATATE.

Methods: We present a case of right carotid paraganglioma patient in whom complete surgical excision due to inoperable intracranial extension was not possible. He was treated with 177 Lu PRRT and external beam radiotherapy. A dosimetric evaluation was performed after 177 Lu PRRT administration.

Results: His posttreatment 68-Ga-DOTANOC positron emission tomography-computed tomography showed partial treatment response with >50% reduction in target tumor volume.

Conclusion: 177 Lu-DOTATATE is a good alternative treatment for treatment of paraganglioma and has a therapeutic effect, even in advanced paraganglioma.

Validation Studies of Theranostic Glycoconjugates in Metastatic Melanoma

Current and Future Therapeutic Radiopharmaceuticals

Nilesh Wagh, Sanjay Thamake, Mengshi Li 1 , David Ranganathan,

Michael Schultz 1 , Ebrahim. S. Delpassand, Izabela Tworowska


Radiomedix Inc., 1 The University of Iowa, Iowa, USA

Introduction: The goal of our studies is to develop 203 Pb/ 212 Pb-"theranostic" platform to advance image-guided therapy and to detect and deliver therapeutic radiation dose precisely to metastatic melanoma cells. The RMX-GC compounds validated in these studies are glucosamine-conjugates that target differences in metastatic melanoma metabolism and upregulation of glucose transporter 1 (GLUT1) receptors, compared to normal cells.

Methods: Two glucosamine derivatives, DOTA-RMX-GC-08 and TCMC-RMX-GC-15, were synthesized using click chemistry approach. 203 Pb-radiolabeling was performed in mild conditions in NH 4 OAc (pH = 5.6). Radiochemical stability of agents, their GLUT targeting properties, and internalization were determined in vitro in cellular uptake studies using A357 (BRAF mutant), MeWo (BRAF WT), and B16 (F10). The in vivo pharmacokinetics of agents was investigated in biodistribution studies of B16 (F10) mice xenografts.

Results: DOTA-RMX-GC-08 and TCMC-RMX-GC-15 were synthesized with chemical purity of 90%, analyzed by reversed phase high-performance liquid chromatography and liquid chromatography-mass spectroscopy. The radiochemical purity of agents was >95% and they have showed high in vitro stability up to 72 h of postlabeling. Cellular studies confirmed GLUT-specific accumulation of radiotracer in tested cancer cell lines, with values ranging from 5.3% to 6.8% ID/mg during the first 3 h of incubation. There was dose-dependent correlation between uptake of 203 Pb-RMX-GC and concentration of GLUT competitors (glucose, glucosamine, and cytochalasin B). In vivo biodistribution studies confirmed tumor-specific accumulation of 203 Pb-DOTA-RMX-GC-08 and 203 Pb-TCMC-RMX-GC-15 (5.67% ± 2.76% ID/g and 3.55% ± 0.04% ID/g at 30 min, respectively). The 203 Pb-TCMC-GC-15 showed more rapid tumor accumulation compared to 203 Pb-DOTA-BNCO-GC. The clearance of both agents preceded through the renal system with limited accumulation in other off-target organs (liver, lung)

Summary: Two 203 Pb-labeled glucosamine conjugates have shown promising pharmacokinetic characteristic and radiochemical stability required for targeted image-guided therapy. The 203 Pb-RMX-GC diagnostic agents can be potentially used to select patients who can benefit from precisely delivered therapeutic alpha particle radiation dose to metastatic melanoma cells using 212 Pb.

Comparison of Calibration Factors of Ra-223 in Commercial Radionuclide Dose Calibrators

Dosimetry

Milena Dimcheva, Sonya Sergieva, Bozhil Robev 1

Department of Nuclear Medicine, Sofia Cancer Center, 1 Department of Medical Oncology, University Hospital St. Ivan Rilski, Sofia, Bulgaria

Ra-223 predominantly emits α-particles that deliver high linear energy transfer (LET, 95.3%, energy range 5.00-7.05 MeV), with a short range of approximately <0.1 mm (2-10 tumor cell diameters). It has a half-life of 11.4 days and decays through a series of short-lived daughter isotopes to stable lead, Pb-207. The specific activity of Ra-223 is 1.9 MBq (51.4 μCi)/ng. Other particles emitted are low-LET β-particles (3.6%, average energies 0.445 MeV and 0.492 MeV) and γ-irradiation (1.1%, energy range of 0.01-1.27 MeV) (Xofigo-PI, 2016). The dosing scheme of Ra-223 is 55 kBq (1.45 μCi)/kg body weight, given at 4-week intervals for six injections. Ra-223 is provided as a ready to use liquid, and the volume of agent administered to a given patient to achieve the required dose should be calculated using a combination of the patient's body weight (kg), the radioactive concentration of the product (1.100 kBq/mL; 37 μCi/mL) at the reference date (given on the vial), and the decay correction factor to correct for physical decay of Ra-223 (information supplied in the package insert) (Xofigo-PI, 2016; Xofigo-SPC, 2016). In the clinical setting, dosage measurements of Ra-223 are normally measured initially in a standard glass vial, and aliquot of the solution is then usually withdrawn into a syringe before the administration. Both for general quality assurance good practice and for additional guarantees for patient safety, a confirmatory measurement of the syringe is almost obligatory. Because of the different geometries and elemental compositions between plastic syringes and glass vials, the calibration factors for syringes may well be significantly different from those for the glass containers. The magnitude of these differences depends on the energies of the emitted photons. Concurrent with the primary standardization of Ra-223, the Radioactivity Group at National Institute of Standards and Technology (NIST) established that the calibration factors currently in use for clinical trials give average activity readings 5.7%-8.7% higher than the NIST calibrated activity. The present development of secondary standards determines calibration settings for the most commonly used dose calibrators for the standard 5 mL NIST ampoule geometry and for clinically relevant geometries. Because the characteristics (wall thickness, composition, etc.,) of the sample container affect the extent to which source radiation is attenuated, accurate activity measurements must be geometry-specific. In conclusion, the prime function of secondary standard dosimetry laboratory is to provide calibration services. After calibrating the radionuclide dose calibrator, calibration factor is provided for radiation detectors to correct the response to true value. Calibration factor is a quotient of the conventional true value and the indicated value corrected to the reference condition.

Graphene Oxide/Polyvinyl Chloride Nanocomposite: A New Dosimeter for Medical Gamma Radiation Applications

Dosimetry

Shahzad Feizi

Nuclear Science and Technology Research Institute, Tehran, Iran

Background: Graphene promising advantageousness in almost every niche area of modern applications stems from the unique combination of several excellent physiochemical properties in its two-dimensional (2D) nanostructure. The gamut of its flourishing applications not only includes gas and electrochemical energy storage systems, nanocomposites, nanoadsorbents, nanophotonic and photovoltaic devices, ultrafast field-effect transistors, and ultrasensitive nanosensors but has also even pioneered smart drug or gene delivery systems and cell culture scaffolds in nanomedicine recently.

Methods: Graphene oxide-polyvinyl chloride (GO/PVC) composite was prepared using tetrahydrofuran solvent-assisted dispersion of characterized nanoflakes of GO in polymer matrix. Electrical percolation threshold of GO/PVC nanocomposite was determined through a finite element simulation method with a 2D model and compared with experimental results. A conductive cell with two silver coated walls was designed and fabricated for exploring dosimetric properties of the composite. Some characteristics of the new nanocomposite such as linearity of dose response, repeatability, sensitivity, and angular dependence are investigated.

Results: According to 2D proposed method, obtained data associated to electrical conductivity of the polymer-GO composite for PVC matrix plotted in different GO weight percentages and had good compatibility (validity) with experimental data.

Conclusion: The dose response is linear in the 17-51 mGy dose range, and it can be introduced for gamma radiation dosimetry in diagnostic activities.

Peptide Receptor Radionuclide Therapy (Lu-DOTA) with Capacitabine and Temozolamide in Advanced Low-grade Neuroendocrine Tumor: A Dosimetry Evaluation

Dosimetry

Vineet Pant, Ishita Barat Sen, Sugandha Dureja, Parul Thakral

Fortis Memorial Research Institute, Gurgaon, Haryana, India

Background: Low-grade neuroendocrine tumors (NETs) arise in many body areas and particularly in gastropancreatic tissues and the small bowel. Peptide receptor radionuclide therapy (PRRT) is an effective treatment option for patients with well-differentiated somatostatin receptor-expressing NETs. Calculation of the absorbed dose is important for evaluation of risk and for predicting the response of PRRT. Capecitabine and temozolomide chemotherapy can be safely combined with standard therapeutic activities of 177 Lu octreotate radiopeptide for advanced NETs. We present data of dosimetry analysis of six patients using radiosensitizing chemotherapy with capecitabine and temozolomide in combination with 177 Lu octreotate.

Methods: Dosimetry was performed according to the MIRD scheme with modification for our conditions at our department. Planar whole-body scintigraphies were performed at 1, 48, and 72 h postinjection. Images were analyzed by regions of interest with Hermes and time-dependent organ and tumor activities were determined.

Results: In six patients of NET receiving PRRT in combination with capecitabine, the cumulative doses were calculated for whole body, individual organ, and target lesions. The cumulative doses for nontarget organs were well below toxic thresholds. No scintigraphic uptake was seen in the bone marrow.

Conclusion: Capecitabine and temozolomide chemotherapy can be safely combined with standard therapeutic activities of PRRT for advanced NETs. The dosimetric analysis can help us in predicting possible toxicity and it can also play an important role in understanding therapy response.

Selective Internal Radiotherapy for Liver Metastasis: Does Tumoral dose Influence Time to Progression?: A Comparison between the 99m Tc-MAA Workup and 90Y Bremsstrahlung Imaging

Dosimetry

Kousigan Vadivelu, Shaunak Navalkissoor 1

Kings College London, 1 Royal Free London Hospital, London, UK

Background: Patients who are poor surgical candidates for surgical resection of liver tumors are contraindicated,selective internal radiotherapy (SIRT) provides a better local tumor burden control as a regional hepatic therapeutic modality. Patients who are poor surgical candidates or in whom surgical.

Aim: To assess the relationship between the dose estimation from 99m Tc-MAA and dose to tumor with 90Y Bremsstrahlung imaging. With respect to tumor dose, identify significant time to progression benefit.

Objectives: (a) Using single photon emission computed tomography/computed tomography (SPECT/CT) and contrast CT imaging of the liver, to analyze the correlation between pretherapeutic 99m Tc-MAA dose estimation and post 90Y-SIRT therapy dose to the liver metastases. (b) To evaluate whether humoral dose prolongs time to progression.

Methods: A retrospective analysis of patients (n = 21) who underwent SIRT was performed. Analysis of CT of the abdomen imaging, pretherapeutic 99m Tc-MAA SPECT/CT imaging, and post-90Y-SIRT imaging was undertaken. Response to therapy at 3 months posttherapy was analyzed using RECIST criteria (CT imaging). Dose to tumor and liver parenchyma was compared using t-test. A multivariate analysis of different tumor characteristics against the tumor dose was performed. Using Kaplan-Meier curve, time to progression was plotted.

Results: The mean estimated and administered dose to the tumor was 116 Gy and 103 Gy, respectively. The average time to progression in the liver and extrahepatic tissues in patients who had extrahepatic disease at the time of SIRT was 8.3 months and 6.5 months, respectively. There was no correlation between dose and time to progression.

Conclusions: SIRT is a safe and effective hepatic regional therapeutic modality. Control of tumor burden with SIRT in the liver leads to slow time to progression.

