ABSTRACTS OF THE 14TH INTERNATIONAL CONFERENCE ON RADIOPHARMACEUTICAL THERAPY (ICRT 2019) & WORLD ASSOCIATION OF RADIOPHARMACEUTICAL AND MOLECULAR THERAPY (WARMTH), 22-25 AUGUST 2019, NANJING
Year : 2019 | Volume
: 18 | Issue : 3 | Page : 324--344
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. Poster Presentations.World J Nucl Med 2019;18:324-344
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. Poster Presentations. World J Nucl Med [serial online] 2019 [cited 2019 Sep 16 ];18:324-344
Available from: http://www.wjnm.org/text.asp?2019/18/3/324/241904
Double Agent Radionuclide Therapy for Differentiated Thyroid Cancer with Bone Metastases: The First Experience of Simultaneous Administration of 131I and 153Sm-EDTMP
Andrey Shrinov1, Valeriy Krylov1, Ekaterina Borodavina1, Tatiana Kochetova1, Andrey Kaprin2, Oksana Timohina1, Tamara Geliashvili1, Karina Petrosian1
1A. Tcib Medical Radiological Research Center, Obninsk, 2NMICR, Moscow, Russia
About 12,000 new cases of differentiated thyroid cancer (DTC) are registered in Russia annually. The majority of cases have good prognosis after surgery with or without subsequent radioiodine therapy (RIT). The presence of distant metastases, especially bone metastases, and advanced age worsens the prognosis even in cases with high radioiodine (RI) uptake. Usually bone metastases are painful, requiring analgesics. Bone seeking radiopharmaceuticals may be useful as well as RIT for patients with bone metastases. For this group of patients may be useful double agent radionuclide therapy (DART) with sequential administration of 153Sm-EDTMP and RI. 28 DTC patients (18 women and 10 men) with bone or bone and lung metastases were treated this way since 2009. Age ranged from 33 to 76 years (average 56±2.3). In the majority of cases 153Sm-EDTMP was administered firstly, the next day after bone scan and SPECT/CT RI was administered with following SPECT/CT. DART (153Sm-EDTMP + RI) was applied from 1 to 10 times in each case (6±2). It was well tolerated; no significant bone marrow suppression or any other adverse events were observed. Marked reduction of pain or its complete disappearance and stabilization of bone metastases was achieved in all cases. In cases of progression disease RIT stopped, the treatment followed with sorafenib or lenvantinib and 153Sm-EDTMP if it’s necessary. Thus, DART (153Sm-EDTMP + RI therapy) demonstrated good palliative and cytotoxic effect without increase toxicity.
Radiolabeled Tamoxifen: A Theranostic Tool for Estrogen Expressing Cancers
Anupriya Chhabra1, Jaya Shukla1, Rajender Kumar1, Rakhee Vatsa1, Amanjit Bal1, Gurpreet Singh1, Bhagwant R Mittal1
1Department of Nuclear Medicine and PET, Postgraduate Institute of Medical Education and Research, Chandigarh, India
Background: Tamoxifen is an FDA approved drug for estrogen receptor (ER) expressing breast cancers. Radiolabeling of tamoxifen with Tc-99m/Re-188 will lead to the development of theranostic radiopharmaceutical for ER expressing breast cancer patients. Methods: Tamoxifen was radiolabelled in-house via Tc-99m and Re-188 tricarbonyl core. In-vitro receptor binding studies were performed in ER and non-ER expressing cell lines. Biodistribution studies were performed in rats. Tc-99m-tamoxifen and F-18-FDG PET/CT imaging was performed in three patients. Results: Tamoxifen was radiolabeled with Tc-99m and Re-188 with more than 95% radiochemical purity. Tc-99m-tamoxifen demonstrated 30% binding towards ER. Binding was inhibited by 72% when pretreated with 50 molar excess tamoxifen. Only 1-3% binding was observed with non-ER cells. MTT assay for cytotoxicity demonstrated 93.4% cell killing with 2 µg tamoxifen in Re-188-tamoxifen complex (40 µCi,), 71.5% with tamoxifen alone (20 µg,) and 36.9% with Re-188 alone (40 µCi), Normal biodistribution of Tc-99m-tamoxifen was seen in breast, heart, liver, lungs and spleen. Tc-99m-tamoxifen SPECT/CT image of the two patients showed uptake in breast and other lesions. The images were in concordance with F-18-FDG PET/CT findings. Uptake of Tc-99m-tamoxifen was not observed in third patient as she was already taking tamoxifen (20mg/day) from last six months. However, breast and other metastatic lesions were visualized on 18F-FDG PET/CT scan results. Conclusion: This study suggest that Tc-99m-tamoxifen is useful for ER imaging and Re-188-tamoxifen can be used as targeted radionuclide therapy for ER expressing metastatic cancers. More patient data is needed to validate the findings.
Incidence of Metastatic Disease in Low Risk Differentiated Thyroid Carcinoma Patients
Bridget Chappell1, Sze Ting Lee2, Andrew Scott2
1Department of Medicine, University of Melbourne, Austin Hospital, 2Department of Molecular Imaging and Therapy, Austin Health, Heidelberg, Melbourne, VIC, Australia
Background: 131I-NaI use for remnant ablation in patients who have undergone thyroidectomy for differentiated thyroid carcinoma (DTC) is long established with 85% of DTC patients cured by 131I-NaI therapy surgery in combination with surgery and TSH suppression. The presence of distant metastatic disease at initial presentation is low with disease being confined to the thyroid and local lymph glands. Low risk DTC Patient preparation for initial 131I-NaI treatment can use administration of recombinant human thyrotropin-(rTSH) instead of thyroxine cessation to elevate TSH levels. The use of rTSH (Thyrogen®) stimulation followed by 131INaI ablation dose for low risk DTC patients with low clinical suspicion of metastatic disease is standard practice at our institution. Aim: To determine the incidence of previously undiagnosed metastatic disease in low risk DTC patients undergoing initial Thyrogen® stimulation before 131I-NaI ablation. Method: A retrospective review was performed on consecutive low risk DTC patients presenting for initial post thyroidectomy Thyrogen® stimulation and 131I-NaI ablation from 2014-2018. Patient demographics, surgery type, histopathology, post ablation imaging results – including thyroid bed uptake and presence of 131I avid metastatic disease were collected. Statistical analysis was performed. Results: A total of 108 patients with DTC reviewed with a follow up range of 12-61 months. The 131I post ablation imaging results were analysed and the incidence of 131I avid metastatic disease calculated, characterised and possible causal factors investigated. The incidence of undiagnosed 131I avid metastatic disease in the Thyrogen® low risk patient population was 5.5% (n=6) and 0.9% for distant metastases. Of this metastatic disease group 83% (n=5) of patients had regional lateral lymph node involvement and 1 patient with distant 131I avid bone disease. On follow-up (median = 32.5 month) 50% of these patients had undergone further 131I-NaI Therapy. Comparison of the metastatic spread patient group to the remaining 94.5 % of patients without disease spread identified no specific causal factors for the presence of 131I avid metastatic disease. Conclusion: 131I-NaI avid metastatic disease in low risk patients is rare and does not contraindicate the use of Thyrogen® stimulation in low risk DTC.
Busaidy NL, Cabanillas ME. Differentiated thyroid cancer: Management of patients with radioiodine nonresponsive disease. J Thyroid Res 2012;2012:618985. Nixon IJ, Whitcher MM, Palmer FL, Tuttle RM, Shaha AR, Shah JP, et al. The impact of distant metastases at presentation on prognosis in patients with differentiated carcinoma of the thyroid gland. Thyroid 2012;22:884-9.
Baseline Study of Sex Hormones and Multimodal Molecular Imaging of Rhesus Monkeys in Non-Reproductive Season
Chengtao Feng1, Jihua Zhao1, Lilin Chen1, Fei Xie1, Gaohong Zhu1
1Department of Nuclear Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
Objective: To investigate the gonadal function of rhesus monkeys in non-reproductive season by the examination of hormone level and multimode MR, PET/CT molecular imaging. So that we can provide baseline parameters for related experimental studies. Methods: Fifteen female rhesus monkeys in non-reproductive season were divided into three groups according to different physiological stages: before puberty (n = 5), prime fertility period (n = 5) and peri-menopausal (n = 5). All rhesus monkeys were taken sex hormone analysis and whole-body PET/CT, pelvic MRI. The CTmean and SUVmax of uterus, the thickness of intima, binding zone and outer muscle layer were measured, and the ovarian volume (volume = length × width × thickness × 0.5233) was calculated. The three groups were compared by One-way ANOVA, pairwise comparison with LSD or Dunnett t test, and correlation analysis by Pearson method. Results: There were significant differences in FSH, Testo and ESTRD among the three groups (F value: 4.19, 3.91, 6.83, all P < 0.05). FSH increased gradually along with the increase of age, and the FSH of peri-menopausal period was significantly different with the other two groups respectively (t value: 3.39, 3.73, all P < 0.05). Testo decreased gradually along with the increase of age, and the statistical results were similar with FSH (t value: 3.39, 3.46, all P < 0.05). ESTRD increased gradually from before puberty to prime fertility period, but decreased from prime fertility period to peri-menopausal. ESTRD of prime fertility period was higher than the other two groups respectively (t value: 4.77, 3.92, all P < 0.05). ESTRD was consistent with the change trend of AMH, the intimal layer thickness and binding zone of uterus, the CTmean and SUVmax of uterus, ovarian volume. The difference of intimal layer and binding band of uterus in three groups was statistically significant (F value: 18.26, 38.9, all P < 0.05). The intimal layer of prime fertility period was thicker than that of peri-menopausal and before puberty (t value: 7.17, 4.08, P < 0.05). The uterus binding zone of prime fertility period was thicker than that of peri-menopausal and before puberty respectively (t = 7.82, 3.76, P < 0.05). All P < 0.05). The binding zone of prime fertility period was thicker than that of before puberty (t value: 4.54, P < 0.05). There was a positive correlation between the total volume of bilateral ovaries and AMH in all rhesus monkeys (R value: 0.053, P>0.05). Conclusion: The level of FSH and Testo changed with the increase of age in three groups, FSH increased and Testo decreased gradually. It was increased at first and then decreased along with the increase of age at the intimal layer and binding band thickness of uterus, AMH, ESTRD, CTmean and SUVmax of uterus, the ovarian volume. These indexes have certain value in evaluating the development, maturation and degradation of gonadal function in rhesus monkeys in non-reproductive season. It can be used as an observation parameter of anti-reproductive aging intervention in peri-menopausal rhesus monkeys.
Variation in the Absorbed Radiation Dose and PSA Response after Serial Lu-177 PSMA Radioligand Therapy
Christiane Schuchardt1, Stefan Wiessalla1, Aviral Singh1, Jingjing Zhang1, Harshad R Kulkarni1, Dirk Müller1, Richard P Baum1
1Theranostics Center for Molecular Radiotherapy and Molecular Imaging (PET/CT), Bad Berka, Germany
Background/Aims: The aim of our study was to determine the inter-cycle dosimetry variation in patients with metastatic castration-resistant prostate cancer (mCRPC) undergoing at least 2 cycles of Lu-177 PSMA radioligand therapy (PRLT), in correlation with the change in serum PSA after PRLT. Methods: Dosimetry was performed during each PRLT cycle in 10 patients with mCRPC. PSMA expression was verified before therapy using Ga-68 PSMA PET/CT. The patients received at least 2 cycles of PRLT using 3.4-7.5GBq Lu-177 PSMA. The time-dependent biodistribution was determined based on whole-body scintigraphies and SPECT/CT. Dosimetric calculations were performed using OLINDA 2.0. For intra-patient comparison, the following dosimetric parameters were determined for kidneys and metastases: uptake at 20h p.i. and mean absorbed dose. Variations between first and following therapy cycles were also analyzed as mean with respect to the first cycle (=100%). Serum PSA was determined before and every 4 weeks after the first PRLT cycle. Results: In 9 patients, all dosimetric parameters pertaining to metastases demonstrated variations between the first and second therapy cycles: the mean uptake declined by 57% and the average dose by 64%. In contrast, the mean renal uptake increased by 62% and the average renal dose was therefore higher in the following cycles (34%), except for a lower renal dose at the second cycle in 1 patient (-17%). One of the patients showed inverse results, an increase in the tumor uptake (+84%) and dose (+154%) and a decrease in the renal uptake (-9%). However, the renal dose exhibited a mild increment (+19%). Patients with a fall in the absorbed tumor dose also demonstrated a biochemical response (decrease of serum PSA by 41%). The patient exhibiting an increasing PSA after the first cycle revealed a higher absorbed tumor dose during the second PRLT cycle. Conclusion: There is a significant inter-cycle variation of the absorbed tumor and kidney doses, which correlates with the change in PSA after PRLT. A decrease in serum PSA, indicating a therapy response, is therefore associated with a decrease in the absorbed tumor dose during subsequent PRLT cycle and vice versa. Administration of a higher amount of radioactivity in the first cycle seems to be reasonable, since the tumor doses tend to decrease in the subsequent cycles due to therapy response.
