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Sample records for 90y 177lu 68ga

  1. Reducing renal uptake of 90Y- and 177Lu-labeled alpha-melanocyte stimulating hormone peptide analogues

    SciTech Connect

    Miao, Yubin; Fisher, Darrell R.; Quinn, Thomas P.

    2006-06-15

    The purpose of this study was to improve the tumor-to-kidney uptake ratios of 90Y- and 177Lu-[1,2,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-Re-Cys,D-Phe,Arg]alpha-melanocyte stimulating hormone (DOTA-RE(Arg)CCMSH), through coupling a negatively charged glutamic acid (Glu) to the peptide sequence. A new peptide of DOTA-Re(Glu,Arg)CCMSH was designed, synthesized and labeled with 90Y and 177Lu. Pharmacokinetics of 90Y- and 177Lu-DOTA-RE(Glu,Arg)CCNSH were determined in B16/F1 murine melanoma-bearing C57 mice. Both exhibited significantly less renal uptake than 90Y- and 177Lu-DOTA-Re(Arg)CCMSH at 30 min and at 2, 3, and 24 h after dose administration. The renal uptake values of 90Y- and 177Lu-DOTA-Re(Glu,Arg)CCMSH were 28.16% and 28.81% of those of 90Y- and 177Lu-DOTA-RE(Arg)CCMSH, respectively, at 4 hr post-injection. We also showed higher tumor-to-kidney uptake ratios 2.28 and 1.69 times that of 90Y- and 177Lu-DOTA-Re(Arg)CCMSH, respectively, at 4 h post-injection. The90Y- and 177Lu-DOTA-Re(Glu,Arg)CCMSH activity accumulation was low in normal organs except for kidneys. Coupling a negatively charged amino acid (Glu) to the CCMSH peptide sequence dramatically reduced the renal uptake values and increased the tumor-to-kidney uptake ratios of 90Y- and 177Lu-DOTA-Re(Glu,Arg)CCMSH, facilitating their potential applications as radiopharmaceuticals for targeted radionuclide therapy of melanoma.

  2. (90) Y/(177) Lu-labelled Cetuximab immunoconjugates: radiochemistry optimization to clinical dose formulation.

    PubMed

    Chakravarty, Rubel; Chakraborty, Sudipta; Sarma, Haladhar Dev; Nair, K V Vimalnath; Rajeswari, Ardhi; Dash, Ashutosh

    2016-07-01

    Radiolabelled monoclonal antibodies (mAbs) are increasingly being utilized in cancer theranostics, which is a significant move toward tailored treatment for individual patients. Cetuximab is a recombinant, human-mouse chimeric IgG1 mAb that binds to the epidermal growth factor receptor with high affinity. We have optimized a protocol for formulation of clinically relevant doses (~2.22 GBq) of (90) Y-labelled Cetuximab and (177) Lu-labelled Cetuximab by conjugation of the mAb with a suitable bifunctional chelator, N-[(R)-2-amino-3-(paraisothiocyanato-phenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-N,N,N',N″,N″-pentaacetic acid (CHX-A″-DTPA). The radioimmunoconjugates demonstrated reasonably high specific activity (1.26 ± 0.27 GBq/mg for (90) Y-CHX-A″-DTPA-Cetuximab and 1.14 ± 0.15 GBq/mg for (177) Lu-CHX-A″-DTPA-Cetuximab), high radiochemical purity (>95%) and appreciable in vitro stability under physiological conditions. Preliminary biodistribution studies with both (90) Y-CHX-A″-DTPA-Cetuximab and (177) Lu-CHX-A″-DTPA-Cetuximab in Swiss mice bearing fibrosarcoma tumours demonstrated significant tumour uptake at 24-h post-injection (p.i.) (~16%ID/g) with good tumour-to-background contrast. The results of the biodistribution studies were further corroborated by ex vivo Cerenkov luminescence imaging after administration of (90) Y-CHX-A″-DTPA-Cetuximab in tumour-bearing mice. The tumour uptake at 24 h p.i. was significantly reduced with excess unlabelled Cetuximab, suggesting that the uptake was receptor mediated. The results of this study hold promise, and this strategy should be further explored for clinical translation. PMID:27264196

  3. Comparative efficacy of 177Lu and 90Y for Anti-CD20 Pretargeted Radioimmunotherapy in Murine Lymphoma Xenograft Models

    DOE PAGESBeta

    Frost, Sofia H. L.; Frayo, Shani L.; Miller, Brian W.; Orozco, Johnnie J.; Booth, Garrett C.; Hylarides, Mark D.; Lin, Yukang; Green, Damian J.; Gopal, Ajay K.; Pagel, John M.; et al

    2015-03-18

    Purpose Pretargeted radioimmunotherapy (PRIT) is a multi-step method of selectively delivering high doses of radiotherapy to tumor cells while minimizing exposure to surrounding tissues. Yttrium-90 (90Y) and lutetium-177 (177Lu) are two of the most promising beta-particle emitting radionuclides used for radioimmunotherapy, which despite having similar chemistries differ distinctly in terms of radiophysical features. These differences may have important consequences for the absorbed dose to tumors and normal organs. Whereas 90Y has been successfully applied in a number of preclinical and clinical radioimmunotherapy settings, there have been few published pretargeting studies with 177Lu. We therefore compared the therapeutic potential of targetingmore » either 90Y or 177Lu to human B-cell lymphoma xenografts in mice. Methods Parallel experiments evaluating the biodistribution, imaging, dosimetry, therapeutic efficacy, and toxicity were performed in female athymic nude mice bearing either Ramos (Burkitt lymphoma) or Granta (mantle cell lymphoma) xenografts, utilizing an anti-CD20 antibodystreptavidin conjugate (1F5-SA) and an 90Y- or 177Lu-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-biotin second step reagent. Results The two radionuclides displayed comparable biodistributions in tumors and normal organs; however, the absorbed radiation dose delivered to tumor was more than twice as high for 90Y (1.3 Gy/MBq) as for 177Lu (0.6 Gy/MBq). More importantly, therapy with 90Y-DOTAbiotin was dramatically more effective than with 177Lu-DOTA-biotin, with 100% of Ramos xenograft-bearing mice cured with 37 MBq 90Y, whereas 0% were cured using identical amounts of 177Lu-DOTA-biotin. Similar results were observed in mice bearing Granta xenografts, with 80% of the mice cured with 90Y-PRIT and 0% cured with 177Lu-PRIT. Toxicities were comparable with both isotopes. Conclusion 90Y was therapeutically superior to 177Lu for streptavidin-biotin PRIT

  4. Comparative Efficacy of 177Lu and 90Y for Anti-CD20 Pretargeted Radioimmunotherapy in Murine Lymphoma Xenograft Models

    PubMed Central

    Frost, Sofia H. L.; Frayo, Shani L.; Miller, Brian W.; Orozco, Johnnie J.; Booth, Garrett C.; Hylarides, Mark D.; Lin, Yukang; Green, Damian J.; Gopal, Ajay K.; Pagel, John M.; Bäck, Tom A.; Fisher, Darrell R.; Press, Oliver W.

    2015-01-01

    Purpose Pretargeted radioimmunotherapy (PRIT) is a multi-step method of selectively delivering high doses of radiotherapy to tumor cells while minimizing exposure to surrounding tissues. Yttrium-90 (90Y) and lutetium-177 (177Lu) are two of the most promising beta-particle emitting radionuclides used for radioimmunotherapy, which despite having similar chemistries differ distinctly in terms of radiophysical features. These differences may have important consequences for the absorbed dose to tumors and normal organs. Whereas 90Y has been successfully applied in a number of preclinical and clinical radioimmunotherapy settings, there have been few published pretargeting studies with 177Lu. We therefore compared the therapeutic potential of targeting either 90Y or 177Lu to human B-cell lymphoma xenografts in mice. Methods Parallel experiments evaluating the biodistribution, imaging, dosimetry, therapeutic efficacy, and toxicity were performed in female athymic nude mice bearing either Ramos (Burkitt lymphoma) or Granta (mantle cell lymphoma) xenografts, utilizing an anti-CD20 antibody-streptavidin conjugate (1F5-SA) and an 90Y- or 177Lu-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-biotin second step reagent. Results The two radionuclides displayed comparable biodistributions in tumors and normal organs; however, the absorbed radiation dose delivered to tumor was more than twice as high for 90Y (1.3 Gy/MBq) as for 177Lu (0.6 Gy/MBq). More importantly, therapy with 90Y-DOTA-biotin was dramatically more effective than with 177Lu-DOTA-biotin, with 100% of Ramos xenograft-bearing mice cured with 37 MBq 90Y, whereas 0% were cured using identical amounts of 177Lu-DOTA-biotin. Similar results were observed in mice bearing Granta xenografts, with 80% of the mice cured with 90Y-PRIT and 0% cured with 177Lu-PRIT. Toxicities were comparable with both isotopes. Conclusion 90Y was therapeutically superior to 177Lu for streptavidin-biotin PRIT approaches in

  5. Comparative Efficacy of 177Lu and 90Y for Anti-CD20 Pretargeted Radioimmunotherapy in Murine Lymphoma Xenograft Models

    SciTech Connect

    Frost, Sophia; Frayo, Shani; Miller, Brian W.; Orozco, Johnnie J.; Booth, Garrett C.; Hylarides, Mark; Lin, Yukang; Green, Damian J.; Gopal, Ajay K.; Pagel, John M.; Back, Tom; Fisher, Darrell R.; Press, Oliver W.

    2015-03-01

    Pretargeted radioimmunotherapy (PRIT) is a multi-step method of selectively delivering high doses of radiotherapy to tumor cells while minimizing exposure to surrounding tissues. Yttrium-90 (90Y) and lutetium-177 (177Lu) are two of the most promising beta-particle emitting radionuclides used for radioimmunotherapy, which despite having similar chemistries differ distinctly in terms of radiophysical features. These differences may have important consequences for the absorbed dose to tumors and normal organs. Whereas 90Y has been successfully applied in a number of preclinical and clinical radioimmunotherapy settings, there have been few published pretargeting studies with 177Lu. We therefore compared the therapeutic potential of targeting either 90Y or 177Lu to human B-cell lymphoma xenografts in mice.

  6. Survival after somatostatin based radiopeptide therapy with 90Y-DOTATOC vs. 90Y-DOTATOC plus 177Lu-DOTATOC in metastasized gastrinoma

    PubMed Central

    Dumont, Rebecca A; Seiler, Daniela; Marincek, Nicolas; Brunner, Philippe; Radojewski, Piotr; Rochlitz, Christoph; Müller-Brand, Jan; Maecke, Helmut R; Briel, Matthias; Walter, Martin A

    2015-01-01

    We aimed to explore the effects of 90Y-DOTATOC and 90Y-DOTATOC plus 177Lu-DOTATOC on survival of patients with metastasized gastrinoma. Patients with progressive metastasized gastrinoma were treated with repeated cycles of 90Y-DOTATOC or with cycles alternating between 90Y-DOTATOC and 177Lu-DOTATOC until tumor progression or permanent toxicity. Multivariable Cox regression analyses were used to study predictors of survival. A total of 36 patients were enrolled; 30 patients received 90Y-DOTATOC (median activity per patient 11.8GBq; range: 6.1-62.2GBq) and 6 patients received 90Y-DOTATOC plus 177Lu-DOTATOC (median activity per patient: 14.8GBq; range: 7.4-14.8GBq). Response was found in 26 patients (72.2%), including morphological (n=12, 33.3%), biochemical (n=14, 38.9%) and/or clinical response (n=6, 16.2%). A total of 21 patients (58.3%) experienced hematotoxicity grade 1/2, while 1 patient (2.8%) experienced hematotoxicity grade 3; no grade 4 hematotoxicity occurred. Furthermore, 2 patients (5.6%) developed grade 4 renal toxicity; no grade 5 renal toxicity occurred. Responders had a significantly longer median survival from time of enrollment than non-responders (45.1 months, range: 37.1-53.1 months vs. 12.6 months, range: 11.0-14.2, hazard ratio: 0.12 (0.027-0.52), p=0.005). Additionally, there was a trend towards longer median survival with 90Y-DOTATOC plus 177Lu-DOTATOC as compared to 90Y-DOTATOC alone (60.2 months, range: 19.8-100.6 months vs. 27.0 months, range: 4.0-50.0, hazard ratio: 0.21 (0.01-3.98), p=0.16). Response to 90Y-DOTATOC and 90Y-DOTATOC plus 177Lu-DOTATOC therapy is associated with a longer survival in patients with metastasized gastrinoma. Both treatment regimens are promising tools for management of progressive gastrinoma. PMID:25625026

  7. Production of glass microspheres comprising 90Y and (177)Lu for treating of hepatic tumors with SPECT imaging capabilities.

    PubMed

    Poorbaygi, Hosein; Reza Aghamiri, Seyed Mahmoud; Sheibani, Shahab; Kamali-Asl, Alireza; Mohagheghpoor, Elham

    2011-10-01

    Our objective was to determine if glass microspheres impregnated with two radionuclides, (90)Y as source of therapeutic beta emissions and (177)Lu as source of diagnostic gamma emissions can be useful for SPECT imaging during or after application of the (90)Y microspheres for treating of hepatic tumors. The glass-based microspheres labeled with (89)Y and lutetium (YAS (Lu)) or (89)Y and ytterbium (YAS (Yb)) were prepared by the sol-gel process where sol droplets directly were formed to gel microspheres. Results of the neutron activation indicate that such a combination of glass, microspheres allow bio-distribution studies by SPECT imaging with high resolution. PMID:21723135

  8. Evaluation of (68)Ga- and (177)Lu-DOTA-PEG4-LLP2A for VLA-4-Targeted PET Imaging and Treatment of Metastatic Melanoma.

    PubMed

    Beaino, Wissam; Nedrow, Jessie R; Anderson, Carolyn J

    2015-06-01

    Malignant melanoma is a highly aggressive cancer, and the incidence of this disease is increasing worldwide at an alarming rate. Despite advances in the treatment of melanoma, patients with metastatic disease still have a poor prognosis and low survival rate. New strategies, including targeted radiotherapy, would provide options for patients who become resistant to therapies such as BRAF inhibitors. Very late antigen-4 (VLA-4) is expressed on melanoma tumor cells in higher levels in more aggressive and metastatic disease and may provide an ideal target for drug delivery and targeted radiotherapy. In this study, we evaluated (177)Lu- and (68)Ga-labeled DOTA-PEG4-LLP2A as a VLA-4-targeted radiotherapeutic with a companion PET agent for diagnosis and monitoring metastatic melanoma treatment. DOTA-PEG4-LLP2A was synthesized by solid-phase synthesis. The affinity of (177)Lu- and (68)Ga-labeled DOTA-PEG4-LLP2A to VLA-4 was determined in B16F10 melanoma cells by saturation binding and competitive binding assays, respectively. Biodistribution of the LLP2A conjugates was determined in C57BL/6 mice bearing B16F10 subcutaneous tumors, while PET/CT imaging was performed in subcutaneous and metastatic models. (177)Lu-DOTA-PEG4-LLP2A showed high affinity to VLA-4 with a Kd of 4.1 ± 1.5 nM and demonstrated significant accumulation in the B16F10 melanoma tumor after 4 h (31.5 ± 7.8%ID/g). The tumor/blood ratio of (177)Lu-DOTA-PEG4-LLP2A was highest at 24 h (185 ± 26). PET imaging of metastatic melanoma with (68)Ga-DOTA-PEG4-LLP2A showed high uptake in sites of metastases and correlated with bioluminescence imaging of the tumors. These data demonstrate that (177)Lu-DOTA-PEG4-LLP2A has potential as a targeted therapeutic for treating melanoma as well as other VLA-4-expressing tumors. In addition, (68)Ga-DOTA-PEG4-LLP2A is a readily translatable companion PET tracer for imaging of metastatic melanoma. PMID:25919487

  9. Tumour control probability derived from dose distribution in homogeneous and heterogeneous models: assuming similar pharmacokinetics, 125Sn-177Lu is superior to 90Y-177Lu in peptide receptor radiotherapy

    NASA Astrophysics Data System (ADS)

    Walrand, Stephan; Hanin, François-Xavier; Pauwels, Stanislas; Jamar, François

    2012-07-01

    Clinical trials on 177Lu-90Y therapy used empirical activity ratios. Radionuclides (RN) with larger beta maximal range could favourably replace 90Y. Our aim is to provide RN dose-deposition kernels and to compare the tumour control probability (TCP) of RN combinations. Dose kernels were derived by integration of the mono-energetic beta-ray dose distributions (computed using Monte Carlo) weighted by their respective beta spectrum. Nine homogeneous spherical tumours (1-25 mm in diameter) and four spherical tumours including a lattice of cold, but alive, spheres (1, 3, 5, 7 mm in diameter) were modelled. The TCP for 93Y, 90Y and 125Sn in combination with 177Lu in variable proportions (that kept constant the renal cortex biological effective dose) were derived by 3D dose kernel convolution. For a mean tumour-absorbed dose of 180 Gy, 2 mm homogeneous tumours and tumours including 3 mm diameter cold alive spheres were both well controlled (TCP > 0.9) using a 75-25% combination of 177Lu and 90Y activity. However, 125Sn-177Lu achieved a significantly better result by controlling 1 mm-homogeneous tumour simultaneously with tumours including 5 mm diameter cold alive spheres. Clinical trials using RN combinations should use RN proportions tuned to the patient dosimetry. 125Sn production and its coupling to somatostatin analogue appear feasible. Assuming similar pharmacokinetics 125Sn is the best RN for combination with 177Lu in peptide receptor radiotherapy justifying pharmacokinetics studies in rodent of 125Sn-labelled somatostatin analogues.

  10. Anti-CD45 Radioimmunotherapy with 90Y but Not 177Lu Is Effective Treatment in a Syngeneic Murine Leukemia Model

    PubMed Central

    Orozco, Johnnie J.; Balkin, Ethan R.; Gooley, Ted A.; Kenoyer, Aimee; Hamlin, Donald K.; Wilbur, D. Scott; Fisher, Darrell R.; Hylarides, Mark D.; Shadman, Mazyar; Green, Damian J.; Gopal, Ajay K.; Press, Oliver W.; Pagel, John M.

    2014-01-01

    Radioimmunotherapy (RIT) for treatment of hematologic malignancies has primarily employed monoclonal antibodies (Ab) labeled with 131I or 90Y which have limitations, and alternative radionuclides are needed to facilitate wider adoption of RIT. We therefore compared the relative therapeutic efficacy and toxicity of anti-CD45 RIT employing 90Y and 177Lu in a syngeneic, disseminated murine myeloid leukemia (B6SJLF1/J) model. Biodistribution studies showed that both 90Y- and 177Lu-anti-murine CD45 Ab conjugates (DOTA-30F11) targeted hematologic tissues, as at 24 hours 48.8±21.2 and 156±14.6% injected dose per gram of tissue (% ID/g) of 90Y-DOTA-30F11 and 54.2±9.5 and 199±11.7% ID/g of 177Lu-DOTA-30F11 accumulated in bone marrow (BM) and spleen, respectively. However, 90Y-DOTA-30F11 RIT demonstrated a dose-dependent survival benefit: 60% of mice treated with 300 µCi 90Y-DOTA-30F11 lived over 180 days after therapy, and mice treated with 100 µCi 90Y-DOTA-30F11 had a median survival 66 days. 90Y-anti-CD45 RIT was associated with transient, mild myelotoxicity without hepatic or renal toxicity. Conversely, 177Lu- anti-CD45 RIT yielded no long-term survivors. Thus, 90Y was more effective than 177Lu for anti-CD45 RIT of AML in this murine leukemia model. PMID:25460570

  11. Organ doses from hepatic radioembolization with 90Y, 153Sm, 166Ho and 177Lu: A Monte Carlo simulation study using Geant4

    NASA Astrophysics Data System (ADS)

    Hashikin, N. A. A.; Yeong, C. H.; Guatelli, S.; Abdullah, B. J. J.; Ng, K. H.; Malaroda, A.; Rosenfeld, A. B.; Perkins, A. C.