Sn-117m Colloid Radiosynoviorthesis Effects on Canine Osteoarthritis Synovitis as Evaluated by Positron Emission Tomography, Magnetic Resonance Imaging, and Behavioral Measures

Pain Palliation and Radiosynovectomy

Cynthia A. Doerr, Jimmy C. Lattimer 1 , Kimberly A. Selting 1 , Nigel R. Stevenson, John (Jay) M. Donecker, Gilbert R. Gonzales

R-NAV, LLC, 1 Missouri University College of Veterinary Medicine, USA

Background: Radiosynoviorthesis (RSO) is an established therapy for the treatment of osteoarthritis (OA) synovitis. The isotope Sn-117m (t1/2 14d; γ 159 keV, 86%) contains therapeutic monoenergetic conversion electrons (~140 keV, 112%) that have a range in tissue of ~300 μm. Prior data in OA-induced rat models and in normal canine elbows suggest that Sn-117m colloid may represent an ideal agent for use in RSO. A clinical trial using a Sn-117m homogeneous colloid device is enrolling 48 dogs with naturally occurring radiographic Grade 1-2 OA and that dogs also have limping or signs of pain on elbow manipulation. We report the positron emission tomography (PET) and magnetic resonance imaging (MRI) scan results and the owner-assessed pain and activity scores through a canine brief pain inventory (CBPI), of the first six dogs through 6 months of follow-up postinjection.

Methods: Dogs with naturally-occurring Grade 1-2 elbow OA are injected with one of three randomized Sn-117m colloid doses (dosage of each individual dog is also scaled based on weight), are being followed at 1, 3, 6, 9, and 12 months, and are assessed using multiple laboratory, physical, and imaging parameters. PET and MRI imaging was completed through both elbows. Postprocessing of the PET images included fusion of the axial PET images to the T1 fast spin echo sequence derived from the MRI scanner and determination of standard uptake values for a total of 15 cross-sectional images. CBPI is a standardized, validated owner assessment of pain and function, which was completed before clinical visits at baseline, 1, and 3-6 months.

Results: The first six dogs have been followed through 6 months. Dogs in the high and medium dosage groups (n = 3) had sustained improvement in synovitis on PET scoring, following Sn-117m colloid injection that was sustained through 6 months. The low dosage groups (n = 3) showed neither a significant nor sustained response on PET synovitis scoring. Interestingly, the high and medium dosage groups generally demonstrated an improvement in synovitis scores in the uninjected elbow as well. MRI demonstrated that five of the six dogs had improvement in imaging of the injected elbow at 6 months irrespective of dosage. The CBPI demonstrated improvement at some time points in 4 of the 6 subjects. Data on all 48 dogs and available results for PET, MRI, and CBPI will be reported.

Conclusion: The PET and CBPI data indicate that medium to high dosages of Sn-117m colloid provide a durable (at least 6 months) improvement in pain and function of canine elbow joints afflicted with naturally occurring OA, and the PET and MRI data demonstrate an improvement in metabolic and anatomical markers, respectively. Future studies of the product for use in human synovitis conditions are warranted.

223 Ra-dichloride Treatment of Bone Metastases of Patients with Prostatic Cancer: Efficacy and Safety

Pain Palliation and Radiosynovectomy

Ildiko Garai, Anna Kαplαr, Csaba Berczi 1

ScanoMed Ltd., University of Debrecen, Debrecen, 1 Department of Urology, University in Debrecen, Hungary

Background: Ra-223 dichloride is a newly introduced therapeutic option for the treatment of bone metastases. Previous studies confirmed that this alpha-emitting radiopharmaceutical can be used with safety and has benefit not only for subjective complaints but for overall survival too. We analyzed the efficacy and safety of Ra-223 chloride therapy based on our experience.

Patients and Methods: Forty-three (46-80-year olds) prostatic cancer patients with multiple bone metastases completed their Ra223 - dichloride therapy at our institute. One-third of patients had bone metastasis at the time of the diagnosis. Before the treatment, laboratory parameters (prostate-specific antigen, alkalic phosphatase [ALP], hemoglobin [Hb], absolute neutrophils count [ANC], thrombocytes [Thr]) and pain assessed by a ten-point visual score were evaluated. We classified the severity of anemia according to the WHO guideline. The mean visual score was 5 at the beginning of the treatment. 50 kBq/kg Ra-223 chloride was administered intravenous in 6 cycles, with 4 weeks intervals between the cycles using the approved inclusion criteria for the treatment.

Results: Of 43 patients, 29 patients completed six cycles of radiotherapy. Five patients died during the therapy. In two cases, the cause of death was irreversible serious myeloid suppression. In three cases, the cause of death was not likely with the primary prostatic cancer. Furthermore, we had to discontinue the therapy in nine patients: One osteonecrosis of the jaw, three cases due to visceral or brain metastasis, pneumonia developed in one case. In addition, one patient had pathological fracture and three patients had severe myeloid suppression. Only one patient who received all six cycles of therapy died so far. Surprisingly, brain metastases occurred in three cases. The intensity of bone pain significantly reduced with the use of radionuclide therapy based on subjective scores. Hb values showed significant decrease during the therapy cycles. However, the number of Thr and ANC showed decrease as well. The level of ALP significantly reduced at the end of the treatment. Local irritation or tissue damage at the site of administration was not observed in any of these cases.

Conclusion: Ra-223 chloride therapy is a safe and beneficial treatment for patients with osseal metastatic prostatic cancer.

188 Re-HEDP and 188 Re-Zoledronic Acid for Palliative Treatment of Bone Metastases

Pain Palliation and Radiosynovectomy

Tatiana Kochetova, Valeriy Krylov, Lev Voloznev 1 , Roman Bobrov 1 , Maria Beloserova 1 , Olga Spichencova 1

MRRC, 1 MRNC, Russia

Background: Bone metastasis can decrease quality of life and performance status in patients with breast or prostate cancer. Some complications of the presence of bone metastases can also influence survival. We performed a clinical study of bone-seeking 188 Re-based radiopharmaceuticals for treatment patients with bone metastases: 188 Re-HEDP (Phosphoren) and 188 Re-Zoledronic acid (Zoleren).

Methods: From 2012 to 2015, two studies were performed to assess safety and efficacy of new Russian radiopharmaceuticals: 188 Re-HEDP (Phosphoren) and 188 Re-Zoledronic acid (Zoleren). In both cases, 89 SrCl 2 in control group was used. In the first study, only pharmacokinetics and safety were investigated. During the second study also, quality of life was measured by the short-form-36 questionnaire before and 28 and 56 days after treatment. After the treatment, all patients entered into active follow-up period. Overall survival is one of the end-points of the both studies.

Results: 188 Re-Zoledronic acid had better biodistribution and demonstrated less hematological adverse events even in higher doses than 188 Re-HEDP. In both investigations, 89 SrCl 2 demonstrated acceptable toxicity as well. However, patients from the 89 SrCl 2 arm were less tolerant to following cytotoxic regimens. Influence to quality of life was better in women breast cancer patients than in prostate cancer group regardless to radiopharmaceutical. Women received 188 Re-Zoledronic acid had significantly better impact to quality of life compared to 89 SrCl 2 arm. In men, no statistical significant difference was achieved. Survival data are being collected.

Conclusion: Phosphoren is clinically equal to 188 Re-HEDP analogs. Zoleren differs from other 188 Re-based radiopharmaceuticals: It has preferable biodistribution and toxicity profile but can be contraindicated in some cases (osteonecrosis of the jaw, renal insufficient, etc.). Unexpectedly, women with breast cancer demonstrated significantly better impact to quality of life after bone targeted nuclear therapy. These findings are suggestive that not only osteoblastic or osteolytic type but also tumor biology and other factors play significant role in clinical response to radiopharmaceuticals. Unfortunately, there is lack of evidence-based clinical studies in nuclear therapy which can clearly answer how to treat patients with progressive multiple bone metastases.

Improving Radiosynoviorthesis using a Sn-117m Colloid Suspension

Pain Palliation and Radiosynovectomy

Knut Liepe, Gilbert R. Gonzales 1 , Cynthia A. Doerr 1 , Nigel R. Stevenson 1

Klinikum Frankfurt (Oder), Germany, 1 R-NAV, LLC, USA

Background: Radiosynoviorthesis (RSO) colloids in common use are Y-90, Re-186, and Er-169. The isotope Sn-117m (t½ 14 d; γ 159 keV, 86%; e - ~140 keV, 112%) is being used in RSO clinical trials (veterinary and future human) initially as a treatment for smaller arthritic joints. This isotope has demonstrated several advantages that could allow it to replace one or more of the existing commercially available products.

Methods: A homogeneous Sn-117m colloid (HTC) was manufactured under the current Good Manufacturing Practices and characterized. Preclinical Good Laboratory Practice trials with an osteoarthritis (OA) rat model (n = 90) and in normal dogs (n = 5) were performed to evaluate dosage, retention, safety, radiation field, and efficacy. Subsequently, a trial with naturally occurring canine OA is underway to primarily demonstrate efficacy and durability. The dosimetry of Sn-117m in the joint was also modeled with a Monte Carlo simulation.

Results: Tin-117m emits monoenergetic conversion electrons (CEs) that have a range of ~300 μm in synovial tissue. This prevents any possible irradiation of unintended sites such as surrounding tissue and results in a de minimis radiation field. The colloid has the perfect size range (mean ~6 μm; standard deviation <3 μm) to hinder joint leakage while allowing for complete synoviocyte and macrophage phagocytosis and incorporation into the synovial tissue. The HTC remained unchanged after 5 weeks of storage at room temperature. The imaging photon also allows for confirmation of correct placement after injection. The rat OA study showed 99.9% retention out to 10 weeks. Similar results were observed in the canine safety study (99.1% at 6 weeks). Biodistribution measurements over the span of the 6 weeks canine safety study showed little cumulative HTC in the other tissues (0.8%) or excreta (<0.1%). Autoradiography of the canine joint tissues showed that HTC was found to be localized in synoviocytes throughout the joint in all injected elbows. Macrophages containing the Sn-117m colloid were found distributed in all layers of the synovium. This suggests that macrophages had migrated with the Sn-117m colloid from the surface throughout the synovial layers. The longer half-life (14 days) of the Sn-117m would thus provide the opportunity to treat deeper layers of the inflamed synovium before being removed via the lymphatic system. Ongoing canine OA trials demonstrate a durable effect of treatment to 6 months or more. Monte Carlo simulations of the joints confirmed maximum external radiation field measurements for the canine safety trial (~330 μR at 1 m). Synovial tissue doses were almost identical to Er-169 when the Sn-117m injected dosage was scaled to 43% of Er-169.

Conclusions: The HTC containing Sn-117m has excellent properties for RSO in small joints and possibly also larger ones. This is due to the migration of the colloid through the synovial tissue allowing for irradiation at greater depths than the 300 μm CE range, the propitious half-life of Sn-117, and the osculant characteristics of the colloid. Animal trials demonstrate excellent joint retention, safety and ease of handling, efficacy, and durability. Preparation for human trials is underway.

Radionuclide Bone Pain Palliation in Breast Cancer Metastasis

Pain Palliation and Radiosynovectomy

Raluca Mititelu, Catalin Mazilu, Sorin Mititelu, Olga Niculescu

Central University Emergency Military Hospital, Bucharest, Romania

Background: Bone metastases are a serious complication which occurs in advanced phases of cancer patients. Despite the huge advances in early diagnose and newly therapeutic approach of cancer, each year, about 200,000 new cases of painful metastatic bone disease are diagnosed in the United States, 73% of these attributable to breast, prostate, and lung cancers. There is no curative treatment of bone metastases at this moment. Many efforts have continuously been made to determine the reduction of analgesic needs and a better control of pain. The aim of this paper is to present the results of treatment with 89 Sr performed in our department, at patients with breast cancer and metastatic bone disease.

Method: We performed a retrospective review of 15 consecutive patients with breast cancer and widespread bone metastasis which were treated in our department in the past 4 years for refractory bone pain from multiple metastases. We administered 150 MBq, single dose in 13 cases; in two patients, a second dose was administered at 6 or 9 months, respectively. All patients had a bone scan prior administration of the radiopharmaceutical for demonstrating the osteoblastic component of the bone metastasis. In all patients, hematological status and renal function were assessed.