Ferritin-Encapsulated Doxorubicin Nanoparticles for Ferroptosis Enhanced Cancer Therapy
Donghui Pan1, Xinyu Wang1, Runlin Yang1, Min Yang1
1Key Laboratory of Nuclear Medicine, Ministry of Health, Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu, People’s Republic of China
Background: Ferroptosis is a new type of cell death proposed by Dixonin et al. Unlike apoptosis, necrosis, autophagy and other cell death mechanisms, Ferroptosis depends on the iron and the accumulation of lipid reactive oxygen species. Doxorubicin (DOX) is one of anti-tumor chemotherapeutic drugs, which have been used in clinical. DOX showed powerful therapeutic effects on a wide range of cancer, including acute leukemia, lymphoma, breast cancer, and lung cancer. Ferritin (Fn), an iron-containing protein, was designed to encapsulate DOX for targeting and killing transferrin receptor 1 (TFR1) overexpressed tumor cells. DOX can cause oxidative damage to cell in the tumor cells by producing ROS. ROS and intracellular iron play crucial roles in ferroptosis. Thus, in this study, we tried to find out whether the ferroptosis could be induced by ferritin-encapsulated DOX for cancer cell killing. Methods: Ferritin was diluted into saline solution at a concentration of 5 mg/mL first. Then the pH value of the solution was adjusted to 4 approximately by 0.05 N HCl. 2 mL ferritin solution was mixed with 2 mL DOX aqueous solution (0.5 mg/mL) and incubated for 1 h. After that, the products were run through a PD-10 column to remove free Dox. The pH value of the solution was then adjusted to 7 by 0.05 N NaOH. The uptake of Fn-DOX was evaluated by flow cytometric in Hep G2 and HT29 cells. Cells with media were added in 6-well plate (3 × 105 cells/well) and incubated for overnight at 37 °C. Cells were then treated with 0.5 μM free DOX for 2 h or Fn-DOX, with the same concentration of free DOX (0.5 μM), for 15, 30, 60, 120 min. All of cells were collected and evaluated by flow cytometer. HT29 cells were seeded with a density of 1×105 per well in 24-well plates and incubated overnight. Cells were treated with agents for 24 h. After incubation, the culture medium was replaced and cells were washed by PBS for three times. 2.5 mL of fresh medium containing the lipid peroxidation sensor C11-BODIPY was added into each well with the final concentration of 5 µM and incubating cells for another 30 min. After washed by PBS, the cells were observed using a fluorescence microscopy (Olympus). Results: The fabrication process of Fn-DOX was illustrated in Figure 1A. The hydrodynamic size of Fn-DOX was determined by dynamic light scattering (DLS). This resulted in an average hydrodynamic diameter of 12.7 ± 4.1 nm, which is a little larger than that of ferritin (10.3 ± 3.1 nm). The intracellular uptake of Fn-DOX and free DOX in both cell lines were compared by flow cytometry. As shown in Figure 3, cellular uptake of free DOX is almost identical in both cells, this result can be verified from the numerical value. Whereas the uptake of Fn-DOX in both cells showed significant differences. Since HT29 cells have highly expressed transferrin receptors, more Fn-DOX can be transferred into the cells. In other words, high uptake of Fn-DOX is dependent on intracellularly high expression of transferrin receptors and exhibits time-dependent uptake. The cytotoxicity of Fn-DOX, DOX, DOX-Fe, and Ferritin was evaluated in HT29 cells. Ferritin without DOX has almost no toxicity to HT29 cells within 0.5 mg/mL, and the half maximal inhibitory concentration (IC50) were 1.683, 1.330 μM for DOX, and DOX-Fe, respectively. A lower IC50 was observed, the IC50 of Fn-DOX was 1.349 μM, which was closed to DOX-Fe. Conclusions: Utilizing the acidic pH of the cancer environment to achieve nano-system drug delivery has proven to be an effective strategy. In this article, based on the new death form of ferroptosis, we have successfully constructed a new type of nanoparticle consisting of the antitumor drug doxorubicin and exogenous ferritin. The nanoparticle exhibits a small particle size and is characterized by pH sensitivity. More importantly, it has a certain degree of targeting and can be more taken up by tumor cells richer in transferrin receptors. It therefore shows great potential for drug delivery. The accumulation of lipid peroxide was detected by cell staining and flow cytometry, and the decrease of GPX4 protein expression was detected by Western blotting, which were the same as the characteristic of ferroptosis. In summary, the novel nanoparticle Fn-DOX based on ferroptosis provides a new recommendation for targeting killing tumor cells.
Integrin α vβ 3 Receptor Targeted Theragnostics of Osteosarcoma and Lung Metastasis with 68Ga/177Lu-RGD2
Guoqiang Shao1, Lulu Zhang1, Jingjing Fu1, Jisheng Sui2
Departments of 1Nuclear Medicine and 2Orthopaedics, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
Objective: To investigate the value of integrin α vβ 3 targeted microPET/CT imaging with 68Ga-NODAGA-RGD 2 as radiotracer for the detection of osteosarcoma and theranostics of osteosarcoma lung metastasis. Methods: The 68Ga-NODAGA-RGD 2 and 177Lu-NODAGA-RGD 2 were prepared via one-step method and their stability and integrin α vβ 3 binding specificity were investigated in vitro. Forty-one nude mice were injected with human MG63 osteosarcoma to established the animal model bearing subcutaneous osteosarcoma (n=21), osteosarcoma in tibia (n=5), and osteosarcoma pulmonary metastatic (n=15). The microPET-CT imaging was carried out in 3 animal models at 1 hour after tail vein injection of 68Ga-NODAGA-RGD 2. Biodistribution study of 68Ga-NODAGA-RGD 2 was performed in animal model bearing subcutaneous osteosarcoma at 10, 60, and 120 minutes. The animal model bearing pulmonary metastatic osteosarcoma was injected with 177Lu-NODAGA-RGD 2 at 7 weeks after model establishment to observe the therapeutic effect of pulmonary metastatic osteosarcoma. Histological and immunohistochemistry examinations were also done to confirm the establishment of animal model and integrin β 3 expression in animal models bearing subcutaneous osteosarcoma and bearing pulmonary metastatic osteosarcoma. Results: 68Ga-NODAGA-RGD 2 and 177Lu-NODAGA-RGD 2 had good stability in vitro with the 50% inhibitory concentration value of (5.0±1.1) and (6.5±0.8) nmol/L, respectively. The radiochemical purity of 68Ga-NODAGA-RGD 2 at 1, 4, and 8 hours was 98.5%±0.3%, 98.3%±0.5%, and 97.9%±0.4%; while the radiochemical purity of 177Lu-NODAGA-RGD 2 at 1, 7, and 14 days was 99.3%±0.7%, 98.7%±1.2%, and 96.0%±2.8%. 68Ga-NODAGA-RGD 2 microPET-CT showed that the accumulation of 68Ga-NODAGA-RGD 2 in animal models bearing subcutaneous osteosarcoma and osteosarcoma in tibia and in lung metastasis as small as 1-2 mm in diameter of animal model bearing pulmonary metastatic osteosarcoma. Biodistribution study of 68Ga-NODAGA-RGD 2 in animal model bearing subcutaneous osteosarcoma revealed rapid clearance from blood with tumor peak uptake of (3.85±0.84) %ID/g at 120 minutes. The distribution of 177Lu-NODAGA-RGD 2 in lung metastasis was similar with 68Ga-NODAGA-RGD 2. The number and size of osteosarcoma metastasis decreased at 2 weeks after 177Lu-NODAGA-RGD 2 administration and integrin targeting specificity was confirmed by pathology examination. Conclusion: 68Ga-NODAGA-RGD 2 was potential for positive imaging and early detection of osteosarcoma and metastasis. Targeted radiotherapy with 177Lu-NODAGA-RGD 2 was one potential alternative for osteosarcoma lung metastasis.
New Anticancer agent derived from [188Re] Rhenium-Nitro Imidazole Complex Loaded 5th Generation Poly-L-lysine Dendrimer for Computed Tomography-Guided Lung Malignancies In situ treatment
Hafid Belhadj-Tahar1,2, Jindde Chen3, Pieping Song4, Jun Zhao4, Ming Quan3, Caixin Li2, Xingjian Gu4, Nouredine Sadeg1, Guanghua Yang1,2, Yong Gao4
1Nanomedicine Research and Expertise Group, French Association for Medical Research Advancement, (AFPREMED-Canceropole), 2AFPREMED, Toulouse, France, 3Department of Oncology, Tongjy University Medicine, 4Shanghai East Hospital, Shanghai, China
Stereotactic brachytherapy for extensive local tumors offers a very effective treatment option locally without significant complications in medically impaired patients who are not amenable to surgery. In this context, we have recently developed a new potential anticancer agent from Poly-L-Lysins dendrimer as a delivery nano system loaded with diffusible Imidazolic probes complexed with 188-Rhenium (physical half-life: 17 hrs; with b: 2.12 MeV, 71.1% and 1.965 MeV, 25.6% and g: 155 keV, 15.1%) for targeting in particular hypoxic tumors resistant to conventional cancer treatments. The aim of the study reported herein was to evaluate the feasibility of this minimally invasive, percutaneous brachytherapy technique for tumor treatment in the lung. In addition, we assessed the safety profile and therapeutic efficacy of a novel brachytherapy device derived from [188Re]rhenium-ligand as radioactive ligand loaded 5th generation poly-L-lysine dendrimer in patients with unresectable Lung Malignancies. Materials and Methods: The experiment agent “188-Rhenium-ImDendrim” is consisting of 5th generation poly-L-lysine dendrimer (172, 3 kDa, 20 nM) mixed with nitro-imidazole-methyl-1,2,3-triazol-methyl-di-(2-pycolyl) amine at GMP grade and labelled with [188Re]-rhenium. The study was approved by Shanghai East Hospital ethics committee. 5 patients received “188-Rhenium-ImDendrim” directly into lung tumors under CT-guidance, at an activity level of 162 MBq/cc of tumor (range 2 to 7 cm; mean diameter, 4 cm). For voluminous tumors (> 65 cc) the dose is given in divided injection spaced 2 weeks apart (Tumor of 115cc : 2 administrations, Tumor of 180 cc : 3 administrations). Toxicity was assessed by the nature, incidence, and severity of adverse events (Common Toxicity Criteria scores) and by hematology and clinical chemistry parameters. At H0.5, H 4, H24, H36, H72 post- administration of “188-Rhenium-ImDendrim”, the patient get a control scintigraphy with SPECT gamma camera. The response to treatment is evaluated thanks to PET/CT Standardized Uptake Values (SUVs). Results: Stereotactic administrations of “188-Rhenium-ImDendrim” were successfully carried out in all patients under local anesthesia. The radioactive product diffuses homogeneously in the tumor volume and remains 72 hours post-administration with no significant diffusion out site of injection. The One of the 5 patients reported discrete transitive hemoptysis as adverse events, but no serious events were attributable to the study device. All targeted tumors were responding at 12 weeks, with two complete responses. Conclusion: Percutaneous single and iterative administrations of this novel 188-Rhenium-Imdendrim brachytherapy device into lung cancers are safe and well tolerated. The initial data on therapeutic response are promising.