    2016-03-01

    90Y-radioembolization is a palliative treatment for liver cancer. 90Y decays via beta emission, making imaging difficult due to absence of gamma radiation. Since post-procedure imaging is crucial, several theranostic radionuclides have been explored as alternatives. However, exposures to gamma radiation throughout the treatment caused concern for the organs near the liver. Geant4 Monte Carlo simulation using MIRD Pamphlet 5 reference phantom was carried out. A spherical tumour with 4.3cm radius was modelled within the liver. 1.82GBq of 90Y sources were isotropically distributed within the tumour, with no extrahepatic shunting. The simulation was repeated with 153Sm, 166Ho and 177Lu. The estimated tumour doses for all radionuclides were 262.9Gy. Tumour dose equivalent to 1.82GBq 90Y can be achieved with 8.32, 5.83, and 4.44GBq for 153Sm, 166Ho and 177Lu, respectively. Normal liver doses by the other radionuclides were lower than 90Y, hence beneficial for normal tissue sparing. The organ doses from 153Sm and 177Lu were relatively higher due to higher gamma energy, but were still well below 1Gy. 166Ho, 177Lu and 153Sm offer useful gamma emission for post-procedure imaging. They show potential as 90Y substitutes, delivering comparable tumour doses, lower normal liver doses and other organs doses far below the tolerance limit.

  12. Kidney Dosimetry in 177Lu and 90Y Peptide Receptor Radionuclide Therapy: Influence of Image Timing, Time-Activity Integration Method, and Risk Factors

    PubMed Central

    Guerriero, F.; Ferrari, M. E.; Botta, F.; Fioroni, F.; Grassi, E.; Versari, A.; Sarnelli, A.; Pacilio, M.; Amato, E.; Strigari, L.; Bodei, L.; Paganelli, G.; Iori, M.; Pedroli, G.; Cremonesi, M.

    2013-01-01

    Kidney dosimetry in 177Lu and 90Y PRRT requires 3 to 6 whole-body/SPECT scans to extrapolate the peptide kinetics, and it is considered time and resource consuming. We investigated the most adequate timing for imaging and time-activity interpolating curve, as well as the performance of a simplified dosimetry, by means of just 1-2 scans. Finally the influence of risk factors and of the peptide (DOTATOC versus DOTATATE) is considered. 28 patients treated at first cycle with 177Lu DOTATATE and 30 with 177Lu DOTATOC underwent SPECT scans at 2 and 6 hours, 1, 2, and 3 days after the radiopharmaceutical injection. Dose was calculated with our simplified method, as well as the ones most used in the clinic, that is, trapezoids, monoexponential, and biexponential functions. The same was done skipping the 6 h and the 3 d points. We found that data should be collected until 100 h for 177Lu therapy and 70 h for 90Y therapy, otherwise the dose calculation is strongly influenced by the curve interpolating the data and should be carefully chosen. Risk factors (hypertension, diabetes) cause a rather statistically significant 20% increase in dose (t-test, P < 0.10), with DOTATATE affecting an increase of 25% compared to DOTATOC (t-test, P < 0.05). PMID:23865075

  13. Evaluation of Beta-Absorbed Fractions in a Mouse Model for 90Y, 188Re, 166Ho, 149Pm, 64Cu, and 177Lu Radionuclides

    SciTech Connect

    Miller, William H.; Hartmann-Siantar, Christine; Fisher, Darrell R.; Descalle, Marie-Anne; Daly, Tom; Lehmann, Joerg; Lewis, Michael R.; Hoffman, Timothy J.; Smith, Jeff; Situ, Peter D.; Volkert, Wynn A.

    2005-08-01

    Several short-lived, high-energy beta emitters are being proposed as the radionuclide components for molecular-targeted potential cancer therapeutic agents. The laboratory mice used to determine the efficacy of these new agents have organs that are relatively small compared to the ranges of these high-energy particles. The dosimetry model developed by Hui et al. was extended to provide realistic beta-dose estimates for organs in mice that received therapeutic radiopharmaceuticals containing 90Y, 188Re, 166Ho, 149Pm, 64Cu, and 177 Lu. Major organs in this model included the liver, spleen, kidneys, lungs, heart, stomach, small and large bowel, thyroid, pancreas, bone, marrow, carcass, and a 0.025-g tumor. The study as reported in this paper verifies their results for 90Y and extends them by using their organ geometry factors combined with newly calculated organ self-absorbed fractions from PEREGRINE and MCNP. PEREGRINE and MCNP agree to within 8% for the worst-case organ with average differences (averaged over all organs) decreasing from 5% for 90Y to 1% for 177Lu. When used with typical biodistribution data, the three different models predict doses that are in agreement to within 5% for the worst-case organ. The beta-absorbed fractions and cross-organ-deposited energy provided in this paper can be used by researchers to predict mouse-organ doses and should contribute to an improved understanding of the relationship between dose and radiation toxicity in mouse models where use of these isotopes is favorable.

  14. Evaluation of beta-absorbed fractions in a mouse model for 90Y, 188Re, 166Ho, 149Pm, 64Cu, and 177Lu radionuclides.

    PubMed

    Miller, William H; Hartmann-Siantar, Christine; Fisher, Darrell; Descalle, Marie-Anne; Daly, Tom; Lehmann, Joerg; Lewis, Michael R; Hoffman, Timothy; Smith, Jeff; Situ, Peter D; Volkert, Wynn A

    2005-08-01

    Several short-lived, high-energy beta emitters are being proposed as the radionuclide components for molecular- targeted potential cancer therapeutic agents. The laboratory mice used to determine the efficacy of these new agents have organs that are relatively small compared to the ranges of these high-energy particles. The dosimetry model developed by Hui et al. was extended to provide realistic beta-dose estimates for organs in mice that received therapeutic radiopharmaceuticals containing (90)Y, (188)Re, (166)Ho, (149)Pm, (64)Cu, and (177)Lu. Major organs in this model included the liver, spleen, kidneys, lungs, heart, stomach, small and large bowel, thyroid, pancreas, bone, marrow, carcass, and a 0.025-g tumor. The study as reported in this paper verifies their results for (90)Y and extends them by using their organ geometry factors combined with newly calculated organ self-absorbed fractions from PEREGRINE and MCNP. PEREGRINE and MCNP agree to within 8% for the worst-case organ with average differences (averaged over all organs) decreasing from 5% for (90)Y to 1% for (177)Lu. When used with typical biodistribution data, the three different models predict doses that are in agreement to within 5% for the worst-case organ. The beta-absorbed fractions and cross-organ-deposited energy provided in this paper can be used by researchers to predict mouse-organ doses and should contribute to an improved understanding of the relationship between dose and radiation toxicity in mouse models where use of these isotopes is favorable. PMID:16114992

  15. In vivo Localization of 90Y- and 177Lu-Radioimmunoconjugates Using Cerenkov Luminescence Imaging in a Disseminated Murine Leukemia Model

    PubMed Central

    Balkin, Ethan R.; Kenoyer, Aimee; Orozco, Johnnie J.; Hernandez, Alexandra; Shadman, Mazyar; Fisher, Darrell R.; Green, Damian J.; Hylarides, Mark D.; Press, Oliver W.; Wilbur, D. Scott; Pagel, John M.

    2014-01-01

    Cerenkov radiation generated by positron-emitting radionuclides can be exploited for a molecular imaging technique known as Cerenkov Luminescence Imaging (CLI). Data have been limited, however, on the use of medium-to-high energy β-emitting radionuclides of interest for cancer imaging and treatment. We assessed the use of CLI as an adjunct to determine localization of radioimmunoconjugates to hematolymphoid tissues. Radiolabeled 177Lu- or 90Y-anti-CD45 antibody (Ab; DOTA-30F11) was administered by tail vein injection to athymic mice bearing disseminated murine myeloid leukemia with CLI images acquired at times afterward. Gamma counting of individual organs showed preferential uptake in CD45+ tissues with significant retention of radiolabeled Ab in sites of leukemia (spleen and bone marrow). This result was confirmed in CLI images with 1.35 × 105 ± 2.2 × 104 p/sec/cm2/sr and 3.45 × 103 ± 7.0 × 102 p/sec/cm2/sr for 90Y-DOTA-30F11 and 177Lu-DOTA-30F11, respectively, compared to undetectable signal for both radionuclides using the non-binding control Ab. Results showed that CLI allows for in vivo visualization of localized β-emissions. Pixel intensity variability resulted from differences in absorbed doses of the associated energies of the β-emitting radionuclide. Overall, our findings offer a preclinical proof of concept for the use of CLI techniques in tandem with currently available clinical diagnostic tools. PMID:25261237

  16. Influence of cations on the complexation yield of DOTATATE with yttrium and lutetium: a perspective study for enhancing the 90Y and 177Lu labeling conditions.

    PubMed

    Asti, Mattia; Tegoni, Matteo; Farioli, Daniela; Iori, Michele; Guidotti, Claudio; Cutler, Cathy S; Mayer, Pat; Versari, Annibale; Salvo, Diana

    2012-05-01

    The DOTA macrocyclic ligand can form stable complexes with many cations besides yttrium and lutetium. For this reason, the presence of competing cationic metals in yttrium-90 and lutetium-177 chloride solutions can dramatically influence the radiolabeling yield. The aim of this study was to evaluate the coordination yield of yttrium- and lutetium-DOTATATE complexes when the reaction is performed in the presence of varying amounts of competing cationic impurities. In the first set of experiments, the preparation of the samples was performed by using natural yttrium and lutetium (20.4 nmol). The molar ratio between DOTATATE and these metals was 1 to 1. Metal competitors (Pb(2+), Zn(2+), Cu(2+), Fe(3+), Al(3+), Ni(2+), Co(2+), Cr(3+)) were added separately to obtain samples with varying molar ratio with respect to yttrium or lutetium (0.1, 0.5, 1, 2 and 10). The final solutions were analyzed through ultra high-performance liquid chromatography with an UV detector. In the second set of experiments, an amount of (90)Y or (177)Lu chloride (6 MBq corresponding to 3.3 and 45 pmol, respectively) was added to the samples, and a radio-thin layer chromatography analysis was carried out. The coordination of Y(3+) and Lu(3+) was dramatically influenced by low levels of Zn(2+), Cu(2+) and Co(2+). Pb(2+) and Ni(2+) were also shown to be strong competitors at higher concentrations. Fe(3+) was expected to be a strong competitor, but the effect on the incorporation was only partly dependent on its concentration. Al(3+) and Cr(3+) did not compete with Y(3+) and Lu(3+) in the formation of DOTATATE complexes. PMID:22172388

  17. Monte Carlo Calculation of Radioimmunotherapy with 90Y-, 177Lu-, 131I-, 124I-, and 188Re-Nanoobjects: Choice of the Best Radionuclide for Solid Tumour Treatment by Using TCP and NTCP Concepts

    PubMed Central

    Lucas, S.; Feron, O.; Gallez, B.; Masereel, B.; Michiels, C.; Vander Borght, T.

    2015-01-01

    Radioimmunotherapy has shown that the use of monoclonal antibodies combined with a radioisotope like 131I or 90Y still remains ineffective for solid and radioresistant tumour treatment. Previous simulations have revealed that an increase in the number of 90Y labelled to each antibody or nanoobject could be a solution to improve treatment output. It now seems important to assess the treatment output and toxicity when radionuclides such as 90Y, 177Lu, 131I, 124I, and 188Re are used. Tumour control probability (TCP) and normal tissue complication probability (NTCP) curves versus the number of radionuclides per nanoobject were computed with MCNPX to evaluate treatment efficacy for solid tumours and to predict the incidence of surrounding side effects. Analyses were carried out for two solid tumour sizes of 0.5 and 1.0 cm radius and for nanoobject (i.e., a radiolabelled antibody) distributed uniformly or nonuniformly throughout a solid tumour (e.g., Non-small-cell-lung cancer (NSCLC)). 90Y and 188Re are the best candidates for solid tumour treatment when only one radionuclide is coupled to one carrier. Furthermore, regardless of the radionuclide properties, high values of TCP can be reached without toxicity if the number of radionuclides per nanoobject increases. PMID:26136812

  18. Prospects of medium specific activity (177) Lu in targeted therapy of prostate cancer using (177) Lu-labeled PSMA inhibitor.

    PubMed

    Chakraborty, Sudipta; Chakravarty, Rubel; Shetty, Priyalata; Vimalnath, K V; Sen, Ishita B; Dash, Ashutosh

    2016-07-01

    Targeted radionuclide therapy using (177) Lu-labeled peptidomimetic inhibitor of prostate specific membrane antigen (PSMA) viz. PSMA-617 is emerging as one the most effective strategies for management of metastatic prostate cancer, which is one of the leading causes of cancer related death. The aim of the present study is to develop a robust and easily adaptable protocol for formulation of therapeutic dose of (177) Lu-PSMA-617 at hospital radiopharmacy using moderate specific activity (177) Lu available at an affordable cost. Extensive radiochemical studies were performed to optimize the required [PSMA-617] / [Lu] ratio and other parameters to formulate 7.4 GBq dose of (177) Lu-PSMA-617. Based on these, 7.4 GBq therapeutic dose of (177) Lu-PSMA-617 was formulated by incubating 160 µg of PSMA-617 with indigenously produced (177) LuCl3 (555 GBq/µg specific activity of (177) Lu) at 90 °C for 30 min. The radiochemical purity of the formulation was 98.3 ± 0.6% (n = 7) which was retained to the extent of >95% after 7 d in normal saline at room temperature and >96% after 2 d in human serum at 37 °C. Preliminary clinical studies showed specific targeting of the agent in the lesion sites and similar physiological distribution as in diagnostic (68) Ga-PSMA-11 PET scans performed earlier. The developed optimized protocol for formulating therapeutic dose of (177) Lu-PSMA-617 could be useful for large number of nuclear medicine therapy clinics across the world having access to moderate specific activity (177) Lu at an affordable cost. PMID:27264278

  19. Use of Monte Carlo simulations with a realistic rat phantom for examining the correlation between hematopoietic system response and red marrow absorbed dose in Brown Norway rats undergoing radionuclide therapy with {sup 177}Lu- and {sup 90}Y-BR96 mAbs

    SciTech Connect

    Larsson, Erik; Ljungberg, Michael; Martensson, Linda; Nilsson, Rune; Tennvall, Jan; Strand, Sven-Erik; Joensson, Bo-Anders

    2012-07-15

    Purpose: Biokinetic and dosimetry studies in laboratory animals often precede clinical radionuclide therapies in humans. A reliable evaluation of therapeutic efficacy is essential and should be based on accurate dosimetry data from a realistic dosimetry model. The aim of this study was to develop an anatomically realistic dosimetry model for Brown Norway rats to calculate S factors for use in evaluating correlations between absorbed dose and biological effects in a preclinical therapy study. Methods: A realistic rat phantom (Roby) was used, which has some flexibility that allows for a redefinition of organ sizes. The phantom was modified to represent the anatomic geometry of a Brown Norway rat, which was used for Monte Carlo calculations of S factors. Kinetic data for radiolabeled BR96 monoclonal antibodies were used to calculate the absorbed dose. Biological data were gathered from an activity escalation study with {sup 90}Y- and {sup 177}Lu-labeled BR96 monoclonal antibodies, in which blood cell counts and bodyweight were examined up to 2 months follow-up after injection. Reductions in white blood cell and platelet counts and declines in bodyweight were quantified by four methods and compared to the calculated absorbed dose to the bone marrow or the total body. Results: A red marrow absorbed dose-dependent effect on hematological parameters was observed, which could be evaluated by a decrease in blood cell counts. The absorbed dose to the bone marrow, corresponding to the maximal tolerable activity that could safely be administered, was determined to 8.3 Gy for {sup 177}Lu and 12.5 Gy for {sup 90}Y. Conclusions: There was a clear correlation between the hematological effects, quantified with some of the studied parameters, and the calculated red marrow absorbed doses. The decline in body weight was stronger correlated to the total body absorbed dose, rather than the red marrow absorbed dose. Finally, when considering a constant activity concentration, the phantom

  20. Application and dosimetric requirements for 68Ga-labeled somatostatin analogues in targeted radionuclide therapy for gastroenteropancreatic neuroendocrine tumors

    PubMed Central

    Taïeb, David; Garrigue, Philippe; Bardiès, Manuel; Esmaeel, Abdullah Ahmad; Pacak, Karel

    2015-01-01

    Neuroendocrine tumors (NETs) are associated with variable prognosis, with grade 1 and 2 NETs having a more favorable outcome than G3 ones (also called carcinoma). GEP-NET patients need highly individualized interdisciplinary evaluations and treatment. New treatment options have become available (i.e., sunitinib, mTOR inhibitors) with significant improvements in progression-free survival. Peptide receptor radionuclide therapy (PRRT) using 90Y or 177Lu-labeled somatostatin analogs has also shown promise in the treatment of advanced progressive NETs but randomized clinical trials comparing with other modalities are still lacking. SST-targeting represents the essence of theranostics. 68Ga-DOTA-SSTa can be used as companion imaging agents to assist in such a radionuclide therapy selection. 68Ga-DOTA-SSTa PET/CT might also provide critical information for prognosis, tumor response assessement to PRRT, and internal dosimetry. It is also expected that the development of novel receptor-targeting radiopharmaceuticals will contribute to the development of molecular-based personalized medicine approaches. PMID:26384594

  1. Rhabdoid papillary meningioma treated with 177Lu DOTATATE PRRT.

    PubMed

    Makis, William; McCann, Karey; McEwan, Alexander J B

    2015-03-01

    An 18-year-old girl presented with a 3-year history of a recurrent skull base mass confirmed to be a rhabdoid papillary meningioma. The tumor was octreotide avid and metastatic to the lungs, thoracic lymph nodes, and bones, and she was referred for PRRT (peptide receptor radionuclide therapy) with 177Lu DOTATATE. After 3 induction treatment cycles of 177Lu DOTATATE, she experienced significant improvements in her symptoms; however, just before the fourth treatment, she developed cervical spinal cord compression and passed away shortly thereafter. The use of 177Lu DOTATATE therapy in the management of rhabdoid papillary meningioma warrants further research. PMID:25608146

  2. Dosimetry of [177Lu]-DO3A-VS-Cys40-Exendin-4 – impact on the feasibility of insulinoma internal radiotherapy

    PubMed Central

    Velikyan, Irina; Bulenga, Thomas N; Selvaraju, Ramkumar; Lubberink, Mark; Espes, Daniel; Rosenström, Ulrika; Eriksson, Olof

    2015-01-01

    [68Ga]-DO3A-VS-Cys40-Exendin-4 has been shown to be a promising imaging candidate for targeting glucagon like peptide-1 receptor (GLP-1R). In the light of radiotheranostics and personalized medicine the 177Lu-labelled analogue is of paramount interest. In this study we have investigated the organ distribution of [177Lu]-DO3A-VS-Cys40-Exendin-4 in rat and calculated human dosimetry parameters in order to estimate the maximal acceptable administered radioactivity, and thus potential applicability of [177Lu]-DO3A-VS-Cys40-Exendin-4 for internal radiotherapy of insulinomas. Nine male and nine female Lewis rats were injected with [177Lu]-DO3A-VS-Cys40-Exendin-4 for ex vivo organ distribution study at nine time points. The estimation of human organ/total body absorbed and total effective doses was performed using Organ Level Internal Dose Assessment Code software (OLINDA/EXM 1.1). Six more rats (male: n = 3; female: n = 3) were scanned by single photon emission tomography and computed tomography (SPECT-CT). The renal function and potential cell dysfunction were monitored by creatinine ISTAT and glucose levels. The fine uptake structure of kidney and pancreas was investigated by ex vivo autoradiography. Blood clearance and washout from most of the organs was fast. The kidney was the dose-limiting organ with absorbed dose of 5.88 and 6.04 mGy/MBq, respectively for female and male. Pancreatic beta cells demonstrated radioactivity accumulation. Renal function and beta cell function remained unaffected by radiation. The absorbed dose of [177Lu]-DO3A-VS-Cys40-Exendin-4 to kidneys may limit the clinical application of the agent. However, hypothetically, kidney protection and peptidase inhibition may allow reduction of kidney absorbed dose and amplification of tumour absorbed doses. PMID:25973333

  3. Method for preparing high specific activity 177Lu

    SciTech Connect

    Mirzadeh, Saed; Du, Miting; Beets, Arnold L.; Knapp, Jr., Furn F.