Results: Significant pain relief was seen in seven patients; five patients had moderate response. No response was seen in three patients. Most serious side effects were myelosuppression in five patients, which was mild to moderate; pain flare occurred in 8 patients and correlated well with pain relief. There are few studies on the therapeutic effect of bone-seeking agents on pain relief in patients with breast cancer. Efficacy of these agents, particularly of 89 Sr, was well documented in osteoblastic metastasis due to prostate cancer. In breast cancer, due to some lytic component of the bone lesions, it was assumed that efficacy of bone-seeking agents is lower; however, with proper selection of patients, we have obtained good results in terms of pain relief, reduction of analgesic doses, and improvement of life quality.

Conclusions: 89 Sr allows significant pain relief in patients with breast cancer and bone metastasis, with controllable side effects and good compliance of patients. Efforts have to be made to include these agents in treatment algorithm of multiple painful bone metastases and obtain reimbursement from the National Insurance Companies.

Radiosynovectomy: State of the Art 2016

Pain Palliation and Radiosynovectomy

Gynter Moedder

NURAMED - German Centre for Radiosynovectomy, Germany

Radiosynovectomy (RS) is an important proven tool for treatment of chronic inflammatory joint diseases in the context of rheumatologic and orthopedic efforts. Local application of suitable radioactive agents into joints reduces the painful destructive synovial process, thus decreasing pain, effusion/swelling, and improving mobility. Situated between systemic medication and surgery RS is the most promising one of the local conservative therapies concerning efficacy und results. In Germany, RS nowadays is performed in about 50-60,000 joints per year as much as radioiodine therapy in thyroid diseases. Basically, RS is indicated for the local treatment of almost all kinds of chronic synovitis. The main indications for RS are (1) rheumatoid arthritis (2) seronegative spondyloarthropathy (i.e., psoriatic arthritis) (3) hemarthrosis in hemophiliac (4) recurrent joint effusions (i.e., after arthroscopy) (5) pigmented villonodular synovitis (6) osteoarthritis (7) after joint prosthesis: Persistent effusions, polyethylene disease. The most common and approved radiopharmaceuticals for RS are following β-emitters: (1) (90Y) yttrium- citrate ([90Y] colloid), only used for RS of knee joints (2) (186 Re) rhenium sulfide ([ 186 Re] colloid), used for RS of middle-sized joints (3) ( 169 Er) erbium citrate ([ 169 Er] colloid, used for RS of small joints. Physical and radiobiological principles of RS are shown. Diagnostic studies prior to RS are ultrasound study and multiphase scintigraphy with 99m Tc-MDP as the best tool for detecting synovitis (soft-tissue scintigraphy) and bone involvement (bone scintigraphy). Performance of RS requires an excellent puncture technique. Apart from the knee joint, all joints should be punctured by fluoroscopy and often by arthrography. After RS distribution, scintigram confirms the appropriate intra-articular distribution of the radiopharmaceutical (except Erbium-169). Immobilization of the treated joints by a splint for 48 h is helpful in avoiding side effects.

Results: Due to the development of RS already, since 50 years, many early studies do not fulfill the strange criteria of modern evidence-based medicine. However, recently a wealth of well-designed trials has been carried out evaluating the efficacy of RS. Good efficacy of radiosynoviorthesis (RSO) is about 70%-80% for years by only one treatment. In some more difficult cases, fractionated RSO may lead to success. Greater success is reported for rheumatoid diseases than for osteoarthritis, the latter depending on stage of joint damage. Close cooperation with orthopedists and rheumatologists is highly recommended to consider RS in each patient to ensure optimal medical care. The overview is based on the author's highly specialized experience and scientific work since >35 years (in the last decade about nearly 7000 Rs. per year).

Survival and Side Effects Rates of Radionuclide Therapy of Bone Metastases by Sm-153 Oxabifore (Sm-153) with Different Complex and Combined Regimens: Chemo-, Target, Bisphosphonates, and Hormonal Therapies

Pain Palliation and Radiosynovectomy

Nigora Rasulova, Dauranbek Arybzhanov 1 , Shamsutdin Sagdullaev 2 , Vladimir Lyubshin 3 , Yuliya Shakirova 4 , Gayrat Arifhodjaev 4 , Abdulla Abdikhakimov 2 , Valery Krylov 5 , Marat Khodjibekov 6

Republic Specialized Center of Surgery, 2 Regional Tashkent Oncology Clinic, 3 Private Clinic "Vegamed" Tashkent, 4 Republic Specialized Centre of Surgery, 6 Tashkent Medical Academy, Uzbekistan, 1 South Kazakhstan Ontological Clinic, Shimkent, Kazakhstan, 5 Medical Radiological Research Center, Obninsk, Russia

Background: Bone is a common site of metastatic cancer which can either develop later or at the time of presentation. Bone metastasis can affect quality of life, adversely affect performance status, and affect survival. Both, patients with presentation of bone metastases at diagnosis of primary tumor and with relapse of disease need complex approach to therapy. Radionuclide therapy (RNT) has affinity to high bone turnover, by irradiation bone marrow (cancer cells) and specific populations of nerve fibers that innervate skeleton are used for reduction of pain syndrome. However, role of RNT in complex therapy of breast cancer (BC) on the stage of bone metastasis is unclear.

Aim: To estimate side effects and results of possible combinations of different approaches of complex therapies of BC with bone metastasis by integration RNT.

Materials and Methods: Investigated four different combinations of RNT with primary tumor's treatment: RNT + bisphosphonate (BIS); RNT with hormonal therapy (HT) (anastrozole, letrozole, tamoxifen, fulvestrant depending on indications); mono- or poly-chemotherapy (CT) (doxorubicin, cyclophosphamide, vinorelbine, cisplatin, capecitabine, halaven); target therapy (trastuzumab, lapatinib, pejeta). (1) Bis + RNT by Sm-153: n - 72 patients with BC; (2) Bis + HT + Sm-153: n - 38 (BC) patients; (3) Bis + chemo- +RNT: n - 44 (BC) patients; (4) Bis + TT + RNT: n - 15 (BC) patients Sm-153 was injected according to standard protocol 37 MBq/kg of weight. During follow-up period, patients received RNT 1-6 times, with frequency 3-12 months. First injection was done due to pain syndrome, following once for prevention of the pain syndrome.

Statistical Analysis: The results are expressed as the mean ± standard error of the mean for each index. Kaplan-Meier method was applied to analyze survival rate.

Results: Group I, follow-up time (FUT) ranged 3.1-61 months (22.31 ± 16.37 months). 1-, 2-, 3-, 4- and 5- year survival rates were 79.1%, 62.5%, 54.1%, 51.3%, and 47.2%, respectively. In this group, in 4.1% cases, necrosis of low jaw occurred due to long-term bisphosphonates therapy. Group II, FUT ranged 3.7-57.7 months (28.6 ± 16.1 months). 1-, 2-, 3- and 4-year survival rates were 97.3%, 92.1%, 81.5%, and 73.7%, respectively; in this group, there were no side effects. Group III, FUT ranged 3.0-63.3 months (32.6 ± 17.7 months). 1-, 2-, 3-, 4- and 5-year survival rates were 97.7%, 88.6%, 81.8%, 72.7%, and 70.4%, respectively. In one patient (2.2%), heart failure developed; in six patients (13.2%), transitory leukopenia 2-3°; in three patients (6.8%), chronic renal failure due to long-term therapy by bis; in one patient (2.2%), necrosis of low jaw developed. Group IV, FUT ranged 3-63.3 months (32.6 ± 17.7 months). 1-, 2- and 3-year survival rates were 86.7%, 66.7%, and 40.6%, respectively. Within 4.3-30.4 months (19.9 ± 9.4 months), nine died due to brain, lung, and liver metastases.

Conclusion: According to our preliminary results on small groups of patients, all combinations with RNT were relatively safe. More frequently side effects were observed in Group III (Bis + chemo- + RNT). Promising results in survival rates were achieved in all groups of patients.

Production and Characteristics of a Novel Sn-117m Particulate Suspension for Application in Human and Veterinary Radiosynoviorthesis

Pain Palliation and Radiosynovectomy

Nigel R. Stevenson, Jaime Simσn 1 , Scot Ellebracht 1 , Shannon Phillips 1

R-NAV, LLC, 1 IsoTherapeutics Group, LLC, USA

Background: The theranostic isotope, Sn-117m (t½ 14 d; γ 159 keV, 86%; e - ~140 keV, 112%), is being used in radiosynoviorthesis (veterinary and future human) clinical trials as a treatment for smaller and mid-size arthritic joints. The method of manufacturing the Sn-117m particulate suspension is critically important to assure a product with the highest safety, efficacy, and retention profiles. We describe here the Current Good Manufacturing Practice (cGMP) manufacturing of the radiochemical and final product. Characterization, stability, reproducibility, and animal retention studies were also undertaken leading to full safety and efficacy trials in canine subjects. Plans for human trials are underway.

Methods: Sn-117m can be produced with accelerators or reactors. Viable accelerator routes are Sb (p, x) Sn-117m and Cd-116 (α, 3n) Sn-117m. These channels provide moderate quantities of high specific activity (500-20,000 Ci/g) Sn-117m. Reactor production occurs by either Sn-116 (n, γ) or Sn-117 (n, n'γ), with the latter being preferred due to higher yields and specific activities (up to 20 Ci/g). The purified radiochemical is typically received in 4 M HCl. The particulate suspension is produced by slowly raising the pH in a controlled manner. This is achieved by adding urea and cold tin (to bring the specific activity to ~1 Ci/g) and heating the mixture at 90°C for 4 h in a microwave reactor while stirring. Precise control of the ingredients and the formulation environment is required to routinely produce a homogeneous product with a consistently narrow size distribution. Subsequently, the temperature is raised to 130°C for 35 min to sterilize the product. These optimal production parameters for this cGMP process were each previously determined experimentally. The product size distribution, color, clarity, pH, endotoxin content, and sterility are measured. Stability studies were conducted out to 5 weeks.

Results: Sn-117m homogeneous particulate suspensions with a nominal particle size of ~6 μm (standard deviation <3 μm) were consistently manufactured. The ideal nature of this narrow size range was demonstrated in subsequent animal studies that showed >99% retention of the product in the injected joint out to 10 weeks (five half-lives). The product was clear/yellow in color with a slightly milky appearance. The pH of the product was 7.0-8.5. Deviating from these established manufacturing parameters could have a significant impact on the product quality, e.g., it was found that at least 2 h at >85°C was required to complete the precipitation reaction. A study of the poststerilization step demonstrated an acceptable microbial kill-rate above 125°C for 35 min. The stability studies determined that the size, appearance, and pH were unaffected over 5 weeks at room temperature storage conditions.

Conclusions: A new radiosynoviorthesis particulate suspension of Sn-117m is being routinely manufactured under cGMP for canine clinical trials. Sn-117m has dosimetry very similar to Er-169 and the product is easily, reliably, and economically manufactured. The size distribution of the suspension avoids effusion losses and results in complete synoviocyte and macrophage phagocytosis and incorporation into the synovial tissue. The product not only has the right characteristics for treating smaller and mid-size joints but may also be useful in some larger ones. Stability, retention, and subsequent safety and efficacy trials, all confirmed its ideal application for radiosynoviorthesis.

Role of Radiosynovectomy using Yttrium 90 in Management of Knee-joint Bleeding in Hemophilics: A Local Experience in Syria

Pain Palliation and Radiosynovectomy

Majdi Zein

Al Assad University Hospital, Damascus, Syria

Background: In 1977, Ahlberg saw the need to stop the vicious circle of target joints seen in hemophiliacs which causes lifelong disability and interrupts the physical and social activities of the child by this procedure. Over the decades, it has gained acceptance by providing a simple, economic, and effective therapy for them. Radiosynovectomy by injecting radionuclides intra-articular space is well established as an alternative method to decrease joint hemorrhage episodes and to prevent arthropathy in hemophiliacs.