Multi-mode Molecular Functional Imaging in Bone and Muscle Components of Female Rhesus Macaque and Related Hormone Levels
Hao Wang1, Chengtao Feng1, Xiangqing Zhu2, Gaohong Zhu1, Longbao Lv3
1Department of Nuclear Medicine, The First Affiliated Hospital of Kunming Medical University, 2Yunnan Provincial Key Laboratory of Cell Therapy and Translational Medicine, National and Local Joint Engineering Laboratory of Stem Cell and Immune Cell Biomedical Technology, 920th Hospital of Joint Logistics Support Force of PLA, 3Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China
Objective: To measure changes of bone and muscle composition in female rhesus macaques, and to analyse the relationship among bone and muscle composition, serum calcium and related hormones. Methods: 15 female rhesus monkeys were divided into three groups according to age and physiological stages. General situations were assessed by SPECT/CT, the bone mineral density (BMD), muscle fiber content and bone mineral content were measured using dual-energy X-ray absorptiometry, glucose metabolism and CT value in bone were measured using PET/CT, the serum testosterone (T), estradiol (E2), follicle-stimulating hormone (FSH) and parathyroid hormone (PTH) were detected by chemiluminescence method, blood calcium level was tested by automatic biochemical analyzer. The differences of indicators among 3 groups were compared and their correlations were further analyzed. Results: Perimenopausal rhesus monkeys had more bone and joint inflammation and degenerative changes than other groups. The BMD and muscle fiber content of the skull, whole body and the iliac bone were higher in perimenopausal than that of prepubescent period (P < 0.01), the BMD of lumbar spine and femoral head were higher in perimenopausal than that of prepubescent period (P < 0.05), and the bone mineral salt content was higher in perimenopausal than that of reproductive period (P < 0.05) and prepubescent period (P < 0.01). The CTmean value of skull was higher in perimenopausal than that of prepubertal period (P < 0.05), and the SUVmax value of lumbar spine was higher in perimenopausal than that of prepubertal period (P < 0.05). Perimenopausal serum T level was lower than the other two groups (P < 0.05), FSH level was higher in perimenopausal than the other two groups (P < 0.05), E2 level was significantly lower in perimenopausal than that of reproductive period (P < 0.01). The whole body BMD of female rhesus macaques was positively correlated with muscle fiber content (P < 0.01), BMD of skull, left upper limb and lumbar vertebra were positively correlated with CTmean (P <0.01), and the whole body BMD was negatively correlated with T (P <0.05). Conclusions: The BMD of the female rhesus monkey in perimenopausal period is higher than that in prepubescent period, especially in skull, lumbar vertebra, femoral head and iliac crest. CT and dual-energy X-ray bone density analyzer show good consistency in the determination of BMD in the skull, left upper limb and lumbar spine. T, E2 and FSH levels may affect the changes of BMD.
Is Focal Increased 68Ga-SSA Uptake in Uncinate Process Physiologic? A Potential Pitfall in the Diagnosis of Pancreas Neuroendocrine Tumor
Jingjing Fu1, Ali Cahid Civelek2, Feng Wang1
1Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China, 2Division of Nuclear Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
Objective: Pancreas neuroendocrine tumor (Pan-NET) is the most common form of GEP-NET in China, which usually starts insidiously. Early diagnosis of Pan-NET is a great clinical challenge. Aim: To explore physiological uptake of 68Ga-DOTANOC in pancreas and pathological uptake in Pan-NET and determine if the sensitivity of detecting pancreas primary lesion would further improved. Methods: Seventeen consecutive patients with naïve Pan-NET were enrolled in this study from October 2016 to January 2018. Additional 16 patients with suspected GEP-NET initially, who were finally confirmed benign gastric-intestinal disease served as control. All patients underwent 68Ga-DOTANOC PET/CT. Regions of interest (ROIs) were drawn over the uncinate process, neck, body and tail of pancreas, primary tumor, liver, and used to generate the maximum of standard uptake value (SUVmax). Results: 68Ga-DOTANOC PET/CT showed the pancreas uncinate process had moderate tracer uptake with SUVmax 8.64±3.96. The neck, body and tail of pancreas had mild tracer uptake (2.49±0.76). Whereas, SSA-avid pancreatic primary tumor showed SUVmax 26.34±17.31. The SUVmax of normal liver was 9.75±2.94. Conclusion: The present study shows variable physiologic 68Ga-DOTANOC distribution in the pancreas. This variable tracer distribution, a pitfall, when recognized could aid the interpreting physicians in detecting primary lesions in the uncinate process of the pancreas. The cut-off SUVmax value for the pancreatic uncinate process should be further validated with larger cohorts. Use of such SUVmax cut-off value might improve the diagnostic accuracy of the 68Ga-DOTANOC PET/CT for Pan-NET and promote precision medicine.
177Lu-PSMA-617 Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer Patients with a Single Functioning Kidney
Jingjing Zhang1, Harshad R Kulkarni1, Aviral Singh1, Christiane Schuchardt1, Karin Niepsch1, Thomas Langbein1, Richard P Baum1
1THERANOSTICS Center for Molecular Radiotherapy and Precision Oncology, ENETS Center of Excellence, Zentralklinik Bad Berka, Bad Berka, Germany
Background: The aim of this study was to assess the safety, tolerability, and effects on renal function as well as therapeutic efficacy of PSMA targeted radioligand therapy (PRLT) using 177Lu-labeled PSMA-617 in patients with mCRPC and a single functioning kidney. Methods: Sixteen patients (aged 53-78 y) with a single functioning kidney received 177Lu-PSMA-617 PRLT between March 2015 and October 2018. Results: The median administered activity was 22.1 GBq (range, 15.4-33.8 GBq). The calculated absorbed radiation dose to the kidney per cycle was 5.3±2.1 Gy (0.81±0.32 Gy/GBq). Renal function was already impaired at baseline in 43.7% of patients, including CTCAE grade 1 renal impairment in 25.0% and CTCAE grade 2 in 18.8%. Grade 1 and 2 renal impairment, respectively, were present in 37.5% and 6.3% of the patients after the first PRLT cycle and in 31.3% and 12.5% after the second cycle. No CTCAE grade 3 or 4 nephrotoxicity was observed during or after treatment. There was no significant change in either TER or the ratio of TER to lower-limit TER after the last cycle of treatment (P>0.05). The median overall survival has yet to be reached with a median follow-up time of 19.3 mo (range, 5.8-45.3 mo). Conclusion: In patients with a single functioning kidney, 177Lu-PSMA-617 PRLT is feasible, seems to be effective, and is well tolerated, without any signs of acute or subacute nephrotoxicity during a mean follow-up of nearly 2 y (and up to 45.3 mo). Further long-term follow-up of this special patient group is warranted.
Pregnancy and Delivery after Peptide Receptor Radionuclide Therapy without Sequelae: A Health Outcome in Young NEN Patients Received 177Lu/ 90Y Labelled Somatostatin Analogues
Jingjing Zhang1, Harshad R Kulkarni1, Aviral Singh1, Christiane Schuchardt1, Richard P Baum1
1THERANOSTICS Center for Molecular Radiotherapy and Precision Oncology, ENETS Center of Excellence, Zentralklinik Bad Berka, Bad Berka, Germany
Background: To date, little is known about pregnancy outcomes in patients who have received therapeutic activities of radiolabeled somatostatin analogues for peptide receptor radionuclide therapy (PRRT), keeping in mind probable negative radiation effects. Methods: Clinical features, treatment parameters, pregnancy and birth outcomes in four young NEN patients (3 females; age, 28-39 y), who successfully gave birth to (or fathered) a child after having received PRRT with 177Lu/90Y labelled DOTATATE/DOTATOC/DOTA-JR11 between 2008 and 2018. Results: The median administered activity was 20 GBq (range 13–27 GBq) in 3-4 cycles. Treatment was tolerated extremely well by all patients without significant adverse effects. After 3-4 cycles of PRRT, CR was achieved in 2/4 and PR in 2/4 by both, EORTC and RECIST criteria. Conception in one female patient was by in-vitro fertilization, whereas the mode of conception was natural in the other 3 cases. All the new-borns were healthy and exhibited no malformations. All the children had normal development in the follow-up period until April 2019. One male patient has actually fathered another child. The intervals from first PRRT to birth were 20, 37, 52, 83 and 95 months, whereas that from last PRRT cycle to birth were 12, 27, 42, 67 and 84 months, respectively. Conclusion: Our results indicate that pregnancy and birth without sequelae are possible in patients with NEN who have been treated with PRRT. Radiopeptide therapy offers a perspective for patients in the reproductive age group who plan conception despite having received or are due to undergo PRRT.
Effect of High dose Radioiodine Therapy on Salivary Gland Function
Karan Singh Tanwar1, Nivedita Rana1, Rakhee Vatsa1, Anish Bhattacharya1, Bhagwant Rai Mittal1
1Department of Nuclear Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, India
Background: Radioiodine (I-131) is used as an effective and non-invasive treatment for the thyroid malignancies. Salivary gland is one of the most affected non-target organ. The present study aims to quantitatively analyze the damage to the salivary glands caused due to radioiodine therapy (RIT) for thyroid ablation. Methods: A total of 20 patients (6 males and 14 females) with differentiated thyroid carcinoma were enrolled in the study. Baseline dynamic salivary scintigraphy was performed in all patients using 185-370MBq Tc-99m pertechnetate. Post therapy salivary scintigraphy was performed 10-20 days after RIT (5- 7.4 GBq of I-131). Time activity curves obtained after pre and post therapy dynamic salivary scintigraphy were used for semi-quantitative analysis. Uptake ratio (UR), ejection fraction (EF%) and maximum accumulation (MA%) were calculated by drawing region of interest over composite image of each of parotid and submandibular glands. Paired t-test was used for comparison of the parameters obtained. Results: Significant changes were observed in UR and EF% of both parotid and submandibular gland (p-value <0.05). No considerable changes were found in the value of MA% of left parotid gland and both submandibular gland in posttherapy scans in comparison to pretherapy scans (p-value >0.05). However, significant difference was observed in the MA% of right parotid gland (p-value=0.025). Conclusion: Based on the semi-quantitative analysis, deterioration of salivary gland function after radioiodine therapy was found to be more in parotid gland in comparison to submandibular gland.
Management of Complicated Carcinoid Disease during PRRT
Karuna Luthra1, Vikram Lele1, Nihar Mehta1, Pankaj Kumar1
1Jaslok Hospital and Research Centre, Mumbai, Maharashtra, India
Carcinoid Heart disease (CHD) and Carcinoid Crisis (CC) are chronic and acute complications of Neuro-endocrine tumors (NET). In our experience with PRRT for 122 patients, we have encountered CHD in 3 patients, and CC in 3 – all were midgut NETs. CHD in 2 patients was medically managed alongside PRRT cycles; one patient – a young male with advanced CHD posed a management challenge and will be discussed in detail. He had grade 2 NET of ileo-caecal junction with multiple liver metastases. DOTA PET-CT showed high SSTR expression in lesions and disease progression even after Sandostatin and Everolimus therapy. He was referred for PRRT with poor general condition with severe fatigue, weight loss, ascites, pedal edema – Echocardiography showed right heart failure with CHD causing severe pulmonary and tricuspid valve dysfunction. Tricuspid valve replacement was not deemed feasible by cardiothoracic surgeons. His disease was managed by combination of Lu177-DOTATATE PRRT and Caval Valve Implantation (CAVI) - which was performed for the first time in India. Combination of PRRT and Transarterial placement of Tric valve in inferior vena cava resulted in significant improvement in his heart failure symptoms as well as general condition with reduction in Atrial pro-bnp and serum Serotonin levels. 2 cases of CC were seen during first cycle of PRRT, whereas 1 occured during 3rd cycle. Their management with short acting Somatostatin analogue will be discussed. These cases reiterate the importance of screening patients with midgut secretory NETs for CHD and watching out for CC in them during PRRT.