    2004-04-06

    A method of separating lutetium from a solution containing Lu and Yb, particularly reactor-produced .sup.177 Lu and .sup.177 Yb, includes the steps of: providing a chromatographic separation apparatus containing LN resin; loading the apparatus with a solution containing Lu and Yb; and eluting the apparatus to chromatographically separate the Lu and the Yb in order to produce high-specific-activity .sup.177 Yb.

  4. Biodistribution and Dosimetry of 177Lu-tetulomab, a New Radioimmunoconjugate for Treatment of Non-Hodgkin Lymphoma

    PubMed Central

    Repetto-Llamazares, Ada H V; Larsen, Roy H; Mollatt, Camilla; Lassmann, Michael; Dahle, Jostein

    2013-01-01

    The biodistribution of the anti-CD37 radioimmunoconjugate 177Lu-tetraxetan-tetulomab (177Lu-DOTA-HH1) was evaluated. Biodistribution of 177Lu-tetraxetan-tetulomab was compared with 177Lu-tetraxetan-rituximab and free 177Lu in nude mice implanted with Daudi lymphoma xenografts. The data showed that 177Lu-tetulomab had a relevant stability and tumor targeting properties in the human lymphoma model. The half-life of 177Lu allowed significant tumor to normal tissue ratios to be obtained indicating that 177Lu-tetraxetan-tetulomab could be suitable for clinical testing. The biological and effective half-life in blood was higher for 177Lu-tetraxetan-tetulomab than for 177Lu-tetraxetan-rituximab. The biodistribution of 177Lu-tetraxetan-tetulomab did not change significantly when the protein dose was varied from 0.01 to 1 mg/kg. Dosimetry calculations showed that the absorbed radiation doses to normal tissues and tumor in mice were not significantly different for 177Lu-tetraxetan-tetuloma b and 177Lu-tetraxetan-rituximab. The absorbed radiation doses were extrapolated to human absorbed radiation doses. These extrapolated absorbed radiation doses to normal tissues for 177Lu-tetraxetan-tetulomab at an injection of 40 MBq/kg were significantly lower than the absorbed radiation doses for 15 MBq/kg Zevalin, suggesting that higher tumor radiation dose can be reached with 177Lu-tetraxetan-tetulomab in the clinic. PMID:23256748

  5. Consequences of meta-stable (177m)Lu admixture in (177)Lu for patient dosimetry.

    PubMed

    Konijnenberg, Mark W

    2015-01-01

    Lutetium-177 ((177)Lu) is a rare earth metal in the lanthanides series which decays by beta emission with a half life of 6.647 days to three excited states and the ground state of (177)Hf. When (177)Lu is produced by neutron capture in (176)Lu, inevitably an admixture is formed of the long-lived isomer (177)mLu. As its half-life of 160.4 days is so much longer than that of (177)Lu, concerns are raised on its possible enhancement in radiation dose to the patient treated with (177)Lu-DOTA-octreotate. This report evaluates this possible enhancement of the absorbed dose, based on the published pharmacokinetic profile of (177)Lu-DOTA-octreotate and assuming an admixture of 1 kBq (177)mLu /MBq (177)Lu (0.1%). PMID:25771362

  6. Optimization of irradiation conditions for {sup 177}Lu production at the LVR-15 research reactor

    SciTech Connect

    Lahodova, Z.; Viererbl, L.; Klupak, V.; Srank, J.

    2012-07-01

    The use of lutetium in medicine has been increasing over the last few years. The {sup 177}Lu radionuclide is commercially available for research and test purposes as a diagnostic and radiotherapy agent in the treatment of several malignant tumours. The yield of {sup 177}Lu from the {sup 176}Lu(n,{gamma}){sup 177}Lu nuclear reaction depends significantly on the thermal neutron fluence rate. The capture cross-sections of both reaction {sup 176}Lu(n,{gamma}){sup 177}Lu and reaction {sup 177}Lu(n,{gamma}){sup 178}Lu are very high. Therefore a burn-up of target and product nuclides should be taken into account when calculating {sup 177}Lu activity. The maximum irradiation time, when the activity of the {sup 177}Lu radionuclide begins to decline, was found for different fluence rates. Two vertical irradiation channels at the LVR-15 nuclear research reactor were compared in order to choose the channel with better irradiation conditions, such as a higher thermal neutron fluence rate in the irradiation volume. In this experiment, lutetium was irradiated in a titanium capsule. The influence of the Ti capsule on the neutron spectrum was monitored using activation detectors. The choice of detectors was based on requirements for irradiation time and accurate determination of thermal neutrons. The following activation detectors were selected for measurement of the neutron spectrum: Ti, Fe, Ni, Co, Ag and W. (authors)

  7. Photoionization spectroscopy for laser extraction of the radioactive isotope 177Lu

    NASA Astrophysics Data System (ADS)

    D'yachkov, A. B.; Firsov, V. A.; Gorkunov, A. A.; Labozin, A. V.; Mironov, S. M.; Panchenko, V. Y.; Semenov, A. N.; Shatalova, G. G.; Tsvetkov, G. O.

    2015-12-01

    The hyperfine structure of the 5 d6 s 2 2D3/2 → 5 d6 s6 p 4F5/2 transition of the radioactive isotope 177Lu has been investigated by laser photoionization spectroscopy. Measured spectra permitted the determination of hyperfine magnetic dipole constants and electric quadrupole constants for ground and excited state as well as the isotope shift of the 177Lu isotope. The data obtained were used to confirm the selective photoionization of 177Lu from a neutron-irradiated sample that initially had a natural isotope composition. A concentration for 177Lu of 50 % was achieved, and the photoionization efficiency was estimated as suitable for technological application.

  8. Thermal neutron capture cross section for the K isomer {sup 177}Lu{sup m}

    SciTech Connect

    Belier, G.; Roig, O.; Daugas, J.-M.; Giarmana, O.; Meot, V.; Letourneau, A.; Marie, F.; Foucher, Y.; Aupiais, J.; Abt, D.; Jutier, Ch.; Le Petit, G.; Bettoni, C.; Gaudry, A.; Veyssiere, Ch.; Barat, E.; Dautremer, T.; Trama, J.-Ch.

    2006-01-15

    The thermal neutron radiative capture cross section for the K isomeric state in {sup 177}Lu has been measured for the first time. Several {sup 177}Lu{sup m} targets have been prepared and irradiated in various neutron fluxes at the Lauee Langevin Institute in Grenoble and at the CEA reactors OSIRIS and ORPHEE in Saclay. The method consists of measuring the {sup 178}Lu activity by {gamma}-ray spectroscopy. The values obtained in four different neutron spectra have been used to calculate the resonance integral of the radiative capture cross section for {sup 177}Lu{sup m}. In addition, an indirect method leads to the determination of the {sup 177}Lu{sup g} neutron radiative capture cross section.

  9. Tumoral fibrosis effect on the radiation absorbed dose of (177)Lu-Tyr(3)-octreotate and (177)Lu-Tyr(3)-octreotate conjugated to gold nanoparticles.

    PubMed

    Azorín-Vega, E P; Zambrano-Ramírez, O D; Rojas-Calderón, E L; Ocampo-García, B E; Ferro-Flores, G

    2015-06-01

    The aim of this work was to evaluate the tumoral fibrosis effect on the radiation absorbed dose of the radiopharmaceuticals (177)Lu-Tyr(3)-octreotate (monomeric) and (177)Lu-Tyr(3)-octreotate-gold nanoparticles (multimeric) using an experimental HeLa cells tumoral model and the Monte Carlo PENELOPE code. Experimental and computer micro-environment models with or without fibrosis were constructed. Results showed that fibrosis increases up to 33% the tumor radiation absorbed dose, although the major effect on the dose was produced by the type of radiopharmaceutical (112Gy-multimeric vs. 43Gy-monomeric). PMID:25305748

  10. A potencial theranostic agent for EGF-R expression tumors: (177)Lu-DOTA-nimotuzumab.

    PubMed

    Calzada, Victoria; Zhang, Xiuli; Fernandez, Marcelo; Diaz-Miqueli, Arlhee; Iznaga-Escobar, Normando; Deutscher, Susan L; Balter, Henia; Quinn, Thomas P; Cabral, Pablo

    2012-10-01

    In this work Nimotuzumab (monoclonal antibody, recognizes the EGF-R) was radiolabeled with (177)Lu as a potential cancer therapy radiopharmaceutical. In-vitro cell binding studies and in-vivo biodistribution and imaging studies were performed to determine the radiochemical stability, targeting specificity and pharmacokinetics of the (177)Lu-labeled antibody. Nimotuzumab was derivatized with DOTA-NHS at room temperature for 2 hours. DOTA-Nimotuzumab was radiolabeled with (177)LuCl3 (15 MBq/mg) at 37°C for 1 h. The radiochemical purity was assessed by ITLC, silica gel and by RP-HPLC. Binding specificity studies were performed with EGF-R positive A431 human epithelial carcinoma and EGF-R negative MDA-MB-435 breast carcinoma cells. Biodistribution studies were performed in healthy female CD-1 mice at 1 h, 4 h, 24 h, and A431 xenografted nude mice at 10 min, 1 h, 4 h, 24 h, 48 h, and 96 h. SPECT-CT imaging studies were performed in A431 xenografted mice at 24 h post injection. DOTA-Nimotuzumab was efficiently labeled with (177) LuCl(3) at 37°C. The in vitro stability of labeled product was optimal over 24 h in buffered saline and mouse serum. Specific recognition of EGF-R by (177)Lu-DOTA-Nimotuzumab was observed in A431 cell binding studies. Biodistribution studies demonstrated increasing tumor uptake of (177)Lu-DOTA-Nimotuzumab over time, with tumor to muscle ratios of 6.26, 10.68, and 18.82 at 4 h, 24 h, and 96 h post injection. Imaging of A431 xenografted mice showed high uptake in the tumor. (177)Lu-DOTA-Nimotuzumab has the potential to be a promising therapy agent, which may be useful in the treatment of patients with EGF-R positive cancer. PMID:22280117

  11. Theranostic Radiopharmaceuticals Based on Gold Nanoparticles Labeled with (177)Lu and Conjugated to Peptides.

    PubMed

    Ferro-Flores, Guillermina; Ocampo-García, Blanca E; Santos-Cuevas, Clara L; de María Ramírez, Flor; Azorín-Vega, Erika P; Meléndez-Alafort, Laura

    2015-01-01

    Gold nanoparticles (AuNPs) have been proposed for a variety of medical applications such as localized heat sources for cancer treatment and drug delivery systems. The conjugation of peptides to AuNPs produces stable multimeric systems with target-specific molecular recognition. Lutetium- 177 ((177)Lu) has been successfully used in peptide radionuclide therapy. Recently, (177)Lu-AuNPs conjugated to different peptides have been proposed as a new class of theranostic radiopharmaceuticals. These radioconjugates may function simultaneously as molecular imaging agents, radiotherapy systems and thermal-ablation systems. This article covers advancements in the design, synthesis, physicochemical characterization, molecular recognition assessment and preclinical therapeutic efficacy of gold nanoparticles radiolabeled with (177)Lu and conjugated to RGD (-Arg-Gly-Asp-), Lys(3)-Bombesin and Tat(49-57) peptides. PMID:25771363

  12. (177) Lu-5-Fluorouracil a potential theranostic radiopharmaceutical: radiosynthesis, quality control, biodistribution, and scintigraphy.

    PubMed

    Rasheed, Rashid; Tariq, Saleha; Naqvi, Syed Ali Raza; Gillani, Syed Jawad Hussain; Rizvi, Faheem Askari; Sajid, Muhammad; Rasheed, Shahid

    2016-08-01

    The aim of this study is to develop (177) Lu-5-Flourouracil as a potential cancer therapeutic radiopharmaceutical. 5-Flourouracil (5-FU) is widely accepted as an anticancer drug of broad spectrum fame. The labeling of 5-FU was carried out at different set of experimental conditions using high specific activity of (177) LuCl3 . The optimum conditions for maximum radiochemical yield was set: 5-FU (5 mg), (177) LuCl3 (185 MBq), diethylenetriaminepentaacetic acid (10 µg), reaction volume (2 mL), pH (5.5), temperature (80°C), and reaction time (20 min). The radiochemical labeling was assessed with Whatman No. 2 paper, instant thin layer chromatographic, and radio-HPLC, which revealed >94% labeling results with sufficient stability up to 6 h. Serum stability study also showed (177) Lu-5-FU promising stability. Biodistribution study in normal rats and rabbits showed liver, stomach, kidney, and heart as area of increased tracer accumulation just after injection, which decreased to 1.4%, 0.4%, 0.2%, and 0.39% ID/g, respectively, after 72 h. Glomerular filtration rate and cytotoxicity study results of (177) Lu-5-FU showed it had no adverse effect on renal function and nontoxic to blood cells. The promising characteristics of (177) Lu-5-FU, that is, clever elimination from kidney and nontoxic nature toward blood cells make it the radiopharmaceutical for further testing in patients for therapeutic purposes. PMID:27444959

  13. Predicting the yield of (177)Lu radionuclide produced by the cyclic irradiation technique.

    PubMed

    Odame Duodu, Godfred; Akaho, Edward H K; Serfor-Armah, Yaw; Nyarko, Benjamin J B; Afi Achoribo, Elom

    2011-03-01

    The feasibility study on the production of (177)Lu radioisotope using a low power research reactor has been conducted. A reliable method for predicting the yield of (177)Lu produced using the cyclic activation technique based on the Westcott formalism has been established. A specific activity of 243.24 mCi/g was obtained when a (176)Lu(2)O(3) of natural abundance was irradiated for 4 h and decayed for 20 h for four cycles at GHARR-1 with a neutron flux of 5.0×10(11) ncm(-2)s(-1). PMID:21177113

  14. Esthesioneuroblastoma (olfactory neuroblastoma) treated with 111In-octreotide and 177Lu-DOTATATE PRRT.

    PubMed

    Makis, William; McCann, Karey; McEwan, Alexander J B

    2015-04-01

    A 51-year-old man with a recurrent metastatic esthesioneuroblastoma (olfactory neuroblastoma) was referred for peptide receptor radionuclide therapy (PRRT). He received 4 treatments of 111In-octreotide over 8 months and 3 treatments of 177Lu-DOTATATE over 4 months, which helped alleviate his symptoms and improved his quality of life; however, the tumor ultimately progressed and he passed away shortly thereafter. PRRT with 111In-octreotide or 177Lu-DOTATATE could play a role in the management of esthesioneuroblastoma. PMID:25674857

  15. Extraventricular neurocytoma treated with 177Lu DOTATATE PRRT induction and maintenance therapies.

    PubMed

    Makis, William; McCann, Karey; McEwan, Alexander J B

    2015-03-01

    A 64-year-old woman with a 30-year history of recurrent sellar masses presented with severe headache and rapidly progressive visual field loss in the left eye. She was diagnosed with an extraventricular neurocytoma, which was octreotide positive, and was referred for PRRT (peptide receptor radionuclide therapy) with 177Lu [DOTA0,Tyr3]octreotate (DOTATATE). After 4 induction and 4 maintenance treatment cycles, her headaches resolved, her vision improved, and her sellar mass stabilized. The use of 177Lu DOTATATE PRRT in the management of extraventricular neurocytoma warrants further research. PMID:25608145

  16. Single vial kit formulation of DOTATATE for preparation of (177) Lu-labeled therapeutic radiopharmaceutical at hospital radiopharmacy.

    PubMed

    Mukherjee, Archana; Lohar, Sharad; Dash, Ashutosh; Sarma, Haladhar Dev; Samuel, Grace; Korde, Aruna

    2015-04-01

    The clinical applications of radiolabeled somatostatin analogue (177) Lu-DOTA-Tyr(3) -Thr(8) -Octreotide ((177) Lu-DOTATATE) constitute a promising treatment option for patients with disseminated and inoperable neuroendocrine (NET) tumors. Formulation of (177) Lu-DOTATATE in hospital radiopharmacy under aseptic conditions in a safe and reliable manner is a major constraint for its extensive use. The present work was intended to develop a kit for the safe preparation of the therapeutic radiopharmaceutical, viz. (177) Lu-DOTATATE of high quality that can be easily adapted at conventional hospital radiopharmacies. Single vial kits of DOTATATE were formulated and evaluated for suitability for radiolabeling as well as stability on its storage. Patient dose of (177) Lu-DOTATATE (7.4 GBq) could be successfully prepared using semi-automated in-house setup that assures safe handling and high yields of product of pharmaceutical purity suitable for clinical use. Fast clearance of activity via renal route was observed in preclinical biodistribution studies of (177) Lu-DOTATATE carried out in normal Swiss mice. Deployment of in-house produced (177) LuCl3 , cold kits and easy adaptability of synthesis setup at hospital radiopharmacy for preparation is likely to expand applications of peptide receptor radionuclide therapy. PMID:25765604

  17. Stability and Biodistribution of Thiol-Functionalized and (177)Lu-Labeled Metal Chelating Polymers Bound to Gold Nanoparticles.