Methodology: Thirty hemophilic patients suffering from repeated episodes of bleeding knees were referred to the Nuclear Medicine Department at Al-Assad University Hospital, Damascus, Syria, during the period between 2009 and 2012; baseline radiographs of the knees in the anteroposterior and lateral views were obtained for all patients (at present, an ultrasound scan can evaluate joint space, thickness, and structure of the synovium, even effusion). Three-phase bone scan: Flow within 5-20 min and after 3 h was obtained, scans were taken at baseline, 6 months, and 12 months A dose of 200 mBq Yttrium colloid was injected intra-articular space. Posttherapeutic whole-body scan for leakage was done. Detailed instructions were given to the patients after the procedure. Pain response was evaluated by a 10-step, visual analog scale before, and after1, 3, 6, and 12 months following the procedure.

Results: Within 1 month period prior to radiosynoviorthesis (RSO), all patients had >3 bleeding episodes per month. Following the RSO, number of bleeding episodes dropped significantly during a 6-month follow-up. 40 % of the patients had no bleeding episodes (100 % reduction), 43 % had 80% reduction and in 17% had less than 50% reduction.

Conclusion: Radiosynovectomy presents with a therapeutic effect of 60%-94% for hemophilia A in several studies; our study showed 80%. Radiosynovectomy is a minimally invasive, well-tolerated procedure that can be done on an outpatient basis.

Development of a Web Application to Calculate Maximum Safe Dose of I-131 in High-risk Patients with Differentiated Thyroid Carcinoma

Thyroid Cancer, Dosimetry

Mariela Agolti, Rocio Brezan 1 , Mauro Namias 2 , Javier Bustos 2 , Martνn Rettore 1

CEMENER, Centro Medicina Nuclear Clinica Modelo, 1 Centro de Medicina Nuclear Clinica Modelo, 2 CEMENER, Argentina

Background: We developed a web application that enables us to easily register measurements from whole-body photon counting and blood samples to estimate the maximum 131 I safe activity in patients with differentiated thyroid cancer to prevent pulmonary fibrosis and bone marrow toxicity.

Methods: A web application was created using the Django 1.9 framework developed in Python, based on the EANM guidelines for blood and bone marrow dosimetry. We tested the software in three patients. Two females with metastatic thyroid carcinoma and cervical nodes compromise, and a male with micronodular lung metastases compromises. We prepared the patients as always. We administered 2 mCi to each patient to avoid stunning. We took blood samples and recorded whole-body retention images without collimators at 2, 4, 24, 72, and 144 h postadministration. We also prepared a 250 uCi stability standard for the gamma camera and a 0.67 uCi/ml standard for blood measurements which were used to correct each measurement respectively. We also performed whole-body anteroposterior and posteroanterior images at 48 h and 72 h. Finally, we processed the information to estimate residence times for the whole body and activity concentration in blood. Using this information, we calculated the mean absorbed dose to the blood per unit administered activity. The blood samples were sent to another service to be measured in a scintillation well counter. The software allowed us to plot the activity in blood and total body as a function of time and to estimate the maximum safe activity to be administered.

Results: We found the web application easy to use because the physician only has to complete fields for whole-body and blood measurements in a streamlined way. As a result, we got the maximum safe activity to be administered expressed in mCi. The absorbed dose to the blood did not exceed 2 Gy (a widely accepted limit for bone marrow toxicity). At 48 h after administration, the whole-body retention did not exceed 120 mCi or 80 mCi in the absence or presence of iodine-avid diffuse lung metastases, respectively, to avoid pulmonary fibrosis. This application cannot be used in bone metastasis.

Conclusion: We developed a web application to easily estimate the maximum safe activity for radioiodine administration in differentiated thyroid carcinoma, following the EANM guidelines.

Peptide Receptor Radionuclide Therapy in Medullary Thyroid Cancer

Thyroid Cancer

Gheorghe Anka, Nilica Bernhard,

Irene Virgolini


Medical University of Innsbruck, Innsbruck, Austria

Introduction: The initial therapy for medullary thyroid carcinoma is the surgical sanitation of the tumor. Under optimal therapy, the survival rate for medullary thyroid cancer (MTC) is 80% after 5 years, 60% after 10 years. If there is any distant metastasis at initial diagnosis, the 10-yearsuvival rate is just 40%. Patients with metastatic MTC do respond neither to conventional cytostatic therapy nor to radiation therapy. Another therapy option for metastatic MTC is peptide receptor radionuclide therapy (PRRT) because it specifically attacks tumor cells, and hence, it achieves while keeping side effects on a minimal range a therapeutic effect.

Aim: The aim of this retrospective study was to analyze the data of all the patients who have been treated in the last 16 years for medullary thyroid carcinoma at the University Hospital of Innsbruck. The focus was set on the comparison of the group of patients treated with PRRT to the patients without PRRT.

Research Base and Methods: This study implied 26 patients, 15 men and 11 women, among these 24 patients with pure medullary thyroid carcinoma, one patient with mixed medullary-papillary thyroid carcinoma, and one patient with C-cell-hyperplasia suffering from MEN2A-mutation. All patients suffering from carcinoma got an evaluation of somatostatin receptor status. Seven patients had a positive status, and they all got PRRT.

Results: Of the patients treated with PRRT, three achieved the state of stable disease and one patient achieved partial remission. Three of the seven patients treated with PRRT died. Of the patients who were not able to receive any PRRT because of the negative receptor-status, nine of the 19 are lost to follow-up. Calcitonin-disease-correlation: Nine patients experienced progression of the disease; six of them had a proper correlation with the increase of calcitonin.

Conclusion: Patients of this study who got PRRT treatment showed good results regarding progression-free survival and quality of life.

Efficacy of Radioiodine Treatment in Well-differentiated Thyroid Cancer in Children

Thyroid Cancer

Emerita Barrenechea

St Luke's Medical Center, Philippines

Background: Well-differentiated thyroid cancer (WDTCA) in children is the third most common solid tumor malignancy and the most frequent endocrine malignancy in children. They are more aggressive at the time of diagnosis, with metastases, and have a higher risk for recurrence. The objective of this paper is to determine the efficacy of radioiodine treatment after 5-6 years from therapy.

Materials and Methods: Fifteen pediatric patients with a diagnosis of thyroid carcinoma, aged below 18 years of age were included in a 6-year follow-up after treatment. They underwent thyroidectomy, followed by radioactive iodine (RAI) ablation. The predominantly female population (74%) had papillary thyroid cancer (13 patients) and (2) had follicular. Nodal metastases were seen in 53% and lung metastases were seen in 20% of the patients.

Results: Of the 13 patients who underwent RAI ablation, three patients of lung metastases while two patients with lymph node metastases needed repeat treatments. On follow-up after an average of 6 years, all the 13 patients who underwent RAI ablation are doing well with the lifetime thyroid hormone treatment. The remaining two patients who did not undergo therapy succumbed on the 2 nd and 3 rd year after diagnosis.

Conclusion: WDTCA in children is rare and the biological behavior differs from that of adults. Their presentation is quite aggressive and may be recurrent. Total or near-total thyroidectomy with I-131 ablation reduces mortality and hence is efficacious.

Thyroglobuline Elevated but Negative Iodine Scintigraphy Syndrome: An Analysis of the Data of 79 Patients with Respect to Multiple Risk Factors and Fludeoxyglucose Positron Emission Tomography/Computed Tomography Findings

Thyroid Cancer

Jayanta Das, Soumendranath Ray, Sudipta Nag

Tata Medical Center, Kolkata, West Bengal, India

Aim: To find out the correlation of the possible risk factors in the development of iodine refractory Thyroglobuline Elevated but Negative Iodine Scintigraphy (TENIS) syndrome in differentiated thyroid cancer and corroborate them with fludeoxyglucose positron emission tomography/computed tomography ( 18 F FDG PET-CT) findings.

Materials and Methods: A total number of 780 differentiated thyroid cancer patients received high-dose radioiodine therapy over a period of 4 years. Six months after radioiodine therapy, the patients were evaluated with TSH stimulated thyroglobulin estimation, whole-body I-131 scan, and chest X-ray. Seventy-nine patients had developed TENIS syndrome on follow-up. 18 F FDG PET-CT was performed in all patients to decide further management. The follow-up data were retrospectively analyzed taking into consideration the histopathological findings, focality, extrathyroidal extension, lymph node metastasis, extranodal extension, tumor size, and the imaging findings.

Results: Out of 79 TENIS syndrome patients, 67 patients had papillary thyroid cancer. Five patients had follicular cancer, one patient had mixed papillary and follicular cancer, and the other one had poorly differentiated cancer. In 38% patients, the cancer was multifocal. Extrathyroidal extension was present in 46% of them. Out of 79 TENIS patients, 46 patients had undergone lymph node dissection during initial surgery and lymph node metastasis was present in 88% of them. Extranodal extension was noticed in 48% of patients. Forty-three percent of patients had either T3 or T4 lesions and T2 disease added to it; 68% had larger primary lesion (T2, T3, or T4). On follow-up, whole-body I-131 scan was negative in all of them with elevated thyroglobuline (range 11.3 ng/ml to 15,355 ng/ml). 18 F FDG PET-CT showed metabolically active lesions in 47% of patients and in another 28% CT images of PET-CT showed non FDG avid findings which might contribute to raised thyroglobuline-like cervical lymphadenopathy or lung nodules. Among the patients with FDG avid lesions, 13 individuals had undergone lymph node dissection and histopathology was positive for metastatic disease in 11 (91%) of them. Postoperative pre-I-131 therapy ultrasonography (USG) showed residual thyroid (0.1-1.3 cc) in 6 patients (13%) and apparently involved lymph nodes in 19 (48%) of patients. Out of 19 (68%) patients, 13 patients with abnormal nodes in USG did not show any I-131 avidity in those nodes in the posttherapy scan. Six of these patients showed FDG avid neck nodes in the follow-up PET scans though it may not be exactly the same node which was identified in the initial USG.

Conclusion: 18 F FDG PET-CT could detect lesions possibly leading to elevated thyroglobuline in 76% patients. In the subset of PET-positive patients with FDG avid lesions who underwent neck dissection, the positive predictive value of PET was found to be very high (91.6%). Postoperative USG is of immense importance to predict transition to iodine refractory state especially if the nodes are non-iodine avid in posttherapy scan. Multifocality, extrathyroidal extension, and tumor size appear to be important contributing risk factors, but more number of cases is to be studied to reach a statistically significant conclusion.

13-Cis-Retinoic Acid Therapy in Combination with Recombinant Human Thyrotropin for Treatment of Dedifferentiated Thyroid Cancer: A Pilot Study

Thyroid Cancer

Aashish Gambhir, Indirani Muthukrishnan, Jaykanth Amalachandran, Shilpa Kalal, Avani Jain, Abhishek Khare, Shelley Simon

Apollo Hospitals, Chennai, Tamil Nadu, India

Background: Metastatic-dedifferentiated thyroid cancers are often radioiodine nonavid and have limited therapeutic options. In this regard, retinoids have demonstrated tumor proliferation inhibition and radioiodine reuptake induction making them amenable to radioactive iodine (RAI) metastatic ablation therapy. In this setting, recombinant human thyroid-stimulating hormone (rhTSH) might further aid in increasing radioiodine uptake by thyroid cancer metastasis. The aim of our prospective observational pilot study was to assess benefits of the 13-cis-retinoic acid (13-CRA) treatment to redifferentiate nonfunctional thyroid cancer metastases, followed by rhTSH aided RAI metastatic ablation.