A New Glutathione-Responsive 5-Aminolevulinic Acid Derivative for Photodiagnosis and Photodynamic Therapy of Tumor Cells
Ke Li1, Ling Qiu1, Jianguo Lin1
1Key Laboratory of Nuclear Medicine, Ministry of Health, Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu, China
Background: 5-aminolevulinic acid (5-ALA) and its two esters are clinically approved drugs for diagnosis and photodynamic therapy (PDT) of tumors. However, their pharmacological activities are limited by their instability at physiological condition and lack of tumor selectivity. An ideal 5-ALA prodrug should be stable at physiological condition but active in the lesion area of interest. The concentration of glutathione (GSH) in tumor cells is at least 2-fold higher than that in normal cells, which gives an opportunity to develop GSH-responsive molecular systems for tumor-specific drug delivery. Methods: The GSH-responsive 5-ALA derivative (SA) was synthesized by protection the 5-amino group with a GSH-responsive self-immolative group which contained a disulfide bond. The stability and GSH-responsive properties of SA were measured using ESI-spectrum. The PpIX production induced by SA in tumor cells was studied by monitoring the fluorescence intensity of PpIX. The dark and photo toxicity of SA were evaluated using MTT assays. Results: SA displays excellent stability at pH = 4.0, 7.4 and 9.0. No apparent degradation of SA was observed after 24 h. After 6 h incubation with GSH (10 mM), SA could fully convert into 5-ALA-OMe. In vitro PpIX production induced by SA in Hela, HCT116, A549 and A375 cells were much more effective than its parent compound 5-ALA-OMe. Meanwhile, PpIX production induced by SA was dependent on the intracellular GSH levels. The PDT effect of SA was also powerful than 5-ALA-OMe. The half maximal inhibitory concentration (IC50) value against Hela cells was 62 ± 3 μM. And 100 μM of SA decreased the cell viability of HCT116, A549 and A375 cells to about 13%, 16% and 14% under irradiation, respectively. Conclusion: In summary, we designed and synthesized a GSH-responsive 5-ALA derivative: SA. SA displays remarkable stability at acidic, neutral and basic conditions. The PpIX production induced by SA is positively correlated with the intracellular GSH levels because of its GSH-responsive property. SA also shows much higher PpIX fluorescence intensity and phototoxicity than that of 5-ALA-OMe. Given that tumor cells generally have elevated intracellular GSH levels, SA is a promising 5-ALA prodrug for tumor-specific delivery of 5-ALA.
This work was supported by the National Natural Science Foundation of China (21701062) and the China Postdoctoral Science Foundation (2018M632262).
Artificial Intelligence to Predict Post-Therapy Dosimetry for 177Lu-PSMA I and T Therapy
Kuangyu Shi1, Song Xue1, Andrei Gafita2, Yu Zhao2, Giles Tetteh2, Bjoern Menze2, Ali Afshar-Oromieh1, Matthias Eiber2, Axel Rominger1
1Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
Purpose: The emerging PSMA-targeted radionuclide therapy (RLT) is an effective treatment for metastatic castration-resistant prostate cancer (mCRPC). The European council mandates that treatments should be planned according to the radiation doses delivered to individual patients. However, there is no clinical practical method to predict the dosimetry before RLT, which hampers the realization of treatment planning. Therefore, we aimed to prove the concept to employ artificial intelligence methods to predict the post-therapy dosimetry. Methods: Retrospectively 17 patients with metastatic castration-resistant prostate cancer (mCRPC) treated with 177Lu-PSMA I&T RLT were included in this study. Only those cycles with 68Ga-PSMA-HEBD-CC PET/CT directly before the treatment and at least 3 planar and 1 SPECT/CT dosimetry imaging were selected. Totally 30 cycles of treatments were considered for this proof-of-concept study. Organ-based mean and max SUV uptake were obtained from pretherapy PET/CT scans. Dosimetry was calculated for kidney, liver, spleen and salivary glands using Hermes Hybrid Dosimetry 4.0. Two machine learning methods, a 3-layer fully connected neural network artificial neural network (ANN) and a random forest regression (RFR) model, were established. 10-folder cross validation was applied to verify the trained network. Our results were compared with population-based dosimetry from literature. Results: ANN has better performance than RFR in the dose prediction for liver and salivary glands, while worse performance for kidney and spleen. Combining the advantages, machine learning achieved the dosimetry prediction error of 18.7±16.0% for kidney, 31.4±27.0% for liver, 24.3±16.2% for salivary glands and 32.1±31.4% for spleen. In contrast, the prediction based on literature population mean has significantly larger error (p<0.01), 46.2±50.4% for kidney, 99.5±238.7% for liver, 705.7±377.7% for salivary glands, 62.3±58.9%. Conclusion: The proof of concept study shows that machine learning can significantly reduce the prediction error compared to generally population-based estimation. Artificial intelligence may provide a practical solution to improve the dosimetry-guided treatment planning for RLT.
Acquisition Protocols of Quantitative 177Lu-Dotatate SPECT/Computed Tomography Imaging Based on Different Energy Windows and Collimators
Lei Xu1, Qingle Meng1, Rui Yang1, Feng Wang1, Hongbing Jiang1
1Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
Objective: To explore the optimal acquisition protocols for 177Lu-Dotatate SPECT/CT imaging based on different energy windows and collimators. Methods: The 177Lu SPECT images of a NEMA IEC body phantom with known activity concentration ration (12:1) between filled hollow spheres and uniform background were acquired for 3 different collimators: low energy high resolution (LEHR), medium energy general purpose (MEGP) and high energy general purpose (HEGP). Main energy window was defined around the energy peak 113 keV, 208 keV and 113 keV+208 keV with 20% width. Scatter correction was performed by applying attenuation correction and triple energy window method. Thus 9 different acquisition protocols can be produced, including LEHR_113, LEHR_208, LEHR_113+208, MEGP_113, MEGP_208, MEGP_113+208, HEGP_113, HEGP_208 and HEGP_113+208 in short. The intensity ratio between spheres and background, relative error and conversion factor were measured and corrected for partial volume effect and used to compared the performance of different methods. Results: The contrast of MEGP_208 SPECT image was the worst, whereas better visual resolution images were achieved by MEGP_208 and MEGP_113+208. The measured average intensity ratios of 9 methods were all lower than the real ratio (F=2.659, P=0.040). The relative error of intensity ratio in MEGP_113+208 was the minimum (-1.33±6.40%), and in LEHR_208 was the maximum (-58.34±14.42%). All acquisition protocols showed significant difference in conversion factor (F=4.846, P=0.003). Conclusion: Different acquisition protocols have a significant effect on the results of 177Lu-Dotatate SPECT/CT quantitative imaging. Image quality of MEGP collimator combined with 113 keV+208 keV was the best, and the intensity ratio was closest to the real ratio.
Phosphoenolpyruvate Carboxykinase 1 Reduces 18F-FDG Uptake in Clear Cell Renal Cell Carcinoma
Liang Shi1, Shuxian An2, Jianjun Liu2, Feng Wang1
1Department of Nuclear Medicine, Nanjing Hospital, Affiliated to Nanjing Medical University, Nanjing, 2Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
Phosphoenolpyruvate carboxykinase (PCK1) plays an important role in gluconeogenesis. Suppressing gluconeogenesis is a component of glucose metabolism change in clear cell renal cell carcinoma (ccRCC). Fluorine 18 (18F) fluorodeoxyglucose (FDG) positron emission tomography and computed tomography (PET/CT) is based on the abnormally high rate of glucose metabolism found in cancer cells and is widely used in management of many malignant tumors. However, the relationship between 18F-FDG uptake and PCK1 expression has not been investigated. Methods: Retrospective analysis was conducted on 62 patients with ccRCC who underwent 18F-FDG PET/CT. The relationship between maximum standardized uptake (SUVmax) and the expression of PCK1 was analyzed with immunohistochemical analysis. PCK1 knockdown and overexpression in ccRCC cells were used to examine the role of PCK1 in tumor metabolism, tumorigenesis, and its effect on the expression of hypoxia inducible factor-1α (HIF-1α). Conclusion: PCK1 inhibits 18F-FDG uptake and utilization via the HIF-1α pathway. SUVmax is higher in patients with higher-grade ccRCC than in those with lower-grade ccRCC; this result may be due to the lower PCK1 expression in the former.
Theranostics in Pheochromocytomas /Paragangliomas: Pilot Study in Chinese Population
Lulu Zhang1, Chuan Zhang1, Xiaochen Yao1, Feng Wang1
1Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
Background: Pheochromocytomas and paragangliomas (PHEOs/PGLs) are rare tumors arising from chromaffin tissues in adrenal medulla and in extra-adrenal sites including sympathetic and parasympathetic paraganglia, respectively. The aim of this study was to evaluate SSTR based theranostics in PHEOs/PLs, and compared with 131I-MIBG. Methods: Thirty-eight consecutive patients with suspected or known PHEOs/PGLs were consecutively enrolled in this study. All patients underwent 68Ga-DOTA-NOC PET/CT, whereas twenty patients also underwent 131I-MIBG SPECT/CT in a month. Per-patient and per-lesion analysis was performed, final diagnosis was confirmed by histopathology and follow-up. 68Ga-SSA positive patients were recruited to 177Lu-DOTA-TATE therapy, whereas 131I-MIBG positive patients underwent MIBG therapy. Adverse events were evaluated, tumor response was evaluated by quality of life, serum CGA level, catecholamine and metabolites changes, clinical symptoms and signs release including hypertension improvement, all patients have been followed-up for 1 year. Results: For patient-based analysis, 31 patients were positive while 7 patients were negative on 68Ga-DOTA-NOC PET/CT. The overall sensitivity, specificity and accuracy of 68Ga-DOTA-NOC were 87.9%, 60% and 84.2%, respectively. On a lesion-based analysis, there are totally 218 lesions confirmed by histopathology or imaging follow-up, including 64 bone metastasis and 46 lymphadenopathy. 190 lesions were interpreted as positive while 28 were negative. The overall sensitivity, specificity and accuracy were 89.9%, 77.8% and 89.4%, respectively. Analysis of detection rate and SUVmax was performed in 209 confirmed lesions in 34 cases proved to be PHEOs or PGLs, 188 lesions (89.95%) were detected by 68Ga-DOTA-NOC PET/CT, SUVma was 14.69±16.12. 62 bone metastasis in 13 patients were (62/64,96.9%) and 46 metastatic lymph nodule(46/46, 100%) in 13 patients showed high expression of SSTR, SUVmax was 15.92±14.42 and 23.14±19.84,respectively. 68Ga-DOTA-NOC PET/CT showed higher sensitivity in the detection of lymphadenopathy, remote and visceral metastasis. No significant adverse events were observed in 10 patients after 177Lu-DOTA-TATE therapy, function related symptom and hypertension was significantly released associated with significant reduction of catecholamine and serum CGA. Conclusion: 68Ga-DOTA-NOC PET/CT shows higher sensitivity in the detection of bone metastasis and lymphadenopathy in PHEOs/PGLs, which has great merits for staging and risk stratification of PHEOs/PGLs. PRRT have good response especially in symptom release and quality of life improvement and is tolerable with no evident hematological events and kidney toxicity. Furthermore, present study will pave the way for SSA based theranostics on PHEOs/PGLs.