    PubMed

    Yook, Simmyung; Lu, Yijie; Jeong, Jenny Jooyoung; Cai, Zhongli; Tong, Lemuel; Alwarda, Ramina; Pignol, Jean-Philippe; Winnik, Mitchell A; Reilly, Raymond M

    2016-04-11

    We are studying a novel radiation nanomedicine approach to treatment of breast cancer using 30 nm gold nanoparticles (AuNP) modified with polyethylene glycol (PEG) metal-chelating polymers (MCP) that incorporate 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelators for complexing the β-particle emitter, (177)Lu. Our objective was to compare the stability of AuNP conjugated to MCP via a single thiol [DOTA-PEG-ortho-pyridyl disulfide (OPSS)], a dithiol [DOTA-PEG-lipoic acid (LA)] or multithiol end-group [PEG-pGlu(DOTA)8-LA4] and determine the elimination and biodistribution of these (177)Lu-labeled MCP-AuNP in mice. Stability to aggregation in the presence of thiol-containing dithiothreitol (DTT), L-cysteine or glutathione was assessed and dissociation of (177)Lu-MCP from AuNP in human plasma measured. Elimination of radioactivity from the body of athymic mice and excretion into the urine and feces was measured up to 168 h post-intravenous (i.v.) injection of (177)Lu-MCP-AuNP and normal tissue uptake was determined. ICP-AES was used to quantify Au in the liver and spleen and these were compared to (177)Lu. Our results showed that PEG-pGlu(DOTA)8-LA4-AuNP were more stable to aggregation in vitro than DOTA-PEG-LA-AuNP and both forms of AuNP were more stable to thiol challenge than DOTA-PEG-OPSS-AuNP. PEG-pGlu((177)Lu-DOTA)8-LA4 was the most stable in plasma. Whole body elimination of (177)Lu was most rapid for mice injected with (177)Lu-DOTA-PEG-OPSS-AuNP. Urinary excretion accounted for >90% of eliminated (177)Lu. All (177)Lu-MCP-AuNP accumulated in the liver and spleen. Liver uptake was lowest for PEG-pGlu((177)Lu-DOTA)8-LA4-AuNP but these AuNP exhibited the greatest spleen uptake. There were differences in Au and (177)Lu in the liver for PEG-pGlu((177)Lu-DOTA)8-LA4-AuNP. These differences were not correlated with in vitro stability of the (177)Lu-MCP-AuNP. We conclude that conjugation of AuNP with PEG-pGlu((177)Lu-DOTA)8-LA4 via a multithiol

  18. [177Lu-PSMA-617 therapy, dosimetry and follow-up in patients with metastatic castration-resistant prostate cancer].

    PubMed

    Fendler, Wolfgang P; Kratochwil, Clemens; Ahmadzadehfar, Hojjat; Rahbar, Kambiz; Baum, Richard P; Schmidt, Matthias; Pfestroff, Andreas; Lützen, Ulf; Prasad, Vikas; Heinzel, Alexander; Heuschkel, Martin; Ruf, Juri; Bartenstein, Peter; Krause, Bernd J

    2016-06-28

    Radioligand therapy (RLT) using 177Lu labelled inhibitors of the prostate-specific membrane antigen (177Lu-PSMA) is performed in patients with metastatic castration-resistant prostate cancer (mCRPC) after exhaustion of other options. German University Clinics offer RLT since 2013 on a compassionate use basis. The present consensus document includes recommendations for RLT with 177Lu-PSMA-617. These consensus statements were developed by an expert panel formed by the German Society of Nuclear Medicine (DGN) in December 2015. Statements include recommendations for indication, baseline tests, therapy protocol, concomitant therapy, dosimetry, and follow-up. Consensus recommendations aim to inform the attending medical staff, standardize 177Lu-PSMA-617 RLT, and improve quality of individual patient care. PMID:27350005

  19. Direct evidence for inelastic neutron 'acceleration' by {sup 177}Lu{sup m}

    SciTech Connect

    Roig, O.; Meot, V.; Rosse, B.; Belier, G.; Daugas, J.-M.; Morel, P.; Letourneau, A.; Menelle, A.

    2011-06-15

    The inelastic neutron acceleration cross section on the long-lived metastable state of {sup 177}Lu has been measured using a direct method. High-energy neutrons have been detected using a specially designed setup placed on a cold neutron beam extracted from the ORPHEE reactor in Saclay. The 146{+-}19 b inelastic neutron acceleration cross section in the ORPHEE cold neutron flux confirms the high cross section for this process on the {sup 177}Lu{sup m} isomer. The deviation from the 258{+-}58 b previously published obtained for a Maxwellian neutron flux at a 323 K temperature could be explained by the presence of a low energy resonance. Resonance parameters are deduced and discussed.

  20. Internal radiotherapy and dosimetric study for 111In/ 177Lu-pegylated liposomes conjugates in tumor-bearing mice

    NASA Astrophysics Data System (ADS)

    Wang, Hsin-Ell; Yu, Hung-Man; Lu, Yi-Ching; Heish, Ning-Ning; Tseng, Yun-Long; Huang, Kuang-Liang; Chuang, Kuo-Tang; Chen, Chin-Hsiung; Hwang, Jeng-Jong; Lin, Wuu-Jyh; Wang, Shyh-Jen; Ting, Gann; Whang-Peng, Jacqueline; Deng, Win-Ping

    2006-12-01

    In vivo characterization and dosimetric analysis has been performed to evaluate the potential of pegylated liposomes as carriers of radionuclides in tumor internal radiotherapy. MethodsThe DTPA/PEG-liposomes were synthesized with a medium size of 110 nm, conjugated with 111In/ 177Lu-(oxine) 3 to afford 111In/ 177Lu-liposome. The stability of 111In/ 177Lu-liposome in serum was investigated. The biodistribution, scintigraphic imaging and pharmacokinetics of 111In/ 177Lu-liposomes after intravenous(i.v.) injection into C-26 tumor-bearing BALB/cByJ mice were studied. Radiation dose was estimated by MIRD-III program. ResultsThe incorporation efficiency of 111In/ 177Lu into liposomes was 95%. After incubation at 37 °C for 72 h in serum, more than 83% of radioactivity was still retained in the intact 111In/ 177Lu-liposomes. The biodistribution of 111In-liposomes showed that the radioactivity in the blood decreased from 23.14±8.16%ID/g at 1 h to 0.02±0.00%ID/g at 72 h post-injection (p.i.), while reaching its maximum accumulation in tumors at 48 h p.i., with half-life in blood of 10.2 h. The results were supported by that of 177Lu-liposomes. Scintigraphic imaging with 111In-liposomes showed unambiguous tumor images at 48 h p.i. Dose estimation showed that the absorbed dose in tumor from 177Lu-liposomes was 5.74×10 -5 Gy/MBq. ConclusionsThis study provides an in vivo characterization and dosimetric evaluation for the use of liposome systems as carriers in targeted radionuclide therapy. The results suggest that adequate tumor targeting as well as dose delivered to tumors could be achieved by the use of radionuclide targeted liposomes.

  1. (177)Lu-Labeled Cerasomes Encapsulating Indocyanine Green for Cancer Theranostics.

    PubMed

    Jing, Lijia; Shi, Jiyun; Fan, Di; Li, Yaqian; Liu, Renfa; Dai, Zhifei; Wang, Fan; Tian, Jie

    2015-10-01

    This Article reported the fabrication of a robust theranostic cerasome encapsulating indocyanine green (ICG) by incorporating 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)2000]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid monoamide (DSPE-PEG2000-DOTA), followed by chelating radioisotope of (177)Lu. Its applications in optical and nuclear imaging of tumor uptake and biodistribution, as well as photothermal killing of cancer cells, were investigated. It was found that the obtained cerasome could act efficiently as fluorescence contrast agent as well as nuclear imaging tracer. Encapsulating ICG into cerasome could protect ICG from degradation, aggregation, and fast elimination from body, resulting in remarkable improvement in near-infrared fluorescence imaging, photothermal stability, and in vivo pharmacokinetic profile. Both fluorescence and nuclear imaging showed that such agent could selectively accumulate in tumor site after intravenous injection of the cerasome agent into Lewis lung carcinoma tumor bearing mice, resulting in efficient photothermal ablation of tumor through a one-time NIR laser irradiation at the best time window. The ability to track the uptake of cerasomes on a whole body basis could provide researchers with an excellent tool for developing cerasome-based drug delivery agents, especially the strategy of labeling cerasomes with theranostic radionuclide (177)Lu, enabling the ability of the (177)Lu-labeled cerasomes for radionuclide cancer therapy and even the combined therapy. PMID:26398723

  2. Specific radioactivity of neutron induced radioisotopes: assessment methods and application for medically useful 177Lu production as a case.

    PubMed

    Le, Van So

    2011-01-01

    The conventional reaction yield evaluation for radioisotope production is not sufficient to set up the optimal conditions for producing radionuclide products of the desired radiochemical quality. Alternatively, the specific radioactivity (SA) assessment, dealing with the relationship between the affecting factors and the inherent properties of the target and impurities, offers a way to optimally perform the irradiation for production of the best quality radioisotopes for various applications, especially for targeting radiopharmaceutical preparation. Neutron-capture characteristics, target impurity, side nuclear reactions, target burn-up and post-irradiation processing/cooling time are the main parameters affecting the SA of the radioisotope product. These parameters have been incorporated into the format of mathematical equations for the reaction yield and SA assessment. As a method demonstration, the SA assessment of 177Lu produced based on two different reactions, 176Lu (n,γ)177Lu and 176Yb (n,γ) 177Yb (β- decay) 177Lu, were performed. The irradiation time required for achieving a maximum yield and maximum SA value was evaluated for production based on the 176Lu (n,γ)177Lu reaction. The effect of several factors (such as elemental Lu and isotopic impurities) on the 177Lu SA degradation was evaluated for production based on the 176Yb (n,γ) 177Yb (β- decay) 177Lu reaction. The method of SA assessment of a mixture of several radioactive sources was developed for the radioisotope produced in a reactor from different targets. PMID:21248665

  3. Production, biodistribution assessment and dosimetric evaluation of 177Lu-TTHMP as an agent for bone pain palliation

    PubMed Central

    Zolghadri, Samaneh; Yousefnia, Hassan; Jalilian, Amir Reza; Ghannadi-Maragheh, Mohammad

    2015-01-01

    Objective(s): Recently, bone-avid radiopharmaceuticals have been shown to have potential benefits for the treatment of widespread bone metastases. Although 177Lu-triethylene tetramine hexa methylene phosphonic acid (abbreviated as 177Lu-TTHMP), as an agent for bone pain palliation, has been evaluated in previous studies, there are large discrepancies between the obtained results. In this study, production, quality control, biodistribution, and dose evaluation of 177Lu-TTHMP have been investigated and compared with the previously reported data. Methods: TTHMP was synthesized and characterized, using spectroscopic methods. Radiochemical purity of the 177Lu-TTHMP complex was determined using instant thin-layer chromatography (ITLC) and high performance liquid chromatography (HPLC) methods. The complex was injected to wild-type rats and biodistribution was studied for 7 days. Preliminary dose evaluation was investigated based on biodistribution data in rats. Results: 177Lu was prepared with 2.6-3 GBq/mg specific activity and radionuclide purity of 99.98%. 177Lu-TTHMP was successfully prepared with high radiochemical purity (>99%). The complex showed rapid bone uptake, while accumulation in other organs was insignificant. Dosimetric results showed that all tissues received almost insignificant absorbed doses in comparison with bone tissues. Conclusion: Based on the obtained results, this radiopharmaceutical can be a good candidate for bone pain palliation therapy in skeletal metastases.

  4. The use of (68)Ga DOTATATE PET/CT for diagnostic assessment and monitoring of (177)Lu DOTATATE therapy in pituitary carcinoma.

    PubMed

    Novruzov, Fuad; Aliyev, Jamil A; Jaunmuktane, Zane; Bomanji, Jamshed B; Kayani, Irfan

    2015-01-01

    A 68-year-old man, with a history of pituitary surgery and radiation therapy for pituitary macroadenoma 20 years earlier, presented with a pituitary mass and enlarging lesions within the posterior fossa and spinal canal. Biopsy revealed low-grade pituitary carcinoma. PET/CT scan showed multiple foci of increased Ga DOTATATE activity including pituitary and posterior fossa lesions. After 3 fractions of Lu DOTATATE therapy, the tumor remained stable over 4 years on MRI and Ga DOTATATE scans. This case illustrates the benefit of Ga DOTATATE PET/CT in malignant pituitary disease to assess potential for somatostatin receptor therapy with Lu DOTATATE and monitor treatment. PMID:25275413

  5. 68Ga-DOTA-NOC PET and peptide receptor radionuclide therapy in management of bilateral ovarian metastases from gastrointestinal carcinoid.

    PubMed

    Singla, Suhas; Gupta, Santosh; Reddy, Rama Mohan; Durgapal, Prashant; Bal, C S

    2012-12-01

    The management of neuroendocrine tumours is challenging when curative surgery is ruled out because of distant metastases. We report a case of gastrointestinal carcinoid with bilateral ovarian metastases in a 50-year-old female who received octreotide therapy followed by peptide receptor radionuclide therapy and surgery thereafter. Somatostatin receptor expression on neuroendocrine tumours has implications in diagnosis and therapy. (68)Ga-DOTA-NOC PET is a recent advancement in the field of somatostatin receptor imaging. The lesions which demonstrate tracer uptake on positron emission tomographic studies can be further planned for treatment with octreotide and (177)Lu-DOTA-TATE. The case in discussion responded well to non-invasive treatment options before proceeding to definitive surgical management. PMID:23107835

  6. Gamma camera calibration and validation for quantitative SPECT imaging with (177)Lu.

    PubMed

    D'Arienzo, M; Cazzato, M; Cozzella, M L; Cox, M; D'Andrea, M; Fazio, A; Fenwick, A; Iaccarino, G; Johansson, L; Strigari, L; Ungania, S; De Felice, P

    2016-06-01

    Over the last years (177)Lu has received considerable attention from the clinical nuclear medicine community thanks to its wide range of applications in molecular radiotherapy, especially in peptide-receptor radionuclide therapy (PRRT). In addition to short-range beta particles, (177)Lu emits low energy gamma radiation of 113keV and 208keV that allows gamma camera quantitative imaging. Despite quantitative cancer imaging in molecular radiotherapy having been proven to be a key instrument for the assessment of therapeutic response, at present no general clinically accepted quantitative imaging protocol exists and absolute quantification studies are usually based on individual initiatives. The aim of this work was to develop and evaluate an approach to gamma camera calibration for absolute quantification in tomographic imaging with (177)Lu. We assessed the gamma camera calibration factors for a Philips IRIX and Philips AXIS gamma camera system using various reference geometries, both in air and in water. Images were corrected for the major effects that contribute to image degradation, i.e. attenuation, scatter and dead- time. We validated our method in non-reference geometry using an anthropomorphic torso phantom provided with the liver cavity uniformly filled with (177)LuCl3. Our results showed that calibration factors depend on the particular reference condition. In general, acquisitions performed with the IRIX gamma camera provided good results at 208keV, with agreement within 5% for all geometries. The use of a Jaszczak 16mL hollow sphere in water provided calibration factors capable of recovering the activity in anthropomorphic geometry within 1% for the 208keV peak, for both gamma cameras. The point source provided the poorest results, most likely because scatter and attenuation correction are not incorporated in the calibration factor. However, for both gamma cameras all geometries provided calibration factors capable of recovering the activity in

  7. Metastatic Bone Pain Palliation using 177Lu-Ethylenediaminetetramethylene Phosphonic Acid

    PubMed Central

    Alavi, Mehrosadat; Omidvari, Shapour; Mehdizadeh, Alireza; Jalilian, Amir R.; Bahrami-Samani, Ali

    2015-01-01

    177Lu-ethylenediaminetetramethylene phosphonic acid (EDTMP) is presently suggested as an excellent bone seeking radionuclide for developing metastatic bone pain (MBP) palliation agent owing to its suitable nuclear decay characteristics. To find the exact dosage and its efficiency, this clinical study was performed on the human being, using 177Lu-EDTMP for MBP palliation. 177Lu-EDTMP was prepared by Iran, atomic energy organization. Thirty consecutive patients with determined tumors, incontrollable MBP, and positive bone scan at 4 weeks before the beginning of the study participated in this study in the nuclear medicine ward. 177Lu-EDTMP in the form of sterile slow IV injection was administered with a dose of 29.6 MBq/kg. Short form of brief pain inventory questionnaire was used to evaluate the efficiency of the intervention. Questionnaires were filled out by an expert nuclear physician every 2 weeks while the cell blood count was also checked every 2 weeks up to 12 weeks for evaluation of bone marrow suppression and hematological toxicity. Furthermore, whole body scan was done at days 1, 3, and 7. Twenty-five patients showed a significant pain relief since 2 weeks after the injection, and continued until the end of the follow up period (12 weeks). There were no significant early complications such as bone marrow suppression, hematological toxicity, and no systemic adverse effects. No complication was observed in renal function. Twenty one patients showed flare phenomenon that was started after the 12.2 ± 1.78 h lasting for 38.4 ± 23.08. Sixteen patients (53%) were completely treated; nine patients (30%) showed a partial response, and five patients (17%) had no response to treatment. Total response to treatment was achieved in 25 patients (83%). At the end of the evaluation, no bone marrow suppression or hematologic toxicity was observed. 177Lu-EDTMP has shown suitable physical and biological properties with good results in long term bone pain relief for patients

  8. Meningiomas: A Comparative Study of 68Ga-DOTATOC, 68Ga-DOTANOC and 68Ga-DOTATATE for Molecular Imaging in Mice

    PubMed Central

    Soto-Montenegro, María Luisa; Peña-Zalbidea, Santiago; Mateos-Pérez, Jose María; Oteo, Marta; Romero, Eduardo; Morcillo, Miguel Ángel; Desco, Manuel

    2014-01-01

    Purpose The goal of this study was to compare the tumor uptake kinetics and diagnostic value of three 68Ga-DOTA-labeled somatostatin analogues (68Ga-DOTATOC, 68Ga-DOTANOC, and 68Ga-DOTATATE) using PET/CT in a murine model with subcutaneous meningioma xenografts. Methods The experiment was performed with 16 male NUDE NU/NU mice bearing xenografts of a human meningioma cell line (CH-157MN). 68Ga-DOTATOC, 68Ga-DOTANOC, and 68Ga-DOTATATE were produced in a FASTLab automated platform. Imaging was performed on an Argus small-animal PET/CT scanner. The SUVmax of the liver and muscle, and the tumor-to-liver (T/L) and tumor-to-muscle (T/M) SUV ratios were computed. Kinetic analysis was performed using Logan graphical analysis for a two-tissue reversible compartmental model, and the volume of distribution (Vt) was determined. Results Hepatic SUVmax and Vt were significantly higher with 68Ga-DOTANOC than with 68Ga-DOTATOC and 68Ga-DOTATATE. No significant differences between tracers were found for SUVmax in tumor or muscle. No differences were found in the T/L SUV ratio between 68Ga-DOTATATE and 68Ga-DOTATOC, both of which had a higher fraction than 68Ga-DOTANOC. The T/M SUV ratio was significantly higher with 68Ga-DOTATATE than with 68Ga-DOTATOC and 68Ga-DOTANOC. The Vt for tumor was higher with 68Ga-DOTATATE than with 68Ga-DOTANOC and relatively similar to that of 68Ga-DOTATOC. Conclusions This study demonstrates, for the first time, the ability of the three radiolabeled somatostatin analogues tested to image a human meningioma cell line. Although Vt was relatively similar with 68Ga-DOTATATE and 68Ga-DOTATOC, uptake was higher with 68Ga-DOTATATE in the tumor than with 68Ga-DOTANOC and 68Ga-DOTATOC, suggesting a higher diagnostic value of 68Ga-DOTATATE for detecting meningiomas. PMID:25369268

  9. Prospective of 68Ga-Radiopharmaceutical Development

    PubMed Central

    Velikyan, Irina

    2014-01-01

    Positron Emission Tomography (PET) experienced accelerated development and has become an established method for medical research and clinical routine diagnostics on patient individualized basis. Development and availability of new radiopharmaceuticals specific for particular diseases is one of the driving forces of the expansion of clinical PET. The future development of the 68Ga-radiopharmaceuticals must be put in the context of several aspects such as role of PET in nuclear medicine, unmet medical needs, identification of new biomarkers, targets and corresponding ligands, production and availability of 68Ga, automation of the radiopharmaceutical production, progress of positron emission tomography technologies and image analysis methodologies for improved quantitation accuracy, PET radiopharmaceutical regulations as well as advances in radiopharmaceutical chemistry. The review presents the prospects of the 68Ga-based radiopharmaceutical development on the basis of the current status of these aspects as well as wide range and variety of imaging agents. PMID:24396515

  10. 177Lu-labeled HPMA Copolymers Utilizing Cathepsin B and S Cleavable Linkers: Synthesis, Characterization and Preliminary In Vivo Investigation in a Pancreatic Cancer Model

    PubMed Central

    Ogbomo, Sunny M.; Shi, Wen; Wagh, Nilesh K; Zhou, Zhengyuan; Brusnahan, Susan K.; Garrison, Jered C.