Methods: Twenty-one cycles of 13-CRA was administered in eight patients, three had follicular and five had papillary thyroid carcinoma with radioiodine nonavid predominantly pulmonary (75%) and skeletal (50%) metastatic disease. The patients were enrolled from 2009 to 2016 and 13-CRA was administered in a dose of 1.0 mg/kg/day over 1 st week and then 1.5 mg/kg for 6-8 weeks with each cycle, followed by RAI therapy performed under rhTSH stimulation. Six patients had undergone prior multiple treatments including radiotherapy and radioiodine ablation while two patients had non iodine avid metastatic disease at presentation itself. The redifferentiating effect of 13-CRA was evaluated by serum thyroglobulin (Tg) measurements before and after cessation of radioiodine treatment, qualitative analysis of iodine uptake on the posttherapeutic whole-body scan and computed tomography-based anatomical evidence of metastasis size.

Results: All patients tolerated 13-CRA well without any significant major adverse effect. Transient minor side effects most commonly dryness of lips were present in all patients but resolved within 2 weeks after 13-CRA cessation. The absence of thyroid withdrawal avoided potential synergistic deleterious effects of 13-CRA and hypothyroidism. 13-CRA in conjunction with rhTSH RAI therapy-induced radioiodine uptake in all patients on posttherapy scans. All patients were followed up for an average duration of 3.6 years post-first 13-CRA treatment (2-6 years). Three (37.5%) patients demonstrated good response with significant reduction in serum Tg levels, size of metastasis, and iodine uptake in follow-up scans. Four (50%) patients showed stable disease with stable persistently elevated serum Tg levels. One patient had progressive disease with brain metastasis and death after 6 years of follow-up. Four patients could not undergo further 13-CRA and RAI owing to cumulative dose administered over 1000 mCi and hence were selected for tyrosine kinase inhibitor (TKI) therapy. Three of these patients showed significant adverse effects and discontinued TKI in average duration of 2.9 months without any significant clinico-biochemical evidence of response noted in a follow-up of up to 12 months.

Conclusion: Our results demonstrate that 13-CRA in conjunction with rhTSH exerts redifferentiation with induction of radioiodine uptake resulting in a measurable response and stable disease in nearly 90% of patients. Addition of rhTSH to the protocol avoided hypothyroidism, thereby ensuring a better quality of life and patient compliance to treatment.

Outcome of Radioiodine Therapy in Hürthle Cell Carcinoma of Thyroid: A Tertiary Center Experience

Thyroid Cancer

Raihan Hussain, Sadia Sultana, Rahima Perveen, Mohammad Simoon Salekin

National Institute of Nuclear Medicine and Allied Sciences, BAEC, Dhaka, Bangladesh

Background: Hόrthle cell thyroid carcinoma (HCTC) of the thyroid is a variant of follicular cancer which is considered by many as a more aggressive disease than the usual well-differentiated carcinoma of the thyroid. It is generally believed that patients with HCTC do not accumulate radioactive iodine and have a poor prognosis. The aim of this study was to report the treatment and outcomes of patients with HCTC.

Methods: A total of 12 patients (11 females, 1 males) having mean age of 45.75 ± 12.07 years at diagnosis during the last 15 years (2001-2015) treated and followed up at the National Institute of Nuclear Medicine and Allied Sciences, Dhaka, Bangladesh, were analyzed. All were histologically proven HCTC. Three patients had skeletal metastases and one developed a second carcinoma (adenocarcinoma of stomach). All had total or near-total thyroidectomy, followed by I-131 ablation. Posttherapy scan showed significant uptake in the metastatic sites. Two patients were also advised for external beam radiotherapy (EBRT). Follow-ups were done according to our protocol (Society of Nuclear Medicine, Bangladesh Guidelines, 2002, 2014). Eventually, the disease-free criteria were considered as having negative I-131 whole-body scan with very low serum thyroglobulin.

Results: I-131 was administered according to our protocol (dose varied from 75 mCi to 250 mCi, depending on the stage and progress of the disease). Among the 12 patients, one received 6 doses, one 3 doses, two 2 doses, and rest single doses. A patient having very aggressive disease with multiple skeletal metastases in the skull and hip received a total of 1275 mCi along with two cycles of EBRT. The patient did survive for 9 years even with advanced condition on diagnosis. One patient developed adenocarcinoma of stomach with secondary bony metastases and was managed with chemotherapy, the condition improved, and became disease free. Out of the total 12 patients received I-131 ablative doses, 11 eventually became disease free.

Conclusion: Although the number of the patients is small, we did not see any difference of outcome with the published reports of well-differentiated thyroid carcinoma and the HCTC in our analysis. I-131 was well taken up in the disease sites and seems to be well controlled. It can be concluded that I-131 may be equally effective in the treatment of HCTC.

Clinical and Histopathological Characteristics of Differentiated Thyroid Carcinoma among Pediatric Population and its Treatment Outcome

Thyroid Cancer

Phay Phay Khor, Teck Huat Wong, Siti Zarina Amir Hassan

Hospital Kuala Lumpur, Lumpur, Malaysia

Background: Differentiated thyroid carcinoma in pediatric population is uncommon. However, there have been reports on its increasing incidence. To date, data on differentiated thyroid carcinoma among pediatric population in Malaysia are lacking.

Methods: We reviewed all the medical records of patients aged 18 years old or less, who were treated in our center from 2003 to 2015. Demographics, clinical, histopathological findings and its treatment outcome were evaluated.

Results: A total of 65 patients were identified. Mean age at diagnosis was 14.9 years with a female predominance (78.5%). Seven patients were <10 years old, in which 4 years old being the youngest. 75.4% were Malay patients. Six patients had family history of thyroid cancer. 30.8% underwent total thyroidectomy and modified radical neck dissection, followed by 33.8% total thyroidectomy and 35.4% staged surgery (hemithyroidectomy followed by completion). Papillary thyroid carcinoma constituted 76.9% of total cases, followed by follicular thyroid carcinoma. 61.5% were T1 and T2 tumor and 53.8% were unifocal. However, lymphovascular invasion and nodal metastasis were found in more than half of the patients' histopathology report. At presentation, 50.8% of patients had locoregional disease and 29.2% had distant metastasis. Of the distant metastases, lung metastasis was found in 18 patients and one patient with bone metastasis. In age group of <10 years, 6 out of 7 patients presented with distant metastasis at presentation, solely lung metastasis. Fixed dosing of radioiodine ablation was prescribed. Mean number of radioiodine ablation was 4.26 with mean cumulative dose of 469.8 mCi. Sixty percent of total patients had achieved complete remission. In the remaining 26 patients with persistent disease, 13 patients had locoregional disease, 9 lung metastases, and 4 patients had dedifferentiated disease. During the course of the treatment, six patients had repeated radical neck dissection and three patients had external beam radiotherapy to the neck. Two patients with lung metastasis managed to undergo I-131 dosimetry and were given as high as 500 mCi. Mean duration of follow-up was 4.9 years (range 1-16 years). No mortality and significant morbidity was reported. Two patients were found to have bone marrow suppression after cumulative I-131 activities exceeded 1000 mCi. However, it showed spontaneous resolution after radioiodine was withheld.

Conclusion: Our study found that most pediatric patients presented with a more advanced disease at diagnosis. This trend is particularly evident in the age group of <10 years. Despite this, they do have a favorable prognosis and outcome.

Blood Neutrophil-to-Lymphocyte Ratio Correlates with Tumor Prognosis in Patients with Papillary Thyroid Cancer

Thyroid Cancer

Peiyong Li, Cao Yan

Department of Nuclear Medicine, School of Medicine, Ruijin Hospital, Shanghai Jiaotong University, Shanghai, China

Background: To investigate whether the blood neutrophil-to-lymphocyte ratio (NLR) is a risk factor of papillary thyroid cancer.

Methods: Total white blood cell and differential counts of 41 papillary thyroid cancer patients were compared with those of 35 sex-matched patients who underwent fine needle biopsy for benign thyroid nodules. Pre- and post-operative blood NLRs in the thyroid cancer patient groups (NLR1, NLR2) and control group (NLR0) were calculated. Clinicopathological variables were stratified by NLR tertiles and analyzed.

Results: Various blood indexes in the benign and malignant groups showed no significant differences (P > 0.05), except thyroid-stimulating hormone. Both tumor size and American Thyroid Association (ATA) risk showed significant differences in NLR tertiles of the thyroid cancer groups (P = 0.001 and P = 0.035). No difference between NLR1 and NLR2 was observed (P = 0.085). Correlation analysis showed that a higher NLR was observed in patients with larger tumors in both benign and malignant groups (r = 0.421, P = 0.006, r = 0.366, P = 0.03). NLR1 was higher in the group with tumors larger than 1 cm (P = 0.019) and was positively correlated with ATA (r = 0.446, P = 0.03). NLR1 in the ATA low-risk group significantly differed from those in the intermediate- and high-risk groups (P = 0.005, P = 0.002).

Conclusion: NLR1 was closely related to the size of thyroid cancer. The increase in NLR1 affected the ATA risk and prognosis of thyroid carcinoma.

Effects of Thyroxin Withdrawal in Patients with Differentiated Thyroid Cancer

Thyroid Cancer

Sayedur Rahman Miah, Reajul Islam, Masud Parvej

Institute of Nuclear Medicine and Allied Sciences, Bangladesh Atomic Energy Commission, Comilla, Bangladesh

Background: Thyroidectomy, radioactive iodine (RAI) therapy, and thyroid-stimulating hormone (TSH) suppression with thyroxin are the established forms of treatment for differentiated thyroid cancer (DTC). An elevated level of TSH is needed for the RAI treatment to be effective. To achieve this rise in TSH, patients may be instructed for withdrawal of thyroxin. Thyroxin withdrawal affects multiple organs and systems. The aim of this study was to see the effects of thyroxin withdrawal in patients with DTC.

Materials and Methods: Twenty-one patients who underwent total thyroidectomy due to DTC and who were candidates for RAI therapy from July 2015 to May 2016 were enrolled in the study. Their body weight and blood pressure (systolic and diastolic) were recorded, and their lipid profiles and serum TSH were measured before and 2-8 weeks after thyroxin withdrawal. The parameters were compared with the paired t-test. P < 0.05 was considered statistically significant.

Results: The mean body weight before and after thyroxin withdrawal was 57.9 ± 10.3 kg and 63.4 ± 13.7 kg (P < 0.0001). Their systolic and diastolic blood pressure were 107.3 ± 7.8 mmHg and 125.9 ± 14.3 mmHg and 75.7 ± 7.8 mmHg and 88.4 ± 5.8 mmHg (P < 0.0001) before and after thyroxin withdrawal. TSH is increased significantly from 1.9 ± 1.6 mIU/L to 45.4 ± 24.36 before and after thyroxin (P < 0.0001). The serum concentration of all lipids was significantly increased after withdrawal (P < 0.0001).

Conclusion: The study showed that thyroxin withdrawal increase body weight and blood pressure and altered the lipid concentration significantly which are not desirable. Their clinical importance should be investigated in future.

High-dose Radioactive Iodine Therapy (Capsule vs. Solution) of Differentiated Thyroid Carcinoma in Myanmar: A Very Primitive Theragnostics

Thyroid Cancer

Khin Pa Pa Myo, Hayman Soe

Ministry of Health, Myanmar

Background: Differentiated thyroid carcinoma (DTC) is the fifth most common cancer among the young women in Myanmar. Papillary carcinoma of thyroid (PCT) is 10 times more common than follicular carcinoma of thyroid (FCT) because of the dietary habit of Myanmar people (Salty fish?). Radioactive iodine ( 131 I) therapy at low dose (50 mCi) has been practicing for DTC since 1990. Because of insufficient dose, recurrence and dedifferentiation of the disease are noted. The trend change to high dose therapy (100-200 mCi) in relation to serum thyroid-stimulating hormone (TSH) level, serum thyroglobulin (Tg) level, and 131 I diagnostic whole-body scan (WBS) in 2015.

Methods: Sixteen cases of PCT and 2 cases of FCT were treated with high dose 131 I therapy from April 2015 to April 2016. Only three out of the PCT cases had high-dose 131 I capsule therapy, and the rest were on 131 I solution therapy. All of the cases had undergone serum TSH level, serum Tg and anti-Tg level, 131 I diagnostic WBS, and chest X-ray. Only one case of FCT with distant metastases and rising serum Tg level had undergone 18 F-fludeoxyglucose ( 18 F-FDG) scan. All of the treated cases had taken thyroxin suppressive therapy after 131 I therapy.