Efficacy and Safety of 177Lu-PSMA-617 Radioligand Therapy in Metastatic Castration Resistant Prostate Cancer Patients
Madhav Prasad Yadav1, Sanjana Ballal1, Chandrasekhar Bal1
1Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India
Purpose: The aim of this study was to evaluate the efficacy and safety of 177Lu-PSMA-617 radioligand therapy (RLT) in metastatic castration resistant prostate cancer (mCRPC). Methods: In this prospective, single-arm, single-institutional study, 90 mCRPC patients with progressive disease on second-line hormonal therapy and/or docetaxel chemotherapy were recruited for the study. All patients underwent diagnostic 68Ga-PSMA-HBED-CC PET/CT, prior to inclusion for therapy. Included patients underwent 177Lu-PSMA-617 therapy at 8 -12 weekly intervals. The primary end-point was to assess the overall survival. The secondary and co-secondary end-points included biochemical response assessment as per the PCWG3 criteria, progression-free survival, radiological and molecular response criteria, clinical response, safety profile, and disease control rates (DCR). Results: The median age of patients was 66.5 years (range: 30-88 years). The median activity administered per cycle was 3.7-8 GBq ranging from 1-7 cycles and were followed-up over a median duration of 28 months. At 2-3 month interval after the first therapy and the end of the assessment, >50% decline in PSA was observed in 32.2% and 45.5%, respectively. Univariate analysis did not reveal any patient parameters associated with PSA decline. Radiographic response by diagnostic CT revealed partial remission (PR) in 23% (16/69), stable disease (SD) in 54% (37/69), and progressive disease (PD) in 23% (16/69) of patients. Molecular tumor response by PERCIST 1 criteria revealed 19/69 (27.5%) patients with PR, 30/69 23% (43.5%) with SD, and 20/69 (29%) with PD. The disease control rate according to the radiographic and molecular response was 77% and 71% respectively. The median overall survival and median progression-free survivals were 14 and 11.8 months, respectively. Toxicities related to RLT were low and transient with no serious adverse effects. Conclusion: 177Lu-PSMA-617 radionuclide therapy is a safe and effective approach to the treatment of mCRPC patients.
Role of Radiosynovectomy Using Yttrium 90 in Management of Knee-Joint Bleeding in Hemophiliacs, Local Experience at Syria- Damascus
1Department of Nuclear Medicine, Unversity Hospital, Damascus, Syira
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 hemophilia. Methodology: 45 hemophilic patients suffering from repeated episodes of bleeding knees were referred to the nuclear medicine department at Al-Assad University Hospital –Damascus during the period between 2009-2018, Baseline radiography of the knees in the AP and lateral views were obtained for all patients (presently an ultrasound scan can evaluate joint space, thickness & structure of the synovium, even effusion). Three-phase bone scan: flow, within 5-20 mins and after 3 hours was obtained, scan were taken at baseline, 6, and 12 months. A dose of 200 mBq Yttrium colloid was injected intra-articular space. Post-therapeutic 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 analogue scale before,1,3,6 and 12 month following the procedure. Results: Within one month period prior to RSO, all patients had more than 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) 45% had 80% reduction and 15% had less than 50% reduction. Conclusion: Radiosynovectomy presents with a therapeutic effect of 60 to 94% for HA in several studies, our study showed 80%. Radiosynovectomy is a minimally invasive, well-tolerated procedure that can be done on an outpatient basis.
Design of Delay Tank and Its Value in Safe Elimination of Radioactivity in High Dose Therapy Ward
Manumon Molathu Chandran1, Basant Malpani2, Shrikant Vasantrao Solav1, Parag Deshmukh1
1Dr. Solav’s SPECT Lab, Pune, 2Radiation Medicine Centre, Bhabha Atomic Research Centre, Mumbai, Maharashtra, India
Design of delay tank and its value in safe elimination of radioactivity in high dose therapy ward radioactivity in nuclear medicine used for therapy purpose is largely Iodine 131 related. Once administered in patients it is said to be excreted predominantly from the urinary system as there is significant reabsorption of iodine from GI tract. A radioactive delay tank is mandatory as per regulatory agency in managing excretory waste from patients administered with high dose radioiodine therapy. We designed and constructed a different method for collection of waste in delay tanks to minimize the risk of discharging radioactive waste in general sewage. Our plan was to separately collect urine waste in a specially constructed “Urine Waste Tank”. Four delay tanks were constructed in 2013.Tanks 1 and 2 received only urinary drainage pipes from male and female urinals. Tank 3 and 4 received excreta from Western Commode, bath and wash basin (general discharge). Four therapy wards were built for isolation of patients post high dose therapy. Each room has a single occupancy bed. Toilets are attached to each room. Delay tank operations. General discharge was alternatively diverted either to tank 3 or tank 4. Level indicators were installed in all the four tanks and a record was maintained in the period 2014 -2019. Conclusion: Making separate provisions for discharge of urinary and general waste enhances the efficiency of waste management in isolation wards of nuclear medicine department. The radioactivity discharged is below measurable limits because of significant delay and decay.
Radiolabeling and Evaluation of isoDGR Derivative Using Radioactive Cooper
Masayuki Hanyu1, Lin Xie1, Kuan Hu1, Zhimin Yang1, Yiding Zhang1, Hisashi Suzuki1, Ming-Rong Zhang1
1Department of Radiopharmaceuticals Development, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Anagawa, Inage-ku, Chiba, Japan
Integrins play a pivotal role in many physiological processes such as neo-angiogenesis, cell adhesion and proliferation, and thus are key proteins in pathological disorders such as cancer metastasis, thrombosis, osteoporosis, and autoimmune diseases. For molecular imaging agents based on small peptidic integrin ligands, such as the αvβ3-integrin ligand c(RGDfK), has been found to greatly improve target affinities and in vivo performance. Kessler et al. described the systematic screening of c(-phgisoDGR-X-) lead motif aiming to confer to the small lead pentapeptide selectivity toward the Fn-binding integrins α5β1 and αvβ6. The cyclic peptide c(-phg-isoDGR-k-) displayed an antagonistic activity for α5β1 (IC50: 8.7 nM), thus representing the first report of a small-sized, highly active, cyclic peptide selectively targeting α5β1 integrins. Cu-64 labeled ligands are useful in PET studies because of the clinically suitable nuclear properties of Cu-64 and its availability at high molar activity. This property allows sufficient time for clearance of non-specific radioactivity from background tissues to increase image contrast, which requires long times to circulate throughout the whole body. Moreover, Cu-64 labeled ligands are demonstrably effective for radioimmunotherapy. Meanwhile, Cu-67 is one of the most promising radioactive metals for radiotherapy. Here, we report radiolabeling and evaluation of c (-phg-isoDGR-k(DOTA)-) using radioactive cooper.
Frank AO, Otto E, Mas-Moruno C, Schiller HB, Marinelli L, Cosconati S, et al. Conformational control of integrin-subtype selectivity in isoDGR peptide motifs: A biological switch. Angew Chem Int Ed Engl 2010;49:9278-81. Bochen A, Marelli UK, Otto E, Pallarola D, Mas-Moruno C, Di Leva FS, et al. Biselectivity of isoDGR peptides for fibronectin binding integrin subtypes α5β1 and αvβ6: Conformational control through flanking amino acids. J Med Chem 2013;56:1509-19.
Incidence of Radioiodine-Refractory Differentiated Thyroid Carcinoma in the Institute of Nuclear Medicine and Allied Sciences, Dhaka
Sayedur Rahman Miah1, Fatema Sultana Hoque1, Selim Reza1, Rubina Begum1
1Institute of Nuclear Medicine and Allied Sciences, Dhaka, Bangladesh
Background: Radioiodine is one of the treatment options for differentiated thyroid carcinoma (DTC) following total or near total thyroidectomy. However, 5-15% of patients become refractory to radioiodine. The purpose of the study was to see the incidence of radioiodine-refractory differentiated thyroid carcinoma (RR-DTC). Materials and Methods: A total of 235 differentiated thyroid carcinoma patients treated with high dose radioiodine were studied retrospectively. The mean follow up period was 6.9 ± 5 years. Thyroid bed remnant was designated as significant whenever there was radiotracer concentration in thyroid bed with Tc-99m pertechnitate and/or with 131I. Complete ablation was established as: undetectable or suppressed serum Tg levels <2.0 ng/ml and negative on whole body iodine scan. Radioiodine refractory was considered when cumulated dose of radioiodine exceeded 600 mCi with raising thyroglobulin (Tg) level and/or positive whole body iodine scan. Results: Total 235 DTC patients were studied of which 194 were female and 41 were male with female to male ration of 4.7:1. Age ranges of the patients were 15 years to 83 years with mean age 36.7 years. Out of 235, 124 (52.8%) were papillary carcinoma, 64 (27.2%) were follicular variant of papillary carcinoma and 47 (20%) had follicular carcinoma. The study showed that one hundred and ninety nine (84.7%) patients had complete ablation of thyroid tissue or eliminate any suspected micro metastasis or eliminate recurrent disease by radioiodine ablation and thirty six (15.3%) had radioiodine–refractory. Conclusion: The study showed that 15.3% DTC patients become radioiodine-refractory and needs further new treatment options.
Development and Testing of Special Device Dedicated to Automatic Preparation of Capsules for Radioiodine Therapy
Milovan Matovic1, Miroslav Ravlic2, Aleksandar Vukadinovic3, Sanja Vranjes-Djuric3
1Clinical Center Kragujevac, Centre of Nuclear Medicine, Kragujevac, 2Prizma Company, 3Laboratory for Radioisotopes, Vinca Institute of Nuclear Sciences, University of Belgrade, Belgrade, Serbia
It is a fact that production of capsules wich contains high activity of 131I could be dangerous activity of professionals who work in this kind of industry. They can be exposed to high level of radiation exposure doses during manual preparation of capsules with high activities of 131I. We have developed and tested our own automatic system for this purpose. Goal of this paper is to shortly describe function and first results of testing of our system dedicated to automatic capsules filling with high activities of 131I. Our system consists of PC controlled device which is dedicated to precise dosage of 131I solution and filling of capsules with different, previously defined amounts of radioiodine activities. Whole device is located into special chamber shielded by lead bricks. Known fact that radioactive solution volume (in microliters) closely correlates with its activity (in mCi). It is basic principle of our system. First step in the whole process is precise filling of known volume of 131I solution into special syringe, using precise actuator for movement control of piston in the syringe. Next step is filling-out needed volume (i.e. activity) in the capsule by 23G needle. In order to avoid possible contamination, because of 131I is volatile, we decided to use two capsules. One smaller capsule filled with absorber is inside of one bigger capsule. Cap of bigger capsule covers small hole wich remains after filling of smaller capsule. For this part of process we use special precise mechanical/electronic sub-device driven with four step-motors. Next step is measurement of 131I activity in the filled capsule using dose calibrator, and printing it value on the self-adhesive labels. Final step is transport of capsule to lead container and covering it with appropriate lead cover. Our system is controlled by PC and driven by appropriate software developed using Delphia program language. Whole process is automated, watched by two CCD cameras to establish remotely surveillance of whole process. After adjustment of all units, we have done few hundred repetitions of each step of our system we have not find any unpredictable behavior of each part of our system. Also, we found high correlation between number of steps of the piston syringe actuator and injected volume or 131I activity into capsule. Based on our preliminary testing of this system, we can conclude that system could be useful tool in production of capsules filled with high activities of radioiodine 131I. Our system enables to avoid unnecessary radiation exposure of personnel as well as to avoid errors caused by subjective or objective reasons.