    2013-01-01

    Introduction A major barrier to the advancement of therapeutic nanomedicines has been the non-target toxicity caused by the accumulation of the drug delivery systems in organs associated with the reticuloendothelial system, particularly the liver and spleen. Herein, we report the development of peptide based metabolically active linkers (MALs) that are enzymatically cleaved by cysteine cathepsin B and S, two proteases highly expressed in the liver and spleen. The overall goal of this approach is to utilize the MALs to lower the non-target retention and toxicity of radiolabeled drug delivery systems, thus resulting in higher diagnostic and radiotherapeutic efficacy. Methods In this study three MALs (MAL0, MAL1 and MAL2) were investigated. MAL1 and MAL2 are composed of known substrates of cathepsin B and S, respectively, while MAL0 is a non-cleavable control. Both MAL1 and MAL2 were shown to undergo enzymatic cleavage with the appropriate cathepsin protease. Subsequent to conjugation to the HPMA copolymer and radiolabeling with 177Lu, the peptide-polymer conjugates were renamed 177Lu- metabolically active copolymers (177Lu-MACs) with the corresponding designation 177Lu-MAC0, 177Lu-MAC1 and 177Lu-MAC2. Results In vivo evaluation of the 177Lu-MACs was performed in a HPAC human pancreatic cancer xenograft mouse model. 177Lu-MAC1 and 177Lu-MAC2 demonstrated 3.1 and 2.1 fold lower liver retention, respectively, compared to control (177Lu-MAC0) at 72 h post-injection. With regard to spleen retention, 177Lu-MAC1 and 177Lu-MAC2 each exhibited a nearly fourfold lower retention, relative to control, at the 72 h time point. However, the tumor accumulation of the 177Lu-MAC0 was two to three times greater than 177Lu-MAC1 and 177Lu-MAC2 at the same time point. The MAL approach demonstrated the capability of substantially reducing the non-target retention of the 177Lu-labeled HPMA copolymers. Conclusions While further studies are needed to optimize the pharmacokinetics of the 177Lu

  11. 177Lu-DOTA-HH1, a Novel Anti-CD37 Radio-Immunoconjugate: A Study of Toxicity in Nude Mice

    PubMed Central

    Repetto-Llamazares, Ada H. V.; Larsen, Roy H.; Giusti, Anna Maria; Riccardi, Elena; Bruland, Øyvind S.; Selbo, Pål Kristian; Dahle, Jostein

    2014-01-01

    Background CD37 is an internalizing B-cell antigen expressed on Non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia cells (CLL). The anti-CD37 monoclonal antibody HH1 was conjugated to the bifunctional chelator p-SCN-Bn-DOTA and labelled with the beta-particle emitting radionuclide 177Lu creating the radio-immunoconjugate (RIC) 177Lu-DOTA-HH1 (177Lu-HH1, trade name Betalutin). The present toxicity study was performed prior to initiation of clinical studieswith 177Lu-HH1. Methodology/Principal Findings Nude mice with or without tumor xenografts were treated with 50 to 1000 MBq/kg 177Lu- HH1 and followed for clinical signs of toxicity up to ten months. Acute, life threatening bone marrow toxicity was observed in animals receiving 800 and 1000 MBq/kg 177Lu-HH1. Significant changes in serum concentrations of liver enzymes were evident for treatment with 1000 MBq/kg 177Lu-HH1. Lymphoid depletion, liver necrosis and atrophy, and interstitial cell hyperplasia of the ovaries were also observed for mice in this dose group. Conclusions/Significance 177Lu-DOTA-HH1 was well tolerated at dosages about 10 times above those considered relevant for radioimmunotherapy in patients with B-cell derived malignancies.The toxicity profile was as expected for RICs. Our experimental results have paved the way for clinical evaluation of 177Lu-HH1 in NHL patients. PMID:25068508

  12. Improving quantitative dosimetry in 177Lu-DOTATATE SPECT by energy window-based scatter corrections

    PubMed Central

    Lagerburg, Vera; Klausen, Thomas L.; Holm, Søren

    2014-01-01

    Purpose Patient-specific dosimetry of lutetium-177 (177Lu)-DOTATATE treatment in neuroendocrine tumours is important, because uptake differs across patients. Single photon emission computer tomography (SPECT)-based dosimetry requires a conversion factor between the obtained counts and the activity, which depends on the collimator type, the utilized energy windows and the applied scatter correction techniques. In this study, energy window subtraction-based scatter correction methods are compared experimentally and quantitatively. Materials and methods 177Lu SPECT images of a phantom with known activity concentration ratio between the uniform background and filled hollow spheres were acquired for three different collimators: low-energy high resolution (LEHR), low-energy general purpose (LEGP) and medium-energy general purpose (MEGP). Counts were collected in several energy windows, and scatter correction was performed by applying different methods such as effective scatter source estimation (ESSE), triple-energy and dual-energy window, double-photopeak window and downscatter correction. The intensity ratio between the spheres and the background was measured and corrected for the partial volume effect and used to compare the performance of the methods. Results Low-energy collimators combined with 208 keV energy windows give rise to artefacts. For the 113 keV energy window, large differences were observed in the ratios for the spheres. For MEGP collimators with the ESSE correction technique, the measured ratio was close to the real ratio, and the differences between spheres were small. Conclusion For quantitative 177Lu imaging MEGP collimators are advised. Both energy peaks can be utilized when the ESSE correction technique is applied. The difference between the calculated and the real ratio is less than 10% for both energy windows. PMID:24525900

  13. Development of (177)Lu-DOTA-Dendrimer and Determination of Its Effect on Metal and Ion Levels in Tumor Tissue.

    PubMed

    Kovacs, Luciana; Tassano, Marcos; Cabrera, Mirel; Zamboni, Cibele B; Fernández, Marcelo; Anjos, Roberto M; Cabral, Pablo

    2015-12-01

    Dendrimers are synthetic nanomolecules with well-defined chemical structures. Different strategies have been used for radiolabeling dendrimers with different radioisotopes. In this study, the aim was to conjugate dendrimers with (177)Lu, to observe the in vivo behavior of the labeled compound and to measure the elementary changes in tumor tissue that could be caused by ionizing radiation. PAMAM G4 dendrimers conjugated with DOTA were labeled with (177)Lu. The radiolabeled compound was characterized and its stability was evaluated by reverse phase high performance liquid chromatography. Radiolabeling yield was >98% and stable for 24 hours. Biodistribution studies of (177)Lu-DOTA-dendrimers in C57BL/6 melanoma-bearing mice showed blood clearance with hepatic and renal depuration and tumor uptake. The concentrations of Br, Ca, Cl, Fe, K, Mg, Na, Rb, S, and Zn were determined in tumor tissues of C57BL/6 mice treated with (177)Lu-DOTA-dendrimers and in untreated mice. The results showed decreased concentrations of Br (62%), Ca (24%), Cl (51%), K (12%) and Na (60%) and increased concentrations of Fe (8%), Mg (28%), Rb (100%), S (6%) and Zn (4%) in tumor tissues of mice treated with (177)Lu-DOTA-dendrimers. These data may be useful to evaluate changes in tumor tissues as indicators of damage that could be caused by ionizing radiation. PMID:26625257

  14. H4octapa-Trastuzumab: Versatile Acyclic Chelate System for 111In and 177Lu Imaging and Therapy

    PubMed Central

    Price, Eric W.; Zeglis, Brian M.; Cawthray, Jacqueline F.; Ramogida, Caterina F.; Ramos, Nicholas

    2013-01-01

    A bifunctional derivative of the versatile acyclic chelator H4octapa, p-SCNBn- H4octapa, has been synthesized for the first time. The chelator was conjugated to the HER2/neu-targeting antibody trastuzumab and labeled in high radiochemical purity and specific activity with the radioisotopes 111In and 177Lu. The in vivo behavior of the resulting radioimmunoconjugates was investigated in mice bearing ovarian cancer xenografts and compared to analogous radioimmunoconjugates employing the ubiquitous chelator DOTA. The H4octapa-trastuzumab conjugates displayed faster radiolabeling kinetics with more reproducible yields under milder conditions (15 min, RT, ~94–95%) than those based on DOTA-trastuzumab (60 min, 37 °C ~50–88%). Further, antibody integrity was better preserved in the 111In- and 177Lu-octapatrastuzumab constructs, with immunoreactive fractions of 0.99 for each compared to 0.93–0.95 for 111In- and 177Lu-DOTA-trastuzumab. These results translated to improved in vivo biodistribution profiles and SPECT imaging results for 111In- and 177Lu-octapa-trastuzumab compared to 111In- and 177Lu-DOTA-trastuzumab, with increased tumor uptake and higher tumor-to-tissue activity ratios. PMID:23901833

  15. Evaluation of (177)Lu-CHX-A''-DTPA-Bevacizumab as a radioimmunotherapy agent targeting VEGF expressing cancers.

    PubMed

    Kameswaran, Mythili; Pandey, Usha; Gamre, Naresh; Vimalnath, K V; Sarma, Haladhar Dev; Dash, Ashutosh

    2016-08-01

    This study aimed at the preparation and evaluation of (177)Lu-CHX-A''-DTPA-Bevacizumab for targeting VEGF over-expressing cancers. Bevacizumab conjugated to p-NCS-Bn-CHX-A''-DTPA was radiolabeled with (177)Lu. The radioimmunoconjugate characterized by SE-HPLC exhibited radiochemical purity of 98.0±0.6%. In vitro stability was retained upto 4 days at 37°C. In vitro cell binding studies showed good uptake by VEGF expressing U937 tumor cells. Biodistribution studies in melanoma model showed significant uptake and retention of (177)Lu-CHX-A''-DTPA-Bevacizumab in tumor with reduction in uptake in presence of cold Bevacizumab confirming its specificity to VEGF. PMID:27258216

  16. Uncertainty propagation for SPECT/CT-based renal dosimetry in (177)Lu peptide receptor radionuclide therapy.

    PubMed

    Gustafsson, Johan; Brolin, Gustav; Cox, Maurice; Ljungberg, Michael; Johansson, Lena; Gleisner, Katarina Sjögreen

    2015-11-01

    A computer model of a patient-specific clinical (177)Lu-DOTATATE therapy dosimetry system is constructed and used for investigating the variability of renal absorbed dose and biologically effective dose (BED) estimates. As patient models, three anthropomorphic computer phantoms coupled to a pharmacokinetic model of (177)Lu-DOTATATE are used. Aspects included in the dosimetry-process model are the gamma-camera calibration via measurement of the system sensitivity, selection of imaging time points, generation of mass-density maps from CT, SPECT imaging, volume-of-interest delineation, calculation of absorbed-dose rate via a combination of local energy deposition for electrons and Monte Carlo simulations of photons, curve fitting and integration to absorbed dose and BED. By introducing variabilities in these steps the combined uncertainty in the output quantity is determined. The importance of different sources of uncertainty is assessed by observing the decrease in standard deviation when removing a particular source. The obtained absorbed dose and BED standard deviations are approximately 6% and slightly higher if considering the root mean square error. The most important sources of variability are the compensation for partial volume effects via a recovery coefficient and the gamma-camera calibration via the system sensitivity. PMID:26458139

  17. Uncertainty propagation for SPECT/CT-based renal dosimetry in 177Lu peptide receptor radionuclide therapy

    NASA Astrophysics Data System (ADS)

    Gustafsson, Johan; Brolin, Gustav; Cox, Maurice; Ljungberg, Michael; Johansson, Lena; Sjögreen Gleisner, Katarina

    2015-11-01

    A computer model of a patient-specific clinical 177Lu-DOTATATE therapy dosimetry system is constructed and used for investigating the variability of renal absorbed dose and biologically effective dose (BED) estimates. As patient models, three anthropomorphic computer phantoms coupled to a pharmacokinetic model of 177Lu-DOTATATE are used. Aspects included in the dosimetry-process model are the gamma-camera calibration via measurement of the system sensitivity, selection of imaging time points, generation of mass-density maps from CT, SPECT imaging, volume-of-interest delineation, calculation of absorbed-dose rate via a combination of local energy deposition for electrons and Monte Carlo simulations of photons, curve fitting and integration to absorbed dose and BED. By introducing variabilities in these steps the combined uncertainty in the output quantity is determined. The importance of different sources of uncertainty is assessed by observing the decrease in standard deviation when removing a particular source. The obtained absorbed dose and BED standard deviations are approximately 6% and slightly higher if considering the root mean square error. The most important sources of variability are the compensation for partial volume effects via a recovery coefficient and the gamma-camera calibration via the system sensitivity.

  18. Complete Resolution of Neuroendocrine Tumor Soft Tissue Metastases After 177Lu DOTATATE PRRT Induction and Maintenance Therapy.

    PubMed

    Makis, William; McCann, Karey; Buteau, Francois A; McEwan, Alexander J B

    2015-08-01

    A 60-year-old woman diagnosed with a well-differentiated neuroendocrine tumor metastatic to the liver and lymph nodes was treated with 4 induction cycles and 2 maintenance cycles of (177)Lu [DOTA,(0)Tyr(3)]octreotate (DOTATATE) peptide receptor radionuclide therapy. Her posttreatment imaging showed partial response after 4 induction cycles and complete response after 2 additional maintenance cycles. This case highlights the need for further research into maintenance (177)Lu DOTATATE therapy to improve outcomes in neuroendocrine tumor patients. PMID:25546219

  19. Therapeutic efficacy of 177Lu-CHX-A″-DTPA-hu3S193 radioimmunotherapy in prostate cancer is enhanced by EGFR inhibition or docetaxel chemotherapy

    PubMed Central

    Kelly, Marcus P; Lee, Sze Ting; Lee, F-T; Smyth, Fiona E; Davis, Ian D.; Brechbiel, Martin W; Scott, Andrew M

    2008-01-01

    Background This study investigated the biodistribution and therapeutic efficacy of Lutetium-177 (177Lu) radiolabeled anti-Lewis Y monoclonal antibody hu3S193 radioimmunotherapy (RIT) in mice bearing prostate cancer xenografts. The ability of Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitor AG1478 and docetaxel chemotherapy to enhance the efficacy of RIT was also assessed in vivo. Methods The in vitro cytotoxicity of 177Lu labeled hu3S193 on Ley positive DU145 prostate cancer cells was assessed using proliferation assays, with induction of apoptosis measured by ELISA. The in vivo biodistribution and tumor localization of 177Lu-hu3S193 was assessed in mice bearing established DU145 tumor xenografts. The efficacy and maximum tolerated dose of 177Lu-hu3S193 RIT in vivo was determined by a dose escalation study. EGFR inhibitor AG1478 or docetaxel chemotherapy was administered at sub-therapeutic doses in conjunction with RIT in vivo. Results 177Lu-hu3S193 mediated significant induction of cytotoxicity and apoptosis in vitro. In vivo analysis of 177Lu-hu3S193 biodistribution demonstrated specific targeting of DU145 prostate cancer xenografts, with maximal tumor uptake of 33.2 ± 3.9 %ID/g observed at 120 hr post injection. In RIT studies, 177Lu-hu3S193 caused specific and dose-dependent inhibition of prostate cancer tumor growth. A maximum tolerated dose of 350μCi was determined for 177Lu-hu3S193. Combination of 177Lu-hu3S193 RIT with EGFR inhibitor AG1478 or docetaxel chemotherapy both significantly improved efficacy. Conclusions 177Lu-hu3S193 RIT is effective as a single agent in the treatment of Ley positive prostate cancer models. The enhancement of RIT by AG1478 or docetaxel indicates the promise of combined modality strategies. PMID:18942092

  20. Potential Biomarkers for Radiation-Induced Renal Toxicity following 177Lu-Octreotate Administration in Mice

    PubMed Central

    Schüler, Emil; Larsson, Maria; Parris, Toshima Z.; Johansson, Martin E.; Helou, Khalil; Forssell-Aronsson, Eva

    2015-01-01

    The kidneys are one of the main dose-limiting organs in peptide receptor radionuclide therapy and due to large inter-individual variations in renal toxicity, biomarkers are urgently needed in order to optimize therapy and reduce renal tissue damage. The aim of this study was to investigate the transcriptional, functional, and morphological effects on renal tissue after 177Lu-octreotate administration in normal mice, and to identify biomarkers for radiation induced renal toxicity. Methods C57BL/6N mice were i.v. injected with 0, 30, 60, 90, 120, or 150 MBq 177Lu-octreotate (0, 16, 29, 40, 48, and 54 Gy to the kidneys). At 4, 8, and 12 months after administration, radiation-induced effects were evaluated in relation to (a) global transcriptional variations in kidney tissues, (b) morphological changes in the kidneys, (c) changes in white and red blood cell count as well as blood levels of urea, and (d) changes in renal function using 99mTc-DTPA/99mTc-DMSA scintigraphy. Results In general, the highest number of differentially regulated transcripts was observed at 12 months after administration. The Cdkn1a, C3, Dbp, Lcn2, and Per2 genes displayed a distinct dose-dependent regulation, with increased expression level with increasing absorbed dose. Ifng, Tnf, and Il1B were identified as primary up-stream regulators of the recurrently regulated transcripts. Furthermore, previously proposed biomarkers for kidney injury and radiation damage were also observed. The functional investigation revealed reduced excretion of 99mTc-DTPA after 150 MBq, an increased uptake of 99mTc-DMSA at all dose levels compared with the controls, and markedly increased urea level in blood after 150 MBq at 12 months. Conclusion Distinct dose-response relationships were found for several of the regulated transcripts. The Cdkn1a, Dbp, Lcn2, and Per2 genes are proposed as biomarkers for 177Lu-octreotate exposure of kidney. Correlations to functional and morphological effects further confirm