Results: All the PCT and FCT cases, except one FCT, had no recurrence at 6 months after 131 I high-dose therapy. All of the cases have high serum TSH, high serum Tg, and negative diagnostic WBS, and chest X-ray. A patient with FCT recurrence for years had 18 F-FDG scan positive, showing dedifferentiation and failed to respond to 131 I high-dose therapy. Dry mouth and sore throat but normal blood pictures are the only side effects. Out of 18 patients, 15 patients had pain at thyroid area. The technologist as well as the patient prefers high-dose capsule therapy because of easy handling, but high cost.

Conclusion: Serum Tg is a useful tumor marker for differentiated thyroid cancer for remaining tumor tissue or recurrence. Dedifferentiation of DTC are more metabolically active and are taking up FDG and useful in detecting metastases in 131 I WBS negative cases. Radioactive iodine, 131 I, is the drug of choice in diagnosis and therapy of differentiated thyroid cancer patients (very primitive theragnostic).

Recurrent Well-differentiated Thyroid Carcinoma: Prognosis and Clinical Outcome

Thyroid Cancer

Faria Nasreen, Nurun Nahar

National Institute of Nuclear Medicine and Allied Sciences, Dhaka, Bangladesh

Background: Well-differentiated thyroid carcinoma (WDTC) has excellent outcome after standard treatment. However, there are subsets of patients that develop recurrence with a significant risk for morbidity and mortality from this disease. The objective of the study is to find out the clinical outcome of WDTC patients developing recurrence and analyze the factors influencing recurrence.

Methods: A total of 37 WDTC patients (11 males, 26 females) who received initial treatment (surgery followed by I-131 therapy) between 1994 and 2007 at the National Institute of Nuclear Medicine and Allied Sciences, Dhaka, and later on developed recurrence were enrolled in this study. Demographic data of patient, characteristics of tumor, and treatment were recorded. Status on the last follow-up was noted to assess the outcome.

Results: A total of 28 patients had papillary carcinoma, eight had follicular, and one had follicular variant of papillary carcinoma thyroid. Age range at diagnosis was 18-72 years. Patients <45 years were 24 and patients aged ≥45 years were 13 in number. Twenty-six patients had Stage I, five patients had Stage II, five patients had Stage III, and one patient had Stage IVA at initial presentation. No patient had distant metastasis on initial diagnosis. Twenty-three patients developed local recurrence, 14 patients developed regional recurrence, five patients developed distant metastasis, and five patients had unspecified recurrence. Four patients died during the whole observation period and three of them were cancer related.

Conclusion: WDTC patients receiving proper treatment have a good prognosis even after recurrence. Age ≥45 years, advanced initial staging, and follicular variant were associated with poor prognosis in patients with recurrence.

Positron Emission Tomography/Computed Tomography Imaging in Differentiated Thyroid Carcinoma Patients with Rising Serum Thyroglobulin/Anti Thyroglobulin Antibody

Thyroid Cancer

Sadia Sultana, Fatima Begum, Shamim Momtaz Ferdousi Begum, Nurun Nahar, Raihan Hussain

National Institute of Nuclear Medicine and Allied Sciences, Dhaka, Bangladesh

Background: Thyroglobulin (Tg) is used as tumor marker in the follow-up of patients with differentiated thyroid carcinoma (DTC), following radioactive iodine (RAI) ablation. High serum Tg indicates local recurrence or metastasis and usually associated with positive iodine ( 131 I) whole-body scan (WBS). In some patients, metastatic tissue fails to uptake iodine resulting in negative WBS in spite of high serum Tg. These metastases are usually associated with aggressive clinical behavior and cannot be treated with RAI. Surgery is the only curative treatment option for these iodine-negative metastases. Exact localization of tumor foci is necessary for successful resection. Fludeoxyglucose-positron emission tomography (FDG-PET) has been used for detection of high Tg and negative WBS metastases for many years. The objective of this study was to find out FDG avid metastatic lesions in DTC patients with high-serum Tg or anti-Tg antibody (TgAb) with negative iodine ( 131 I) WBS.

Methods: The study included 16 DTC patients, 12 females and 4 males, with mean age of 44 years (range 26-72 years) who developed elevated Tg or TgAb and negative WBS at different follow-up stages (Mean follow-up period 8 years, range 1-29 years). PET-computed tomography (CT) was indicated for high-serum Tg in 11 patients with negative diagnostic whole-body scan (DxWBS) in seven patients and negative posttherapy whole-body scan (RxWBS) in four patients and rising TgAb in five patients with negative DxWBS in three patients and negative RxWBS in two patients. All of them underwent 18 F-FDG PET-CT scan from January to August 2016 in National Institute on Nuclear Medicine and Allied Sciences, Bangladesh, following the standard protocol.

Results: Among 16 patients, 14 patients showed FDG avid lesions at different sites of body, while in two patients, PET-CT showed no lesion. Among two PET-CT-negative patients, one had rising TG and one had rising TgAb. Among 14 PET-positive patients, FDG avid cervical lymph nodes (Level I-VII) were found in 11 patients, mediastinal lymph nodes in seven patients. One patient had lesion in vocal cord, one patient had multiple FDG avid focal lesions in both lungs, and two patients had axillary lymph nodes. A total of seven patients showed FDG avid bony lesions in different vertebra, ribs, and femur. Five patients showed single site involvement of them, 4 in cervical lymph nodes, and one in mediastinum. Rest nine patients had multiple sites involvement in cervical region, mediastinum, axilla, lung, bones, and vocal cord.

Conclusion: PET-CT imaging gives new insight in the management of DTC patients with noniodine avid lesions.

Role of Fludeoxyglucose Positron Emission Tomography/Computed Tomography in Patients with Differentiated Thyroid Cancer with Negative I-131 Whole-body Scan and Elevated Thyroglobulin

Thyroid Cancer

Thi Minh Chau Trinh, Van Tan Ngo 1 , Dang Ngoc Linh Tran 2 , Khac Nam Vo 2

Department of Nuclear Medicine, Faculty of Medicine, HCMC National University, 1 Department of Nuclear Medicine, Cho Ray Hospital, 2 Department of Nuclear Medicine, HCMC Oncology Hospital, Ho Chi Minh City, Vietnam

Background: Positron emission tomography/computed tomography (PET/CT), a combined metabolic and morphologic imaging technique, has been extensively used in diagnosis and monitoring cancers. The aim of this study is to investigate the value of PET/CT with F-18 fluorodeoxyglucose (FDG) in detecting local recurrent or metastatic lesions in differentiated thyroid carcinoma (DTC) with negative radioiodine whole-body scan (WBS) and elevated thyroglobulin (Tg).

Methods: A retrospective study enrolled 86 papillary thyroid carcinoma patients (Male:Female = 19:67; age: 42 ± 15 years) underwent nearly total thyroidectomy and radioiodine I-131 therapy with negative radioiodine WBS and elevated Tg. These patients were performed FDG PET/CT for detecting local recurrent or metastatic lesions. PET/CT findings were classified as Group 1 with high likely recurrence/metastasis, Group 2 with suspected recurrence/metastasis, Group 3 with thyroid remnant, and Group 4 without recurrence/metastasis or thyroid remnant.

Results: There were 32 patients (37.2%) of Group 1, 32 (37.2%) with Group 2, 8 (9.3%) with Group 3, and 14 (16.3%) with Group 4. Mean serum Tg level was 270.5 ng/ml in patients of Group 1, 82.1 ng/ml in Group 2, 51.4 ng/ml in Group 3, and 32.4 ng/ml in Group 4. There was a significant difference in mean serum Tg among four groups (P = 0.000). Twenty-four of 86 patients (27.9%) underwent biopsy of neck lymph nodes (12 of 32 patients in Group 1, eleven of 32 in Group 2, and one of 8 in Group 3). Among them, twenty-one patients had papillary thyroid carcinoma and three patients had benign lymph nodes. The positive predictive value of metastatic lymph nodes was 91.3% (21/23). One patient had histologically inflammatory lymph node which was consistent with PET/CT findings. Patients with histologically metastatic lymph nodes had mean serum Tg of 148.9 ng/ml (range, 17-1000 ng/ml) and anti-Tg antibody of 70 UI/ml (range, 10-554 UI/ml). PET/CT results led to change the treatment intent in 24/86 patients (27.9%) from planning of hormone or additional I-131 therapy to surgery (9 patients), surgery + I-131 (12 patients) or external radiation (3 patients).

Conclusions: FDG PET/CT is helpful in identifying local recurrent or metastatic lesions in DTC patients with negative radioiodine WBS and elevated Tg after surgery and radioiodine therapy. PET/CT results may change treatment strategy in these patients.

Production and Quality Control of Indium-111 Pentetreotide (OctreoScan™) Radiopharmaceutical in Iran

Treatment of Primary Cancer and Metastatic Disease

Seyed Yousef Fazaeli Hoseini Nezhad

Nuclear Science and Technology Research Institute, Tehran, Iran

Background: 111 In pentetreotide radiopharmaceutical is used extensively for detection of variety of cancers in medicine. Octerotide is a pharmaceutical with a structure similar to somatostatin which administrated via intravenous injection in an 111 In-labeled form. This radiopharmaceutical acts as a theranostic agent with binding to somatostatin receptors. Over the last decade, 111 In pentetreotide has remained the most widely used radiopharmaceutical for the scintigraphic detection and staging of primary and metastatic neuroendocrine tumors.

Methods: In this study, application of this radiopharmaceutical as well as the production and quality control strategies was investigated precisely.

Results: Somatostatin-receptor scintigraphy results were compared with conventional imaging. Tumors with high expression of somatostatin receptors show good and specific uptakes.

Conclusion: The whole process of production of 111 In radionuclide as well as Indium-111 pentetreotide was tested and the result confirmed the ability of production of this radiopharmaceutical in upcoming years in Iran.

A Sn-117m Electroplated Cholangiocarcinoma Stent

Treatment of Primary Cancer and Metastatic Disease

Gilbert R. Gonzales, Suresh C. Srivastava 1 , Nigel R. Stevenson

R-NAV, LLC, 1 Brookhaven National Laboratory, USA

Background: Cholangiocarcinoma is a malignancy of the biliary duct system that compresses and blocks the duct, leading to severe pain and often resulting in ascending cholangitis and death. There is a need for symptomatic treatment of ductal occlusion that has been partially addressed with existing cholangiocarcinoma stents (CCSs). These CCSs are placed in a harsh enzymatic environment and reocclusion and migration of the stent occurs frequently. The ductal CCS presented here is electroplated with a radioactive conversion electron (CE) emitting metallic isotope (i.e., Sn-117m). An electroplating technique that produces micrometallic dendrites or "hillocks" can result in an anchoring effect when the stent expands within the duct to open the occluded duct. The stent is electroplated with Sn-117m that has a short emission energy range of 300 μ. Ductal obstruction is diminished by outward expansion of the stent, tumor mass is irradiated, and dendrites and hillocks on the stent surface reduce migration of the stent.

Methods: During the electroplating process, the stent is coated with Sn-117m on the outer surface of the stent struts with the inner stent surface uncoated to allow for treatment of the ductal wall neoplasm and in order for the inner surface of the stent struts to reendothelialize. A 316L stainless steel 5-10 French, 1.8-15 cm in length stent was used, with a strut design similar to an ACS Multi-Link™ stent. The stent is submerged in the activation and plating solution comprising 0.5 M COCI 2 and 1 M CI at a current density of 5-1 OmA/cm 2 , for about 1-3 min. To prepare the plating solution from the radioactive stannic tin, a weighted piece of high purity cold tin wire is placed in a dissolution vessel along with an aliquot of radioactive tin and 12 M hydrochloric acid to establish equilibrium such that the radioactive tin behaves like the "cold" tin (both as Sn2+). This method produces an electroplated tin layer with substantial dendrite formation to at least 100 μm in length.