Developing a Radiation Safety Culture through Problem Identification and Resolution Using Root Cause Analysis Method
Muhammad Mubashar Hussain1, Musab Riaz1
1Nuclear Institute of Medicine and Radiotherapy (NIMRA), Abbottabad, Khyber, Pakistan
Background: Radiation protection culture is a combination of science, values and ethics, as well as experience. Principles include justification, optimization and dose limitation principles, but also include the sharing of competence by training and education. Problem Identification and resolution (PI&R) can be addressed by using Root Cause Analysis (RCA) method effectively in radiation safety matters. 1. Root causes (RC) are specific underlying causes. 2. RC are those that can be reasonably identified. 3. RC are those for which effective recommendations for preventing recurrences can be generated. Methods: The RCA is a four-step process;
Data Collection: Without complete information of the event, the casual factors and root causes associated with the event cannot be identified. Casual factor charting: It provides a structure for investigators to organize and analyze the information gathered during the investigation and identity gaps and deficiencies in knowledge as the investigation progresses. Root cause (RC) identification: This step involves the use of a decision diagram called the RSC map to identify the underlying reason or reasons for each casual factor. Recommendation Generation and Implementation: RS summary tables can organize the information compiled during data analysis, root cause identification and recommendation.
Results: Using alternative non-ionizing radiation imaging where practical. Reduced radiation exposure. Radiation dose or equipment error reporting. Requiring clinical audits from internal and external sources. Making most of medical inspections to evaluate the status of radiation protection culture in a given facility (radiotherapy, nuclear medicine, diagnosis X-Rays). Conclusions: All radiation workers can be directed towards improved operational focus and to enhanced engagement on reliability, human performance. Radiation protection culture is a learned way of life. Radiation protection professionals play a key role through their presence in the field to coach workers and focus all staff on the operational radiation protection culture.
Significance of Dosimetry in Ensuring Accuracy and Quality during Radiotherapy Application/Significance of Dosimetry in Ensuring Accuracy and Quality for Medical Application
Omondi Collins1, Otwoma David2
1Dosimetry and Radiotracer, Kenya Bureau of Standards, 2National Commission for Science Technology and Innovation, Nairobi, Kenya
The application of X-ray, CT, mammography and radiotherapy in areas of medicine has witnessed significant technological developments in order to enhance patient care. However, while these developments have undoubtedly conferred benefits to a large number of patients, they have also raised concerns for the quality and safety of practices because the use of ionising radiation. Therefore, there is a need to access the impact of these technical developments through measurement with the use of appropriate and internationally recognized dosimetry protocols and standards. The Kenya Bureau of Standards (KEBS) in collaboration with the International Atomic Energy Agency (IAEA) established a Secondary Standards Dosimetry Laboratory (SSDL) in 2008. The SSDL is the custodian of the National measurement Standards in the field of ionizing radiation and provides calibrations in terms of Air Kerma, Personnel Equivalent Dose and Ambient Dose Equivalent at diagnostic and radiation protection levels. The main tasks of the SSDL are to: Realise and maintain the national measurement standards; Provide measurement traceability to the International System of Units (SI) and bridge the gap between the Primary Standards Dosimetry Laboratory (PSDL) and the users of the ionizing radiation measurements; Provide calibrations to end users of equipment on ionizing radiation measurements.
In vitro and In vivo Evaluation of I-131 Labeled Magnetic Silica Nanoparticles: Novel Nanocomposite for Theranostic Applications
Parviz Ashtari1, Fatemeh Keshavarz2, Majid Radpour2, Yousef Fazaeli1, Imliwati Longkumer3
1Radiation Application Research School, Nuclear Science and Technology Research Institute, Tehran, 2Department of Biology, Sanandaj Branch, Islamic Azad University, Sanandaj, Iran, 3Biochemist at North East Cancer Hospital and Research Institut Kamrup, Guwahati, Assam, India
Objective: The nanoparticles using various surface coatings, which cause stable optimal and biomedical properties, can be synthesized. The iodine-131 is one of the useful radionuclides in nuclear medicine. Therefore, the objective of this study was to investigate the synthesis of iodine-131 radioisotope encapsulated and stabilized in the magnetic silicate nanoparticles and in vivo and in vitro evaluations of these nanoparticles as novel radiotracer. Materials and Methods: Silver aqueous solution, as a precipitation agent was used. The radioisotope precipitate adsorbed on magnetite Iron oxide (Fe3O4). This conjugate was used as the core for the synthesis of magnetic silicate nanoparticles. Nanoparticles synthesized according sol-gel method in the reverse microemulsion used tetraethyl orthosilicate (TEOS) and 3-amino propyl tri-ethoxy silane (APTES) as the monomers and precursors. Also their ratio were used for the controlling of functional groups which cause zeta potential and finally for the controlling of the size of nanoparticles. Finally, the entry of the conjugated nanoparticles on MCF-7 breast cancer cell line was studied through the cell culture. Results: The radio-analysis revealed that more than 80 % of the primary iodine-131 was encapsulated in the nanoparticles. The stability tests results showed that the encapsulated iodine-131 cannot release and enter the nanoparticles carrier solution during of washing and scattering. Furthermore, the highest entrance efficiency was about 53-54% during the 2-4 hours from beginning the cultivation. Conclusion: Due to unique properties of iodine-131, Beta and Gamma emitter, the mentioned nanoparticles are able to use for simultaneous diagnosis and treatment of the diseases.
Almost Complete Response after a Single Peptide Receptor Radionuclide Therapy as Initial Treatment for Merkel Cell Carcinoma with Axillary Lymph Node Metastases
Patricia Bautista1, Mary Stephanie Jo Estrada1, Patrick Earl Fernando1
1St. Luke’s Medical Center, Taguig, Metro Manila, Philippines
Merkel cell carcinoma is a rare and aggressive type of skin cancer originating from neuroendocrine cells and often presenting with metastasis upon diagnosis. Risk factors are advanced age, white population, and immunosuppression. It typically affects sun-exposed areas. Conventional treatments include surgery, adjuvant radiotherapy, and chemotherapy while immunotherapy and targeted therapy fall under emerging treatments. Our patient is a 48-year-old Filipino man who noted a slow-growing, skin-colored, left back mass one year prior to excision, and lumps in his left axilla three months prior. Histopathology and immunohistochemical stains revealed metastatic Merkel cell carcinoma that is positive for chromogranin, synaptophysin, panCK, and CK20. Further immunohistochemistry of his masses showed no PD-L1 expression. The patient underwent F-18 FDG PET/CT and Ga-68 DOTATATE PET/CT scans, which showed higher DOTATATE activity than FDG uptake in the multiple, enlarged and confluent left axillary lymph nodes. He consulted a surgeon, a dermatologist and two oncologists but eventually opted to have peptide receptor radionuclide therapy (PRRT) as first-line treatment. He underwent laboratory and other imaging tests, which were all normal. He subsequently received 8.6 GBq of Lu-177 DOTATATE intravenously after adequate hydration, administration of pre-medications, and initiation of Gelofusine infusion. His post-therapy whole body scan with SPECT-CT demonstrated similar radiopharmaceutical distribution as the diagnostic scan. His follow-up Ga-68 DOTATATE PET/CT three months later illustrated minimal residual disease, thereby confirming PRRT as a viable treatment option for this case.
A-Decaying Theragnostic Radioisotopes for CZT SPECT imaging
Raul-Cris Ciobanca1 1Romania
Introduction: Alpha targeted therapy is a novel approach, the use of which in a clinical setting should be expanded. As there are no articles found on this subject, it is of great consideration to pave the way into the future of therapeutic nuclear medicine, starting from the roots of the most widely used imaging technology. Materials and Methods: The nubase2016 database of nuclei was queried for a-decaying isotopes in current clinical testing. Half-life was assumed desirable between 6 hours and 7 days. Imageable gamma energy limits were set for 40 – 220 keV, in concordance with present top CZT whole-body SPECT system commercially available. Selection margin and minimal energy abundance was considered at 5%. Results: A radiation is exhibited by 1127 isotopes. Per se only [211At]Astatine presented both half-lives and gamma energy spectrum whitin the limits set, halving in 2,7 hours, and having delivered the highest gamma radiation dose at 79,2 keV, with an absolute intensity of 20,7%. Half-life of [223Ra]Radium is 11,4 days and its gamma rays are most intense at 269,4 keV. [225Ac]Actinium halves în 9,9 days, emitting gamma rays under the threshold of abundance. Conclusion: This is the first work to describe the use of alpha targeted therapy in conjunction with the emerging CZT SPECT technology. Leading în terms of energy and half-life desirability is [211At]Astatine, followed by [223Ra]Radium and [225Ac]Actinium, the decay of daughter nuclides needing to be understood on the path for a state of well being.
Efficacy of a Fixed Empiric Radioiodine Dose for Graves’ Disease in a Poorly Resourced Region
Sphelele Masikane1, Nozipho Nyakale1
1Discipline of Nuclear Medicine, University of Kwa-Zulu Natal, Durban, KwaZulu-Natal, South Africa
Background: The resources to conduct dosimetry and optimize treatment for radioiodine therapy of Grave’s disease patients are not always readily available in resource-deficient regions, with limited Nuclear Medicine facilities and serving a large population. The calculation of activity required to achieve cure remains debatable and dependent on multiple factors. A standardized fixed activity had been a necessity in our setting to be able to benefit patients, without requiring the excessive arduous preparation that may be required. The aim of this study is to investigate the efficacy of a fixed radioiodine activity in treatment of Grave’s disease. Methods: Patients treated with a fixed dose of 10mCi between the periods of 2014 to 2015 were evaluated. A 2 year post initial treatment review was done to assess treatment response. Results: We included 104 patients, 87 females and 17 males, (mean age 41.1±13.4years). Of the 83 patients with follow up data, there was a 90.4% successful treatment response (36% euthyroid; 64% hypothyroid) with 85.3% responding after only 1 administration, 13.3% required a single repeat and 1.3% a second repeat. There was a total of 8 non-responders. No statistically significant relationship to response to treatment was demonstrable for fT4 (p= 0.468) and TSH (p = 0.137) levels at the time of treatment. There was no correlation of response with gender (p=0.87). Conclusion: A fixed low empiric radioiodine activity of 10mCi may be optimal for curing hyperthyroidism due to Grave’s disease and justification for higher activity should be specified. This method of therapy may be beneficial where resources are limited and where patient numbers are too high.
177Lu-Prostate Specific Membrane Antigen-I and T Prostate Specific Membrane Antigen Radioligand Therapy in Metastatic Castration-Resistant Prostate Cancer: First Clinical Trial in Asia
Ting Bu1, Chuan Zhang1, Shiming Zang1, Feng Wang1
1Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
Objective: The aim of this study was to investigate the safety and efficacy of 177 Lu -labeled prostate specific membrane antigen (PSMA) ligand (PSMA-I&T) in the treatment of metastatic castration-resistant prostate cancer (mCRPC) in Asian ethics. Methods: From August 2017 to December 2018, 31 patients (mean age: 70.6 years old) with mCRPC were consecutively enrolled, institutional review board approval and informed consent was obtained for this study. 68Ga-PSMA-11 PET/CT showed multiple PSMA-avid lesions in all patients before the therapy. 177Lu-PSMA-I&T radioligand therapy with 5.55-7.4GBq in every circle were performed. Hematological status, renal function, and serum prostate specific antigen (PSA) levels were documented before and after treatment. The efficacy was evaluated by the changes of PSA, SUVmax and tumor size on 68Ga-PSMA-11 PET/CT, and clinical follow-up. Results: No acute or severe adverse events were observed during and after 177Lu-PSMA-I&T treatment, no evident kidney toxicity and xerostomia was found in this study. Significant PSA reduction was associated with 177Lu-PSMA- I&T treatment (P=0.023), Of the 31 patients, 6 had elevated PSA levels and disease progression, while 25 patients had variable reduction of PSA, of which 6/31decreased by >30%and 19/31 decreased by >50%. 68Ga-PSMA-11 PET/CT showed SUVmax of metastatic lesion in 25 patients was significantly decreased, 6 patients with significantly diminished metastatic lymph nodule. Conclusion: The present study in Chinese population valicadted 177Lu-PSMA-I&T treatment achieve better response in the treatment of mCRPC, which is easy tolerable and safe.