  1. Evaluation of radiation safety in (177)Lu-PSMA therapy and development of outpatient treatment protocol.

    PubMed

    Demir, Mustafa; Abuqbeitah, Mohammad; Uslu-Beşli, Lebriz; Yıldırım, Özlem; Yeyin, Nami; Çavdar, İffet; Vatankulu, Betül; Gündüz, Hüseyin; Kabasakal, Levent

    2016-06-01

    The aim of this study is to investigate the outpatient treatment protocol and radiation safety of a new-emerging lutetium-177 ((177)Lu) prostate specific membrane antigen (PSMA) therapy. This work analyzed the dose rate of 23 patients treated with 7400 MBq (177)Lu-PSMA at different distances (0, 0.25, 0.50, 1.0 and 2.0 m) and variable time marks (0, 1, 2, 4, 18, 24, 48 and 120 h) after the termination of infusion. Blood samples were withdrawn from 17 patients within the same group at 3, 10, 20, 40, 60 and 90 min and 2, 3, 24 h after termination of infusion. Seven different patients were asked to collect urine for 24 h and a gamma well counter was used for counting samples. Family members were invited to wear an optically stimulated luminescence dosimeter whenever they were in the proximity of the patients up to 4-5 d. The total dose of the medical team including the radiopharmacist, physicist, physician, nurse, and nuclear medicine technologist was estimated by an electronic personnel dosimeter. The finger dose was determined using a ring thermoluminescent dosimeter for the radiopharmacist and nurse. The mean dose rate at 1 m after 4 h and 6 h was 23  ±  6 μSv h(-1) and 15  ±  4 μSv h(-1) respectively. The mean total dose to 23 caregivers was 202.3  ±  42.7 μSv (range: 120-265 μSv). The radiation dose of the nurse and radiopharmacist was 6 and 4 μSv per patient, respectively, whereas the dose of the physicist and physician was 2 μSv. The effective half life of blood distribution and early elimination was 0.4  ±  0.1 h and 5  ±  1 h, respectively. Seven patients excreted a mean of 45% (range: 32%-65%) from the initial activity in 6 h. Our findings demonstrate that (177)Lu-PSMA is a safe treatment modality to be applied as an outpatient protocol, since the dose rate decreases below the determined threshold of  <30 μSv h(-1) after approximately 5 h and degrades to 20 μSv h(-1) after 6

  2. IMPROVED PLANAR KIDNEY ACTIVITY CONCENTRATION ESTIMATE BY THE POSTERIOR VIEW METHOD IN 177LU-DOTATATE TREATMENTS.

    PubMed

    Magnander, Tobias; Svensson, Johanna; Båth, Magnus; Gjertsson, Peter; Bernhardt, Peter

    2016-06-01

    The aims of this study were to determine how different background regions of interest (ROIs) around the kidney represent true background activity in over- and underlying tissues in (177)Lu-DOTA-octreatate ((177)Lu-DOTATATE) treatments and to determine the influence of the background positions on the kidney activity concentration estimates by the conjugate view (ConjV) and posterior view (PostV) methods. The analysis was performed in single-photon emission computed tomography (SPECT) images of 20 patients, acquired 24 h post injection of a (177)Lu-DOTATATE treatment, by a computer algorithm that created planar images from the SPECT data. The ratio between the activity concentration in the background and the true background varied from 0.36 to 2.08 [coefficient of variation (CV) = 25-181 %] and from 0.44 to 1.52 (CV = 16-70 %) for the right and left kidneys, respectively. The activity concentration estimate in the kidneys was most accurate with the PostV method using a background ROI surrounding the whole kidney, and this combination might be an alternative planar method for improved kidney dosimetry in the (177)Lu-DOTATATE treatments. PMID:27012883

  3. IMPROVED PLANAR KIDNEY ACTIVITY CONCENTRATION ESTIMATE BY THE POSTERIOR VIEW METHOD IN 177LU-DOTATATE TREATMENTS

    PubMed Central

    Magnander, Tobias; Svensson, Johanna; Båth, Magnus; Gjertsson, Peter; Bernhardt, Peter

    2016-01-01

    The aims of this study were to determine how different background regions of interest (ROIs) around the kidney represent true background activity in over- and underlying tissues in 177Lu-DOTA-octreatate (177Lu-DOTATATE) treatments and to determine the influence of the background positions on the kidney activity concentration estimates by the conjugate view (ConjV) and posterior view (PostV) methods. The analysis was performed in single-photon emission computed tomography (SPECT) images of 20 patients, acquired 24 h post injection of a 177Lu-DOTATATE treatment, by a computer algorithm that created planar images from the SPECT data. The ratio between the activity concentration in the background and the true background varied from 0.36 to 2.08 [coefficient of variation (CV) = 25–181 %] and from 0.44 to 1.52 (CV = 16–70 %) for the right and left kidneys, respectively. The activity concentration estimate in the kidneys was most accurate with the PostV method using a background ROI surrounding the whole kidney, and this combination might be an alternative planar method for improved kidney dosimetry in the 177Lu-DOTATATE treatments. PMID:27012883

  4. Radiation Nanomedicine for EGFR-Positive Breast Cancer: Panitumumab-Modified Gold Nanoparticles Complexed to the β-Particle-Emitter, (177)Lu.

    PubMed

    Yook, Simmyung; Cai, Zhongli; Lu, Yijie; Winnik, Mitchell A; Pignol, Jean-Philippe; Reilly, Raymond M

    2015-11-01

    Our objective was to construct a novel radiation nanomedicine for treatment of breast cancer (BC) expressing epidermal growth factor receptors (EGFR), particularly triple-negative tumors (TNBC). Gold nanoparticles (AuNP; 30 nm) were modified with polyethylene glycol (PEG) chains (4 kDa) derivatized with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelators for complexing the β-emitter, (177)Lu and with PEG chains (5 kDa) linked to panitumumab for targeting BC cells expressing EGFR. The AuNP were further coated with PEG chains (2 kDa) to stabilize the particles to aggregation. The binding and internalization of EGFR-targeted AuNP ((177)Lu-T-AuNP) into BC cells was studied and compared to nontargeted (177)Lu-NT-AuNP. The cytotoxicity of (177)Lu-T-AuNP and (177)Lu-NT-AuNP was measured in clonogenic assays using BC cells with widely different EGFR densities: MDA-MB-468 (10(6) receptors/cell), MDA-MB-231 (10(5) receptors/cell), and MCF-7 cells (10(4) receptors/cell). Radiation absorbed doses to the cell nucleus of MDA-MB-468 cells were estimated based on subcellular distribution. Darkfield and fluorescence microscopy as well as radioligand binding assays revealed that (177)Lu-T-AuNP were specifically bound by BC cells dependent on their EGFR density whereas the binding and internalization of (177)Lu-NT-AuNP was significantly lower. The affinity of binding of (177)Lu-T-AuNP to MDA-MB-468 cells was reduced by 2-fold compared to (123)I-labeled panitumumab (KD = 1.3 ± 0.2 nM vs 0.7 ± 0.4 nM, respectively). The cytotoxicity of (177)Lu-T-AuNP was dependent on the amount of radioactivity incubated with BC cells, their EGFR density and the radiosensitivity of the cells. The clonogenic survival (CS) of MDA-MB-468 cells overexpressing EGFR was reduced to <0.001% at the highest amount of (177)Lu-T-AuNP tested (4.5 MBq; 6 × 10(11) AuNP per 2.5 × 10(4)-1.2 × 10(5) cells). (177)Lu-T-AuNP were less effective for killing MDA-MB-231 cells or MCF-7 cells with

  5. Anti-EGFRvIII monoclonal antibody armed with 177Lu: in vivo comparison of macrocyclic and acyclic ligands

    PubMed Central

    Hens, Marc; Vaidyanathan, Ganesan; Zhao, Xiao-Guang; Bigner, Darell D.; Zalutsky, Michael R.

    2010-01-01

    Introduction Monoclonal antibody (mAb) L8A4 binds specifically to the epidermal growth factor receptor variant III (EGFRvIII) that is present on gliomas but not normal tissues, and is internalized rapidly after receptor binding. Because of the short range of its β-emissions, labeling this mAb with177Lu would be an attractive approach for the treatment of residual tumor margins remaining after surgical debulking of brain tumors. Materials and Methods L8A4 mAb was labeled with 177Lu using the acyclic ligands [(R)-2-Amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine- pentaacetic acid (CHX-A″-DTPA) and 2-(4-Isothiocyanatobenzyl)-6-methyldiethylene- triaminepentaacetic acid (1B4M-DTPA), and the macrocyclic ligands S-2-(4- Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-tetraacetic acid (C-DOTA) and α-(5-isothiocyanato-2-methoxyphenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid (MeO-DOTA). Paired-label tissue distribution experiments were performed in athymic mice bearing subcutaneous EGFRvIII-expressing U87.)EGFR glioma xenografts over a period of 1 to 8 days to directly compare 177Lu-labeled L8A4 to L8A4 labeled with 125I using N-succinimidyl 4-guanidinomethyl-3-[125I]iodobenzoate ([125I]SGMIB). Results Except with C-DOTA, tumor uptake for the 177Lu-labeled mAb was significantly higher than the co-administered radioiodinated preparation; however, this was also the case for spleen, liver, bone and kidneys. Tumor:normal tissue ratios for 177Lu-1B4M-DTPA-L8A4 and to an even greater extent, 177Lu-MeO-DOTA-L8A4, were higher than those for [125I]SGMIB-L8A4 in most other tissues. Conclusions Tumor and normal tissue distribution patterns for this anti-EGFRvIII mAb were dependent on the nature of the bifunctional chelate used for 177Lu labeling. Optimal results were obtained with 1B4M-DTPA and MeO-DOTA, suggesting no clear advantage for acyclic vs. macrocyclic ligands for this application. PMID:20870149

  6. Targeted Radionuclide Therapy with A 177Lu-labeled Anti-HER2 Nanobody

    PubMed Central

    D'Huyvetter, Matthias; Vincke, Cécile; Xavier, Catarina; Aerts, An; Impens, Nathalie; Baatout, Sarah; De Raeve, Hendrik; Muyldermans, Serge; Caveliers, Vicky; Devoogdt, Nick; Lahoutte, Tony

    2014-01-01

    RIT has become an attractive strategy in cancer treatment, but still faces important drawbacks due to poor tumor penetration and undesirable pharmacokinetics of the targeting vehicles. Smaller radiolabeled antibody fragments and peptides feature highly specific target accumulation, resulting in low accumulation in healthy tissue, except for the kidneys. Nanobodies are the smallest (MW < 15 kDa) functional antigen-binding fragments that are derived from heavy chain-only camelid antibodies. Here, we show that the extend of kidney retention of nanobodies is predominantly dictated by the number of polar residues in the C-terminal amino acid tag. Three nanobodies were produced with different C-terminal amino-acid tag sequences (Myc-His-tagged, His-tagged, and untagged). Dynamic planar imaging of Wistar rats with 111In-DTPA-nanobodies revealed that untagged nanobodies showed a 70 % drop in kidney accumulation compared to Myc-His-tagged nanobodies at 50 min p.i.. In addition, coinfusion of untagged nanobodies with the plasma expander Gelofusin led to a final reduction of 90 %. Similar findings were obtained with different 177Lu-DTPA-2Rs15d nanobody constructs in HER2pos tumor xenografted mice at 1 h p.i.. Kidney accumulation decreased 88 % when comparing Myc-His-tagged to untagged 2Rs15d nanobody, and 95 % with a coinfusion of Gelofusin, without affecting the tumor targeting capacity. Consequently, we identified a generic method to reduce kidney retention of radiolabeled nanobodies. Dosimetry calculations of Gelofusin-coinfused, untagged 177Lu-DTPA-2Rs15d revealed a dose of 0.90 Gy/MBq that was delivered to both tumor and kidneys and extremely low doses to healthy tissues. In a comparative study, 177Lu-DTPA-Trastuzumab supplied 6 times more radiation to the tumor than untagged 177Lu-DTPA-2Rs15d, but concomitantly also a 155, 34, 80, 26 and 4180 fold higher radioactivity burden to lung, liver, spleen, bone and blood. Most importantly, nanobody-based targeted radionuclide

  7. Effect of amplified spontaneous emission on selectivity of laser photoionisation of the 177Lu radioisotope

    NASA Astrophysics Data System (ADS)

    D'yachkov, A. B.; Gorkunov, A. A.; Labozin, A. V.; Mironov, S. M.; Panchenko, V. Ya; Firsov, V. A.; Tsvetkov, G. O.

    2016-06-01

    A significant deselecting effect of amplified spontaneous emission has been observed in the experiments on selective laser photoionisation of the 177Lu radioisotope according to the scheme 5d6s2 2D3/2 → 5d6s6p 4Fo5/2 (18505 cm-1) → 5d6s7s 4D3/2(37194 cm-1) → autoionisation state (53375 cm-1). The effect is conditioned by involvement of non-target isotopes from the lower metastable level 5d6s2 2D5/2(1994 cm-1) into the ionisation process. Spectral filtering of spontaneous emission has allowed us to significantly increase the selectivity of the photoionisation process of the radioisotope and to attain a selectivity value of 105 when using saturating light intensities.

  8. Aminocarboxylate complexes and octreotide complexes with no carrier added 177Lu, 166Ho and 149Pm.

    PubMed

    Li, Wen Ping; Smith, C Jeff; Cutler, Cathy S; Hoffman, Timothy J; Ketring, Alan R; Jurisson, Silvia S

    2003-04-01

    Several aminocarboxylate complexes of the "no carrier added" (NCA) radiolanthanides (149)Pm, (166)Ho and (177)Lu were evaluated using our in vitro hydroxyapatite and serum stability model and in vivo in normal CF-1 mice [10]. The aminocarboxylate chelates evaluated with the NCA radiolanthanides for in vitro stability were EDTA, CDTA, DTPA, MA-DTPA and DOTA. In addition, the NCA radiolanthanide complexes with DTPA-octreotide (DTPA-OCT) were synthesized and evaluated, as a model for a peptide conjugated aminocarboxylate complex. The biodistribution studies of the NCA complexes with DTPA, DOTA and DTPA-OCT showed that the in vitro model correctly predicted the in vivo stability of the radiolanthanide complexes, with Ln-DOTA > Ln-DTPA > Ln-DTPA-OCT. PMID:12745015

  9. Photon strength functions in 177Lu: Study of scissors resonance in high-spin region

    NASA Astrophysics Data System (ADS)

    Bečvář, F.; Krtička, M.; Tomandl, I.; Valenta, S.

    2015-05-01

    The nucleus 177Lu is characteristic by an unusually high value of the thermal-neutron capturing state spin, J = 13/2, and by distinct low-energy rotational bands built on the 7/2+ ground state and the 9/2- level at 150 keV. The γ cascades connecting the capturing state with the members of these bands carry unique information about the role of identical M1 scissors-mode resonances, built according to Brink hypothesis assumingly on each energy level, even in conditions of fast nuclear rotation. With this motivation we measured a set of spectra of two-step γ cascades following the thermal neutron capture in 176Lu. The measurement was performed at neutron beam of the LWR-15 Reactor in Řež. From the analysis of these spectra the common parameters of the scissors resonances were deduced. The obtained results are discussed.

  10. An assessment tumor targeting ability of (177)Lu labeled cyclic CCK analogue peptide by binding with cholecystokinin receptor.

    PubMed

    Cho, Eun-Ha; Lim, Jae Cheong; Lee, So-Young; Jung, Sung-Hee

    2016-07-01

    The cholecystokinin (CCK) receptor is known as a receptor that is overexpressed in many human tumors. The present study was designed to investigate the targeting ability of cyclic CCK analogue in AR42J pancreatic cells. The CCK analogues, DOTA-K(glucose)-Gly-Trp-Nle-Asp-Phe (DOTA-glucose-CCK) and DOTA-Nle-cyclo(Glu-Trp-Nle-Asp-Phe-Lys-NH2) (DOTA-[Nle]-cCCK), were synthesized and radiolabeled with (177)Lu, and competitive binding was evaluated. The binding appearance of synthesized peptide with AR42J cells was evaluated by confocal microscopy. And bio-distribution was performed in AR42J xenografted mice. Synthesized peptides were prepared by a solid phase synthesis method, and their purity was over 98%. DOTA is the chelating agent for (177)Lu-labeling, in which the peptides were radiolabeled with (177)Lu by a high radiolabeling yield. A competitive displacement of (125)I-CCK8 on the AR42J cells revealed that the 50% inhibitory concentration value (IC50) was 12.3 nM of DOTA-glucose-CCK and 1.7 nM of DOTA-[Nle]-cCCK. Radio-labeled peptides were accumulated in AR42J tumor in vivo, and %ID/g of the tumor was 0.4 and 0.9 at 2 h p.i. It was concluded that (177)Lu-DOTA-[Nle]-cCCK has higher binding affinity than (177)Lu-DOTA-glucose-CCK and can be a potential candidate as a targeting modality for a CCK receptor over-expressing tumors. PMID:27430985

  11. The in vivo disposition and in vitro transmembrane transport of two model radiometabolites of DOTA-conjugated receptor-specific peptides labelled with (177) Lu.