Results: Sn-117m stent implantations were used in pig coronary artery as well as New Zealand White rabbit aortic implantations where barotrauma-induced inflammatory cells were inhibited. Vessel Sn-117m dose has been worked out with low, medium, high and "sterilizing" toxic doses of tin-117m.

Conclusion: The Sn-117m-electroplated CCS expands to open the occluded duct with resulting palliation of symptoms. The CE-emitting metallic isotope may also treat the cancer, reducing tumor mass with the embedded metallic dendrites that increase the dosimetric surface area and anchor the stent in place.

Tissue Polypeptide-specific Antigen Estimation as Noninvasive Aid to Personalized Management of Cancer Cervix

Treatment of Primary Cancer and Metastatic Disease

Padmamalika Hazra, Daya Hazra 1 , Gita Jaiswal 2

St John's College, 1 Boston Medical Centre, Soamibagh/S. N. Medical College, Agra, 2 University of Allahabad, Allahabad, Uttar Pradesh, India

Background: Cancer cervix is the leading cause of cancers among Indian women (Million Death Study, Dikshit, 2002), often attributed to uncircumcised partners, human papilloma virus prevalence, and poor hygiene. We have previously described the value of estimation of tissue polypeptide-specific antigen (TPS), an epitope on a cytokeratin 8-18 recognized by the M3 monoclonal created by Bjorklund, (1995), serving as a proliferation marker in personalizing cancer management in head and neck and breast cancers (2015, 2016). We describe here its potential in cancer cervix management.

Methods: TPS was measured by an immunoradiometric sandwich assay based on an 125-I-radiolabeled monoclonal antibody M3 in 40 cases of cervix cancer, 30 untreated and 10 treated as compared to 250 healthy controls. Cancer cases were stratified by anatomical stage, histological grade, and response to therapy classified by UICC criteria as complete remission, partial remission, stable disease, progressive disease, and recurrence.

Results: Mean TPS levels in controls were 51.17 ± 51.21 units/L, with only four having values above 80 and none above 120 U/L. The untreated cervix cancer cases showed progressive and statistically significant TPS elevation both with anatomical stage (cervical intraepithelial neoplasia - 127 units/L, Stage I - 433.3 ± 295.6 U/L, Stage II - 491.9 ± 304.9, Stage III - 544.7 ± 356.3, and Stage IV - 736.4 ± 410.87) and with histological grade (378.8 ± 206 - Grade I, 481.5 ± 337.9 - Grade II, and 875.7 ± 392.9 - Grade III) in untreated cases and similar but lesser values in the corresponding anatomical stages/histological grades in the treated cases. Relapsed patients showed elevation in all cases, and the lead time between elevation and clinical recurrence is under study in serial follow-up.

Conclusions: As in cancer breast as well as head and neck cancers, TPS estimation is a noninvasive, serologic, and economic method of identifying and quantifying proliferative activity, costing about Rs. 350/- ($6) per test. Although the Papanicolaou technique remains the method of choice for primary diagnosis of cancer cervix, TPS assay during follow-up after surgery can serve as a useful aid in planning and evaluating personalized management, and for selecting cases during follow-up for the more expensive imaging methods such as positron emission tomography/computed tomography, especially in patients geographically and socially remote from tertiary management centers.

Outcome of Therapy of Lymphatic Filariasis Documented by Lymphoscintigraphy

Infrastructure development training and education

Birendra Kishore Das, Bhagirathi Dwibedi 1

Utkal Institute of Medical Sciences, 1 Regional Medical Research Centre, Bhubaneswar, Odisha, India

Background: Lymphatic filariasis (LF) is a parasitic disease caused by thin, thread-like filarial worms transmitted to humans by the bite of mosquitoes. The adult worms lie deep in the lymph vessels of the scrotum, groin, armpit, and around the breasts where they may live for 4-6 years. These worms grow and mature in the lymph vessels and produce millions of baby worms called microfilaria, which appear in the peripheral blood at night and can be identified to certain extent by night blood examination. An estimated one billion people are at risk of developing the disease worldwide and a total of 120 million people are indeed infected globally with LF, which is ranked as the second most common cause of physical disability. It is estimated that India has a total of 31.26 million microfilaremics; 7.44 million having lymph edema and 12.88 million suffering from hydrocele.

Materials and Methods: All 102 children in the age group of 5-18 years who were seropositive for Wuchereria bancrofti infection were subjected to lower limb lymphoscintigraphy. The used radiopharmaceutical was sulfur colloid or nonocolloid which was injected subcutaneously in the webs between the first and second toes or fingers. After injection, the patients were asked to walk for about 30 min. Images of the feet, lower limbs (knee and thigh regions), and pelvis were taken at various time intervals up to 2 h and a whole-body scan was taken at the end. Semi-quantitative studies have been done by calculating percentage of tracer accumulated in inguinal lymph nodes in comparison to the site of injection at different time periods after taking regions of interests to ascertain whether this can be used in addition to visual interpretation.

Results: Lymphatic pathology was found in 73 of these 102 children (71%). Eighty percent of the symptomatic and 66% of the asymptomatic children showed abnormality in lymphoscintigraphy. Ultrasonography in these 102 children revealed the presence of adult worm in nine children in form of filarial dance sign. The children were given antifilarial treatment consisting of diethylcarbamazine and albendazole (400 mg) and subjected to follow-up lymphoscintigraphy at an interval of 6 months. Compared with baseline status, improvement of lymphatic flow has been seen in 76%, 100%, and 96% of obstructive cases during follow-up at 6 th , 12 th , and 18 months period, respectively. This is an ongoing study and further evaluation will continue. However, the results so far obtained indicate that the therapeutic effect of treatment in LF can objectively be documented by lymphoscintigraphy.

Conclusions: The results are important in view of the fact that >50% of the infected children are asymptomatic and no other method is capable of demonstrating improvement of lymphatic flow and hence the effect of the treatment. This ongoing study has shown that lymphoscintigraphy is a simple and efficient method to establish the diagnosis and document therapeutic response, particularly in children having no significant clinical manifestation of the disease.

Theragnsotics of Prostate Cancer in Myanmar: Dream and Future Expectations

Infrastructure development training and education

Kyin Myint, War War Wann Maung 1 , May Wathan Myo 1

Ministry of Health, 1 Yangon General Hospital, Ministry of Health, Myanmar

Background: Prostate cancer is the fourth most common malignancy worldwide and the third in men of old age (average 65 years) in Myanmar. Currently, serum prostate-specific antigen (PSA) is the tumor marker of choice with highest positive predictive value in prostate carcinoma. Regarding staging of the disease, computed tomography (CT), magnetic resonance imaging, and 99m Tc-MDP bone scintigraphy are the choices of investigations practicing in Myanmar. The only positron emission tomography-CT (PET-CT) and 18 MeV IBA cyclotron have been installed at the Department of Nuclear Medicine, Yangon General Hospital, in 2015. Two more PET-CT centers are expected to appear in private hospitals of Yangon in 2016. Because of these infrastructures and the evidence-based, promising success of 68 Ga-PSMA and 177 Lu-PSMA theragnostics management of prostate cancer worldwide, this new and effective therapy has to be dreamed for Myanmar prostate cancer patients.

Materials: We plan to treat four prostate cancer patients with 177 Lu-PSMA after proven tissue biopsy, serum PSA level, complete blood picture, and 99m Tc-MDP bone scan for staging, during the period of July to September 2016. Because of budgetary constraint and Government's policy, 68 Ga generator could not be available at the present moment. However, expectation goes to many PET-CT centers with gallium generator in the private hospital in the near future. We are treating the patients with 200 mCi of 177 Lu-PSMA, three doses at interval of 6 weeks. Single photon emission CT imaging will be done after therapy. 177 Lu-PSMA labeling, radiopharmaceutical administration, and radiation protection practice have to be trained at the center locally.

Results: The side effects and response to the therapy will be assessed by symptoms relief, serum PSA level, complete blood picture, and 99m Tc-MDP bone scan. The results will be well documented and present at the multidisciplinary conference for clinical awareness among other colleagues. Then, it will lead to introduction of 68 Ga-PSMA imaging to fulfill the theragnostic strategy in prostate cancer.

Conclusion: This pilot study is the stepping stone of theragnostic nuclear medicine in Myanmar. Cancer is the second most common morbidity and mortality, among noncommunicable diseases in Myanmar. Theragnostics management in prostate cancer is an additional boon to our health-care professionals to upgrade health-care system in Myanmar. This dream study will benefit both public and private sector hospitals and more importantly people of Myanmar.

Challenges and Opportunities in the Localization of Radiopharmaceuticals

Other

Gregory Ηiocson, Adelina Bulos

Philippine Nuclear Research Institute, Metro Manila, Philippines

One of the current initiatives of the Government of the Republic of the Philippines through the Philippine Nuclear Research Institute (PNRI), an agency under the Department of Science and Technology (DOST), is to make the more common diagnostic procedures in nuclear medicine more accessible to the public. To achieve this, the PNRI through the support of the International Atomic Energy Agency and DOST must first set up a good manufacturing practice-grade laboratory that has the capability to derive technetium-99m from imported molybdenum-99. The facility was successfully established and several preproduction runs were conducted in 2015 using Mo-99 from various suppliers to test the quality and compatibility of the raw material. After production, the next phase of the supply chain is the distribution aspect. Along the way, there were challenges that surfaced, one was in the sourcing side of Mo-99 supply, and the other two were in the distribution side. In the supply side, there was a supplier who suddenly had internal problems and deferred its production. It had an adverse impact on the production and pricing strategies. In the distribution side, there were the existing importers of Tc-99m who had to be invited to become distributors of locally produced Tc-99m. The issues in this aspect were on the price that the PNRI had little control given the few choices that it has on the sourcing of imported raw materials. Then, in the distribution side, there are the nuclear medicine centers (NMCs) that only buy the ready-for-use radioactive products from those importers of generators. Most of the NMCs have not yet gone by themselves into the preparation of the compounds with a radioactive component from generators. As a result, the PNRI was not able to utilize yet the new facility. It had to revisit its plans. This year, the PNRI revised its business model. Rather than be the one importing the molybdenum-99 to produce Tc-99m out of it, the PNRI will just let the current importers of generators source their own molybdenum-99 from abroad, and for a fee, let the PNRI process it into generators. On top of this, the PNRI will continue to increase its capability to include, among others, the internal skills to prepare the compounds and be able to directly supply the centers with ready for use products.

Clinical Application of Single Photon Emission Computed Tomography-Computed Tomography Somatostatin-receptor Scintigraphy in some Neuroendocrine Tumors with Rare Localization

Other

Sonya Sergieva, Bozhil Robev 1 , Albena Fakirova 2 , Milena Dimcheva, Radka Hristozkova 2

Department of Nuclear Medicine, Sofia Cancer Center, 1 UH "St. Ivan Rilsky", 2 Department of Pathology, Military Medical Academy, Sofia, Bulgaria

Introduction: The clinical presentation of neuroendocrine tumors (NETs) may vary depending on the site of tumor origin. About 72% of NETs arise in gastrointestinal tract, 25% are bronchopulmonary in origin, and <5% arise at other sites (e.g., thyroid, breast, genitourinary system). Very often, these tumors are locally advanced with distant metastases, inoperable at the moment of diagnosis. According to some EANM guidelines (Bombardieri E. et al. Eur J Nucl Med Mol Imaging 2010; 37:1441-8; Virgolini I. et al. Eur J Nucl Med Mol Imaging 2010; 37: 2004-10; Zaknun J. et al. Eur J Nucl Med Mol Imaging 2013; 40: 800-816), functional imaging procedures applying somatostatin receptor imaging (mainly SSTR2 and SSTR5) using 111 In/ 99m Tc-pentetreotide with single photon emission computed tomography (SPECT) or positron emission tomography (PET) with 68 Ga-labeled somatostatin analogs are used to select essential information for staging, assessing SSTR status, and making decision on the most appropriate therapy regimens. The latest development in the imaging of NETs is the fusion of anatomical and functional SPECT-computed tomography (CT) and PET-CT modalities.