Evaluation of Treatment of Iodine-131 in Advanced Differentiated Thyroid Cancer
Wei Zhang1, Gaohong Zhu1
1The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
Objective: Advanced differentiated thyroid carcinoma is defined as carcinoma that has penetrated the thyroid capsule, involved the surrounding tissues and organs, or accompanied by extensive cervical lymph node metastasis or distant viscera metastasis. Because of its poor surgical treatment effect, the serious influence prognosis, so widely recognized the community of iodine - 131 is the effective treatment, but the late on DTC iodine - 131 therapy effect and influence factors is uncertain, this study through the follow-up of 36 cases of patients with advanced DTC and 50 cases of normal DTC over 1 year of treatment, the specific evaluation of iodine - 131 in the treatment of advanced DTC effect. Methods: The pathological stages, gender, and early treatment age of 50 cases of normal DTC and 36 cases of patients with advanced DTC were measured, and the prognosis was divided into four levels, which were cured, improved, reduced and invalid, by comparing the changes of the thyroid in the thyroid and the WBS, chest CT and the color doppler of the neck. Finally, the data processing was carried out through logistic regression analysis, and the results of the pathological stage, gender and early age were not affected. Results: In the case of the 36 patients with advanced DTC patients, the efficiency was 61.1%, and eight of them were cured, and 10 of the improved results were improved, and four cases were alleviated. Of the 50 cases of normal DTC patients, 45 cases were effective, and the efficiency was 90.00%, and there were 15 cases, 23 cases and 7 cases. Logistic regression analysis shows that the differences between the two groups are statistically significant (p<0.05). The statistical results were not significantly relevant to the gender of the patient and the initial treatment of the patient (p>0.05). Discussion: The study found that iodine -131 had better therapeutic effect on normal DTC patients and late DTC patients, but the effect of normal DTC was better. The biological characteristics of thyroid cancer have a tendency to break through the membrane to the lymph nodes, lungs and bones, and the broad lymph node metastasis and distant metastasis are important factors affecting the prognosis, and it is difficult to remove the lesions from the 2 cm.
Combined Pharmacokinetics Dynamic Contrast-Enhanced Magnetic Resonance Imaging and Intravoxel Incoherent Motion Diffusion-Weighted Imaging to Improve Early Diagnosis of Ductal Carcinoma In Situ
Weijing Tao1, Genji Bai1, Shuzhong Wang1
1Department of Radiology, The Affiliated Huai’an No. 1 People’s Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
Purpose: Ductal carcinoma in situ (DCIS) is a precursor of invasive ductal breast carcinoma (IDC). This study aimed to use dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) for the early diagnosis of DCIS. Methods: Forty-seven patients, including 25 with DCIS (age: 28–70 years, mean age: 48.7 years) and 22 with benign disease (age: 25–67 years, mean age: 43.1 years) confirmed by pathology, underwent DCE-MRI and IVIM-DWI in this study. The quantitative parameters Ktrans, Kep, Ve, Vp, and D, f, D* were obtained by post-processing of DCE-MRI and IVIM-DWI images with Omni-Kinetics and MITK-Diffusion software, respectively. Parameters were analyzed statistically using GraphPad Prism and MedCalc software. Results: All low-grade DCIS lesions demonstrated mass enhancement with clear boundaries, while most middle-grade and high-grade DCIS lesions showed non-mass-like enhancement (NMLE). DCIS lesions were significantly different from benign lesions in terms of Ktrans, Kep, and D (t = 5.959, p < 0.0001; t = 5.679, p < 0.0001; and t = 5.629, p < 0.0001, respectively). The AUC of Ktrans, Kep, D and the combined indicator of Ktrans, Kep and D were 0.936, 0.902, 0.860 and 0.976, respectively. There was a statistical difference in diagnostic efficacy only between D and the combined indicator (Z = 2.408, p = 0.0161). Conclusion: DCE-MRI and IVIM-DWI could make for the early diagnosis of DCIS, and reduce the misdiagnosis of DCIS and over-treatment of benign lesions.
Construction of Novel Ferritin-based Nanodrug and Preliminary Study for Anticancer Therapy
Xinyu Wang1, Yaoqi Li1, Min Yang1
1Molecular Imaging Center, Jiangsu Institute of Nuclear Medicine, Xiuma, Jiangsu, China
Background: Ferroptosis is a form of iron and reactive oxygen species-dependent cell death, and autophagy is the process by which intracellular components fuse with lysosomes to form autophagosomes and degrade the contents of the package. Both have been shown to induce cancer cell death. However, there are few studies on the combination of ferroptosis and autophagy in the treatment of cancer. In this study, we constructed a novel ferritin nanodrug, NFER, which containing the hydrophobic drugs Erastin and rapamycin, and could induce cancer cell death through a dual pathway of autophagy and ferroptosis, which may provide new strategies for cancer therapy. Methods: The preparation method of nanodrug NFER was ultrasonic emulsification. The particle size, zeta potential, and in vitro stability of NFER were measured by the Dynamic Light Scattering instrument. ICP-MS was used to detect the content of iron in NFER. The loading efficiency and encapsulation efficiency of NFER were measured by high performance liquid chromatography (HPLC) assay. The morphology of NFER was examined by transmission electron microscopy (TEM). The ferritin content of NFER was detected by BCA protein detection kit. Human pheochromocytoma poorly differentiated PC12 cells, mouse breast cancer 4T1 cells, mouse fibroblast L929 cells were cultured for cell uptake assay, cytotoxicity test, and the reversal effect of related inhibitory drugs. Light microscopy was used to observe the degree of cell membrane lipid oxidation, while flow cytometry was used to quantified the degree of intracellular membrane lipid oxidation and lipid peroxide. Western blot was detected the protein expression of glutathione peroxidase-4 (GPX4), autophagy-associated protein 7 (Atg-7), trace related protein light chain (LC3), and ferritin heavy chair (FTH1). The biocompatibility of NFER in the blood was evaluated by hemolysis test. A nude mouse model was constructed, then the uptake stay experiment in the tumor of NFER and the inhibition of tumor regrowth were evaluated. Results: Nanodrug NFER was successfully prepared by emulsification. The particle size was 78.8 nm, the zeta potential was -25.9 ± 3.3 mV, and the stability in vitro of NFER was good. The encapsulation efficiency and loading efficiency of NFER were positively correlated with the concentration of erastin and rapamycin. Erastin and rapamycin could reach a release equilibrium after 24 and 36 hours, respectively, with a maximum of more than 30%. The contents of iron and ferritin in NFER were 2.47 mg / kg and 7 mg / mL. The cellular uptake of NFER was up to 53 times that of the blank control group and it could kill cancer cell at a lower concentration. Besides, we observed that autophagy inhibitors or ferroptosis inhibitors can significantly reverse the reduced cell death rates. Treatment of cells with NFER resulted in an increase in LC3-II relative to LC3-I, as well as accumulation of Atg-7, meaning that the cells experienced significant autophagy. At the same time, an increase in the ferritin heavy chain (FTH1) indicated that NFER induced autophagy, which in turn caused degradation of ferritin. Furthermore, the accumulation of lipid peroxidation and reactive oxygen species (ROS) in cells and cell membranes, as well as inactivation of GPX4 were observed in cells suggested that the ferroptosis process was also evident in cell death. In addition, the results of the in vivo experiments indicated that NFER could stay in the tumor for a long time and had a significant inhibitory effect on the tumor. Conclusions: In this study, we successfully prepared a novel nanodrug NFER, which uses ferritin as a carrier to load two hydrophobic drugs that induce different cell death pathways. A series of characterization experiments confirmed its excellent physical and chemical properties. It was the first time to kill cancer cells by autophagy/ferroptosis dual pathways which could be verified by in vitro experiments. In addition, we observed that NFER can significantly inhibit the regrowth of tumor tissue. In summary, it exhibited good anti-cancer effects in vitro and in vivo, which could provide a new method for cancer therapy.
Detection of Plasma Catecholamines in Human Pheochromocytoma and Primary Hypertension Based on Liquid Chromatography Tandem Mass Spectrometry
Xue Xue1, Hucheng Chen1, Ping He1, Yuan Lv1, Yu Yang1, Feng Wang1, Wei Qu1, Zizheng Wang1
1Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
Background: The measurement of plasma catecholamines (CAs) including dopamine (DA), epinephrine (E), and norepinephrine (NE) and their derivatives including metanephrine (MN), normetanephrine (NMN), vanillylmandelic acid (VMA), and homovanillic acid (HVA) has been used in the diagnosis of pheochromocytoma and paraganglioma (PPGL) and primary hypertension (PH) but are typically detected individually when clinical testing. In this study, pre-column derivatization with dansyl chloride (DNS-Cl) combined with an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed to simultaneously quantify HVA, VMA, MN, NMN, DA, E, and NE in the plasma from patients with PPGL and PH. Methods: Plasma samples were extracted by acetonitrile and derivatized with DNS-Cl, followed by reverse phase separation and triple quadruple detection. Quantification of the CAs and their derivatives in 10 PPGL, 10 PH, and 100 healthy subjects was performed by UPLC-MS/ MS analysis. Results: All the values of detected CAs/derivatives were in the linearity ranges of the fitted curves. The expression levels of the seven CAs in the PPGL and PH patients were significantly higher than the healthy controls, suggesting increased CA production in the former. There were significant differences in plasma NE, NMN, and VMA levels between the PPGL and PH patients, but there was no significant difference in plasma E, MN, DA, and HVA. A discriminant analysis showed that 90% of the final cases were classified correctly based on the detected CAs/derivatives. Conclusions: Our results show that the combined detection of the seven CAs/derivatives could be used for the clinical diagnosis of PPGL and PH.
A Novel Method for Early Monitoring of Chimeric Antigen Receptor T Cells
Wang Yan1, Wu Qiong1, Cheng Kai1, Pan Donghui1, Yang Min1
1Jiangsu Institute of Nuclear Medicine, Xiuma, Jiangsu, China
Purpose: Chimeric antigen receptor (CAR) T cells immunotherapy is one of the most subversive technologies for cancer treatment. A typical example is the Emily’s story, a 7-year-old girl with acute lymphoblastic leukemia (ALL), who was the first child in the world received CART cell therapy in 2012, and has survived for 7 years. However, responses to this therapy are various. So early screening patient is very urgent. Recently, 89Zr-oxine has been mostly used for cell labeling in preclinical study. With PET imaging, the biodistribution of CART cells injected can be clearly shown. But the main obstacle is high and long-term radiation exposure to cells and other normal organs such as lung, liver and spleen. So far, no clinical CAR T cell studies of 89Zr directly labeled have been reported. In this study, we want to develop a new method using short half-life nuclides 68Ga for early and safe tracking CAR T cells. Method: First, 68Ga-oxine/89Zr-oxine complex was generated at room temperature. Secondly, 68Ga-oxine/89Zr-oxine solution and CAR T cells were incubated in PBS to prepare labeled CART cell, the cell viability and stability were detected after labeled completely. Thirdly, the biodistribution of 68Ga/89Zr labeled CAR T cells were dynamically monitored with micro PET in NOG mice. Results: 68Ga/89Zr-oxine can be achieved at 37 ° C and pH 5-6 for 15 min. The radiochemical purity was >90% by TLC. 68Ga/89Zr-oxine labeled with CAR T cells at room temperature for 15 min with about 20% yield. Specific activity below 370 KBq/106 cells, no effect on cell viability (>90%). Micro PET imaging showed that after intravenous administration of 68Ga or 89Zr-oxine labeled CART cells, the radioactivity was initially concentrated in the lung, subsequently distribution in the liver and spleen. During the 6 h dynamic monitoring, the radio uptake of lung and spleen were basically the same between 68Ga-oxine and 89Zr-oxine labeled CART cells. Discussion: CAR T cells can be labeled with 68Ga-oxine and 89Zr-oxine, with high viability after labeling (>90%). Within 6 h monitoring, the same biological behaviors were observed between 68Ga and 89Zr labeled CAR T cells in NOG mice. In conclusion, 68Ga-oxine labeled CART cell is promising for early diagnosis and safe screening patients with CAR-T cell therapy.