    PubMed

    Volková, Marie; Mandíková, Jana; Bárta, Pavel; Navrátilová, Lucie; Lázníčková, Alice; Trejtnar, František

    2015-01-01

    In vivo metabolism of the radiolabelled receptor-specific peptides has been described; however, information regarding the pharmacokinetic behaviour of the degradation products within the body is very scarce. The present study was designed to obtain new knowledge on the disposition and elimination of low-molecular radiometabolites of receptor-specific peptides in the organism and to reveal the potential involvement of selected membrane transport mechanisms in the cellular uptake of radiometabolites, especially in the kidney. The study compared pharmacokinetics of two radiometabolites: a final metabolite of somatostatin analogues, (177)Lu-DOTA-DPhe, and a tripeptide metabolite of (177)Lu-DOTA-minigastrin 11, (177)Lu-DOTA-DGlu-Ala-Tyr. Their pharmacokinetics was compared with that of respective parent (177)Lu-radiopeptide. Both radiometabolites exhibited relative rapid clearing from most body tissues in rats in vivo along with predominant renal excretion. The long-term renal retention of the smaller radiometabolite (177)Lu-DOTA-DPhe was lower than that of (177)Lu-DOTA-DGlu-Ala-Tyr. An uptake of (177)Lu-DOTA-DPhe by human renal influx transporter organic cation transporter 2 was found in vitro in a cellular model. The study brings the first experimental data on the in vivo pharmacokinetics of radiometabolites of receptor-specific somatostatin and gastrin analogues. The found results may indicate a negative correlation between the degree of decomposition of the parent peptide chain and the renal retention of the metabolite. PMID:26526343

  12. Fast voxel-level dosimetry for (177)Lu labelled peptide treatments.

    PubMed

    Hippeläinen, E; Tenhunen, M; Sohlberg, A

    2015-09-01

    In peptide receptor radionuclide therapy (PRRT), voxel-level radiation absorbed dose calculations can be performed using several different methods. Each method has it strengths and weaknesses; however, Monte Carlo (MC) simulation is presently considered the most accurate method at providing absorbed dose distributions. Unfortunately MC simulation is time-consuming and often impractical to carry out in a clinical practice. In this work, a fast semi-Monte Carlo (sMC) absorbed dose calculation method for (177)Lu PRRT dosimetry is presented. The sMC method is based on a local electron absorption assumption and fast photon MC simulations. The sMC method is compared against full MC simulation code built on PENELOPE (vxlPen) using digital phantoms to assess the accuracy of these assumptions.Due to the local electron absorption assumption of sMC, the potential errors in cross-fire dose from electrons and photons emitted by (177)Lu were first evaluated using an ellipsoidal kidney model by comparing vxlPen and sMC. The photon cross-fire dose from background to kidney and kidney to background with varying kidney-to-background activity concentration ratios were calculated. In addition, kidney to kidney photon and electron cross-dose with different kidney to kidney distances were studied. Second, extended cardiac-torso (XCAT) phantoms were created with liver lesions and with realistic activity distributions and tissue densities. The XCAT phantoms were used to simulate SPECT projections and 3D activity distribution images were reconstructed using an OSEM algorithm. Image-based dose rate distributions were calculated using vxlPen and sMC. Total doses and dose rate volume histograms (DrVH) produced by the two methods were compared.The photon cross-fire dose from the kidney increased the background's absorbed dose by 5% or more up to 5.8 cm distance with 20 : 1 kidney to background activity concentration ratio. On the other hand, the photon cross-fire dose from the background to

  13. Fast voxel-level dosimetry for 177Lu labelled peptide treatments

    NASA Astrophysics Data System (ADS)

    Hippeläinen, E.; Tenhunen, M.; Sohlberg, A.

    2015-09-01

    In peptide receptor radionuclide therapy (PRRT), voxel-level radiation absorbed dose calculations can be performed using several different methods. Each method has it strengths and weaknesses; however, Monte Carlo (MC) simulation is presently considered the most accurate method at providing absorbed dose distributions. Unfortunately MC simulation is time-consuming and often impractical to carry out in a clinical practice. In this work, a fast semi-Monte Carlo (sMC) absorbed dose calculation method for 177Lu PRRT dosimetry is presented. The sMC method is based on a local electron absorption assumption and fast photon MC simulations. The sMC method is compared against full MC simulation code built on PENELOPE (vxlPen) using digital phantoms to assess the accuracy of these assumptions. Due to the local electron absorption assumption of sMC, the potential errors in cross-fire dose from electrons and photons emitted by 177Lu were first evaluated using an ellipsoidal kidney model by comparing vxlPen and sMC. The photon cross-fire dose from background to kidney and kidney to background with varying kidney-to-background activity concentration ratios were calculated. In addition, kidney to kidney photon and electron cross-dose with different kidney to kidney distances were studied. Second, extended cardiac-torso (XCAT) phantoms were created with liver lesions and with realistic activity distributions and tissue densities. The XCAT phantoms were used to simulate SPECT projections and 3D activity distribution images were reconstructed using an OSEM algorithm. Image-based dose rate distributions were calculated using vxlPen and sMC. Total doses and dose rate volume histograms (DrVH) produced by the two methods were compared. The photon cross-fire dose from the kidney increased the background’s absorbed dose by 5% or more up to 5.8 cm distance with 20 : 1 kidney to background activity concentration ratio. On the other hand, the photon cross-fire dose from the background to

  14. Formation of medical radioisotopes 111In, 117 m Sn, 124Sb, and 177Lu in photonuclear reactions

    NASA Astrophysics Data System (ADS)

    Danagulyan, A. S.; Hovhannisyan, G. H.; Bakhshiyan, T. M.; Avagyan, R. H.; Avetisyan, A. E.; Kerobyan, I. A.; Dallakyan, R. K.

    2015-06-01

    The possibility of the photonuclear production of radioisotopes 111In, 117 m Sn, 124Sb, and 177Lu is discussed. Reaction yields were measured by the gamma-activation method. The enriched tin isotopes 112, 118Sn and Te and HfO2 of natural isotopic composition were used as targets. The targets were irradiated at the linear electron accelerator of Alikhanian National Science Laboratory (Yerevan) at the energy of 40 MeV. The experimental results obtained in this way reveal that the yield and purity of radioisotopes 111In and 117 mSn are acceptable for their production via photonuclear reactions. Reactions proceeding on targets from Te and HfO2 of natural isotopic composition and leading to the formation of 124Sb and 177Lu have small yields and are hardly appropriate for the photoproduction of these radioisotopes even in the case of enriched targets.

  15. Distinct microRNA Expression Profiles in Mouse Renal Cortical Tissue after 177Lu-octreotate Administration

    PubMed Central

    Schüler, Emil; Parris, Toshima Z.; Helou, Khalil; Forssell-Aronsson, Eva

    2014-01-01

    Aim The aim of this study was to investigate the variation of the miRNA expression levels in normal renal cortical tissue after 177Lu-octreotate administration, a radiopharmaceutical used for treatment of neuroendocrine cancers. Methods Female BALB/c nude mice were i.v. injected with 1.3, 3.6, 14, 45, or 140 MBq 177Lu-octreotate, while control animals received saline. The animals were killed at 24 h after injection and total RNA, including miRNA, was extracted from the renal cortical tissue and hybridized to the Mouse miRNA Oligo chip 4plex to identify differentially regulated miRNAs between exposed and control samples. Results In total, 57 specific miRNAs were differentially regulated in the exposed renal cortical tissues with 1, 29, 21, 27, and 31 miRNAs identified per dose-level (0.13, 0.34, 1.3, 4.3, and 13 Gy, respectively). No miRNAs were commonly regulated at all dose levels. miR-194, miR-107, miR-3090, and miR-3077 were commonly regulated at 0.34, 1.3, 4.3, and 13 Gy. Strong effects on cellular mechanisms ranging from immune response to p53 signaling and cancer-related pathways were observed at the highest absorbed dose. Thirty-nine of the 57 differentially regulated miRNAs identified in the present study have previously been associated with response to ionizing radiation, indicating common radiation responsive pathways. Conclusion In conclusion, the 177Lu-octreotate associated miRNA signatures were generally dose-specific, thereby illustrating transcriptional regulation of radiation responsive miRNAs. Taken together, these results imply the importance of miRNAs in early immunological responses in the kidneys following 177Lu-octreotate administration. PMID:25386939

  16. Pharmacokinetic digital phantoms for accuracy assessment of image-based dosimetry in 177Lu-DOTATATE peptide receptor radionuclide therapy

    NASA Astrophysics Data System (ADS)

    Brolin, Gustav; Gustafsson, Johan; Ljungberg, Michael; Sjögreen Gleisner, Katarina

    2015-08-01

    Patient-specific image-based dosimetry is considered to be a useful tool to limit toxicity associated with peptide receptor radionuclide therapy (PRRT). To facilitate the establishment and reliability of absorbed-dose response relationships, it is essential to assess the accuracy of dosimetry in clinically realistic scenarios. To this end, we developed pharmacokinetic digital phantoms corresponding to patients treated with 177Lu-DOTATATE. Three individual voxel phantoms from the XCAT population were generated and assigned a dynamic activity distribution based on a compartment model for 177Lu-DOTATATE, designed specifically for this purpose. The compartment model was fitted to time-activity data from 10 patients, primarily acquired using quantitative scintillation camera imaging. S values for all phantom source-target combinations were calculated based on Monte-Carlo simulations. Combining the S values and time-activity curves, reference values of the absorbed dose to the phantom kidneys, liver, spleen, tumours and whole-body were calculated. The phantoms were used in a virtual dosimetry study, using Monte-Carlo simulated gamma-camera images and conventional methods for absorbed-dose calculations. The characteristics of the SPECT and WB planar images were found to well represent those of real patient images, capturing the difficulties present in image-based dosimetry. The phantoms are expected to be useful for further studies and optimisation of clinical dosimetry in 177Lu PRRT.

  17. Biokinetics and dosimetry with 177Lu-DOTA-TATE in athymic mice with induced pancreatic malignant tumours

    NASA Astrophysics Data System (ADS)

    Rodríguez-Cortés, J.; de Murphy, C. Arteaga; Ferro-Flores, Ge; Pedraza-López, M.; Murphy-Stack, E.

    Malignant pancreatic tumours induced in athymic mice are a good model for peptide receptor targeted radiotherapy. The objective of this research was to determine biokinetic parameters in mice, in order to estimate the induced pancreatic tumour absorbed doses and to evaluate an `in house' 177Lu-DOTA-TATE radiopharmaceutical as part of preclinical studies for targeted therapy in humans. AR42J murine pancreas cancer cells expressing somatostatin receptors, were implanted in athymic mice (nD22) to obtain biokinetic and dosimetric data of 177Lu-DOTA-TATE. The mean tumour uptake 2 h post injection was 14.76±1.9% I.A./g; kidney and pancreas uptake, at the same time, were 7.27±1.1% I.A./g (1.71±0.90%/organ) and 4.20±0.98% I.A./g (0.42±0.03%/organ), respectively. The mean absorbed dose to tumour, kidney and pancreas was 0.58±0.02 Gy/MBq; 0.23±0.01 Gy/MBq and 0.14±0.01 Gy/MBq, respectively. These studies justify further dosimetric estimations to ensure that 177Lu-DOTA-TATE will act as expected in humans.

  18. Pharmacokinetic digital phantoms for accuracy assessment of image-based dosimetry in (177)Lu-DOTATATE peptide receptor radionuclide therapy.

    PubMed

    Brolin, Gustav; Gustafsson, Johan; Ljungberg, Michael; Gleisner, Katarina Sjögreen

    2015-08-01

    Patient-specific image-based dosimetry is considered to be a useful tool to limit toxicity associated with peptide receptor radionuclide therapy (PRRT). To facilitate the establishment and reliability of absorbed-dose response relationships, it is essential to assess the accuracy of dosimetry in clinically realistic scenarios. To this end, we developed pharmacokinetic digital phantoms corresponding to patients treated with (177)Lu-DOTATATE. Three individual voxel phantoms from the XCAT population were generated and assigned a dynamic activity distribution based on a compartment model for (177)Lu-DOTATATE, designed specifically for this purpose. The compartment model was fitted to time-activity data from 10 patients, primarily acquired using quantitative scintillation camera imaging. S values for all phantom source-target combinations were calculated based on Monte-Carlo simulations. Combining the S values and time-activity curves, reference values of the absorbed dose to the phantom kidneys, liver, spleen, tumours and whole-body were calculated. The phantoms were used in a virtual dosimetry study, using Monte-Carlo simulated gamma-camera images and conventional methods for absorbed-dose calculations. The characteristics of the SPECT and WB planar images were found to well represent those of real patient images, capturing the difficulties present in image-based dosimetry. The phantoms are expected to be useful for further studies and optimisation of clinical dosimetry in (177)Lu PRRT. PMID:26215085

  19. Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE in individuals with neck or mediastinal paraganglioma (PGL).

    PubMed

    Zovato, S; Kumanova, A; Demattè, S; Sansovini, M; Bodei, L; Di Sarra, D; Casagranda, E; Severi, S; Ambrosetti, A; Schiavi, F; Opocher, G; Paganelli, G

    2012-05-01

    Paragangliomas (PGLs) are neuroendocrine tum-ors that arise embryologically from the neural crest. Sympathetic PGLs can be located in the thoracic-abdominal region while parasympathetic PGLs are mainly situated in the head and neck region. Most PGLs are sporadic, but in 30% of cases they are hereditary (associated with mutations of SDHB, SDHC, SDHD, SDHAF2, SDHA, TMEM, MAX, and VHL); they can be classified into 4 different paraganglioma syndromes: PGL1, PGL2, PGL3, and PGL4. Surgery is the treatment of choice for both sympathetic and parasympathetic PGLs. Other types of treatment include medical agents (such as gemcitabine, cisplatin, or sunitinib) and radiotherapy (external-beam radiotherapy or stereotactic surgery). Surgery and radiotherapy, however, can cause important side effects such as vascular complications and peripheral nerve damage (hypoglossal, recurrent laryngeal, glossopharyngeal, and vagus). Another possible treatment option is the use of peptide receptor radionuclide therapy (PRRT), including PRRT with 177Lu-DOTATATE. We studied 4 patients with hereditary nonmetastatic paraganglioma syndrome type 1 (PGL1), with progressive disease, in whom surgical excision was not possible. They were treated with 177Lu-DOTATATE (3-5 cycles) and all had a partial response (PR) or a stable disease (SD) to the treatment. In conclusion, a good alternative treatment when surgical or radiation therapy are contraindicated could be radiometabolic therapy with 177Lu-DOTATATE. PMID:22566197

  20. [177Lu-DOTA]0-D-Phe1-Tyr3-Octreotide (177Lu-DOTATOC) For Peptide Receptor Radiotherapy in Patients with Advanced Neuroendocrine Tumours: A Phase-II Study

    PubMed Central

    Baum, Richard P.; Kluge, Andreas W.; Kulkarni, Harshad; Schorr-Neufing, Ulrike; Niepsch, Karin; Bitterlich, Norman; van Echteld, Cees J.A.

    2016-01-01

    Purpose: To characterise efficacy and safety of 177Lu-DOTATOC as agent for peptide receptor radiotherapy (PRRT) of advanced neuroendocrine tumours (NET). Patients and methods: Fifty-six subjects with metastasized and progressive NET (50% gastroenteral, 26.8% pancreatic, 23.2% other primary sites) treated consecutively with 177Lu-DOTATOC were analysed retrospectively. Subjects were administered 177Lu-DOTATOC (mean 2.1 cycles; range 1-4) as 7.0GBq (median) doses at three-monthly intervals. Efficacy was analysed using CT and/or MRI according to RECIST 1.1 criteria and results were stratified for the number of administered cycles and the primary tumour origin. Results: In the total NET population (A), median progression-free (PFS) and overall survival (OS) were 17.4 and 34.2 months, respectively, assessed in a follow-up time (mean ± SD) of 16.1 ± 12.4 months. In patients receiving more than one cycle, mean follow-up time was 22.4 ± 11.0 months for all NETs (B) and PFS was 32.0 months for all NETs (B), 34.5 months for GEP-NET (C), and 11.9 months for other NETs (D). Objective response rates (Complete/Partial Responses) were 33.9%, 40.6%, 54.2%, and 0% for A, B, C, and D groups, respectively, while disease control rates in the same were 66.1%, 93.8%, 100%, and 75%. Complete responses (16.1%, 18.8% and 25.0% for groups A, B and C) were high, 78% of which were maintained throughout the follow up. There were no serious adverse events. One case of self-limiting grade 3 myelotoxicity was reported. Although 20% of patients had mild renal insufficiency at baseline, there was no evidence of exacerbated or de novo renal toxicity after treatment. Conclusion: 177Lu-DOTATOC is a novel agent for PRRT with major potential to induce objective tumour responses and sustained disease control in progressive neuroendocrine tumours, even when administered in moderate activities. The observed safety profile suggests a particularly favourable therapeutic index, including in patients with

  1. Indirect Production of No Carrier Added (NCA) (177)Lu from Irradiation of Enriched (176)Yb: Options for Ytterbium/Lutetium Separation.

    PubMed

    Dash, Ashutosh; Chakravarty, Rubel; Knapp, Furn F Russ; Pillai, Ambikalmajan M R

    2015-01-01

    This article presents a concise review of the production of no-carrier-added (NCA) (177)Lu by the 'indirect' route by irradiating ytterbium-176 ((176)Yb)-enriched targets. The success of this production method depends on the ability to separate the microscopic amounts of NCA (177)Lu from bulk irradiated ytterbium targets. The presence of Yb(+3) from the target in the final processed (177)Lu will adversely affect the quality of (177)Lu by decreasing the specific activity and competing with Lu(+3) complexation since ytterbium will follow the same coordination chemistry. Ytterbium and lutetium are adjacent members of the lanthanide family with very similar chemical properties which makes the separation of one from the other a challenging task. This review provides a summary of the methods developed for the separation and purification of NCA (177)Lu from neutron irradiated (176)Yb-enriched targets, a critical assessment of recent developments and a discussion of the current status of this (177)Lu production method. PMID:25771377

  2. Semi-automatic 3D-volumetry of liver metastases from neuroendocrine tumors to improve combination therapy with 177Lu-DOTATOC and 90Y-DOTATOC

    PubMed Central

    Cieciera, Matthaeus; Kratochwil, Clemens; Moltz, Jan; Kauczor, Hans-Ulrich; Holland-Letz, Tim; Choyke, Peter; Mier, Walter; Haberkorn, Uwe; Giesel, Frederik L.

    2016-01-01

    PURPOSE Patients with neuroendocrine tumors (NET) often present with disseminated liver metastases and can be treated with a number of different nuclides or nuclide combinations in peptide receptor radionuclide therapy (PRRT) depending on tumor load and lesion diameter. For quantification of disseminated liver lesions, semi-automatic lesion detection is helpful to determine tumor burden and tumor diameter in a time efficient manner. Here, we aimed to evaluate semi-automated measurement of total metastatic burden for therapy stratification. METHODS Nineteen patients with liver metastasized NET underwent contrast-enhanced 1.5 T MRI using gadolinium-ethoxybenzyl diethylenetriaminepentaacetic acid. Liver metastases (n=1537) were segmented using Fraunhofer MEVIS Software for three-dimensional (3D) segmentation. All lesions were stratified according to longest 3D diameter >20 mm or ≤20 mm and relative contribution to tumor load was used for therapy stratification. RESULTS Mean count of lesions ≤20 mm was 67.5 and mean count of lesions >20 mm was 13.4. However, mean contribution to total tumor volume of lesions ≤20 mm was 24%, while contribution of lesions >20 mm was 76%. CONCLUSION Semi-automatic lesion analysis provides useful information about lesion distribution in predominantly liver metastasized NET patients prior to PRRT. As conventional manual lesion measurements are laborious, our study shows this new approach is more efficient and less operator-dependent and may prove to be useful in the decision making process selecting the best combination PRRT in each patient. PMID:27015320

  3. Detailed evaluation of different (68)Ge/(68)Ga generators: an attempt toward achieving efficient (68)Ga radiopharmacy.