Purpose: The aim of this work was to obtain clinical application of SPECT-CT scintigraphy with 99m Tc-Tektrotyd in diagnosis, staging, and follow-up of patients (pts) with some rare NETs.

Materials and Methods: Thirty-two pts (18 females; 14 males) with various NETs were studied: (1) one with epiglottic NET and one with NET in the nasal cavity, (2) five with thymic carcinoids, (3) 11 with medullary thyroid carcinoma, (4) three with prostatic NET, (5) two with ovary NET, (6) five with breast NET, (7) two with urinary bladder NET, (8) two with gallbladder NET. Forty-six examinations including SPECT-CT studies of the neck and chest and/or abdomen and pelvis were performed 2-4 h postintravenous injection of 740 MBq (mean dosage) 99m Tc-HYNIC-TOC (Tektrotyd, Polatom). This tracer has high affinity to SSTR2 and lower to SSTR3 and SSTR5. SPECT-CT gamma camera Symbia T2, Siemens, was used with low-dose CT. Acquisition parameters include settings at 130 KeV; 30 mA; 3-5 mm slice thickness. Our results were interpreted based on all other clinical and radiological data.

Results: Mixed secondary lymphatic lesions were observed in a pt with epiglottic NET - some of them with intensive uptake, in other tumor masses tracer concentration, were very low, significant of insufficient expression of somatostatin receptors because of the cell dedifferentiation. Additional locoregional enlarge lymph nodes were scanned in the pt with nasal cavity NET; this SPECT-CT image was used for determination of gross tumor volume in radiotherapy planning. For exact N- and M-staging, somatostatin scintigraphy was performed in all pts: 18 of them were with locoregional lymphadenopathy; five pts were with distant liver, bone, or pulmonary metastatic lesions over expressing somatostatin receptors. In one pt with prostatic NET, some of the bone metastatic lesions were imaged without tracer uptake, but liver and lymphatic NETs were with intensive tracer accumulation. Functional imaging results were compared to biochemical evaluation of tumors that secret markers - chromogranin A (CgA)/calcitonin/prostate-specific antigen (PSA) respectively. Some pts were followed after complex treatment: (1) Partial response was observed in three pts: ≥30% decrease in the sum of the longest diameters of two target lesions compared with baseline or disappearance of >50% of hot spots with decreased level of tumor markel level. (2) Stable disease - in five pts: Persistence of one or more lesions and/or the maintenance of tumor marker level above the normal limits - CgA. (3) Progressive disease - in eight pts: Appearance of one or more new lesions and/or unequivocal progression of existing lesions. Therapeutic scheme was changed in these patients.

Conclusion: Clinical role of SPECT-CT somatostatin receptor scintigraphy in patients with NETs can be summarized as follows: (1) Anatomical cross-sectional CT data increase specificity and sensitivity of the standard nuclear medicine approaches because of their excellent spatial resolution and morphological data. (2) SPECT-CT images provide differential diagnosis of the most of uncertain scintigraphic lesions - malignant from physiological uptake, reducing false positive results, and inconclusive studies, and thus improving the certainty and accuracy of SPECT images, especially in the regions below the diaphragm. (3) To image primary tumor in cases with metastatic lesions from tumor with UPO. (4) To assess SSTR expression to predict an individual response to therapy and thus could effectively influence the management of individuals with NETs. (5) For correct N- and M-staging of NETs. (6) For monitoring of treatment response - complete, partial, stable, or progressive disease. (7) In patients with negative somatostatin-receptor scintigraphy, PET-CT studies should be performed. SPECT-CT with 99m Tc-Tektrotyd is a potential new tool for staging and follow-up of patients with NETs in the coming years.

Tailor-made Re-188 Skin Patch for Radionuclide Therapy of Keloids

Other

Jaya Shukla, Priya Bhusari, Rakhee Vatsa, Dipankar De, Sendhil Kumaran, Sanjeev Handa, Bhagwant R. Mittal

Postgraduate Institute of Medical Education and Research, Chandigarh, India

Background: Keloids are benign dermal fibroproliferative tumors without malignant potential. Many treatment modalities have been used either alone or in combination for the treatment of keloids. These include medical therapies, cryotherapy, external beam radiotherapy, photodynamic, laser, interferon, and silicone gel. However, no therapy has come up with markable success. The radionuclide therapy with the help of tailor-made patches for external application onto the keloidal scar may be the treatment of choice. Beta (β) emitters, due to high linear energy transfer and low tissue penetration, are best suited for this purpose. Tailor-made radioactive skin patches can be applied topically to destroy the fibrotic tissue of keloid.

Methods: Re-188 was freshly eluted from W-188/Re-188 generator and colloid was prepared. 188 Re-colloid was spread uniformly onto the cellulose paper on premarked 1 cm 2 area, dried and laminated with transparent adhesive tape. The image of Re-188 colloid-coated paper was acquired using gamma camera to evaluate the distribution of radioactivity on the patch using different patterns of the regions of interests (ROIs). ROIs were drawn and counts were recorded to study the distribution using different patterns. Before the treatment, clinical photograph of the lesion was taken. A trace was prepared and the area of the lesion was calculated. The tailor-made Re-188 colloid patches were prepared using 0.5-0.75 mCi/cm 2 Re-188. The patch was applied on the lesion with the help of adhesive tape for 3 h on day 1 and day 3. The cumulative absorbed dose was calculated and recorded. The patients were called for follow ups after 1, 3, 6, and 12 months posttherapy. Treatment was repeated at least 3 months after the previous therapy. The patients with multiple keloids were treated in multiple sitting to reduce the radiation load. The dose was reduced for newly developed small keloids to 0.5 mCi/cm 2 .

Results: The radioactivity was immobilized on patches. The gamma camera images demonstrated uniform distribution of radioactivity on the patches in different ROIs drawn on the processed images. The dose delivered to patients was between 100 and 150 mGy/cm 2 . The patients treated with Re-188 patch showed symptomatic relief in itching, pain and pruritus (40%-50% after the first therapy). The size and thickness of the keloid lesion were also reduced. Some patients opted for repeat therapy. The reduced dose was applied on small new keloids; however, the flattening of the scar was observed in these lesions.

Conclusions: The laminated radioactive patch can be used as an effective, noninvasive, and painless procedure for the treatment of skin keloids.

Sentinel Node Imaging in Breast Cancer

Other

Qaisar Siraj

Ministry of Health, Kuwait

Axillary nodal status is the most powerful prognostic factor predicting recurrence and survival in breast cancer. Although axillary node dissection (AND) is the staging procedure to determine systemic spread, it has significant drawbacks in terms of morbidity, and therefore, it has been supplanted by sentinel node biopsy procedure in patients with early-stage biopsy-proven breast carcinoma without cytologically or histologically proven axillary lymph node metastases for which removal of primary tumor and AND would be indicated. Sentinel lymph node (SLN) imaging/biopsy in breast cancer is aimed at identifying and removing the sentinel node(s) draining the breast cancer. If the SLN is free of tumor, then it is highly unlikely that subsequent nodes along the same pathway will contain metastasis. Complete AND can therefore be replaced by the less aggressive selective resection of the SLNs only. Sentinel node imaging and biopsy is now the de facto standard-of-care in breast cancer patients; however, the methodology is highly nonstandardized with proponents of a variety of techniques. Published studies provide evidence to support that the false negative results do not differ with the injection site though superficial injections are better for axillary staging and deep injections for detection of SLN in the extra axillary nodal basins. Preoperative lymphoscintigraphic imaging is highly recommended as it improves accuracy, reduces morbidity, and allows speedy identification of SLN. Indications for sentinel lymph node biopsy have been extended to encompass most patients with nonmetastatic breast cancer.

68 Ga-Prostate-Specific Membrane Antigen-Theranostics and 223 Ra in Prostate Cancer: An Innsbruck Experience

Irene Virgolini, S. Buxbaum, L. Scarpa, K. Fink, B. Nilica, B. Neururer, J. Bektic 1 , C. Decristoforo, P. Lukas 2 , W. Horninger 1


Departments of Nuclear Medicine, 1 Urology and 2 Radiation Oncology, Medical University of Innsbruck, Innsbruck, Austria

Background: Progression to androgen independence is the first cause of mortality in metastasized castration-resistant prostate cancer (CRPC) patients. For this reason, a targeted theranostic approach based on increased expression of prostate-specific membrane antigen (PSMA) on PC cells is an attractive and quickly developing treatment option. At the Medical University of Innsbruck, the condition of all CRPC patients was discussed in the institutional tumor board. Patients with extensive skeletal metastases usually receive 223 Ra treatment (Xofigo® , 6 × 50 kBq/kg monthly), and patients who show skeletal and soft tissue metastases and who show progressive disease under a combination therapy of 223 Ra and enzalutamide are scheduled for experimental 177 Lu-PSMA617 therapy.

Methods: From 35 patients receiving 223 Ra-treatment (2014-2016), the dropout rate was 13/35 due to tumor progression. Stable disease was found in two patients, minor response in two patients, and a mixed response was observed in two patients. In 1/35 Grade 3, thrombocytopenia was found despite of heavy pretreatment. The first ten consecutive patients with progressive CRPC were selected for 177 Lu-PSMA617 therapy on the basis of PSMA-targeted 68 Ga-PSMA-HBED-CC positron emission tomography/computed tomography (PET/CT) diagnosis showing extensive and progressive tumor load. Following dosimetry along with the 1st therapy, cycle restaging ( 68 Ga-PSMA-HBED-CC and 18 F-NaF-PET/CT) was performed after 2 and 3 therapy cycles (each cycle of 6.1 ± 0.3 GBq, range 5.4-6.5 GBq) given intravenously over 30 min, 9 ± 1 weeks apart. PET/CT scans were compared to 177 Lu-PSMA617 24 h whole body scans and contrast-enhanced dual phase CT. Detailed comparison of maximum standardized uptake value and absorbed tumor doses was performed.

Results: 177 Lu-PSMA617 dosimetry indicated high tumor doses for bone lesions (3.4 ± 1.9 Gy/GBq; range 1.1-7.2 Gy/GBq), lymph nodes (2.6 ± 0.4 Gy/GBq; range 2.3-2.9 Gy/GBq) as well as liver metastases (2.4 ± 0.8 Gy/GBq; range 1.7-3.3 Gy/GBq) whereas the dose for tissues/organs was acceptable in all patients for an intention-to-treat activity of 18 ± 0.3 GBq. Three patients showed partial remission, three mixed response, one stable, and three progressive disease. 68Ga-PSMA-HBED-CC PET/CT response was well correlating with a decline of 177 Lu-PSMA617 whole body uptake but not with 18 F-NaF PET/CT follow-up as well as serum prostate-specific antigen levels. Three patients who had previously received 223 Ra-therapy showed mixed response (n = 1), partial remission (n = 1), or progressive disease (n = 1).

Conclusion: We conclude that CRPC patients should be treated earlier during the course of the disease, and patients with lymph node and visceral metastases should receive 177 Lu-PSMA617 treatment. Our data suggest that the 68 Ga/ 177 Lu-PSMA-targeted theranostic concept could evolve into an important treatment option for metastasized CRPC. We conclude that 177 Lu-PSMA617-ligand therapy in patients with CRPC is clinically safe and can be effective in patients with progressive CRPC. A larger prospective study is needed to address the multitude of questions arising with this new treatment modality, especially to timing, dosing, and response evaluation. Furthermore, the potential of combined 177 Lu-PSMA617 with 223 Ra therapy and/or radiosensitizing chemotherapeutic drugs should be further explored.




 

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