This work was supported by National Significant New Drugs Creation Program (2017ZX09304021), Jiangsu Provincial Medical Innovation Team (CXTDA2017024), CAR T cells were provided by Shanghai Unicar-Therapy Bio-Medicine Technology Co., Ltd.
The New Correlation between Familial Pheochromocytoma and Molecular Mutation Patterns
Yang Yu1, Xiumei Zhang1, Feng Wang1, Zizheng Wang1
1Department of Nuclear Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
Background: Some specific gene mutation plays an important role in the pathogenesis of human familial pheochromocytoma (FPCC) , however little is known about the possible role of molecular mutation patterns in FPCC development. We report the cancer and inherited diseases associated gene panels analysis of FPCC (isolated pheochromocytoma, confirmed by clinical examination), aiming to identify gene mutations specific to FPCC which may contribute to the disease development. Methods: The Ion AmpliSeq™Cancer Hotspot Panel v2 (designed to amplify 207 amplicons covering approximately 2,800 COSMIC mutations from 50 oncogenes and tumor suppressor genes) and Inherited Disease Panel (designed to amplify 10500 amplicons covering mutations for over 300 genes in over 700 unique inherited diseases, according to NCBI ClinVar database) analysis was performed using Ion Torrent PGM on peripheral blood DNA extracted from FPCC subjects (n=2, two patients of isolated pheochromocytoma from one family, father and his son) , subjects with pheochromocytoma accompanying thyroid carcinoma (PCC-TC, n=2, from different family) and normal subjects (n=2, from different family). Gene mutations analysis was performed using Ion Reporter software. During the next generation sequencing work flow, strict quality control was carried out in DNA purification, library construction, template preparation and sequencing. All candidate gene mutation sites were confirmed by sanger sequencing. Results: Comparison of FPCC with PCC-TC and normal subjects identified 45 significant gene mutation positions, including 1 site of cancer associated gene and 44 sites of inherited diseases associated genes. 30 genes were found to have differential mutation patterns in FPCC compared with PCC-TC and normal subjects, including ABCA4, ACTA2, ANK2, CDH23, CFTR, CHAT, CLCN1, COL1A1, COL4A1, COL5A1, DNAH11, DNAH5, DNAH9, DSP, EYS, FANCF, FBN1, GJB3, IDUA, IKBKAP, JAG1, MYLK, PCDH15, PTCH1, RPGRIP1, SPG7, TBX5, USH2A, VCL and VHL. Above all, VHL 10183815 C>G heter mutation (codon 51, 284C>G, Pro95Arg, COSMIC 17699) has been confirmed in von Hippel-Lindau disease. Conclusion: This study is the comprehensive analysis of molecular mutation patterns of FPCC and identifies dozens of gene mutation positions as a potential novel biomarker during FPCC development.
Preliminary Evaluation of Glucagon-Like Peptide-1 Receptor PET in the Diagnosis and Risk Stratification of Pheochromocytomas
Yu Liu1, Mingzhu Li1, Yuping Xu1, Yaoqi Li1, Donghui Pan1, Lizhen Wang1, Junjie Yan1, Xinyu Wang1, Min Yang1
1Jiangsu Institute of Nuclear Medicine, Xiuma, Jiangsu, China
Purpose: Noninvasive imaging methods for the diagnosis and risk stratification of pheochromocytomas (PHEOs) remain a great clinical challenge. The glucagon-like peptide-1 receptor (GLP-1R) has been validated to be overexpressed in PHEOs and therefore may be a reliable target. The aim of this study was to evaluate the performance of GLP-1R PET for PHEOs detection and explore whether GLP-1R PET could be used for the risk stratification of PHEOs. Methods: Cys39-exendin-4 was conjugated to NOTA-MAL and then radiolabeled with 68Ga. PC-12 poorly and highly differentiated tumor-bearing mice were injected with 68Ga-NOTA-MAL-Cys39-exendin-4 and observed by microPET and biodistribution studies. The results were compared with 18F-FDG and 131I-MIBG. To further demonstrate the specificity of 68Ga-NOTA-MAL-Cys39-exendin-4 for PHEOs, we additionally performed GLP-1R PET imaging on SKOV3 tumor-bearing mice. Besides, properties of 68Ga-NOTA-MAL-Cys39-exendin-4 and GLP-1R expression in tumors were also evaluated by cell uptake, immunohistochemistry (IHC), and western blot studies. Results: 68Ga-NOTA-MAL-Cys39-exendin-4 was synthesized with a yield of 91.6 ± 2.8% and the reaction could be completed within 20 min. In vitro cell uptake studies validated its high specificity. After intravenously injection in the tail of mice, the concentration of the tracer in blood showed a logarithmic decrease and was almost zero at 120 min. PET images showed promising tumor visualization with high uptake (1.88 ± 0.10 %ID/g and 1.09 ± 0.003 %ID/g for PC-12 poorly and highly differentiated tumors at 30min after injection, respectively). There was a significant difference in the uptake of 68Ga-NOTA-MAL-Cys39-exendin-4 between PC-12 poorly and highly differentiated tumors (p < 0.001), but no significant difference could be observed by 18F-FDG PET. The SKOV3 tumors couldn’t be found using GLP-1R PET due to the tumor uptake was too low. Biodistribution results confirmed the findings of GLP-1R PET and demonstrated that 131I-MIBG couldn’t be used for the risk stratification of PHEOs. The western blot results showed that the expression of GLP-1R was higher in PC-12 poorly differentiated tumors than that in PC-12 highly differentiated tumors and the SKOV3 tumors showed nearly no expression of GLP-1R. IHC staining revealed differences in GLP-1R expression between PC-12 poorly and highly differentiated tumor tissues. Discussion: In this study, we designed and synthesized a novel radiotracer 68Ga-NOTA-MAL-Cys39-exendin-4 and confirmed that this tracer could specifically target GLP-1R with favorable pharmacokinetic properties in blood. The results of microPET and biodistribution studies demonstrated the feasibility of GLP-1R PET for the diagnosis and risk stratification of PHEOs. Further studies should be conducted to reduce the radioactivity in kidney. Besides, the risk stratification of PHEOs in this study was initially based on poor and high differentiation. More studies are needed to establish a more precise association between GLP-1R PET imaging, GLP-1R expression, and the risk stratification of PHEOs.
Resting-State Functional Magnetic Resonance Imaging Analysis in Amyotrophic Lateral Sclerosis by Group
Yu Z’hang1, BiYun Zhang1
1Jiangsu TCM Hospital, Nanjing, China
Objective: To investigate the brain activity in resting state of patients with amyotrophic lateral sclerosis (ALS) by group independent component analysis (GICA) and ROI-based correlation analysis. Materials and Methods: 30 patients with ALS and 30 normal age-matched volunteers as controls were scanned with 3.0T MRI. All data were preprocessed with such software as SPM8 and REST, followed by compare resting-state function network in whole brain between the two groups with software of GICA to detect changes that exist in brain functional networks. Additionally, by software of REST, we study the changed brain functional network with ROI-based correlation analysis. Results: GICA analysis revealed 5 typical brain networks among which the sensorimotor network and the so-called default mode network showed distinct differences between patients and controls. The sensorimotor network showed less activation in patients in several regions including the right primary motor cortex, sensory area and supplementary motor area, and an increased activation of posterior cingulate cortex. The default mode network network showed group differences in the middle prefrontal cortex. In addition, the ROIs coupling in sensorimotor network showed significant intrahemispheric changes in connectivity of right primary motor cortex and supplementary motor area, and interhemispheric changes in connectivity of right primary motor cortex and left primary motor cortex. Conclusion: We propose that resting state GICA analysis affords a new and simple means to assess ALS neurofunctional alterations in motor network and extra-motor network. And ROI-based correlation coefficient may be used to quantificate the brain function connectivity. The combination of GICA and ROI-based correlation analysis may provide a new insight into rest-state functional connectivity of ALS, and help us make better sense of the pathogenesis. Furthermore, the neuroimaging methodology may be utilized for those with “possible” or “suspected” ALS by identifying reliable neural biomarkers.
Enhancement of 211At Uptake for Thyroid Cancer Therapy
Yuwei Liu1, Tadashi Watabe1, Kazuko Kaneda-Nakashima2, Yoshifumi Shirakami1, Kazuhiro Ooe1, Atsushi Toyoshima3, Eku Shimosegawa4, Mitsuhiro Fukuda5, Atsushi Shinohara6, Jun Hatazawa1
Departments of 1Nuclear Medicine and Tracer Kinetics and 4Molecular Imaging in Medicine, Osaka University Graduate School of Medicine, 2Project Research Center for Fundamental Sciences, Core for Medicine and Science Collaborative Research and Education, Osaka University Graduate School of Science, 3Division of Science, Institute for Radiation Sciences, Osaka University, 5Research Center for Nuclear Physics, Osaka University, 6Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka Osaka, Suita, Japan
Background: Astatine (At) is increasingly focusing attention in theragnostics because of its similar chemical properties to iodine and of its alpha particles which have shorter range in tissue compared with beta particles. In the previous study, we revealed that treated with ascorbic acid, the radiochemical purity of astatide in 211At solution and 211At uptake by the thyroid gland increased. Methods: 211At solution without ascorbic acid (AA- solution) and 211At solution treated with ascorbic acid (AA+ solution) were prepared. Uptake by the thyroid gland were compared between the two solutions by normal rats and cellular uptake analysis was performed with K1-NIS cells. 1MBq, 0.4MBq, 0.1MBq AA+ solution and saline were injected at K1-NIS xenograft mice, body weights, tumor size and survival rates were followed. Results: Compared with AA- solution, treated with AA+ solution increased the uptake by the thyroid gland in normal rats and uptake in K1-NIS cells. In the mouse xenograft model, tumor growth was inhibited by AA+ solution with a dose-dependent manner until 8 weeks after injection and mice in 211At groups showed better survival compared with mice in the control group. Conclusion: Significant enhancement of 211At uptake in the thyroid gland and K1-NIS cells were showed using 211At solution treated with ascorbic acid. AA+ solution showed dose-dependent treatment effects for K1-NIS xenograft mice, suggesting application of 211At to the targeted radionuclide therapy of the thyroid cancer.
The Application Value of PET/CT Evaluation Standard PERCIST in the Treatment of Invasive Non-Hodgkin’s Lymphoma
Zi-Yan Wang1, Cheng-Tao Feng1, Hao Zheng1, Rui He1, Li-Lin Chen1, Hao Wang1, Gao-Hong Zhu1
1Department of Nuclear Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
Objective: To explore the application value of PET/CT evaluation standard PERCIST in the treatment of invasive non-hodgkin’s lymphoma. Method: From June 2017 to December 2018, 30 patients with pathological confirmed invasive non-hodgkin’s lymphoma were enrolled, and all of them received 18F-FDG PET/CT scans before and after therapy. Then all the patients received RECIST1.1, PERCIST1.0 and EORTC to evaluate the therapeutic efficacy, respectively. Result: For the invasive non-hodgkin’s lymphoma, there was a poor agreement in response classification both between RECIST1.1 and PERCIST1.1 and between RECIST1.1 and EORTC. There was a good agreement in response control rate between all of them while the response rate according to the RECIST criteria was significantly lower than according to the EORTC and PERCIST criteria. Conclusion: There was a significant difference between response rate of RECIST criteria (which based on anatomical structure) and EORTC, PERCIST criteria(both of which based on metabolite) for response evaluation in patients with invasive non-hodgkin’s lymphoma treated with chemotherapy. Compared to EORTC standard, PERCIST1.0 with SULpeak as the main index is more accurate and reliable.