    PubMed

    Chakravarty, Rubel; Chakraborty, Sudipta; Ram, Ramu; Vatsa, Rakhee; Bhusari, Priya; Shukla, Jaya; Mittal, B R; Dash, Ashutosh

    2016-03-01

    The present study is aimed at carrying out a comparative performance evaluation of different types of (68)Ge/(68)Ga generators to identify the best choice for use in (68)Ga-radiopharmacy. Over the 1 year period of evaluation, the elution yields from the CeO2-based and SiO2-based (68)Ge/(68) Ga generators remained almost consistent, in contrast to the sharp decrease observed in the elution yields from TiO2 and SnO2-based generators. The level of (68)Ge impurity in (68)Ga eluates from the CeO2 and SiO2-based (68)Ge/(68)Ga generator was always <10(-3)%, while this level increased from 10(-3)% to 10(-1)% in case of TiO2 and SnO2-based generators. The level of chemical impurities in (68)Ga eluates from CeO2 and SiO2-based (68)Ge/(68)Ga generators was negligibly low (<0.1 ppm) in contrast to the significantly higher level (1-20 ppm) of such impurities in eluates from other two generators. As demonstrated by radiolabeling studies carried out using DOTA-coupled dimeric cyclic RGD peptide derivative (DOTA-RGD2), CeO2-PAN and SiO2-based generators are directly amenable for radiopharmaceutical preparation, whereas the other generators can be only used after post-elution purification of (68)Ga eluates. Clinically relevant dose of (68)Ga-DOTA-RGD2 was prepared in a hospital radiopharmacy for non-invasive visualization of tumors in breast cancer patients using positron emission tomography. PMID:26833686

  4. Evaporation-based Ge/.sup.68 Ga Separation

    DOEpatents

    Mirzadeh, Saed; Whipple, Richard E.; Grant, Patrick M.; O'Brien, Jr., Harold A.

    1981-01-01

    Micro concentrations of .sup.68 Ga in secular equilibrium with .sup.68 Ge in strong aqueous HCl solution may readily be separated in ionic form from the .sup.68 Ge for biomedical use by evaporating the solution to dryness and then leaching the .sup.68 Ga from the container walls with dilute aqueous solutions of HCl or NaCl. The chloro-germanide produced during the evaporation may be quantitatively recovered to be used again as a source of .sup.68 Ga. If the solution is distilled to remove any oxidizing agents which may be present as impurities, the separation factor may easily exceed 10.sup.5. The separation is easily completed and the .sup.68 Ga made available in ionic form in 30 minutes or less.

  5. Radiolanthanide-labeled monoclonal antibody CC49 for radioimmunotherapy of cancer: biological comparison of DOTA conjugates and 149Pm, 166Ho, and 177Lu.

    PubMed

    Mohsin, Huma; Jia, Fang; Sivaguru, Geethapriya; Hudson, Michael J; Shelton, Tiffani D; Hoffman, Timothy J; Cutler, Cathy S; Ketring, Alan R; Athey, Phillip S; Simón, Jaime; Frank, R Keith; Jurisson, Silvia S; Lewis, Michael R

    2006-01-01

    The radiolanthanides 149Pm, 166Ho, and 177Lu have decay characteristics suitable for radioimmunotherapy (RIT) of cancer. N-Hydroxysulfosuccinimidyl DOTA (DOTA-OSSu) and methoxy-DOTA (MeO-DOTA) were conjugated to the anti-TAG-72 monoclonal antibody CC49 for radiolabeling with 149Pm, 166Ho, and 177Lu. While both DOTA conjugates could be labeled to high specific activity with 177Lu, MeO-DOTA afforded superior conjugate stability, radiolabeling, and radiochemical purity. Pilot biodistributions in nude mice bearing LS174T human colon carcinoma xenografts demonstrated that MeO-DOTA afforded higher tumor uptake and lower kidney retention of 177Lu than DOTA-OSSu. The in vitro stability of 149Pm-, 166Ho-, and 177Lu-MeO-DOTA-CC49 was evaluated using serum and hydroxyapatite assays. Serum stability of radiolanthanide-labeled MeO-DOTA-CC49 followed a trend based on the coordination energies of the radiometals, with 177Lu showing the highest stability after 96 to 168 h at 37 C. In contrast, MeO-DOTA-CC49 labeled with all three radiolanthanides was >92% stable to hydroxyapatite challenge for 168 h at 37 C. Comprehensive biodistributions of 149Pm-, 166Ho-, and 177Lu-MeO-DOTA-CC49 were obtained in LS174T-bearing nude mice. Maximum tumor uptakes were 100.0% ID/g for 149Pm at 96 h, 69.5% ID/g for 166Ho at 96 h, and 132.4% ID/g for 177Lu at 168 h. Normal organ uptakes were generally low, except in the liver, spleen, and kidney at early time points. By 96 to 168 h postinjection, nontarget organ uptake decreased to approximately 7% ID/g (kidney), 12% ID/g (spleen), and 20% ID/g (liver) for each radiolanthanide. When labeled with 149Pm, 166Ho, and 177Lu, MeO-DOTA-CC49 has potential for RIT of colorectal cancer and other carcinomas. PMID:16536481

  6. Radionuclide therapy of HER2-positive microxenografts using a 177Lu-labeled HER2-specific Affibody molecule.

    PubMed

    Tolmachev, Vladimir; Orlova, Anna; Pehrson, Rikard; Galli, Joakim; Baastrup, Barbro; Andersson, Karl; Sandström, Mattias; Rosik, Daniel; Carlsson, Jörgen; Lundqvist, Hans; Wennborg, Anders; Nilsson, Fredrik Y

    2007-03-15

    A radiolabeled anti-HER2 Affibody molecule (Z(HER2:342)) targets HER2-expressing xenografts with high selectivity and gives good imaging contrast. However, the small size (approximately 7 kDa) results in rapid glomerular filtration and high renal accumulation of radiometals, thus excluding targeted therapy. Here, we report that reversible binding to albumin efficiently reduces the renal excretion and uptake, enabling radiometal-based nuclide therapy. The dimeric Affibody molecule (Z(HER2:342))(2) was fused with an albumin-binding domain (ABD) conjugated with the isothiocyanate derivative of CHX-A''-DTPA and labeled with the low-energy beta-emitter (177)Lu. The obtained conjugate [CHX-A''-DTPA-ABD-(Z(HER2:342))(2)] had a dissociation constant of 18 pmol/L to HER2 and 8.2 and 31 nmol/L for human and murine albumin, respectively. The radiolabeled conjugate displayed specific binding to HER2-expressing cells and good cellular retention in vitro. In vivo, fusion with ABD enabled a 25-fold reduction of renal uptake in comparison with the nonfused dimer molecule (Z(HER2:342))(2). Furthermore, the biodistribution showed high and specific uptake of the conjugate in HER2-expressing tumors. Treatment of SKOV-3 microxenografts (high HER2 expression) with 17 or 22 MBq (177)Lu-CHX-A''-DTPA-ABD-(Z(HER2:342))(2) completely prevented formation of tumors, in contrast to mice given PBS or 22 MBq of a radiolabeled non-HER2-binding Affibody molecule. In LS174T xenografts (low HER2 expression), this treatment resulted in a small but significant increase of the survival time. Thus, fusion with ABD improved the in vivo biodistribution, and the results highlight (177)Lu-CHX-A''-DTPA-ABD-(Z(HER2:342))(2) as a candidate for treatment of disseminated tumors with a high level of HER2 expression. PMID:17363599

  7. MIRD Pamphlet No. 26: Joint EANM/MIRD Guidelines for Quantitative 177Lu SPECT Applied for Dosimetry of Radiopharmaceutical Therapy.

    PubMed

    Ljungberg, Michael; Celler, Anna; Konijnenberg, Mark W; Eckerman, Keith F; Dewaraja, Yuni K; Sjögreen-Gleisner, Katarina; Bolch, Wesley E; Brill, A Bertrand; Fahey, Frederic; Fisher, Darrell R; Hobbs, Robert; Howell, Roger W; Meredith, Ruby F; Sgouros, George; Zanzonico, Pat; Bacher, Klaus; Chiesa, Carlo; Flux, Glenn; Lassmann, Michael; Strigari, Lidia; Walrand, Stephan

    2016-01-01

    The accuracy of absorbed dose calculations in personalized internal radionuclide therapy is directly related to the accuracy of the activity (or activity concentration) estimates obtained at each of the imaging time points. MIRD Pamphlet no. 23 presented a general overview of methods that are required for quantitative SPECT imaging. The present document is next in a series of isotope-specific guidelines and recommendations that follow the general information that was provided in MIRD 23. This paper focuses on (177)Lu (lutetium) and its application in radiopharmaceutical therapy. PMID:26471692

  8. Cyclotron production of (68)Ga via the (68)Zn(p,n)(68)Ga reaction in aqueous solution.

    PubMed

    Pandey, Mukesh K; Byrne, John F; Jiang, Huailei; Packard, Alan B; DeGrado, Timothy R

    2014-01-01

    The objective of the present work is to extend the applicability of the solution target approach to the production of (68)Ga using a low energy cyclotron. Since the developed method does not require solid target infrastructure, it offers a convenient alternative to (68)Ge/(68)Ga generators for the routine production of (68)Ga. A new solution target with enhanced heat exchange capacity was designed and utilized with dual foils of Al (0.20 mm) and Havar (0.038 mm) separated by helium cooling to degrade the proton energy to ~14 MeV. The water-cooled solution target insert was made of Ta and its solution holding capacity (1.6 mL) was reduced to enhance heat transfer. An isotopically enriched (99.23%) 1.7 M solution of (68)Zn nitrate in 0.2 N nitric acid was utilized in a closed target system. After a 30 min irradiation at 20 μA, the target solution was unloaded to a receiving vessel and the target was rinsed with 1.6 mL water, which was combined with the target solution. An automated module was used to pass the solution through a cation-exchange column (AG-50W-X8, 200-400 mesh, hydrogen form) which efficiently trapped zinc and gallium isotopes. (68)Zn was subsequently eluted with 30 mL of 0.5 N HBr formulated in 80% acetone without any measurable loss of (68)Ga. (68)Ga was eluted with 7 mL of 3 N HCl solution with 92-96% elution efficiency. The radionuclidic purity was determined using an HPGe detector. Additionally, ICP-MS was employed to analyze for non-radioactive metal contaminants. The product yield was 192.5 ± 11.0 MBq/μ·h decay-corrected to EOB with a total processing time of 60-80 min. The radionuclidic purity of (68)Ga was found to be >99.9%, with the predominant contaminant being 67Ga. The ICP-MS analysis showed small quantities of Ga, Fe, Cu, Ni and Zn in the final product, with (68)Ga specific activity of 5.20-6.27 GBq/μg. Depending upon the user requirements, (68)Ga production yield can be further enhanced by increasing the (68)Zn concentration in the

  9. Mechanisms of Cell Killing Response from Low Linear Energy Transfer (LET) Radiation Originating from 177Lu Radioimmunotherapy Targeting Disseminated Intraperitoneal Tumor Xenografts

    PubMed Central

    Yong, Kwon Joong; Milenic, Diane E.; Baidoo, Kwamena E.; Brechbiel, Martin W.

    2016-01-01

    Radiolabeled antibodies (mAbs) provide efficient tools for cancer therapy. The combination of low energy β−-emissions (500 keVmax; 130 keVave) along with a γ-emission for imaging makes 177Lu (T1/2 = 6.7 day) a suitable radionuclide for radioimmunotherapy (RIT) of tumor burdens possibly too large to treat with α-particle radiation. RIT with 177Lu-trastuzumab has proven to be effective for treatment of disseminated HER2 positive peritoneal disease in a pre-clinical model. To elucidate mechanisms originating from this RIT therapy at the molecular level, tumor bearing mice (LS-174T intraperitoneal xenografts) were treated with 177Lu-trastuzumab comparatively to animals treated with a non-specific control, 177Lu-HuIgG, and then to prior published results obtained using 212Pb-trastuzumab, an α-particle RIT agent. 177Lu-trastuzumab induced cell death via DNA double strand breaks (DSB), caspase-3 apoptosis, and interfered with DNA-PK expression, which is associated with the repair of DNA non-homologous end joining damage. This contrasts to prior results, wherein 212Pb-trastuzumab was found to down-regulate RAD51, which is involved with homologous recombination DNA damage repair. 177Lu-trastuzumab therapy was associated with significant chromosomal disruption and up-regulation of genes in the apoptotic process. These results suggest an inhibition of the repair mechanism specific to the type of radiation damage being inflicted by either high or low linear energy transfer radiation. Understanding the mechanisms of action of β−- and α-particle RIT comparatively through an in vivo tumor environment offers real information suitable to enhance combination therapy regimens involving α- and β−-particle RIT for the management of intraperitoneal disease. PMID:27196891

  10. Mechanisms of Cell Killing Response from Low Linear Energy Transfer (LET) Radiation Originating from (177)Lu Radioimmunotherapy Targeting Disseminated Intraperitoneal Tumor Xenografts.

    PubMed

    Yong, Kwon Joong; Milenic, Diane E; Baidoo, Kwamena E; Brechbiel, Martin W

    2016-01-01

    Radiolabeled antibodies (mAbs) provide efficient tools for cancer therapy. The combination of low energy β(-)-emissions (500 keVmax; 130 keVave) along with a γ-emission for imaging makes (177)Lu (T1/2 = 6.7 day) a suitable radionuclide for radioimmunotherapy (RIT) of tumor burdens possibly too large to treat with α-particle radiation. RIT with (177)Lu-trastuzumab has proven to be effective for treatment of disseminated HER2 positive peritoneal disease in a pre-clinical model. To elucidate mechanisms originating from this RIT therapy at the molecular level, tumor bearing mice (LS-174T intraperitoneal xenografts) were treated with (177)Lu-trastuzumab comparatively to animals treated with a non-specific control, (177)Lu-HuIgG, and then to prior published results obtained using (212)Pb-trastuzumab, an α-particle RIT agent. (177)Lu-trastuzumab induced cell death via DNA double strand breaks (DSB), caspase-3 apoptosis, and interfered with DNA-PK expression, which is associated with the repair of DNA non-homologous end joining damage. This contrasts to prior results, wherein (212)Pb-trastuzumab was found to down-regulate RAD51, which is involved with homologous recombination DNA damage repair. (177)Lu-trastuzumab therapy was associated with significant chromosomal disruption and up-regulation of genes in the apoptotic process. These results suggest an inhibition of the repair mechanism specific to the type of radiation damage being inflicted by either high or low linear energy transfer radiation. Understanding the mechanisms of action of β(-)- and α-particle RIT comparatively through an in vivo tumor environment offers real information suitable to enhance combination therapy regimens involving α- and β(-)-particle RIT for the management of intraperitoneal disease. PMID:27196891

  11. Pre-Clinical Assessment of 177Lu-Labeled Trastuzumab Targeting HER2 for Treatment and Management of Cancer Patients with Disseminated Intraperitoneal Disease

    PubMed Central

    Ray, Geoffrey L.; Baidoo, Kwamena E.; Keller, Lanea M. M.; Albert, Paul S.; Brechbiel, Martin W.; Milenic, Diane E.

    2011-01-01

    Studies from this laboratory have demonstrated the potential of targeting HER2 for therapeutic and imaging applications with medically relevant radionuclides. To expand the repertoire of trastuzumab as a radioimmunoconjugate (RIC) vector, use of 177Lu was investigated. The combination of a 6.7 d half-life, lower energy β−-emissions (500 keV max; 130 keV ave), and an imagable γ-emission make 177Lu an attractive candidate for radioimmunotherapy (RIT) regimens for treatment of larger tumor burdens not possible with α-particle radiation. Radiolabeling trastuzumab-CHX-A″-DTPA with 177Lu was efficient with a specific binding of 60.8 ± 6.8% with HER2 positive SKOV-3 cells. Direct quantitation of tumor targeting and normal tissue uptake was performed with athymic mice bearing subcutaneous and intraperitoneal LS-174T xenografts; a peak tumor %ID/g of 24.70 ± 10.29 (96 h) and 31.70 ± 16.20 (72 h), respectively, was obtained. Normal tissue uptake of the RIC was minimal. Tumor targeting was also demonstrated by γ-scintigraphy. A therapy study administeringescalating doses of 177Lu-trastuzumab to mice bearing three day LS-174T i.p. xenografts established the effective therapeutic dose of i.p. administered 177Lu-trastuzumab at 375 μCi with a median survival of 124.5 d while a median survival of 10 d was noted for the control (untreated) group. In conclusion, trastuzumab radiolabeled with 177Lu has potential for treatment of disseminated, HER2 positive, peritoneal disease. PMID:22229017

  12. Labeling Internalizing Anti-Epidermal Growth Factor Receptor Variant III Monoclonal Antibody with 177Lu: In Vitro Comparison of Acyclic and Macrocyclic Ligands

    PubMed Central

    Hens, Marc; Vaidyanathan, Ganesan; Welsh, Phil; Zalutsky, Michael R.

    2009-01-01

    Introduction The monoclonal antibody (mAb) L8A4, reactive with the epidermal growth factor receptor variant III (EGFRvIII), internalizes rapidly in glioma cells after receptor binding. Combining this tumor specific mAb with the low energy β-emitter 177Lu would be an attractive approach for brain tumor radioimmunotherapy, provided that trapping of the radionuclide in tumor cells after mAb intracellular processing could be maximized. Materials and Methods L8A4 mAb was labeled with 177Lu using the acyclic ligands [(R)-2-Amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid (CHX-A″-DTPA), 2-(4-Isothiocyanatobenzyl)-diethylenetriaminepenta-acetic acid (pSCN-Bz-DTPA), and 2-(4-Isothiocyanatobenzyl)-6-methyldiethylenetriaminepentaacetic acid (1B4M-DTPA) and the macrocyclic ligands S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-tetraacetic acid (C-DOTA) and α-(5-isothiocyanato-2-methoxyphenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (MeO-DOTA). Paired-label internalization and cellular processing assays were performed on EGFRvIII-expressing U87.ΔEGFR glioma cells over 24-h to directly compare 177Lu-labeled L8A4 to L8A4 labeled with 125I using either Iodogen or N-succinimidyl 4-guanidinomethyl-3-[125I]iodobenzoate ([125I]SGMIB). In order to facilitate comparison of labeling methods, the primary parameter evaluated was the ratio of 177Lu to 125I activity retained in U87.ΔEGFR cells. Results All chelates demonstrated higher retention of internalized activity compared with mAb labeled using Iodogen, with 177Lu/125I ratios of >20 observed for the 3 DTPA chelates at 24 h. When compared to L8A4 labeled using SGMIB, except for MeO-DOTA, internalized activity for 125I was higher than 177Lu from 1–8 h with the opposite behavior observed thereafter. At 24 h, 177Lu/125I ratios were between 1.5 and 3, with higher values observed for the 3 DTPA chelates. Conclusions The nature of the chelate used to label this

  13. Pretargeted Radioimmunotherapy of Prostate Cancer with an Anti-TROP-2×Anti-HSG Bispecific Antibody and a 177Lu-Labeled Peptide

    PubMed Central

    Frielink, Cathelijne; Goldenberg, David M.; Sharkey, Robert M.; Lütje, Susanne; McBride, William J.; Oyen, Wim J.G.; Boerman, Otto C.

    2014-01-01

    Abstract TROP-2 is a pancarcinoma marker that is expressed at high levels in many epithelial cancers, including prostate cancer (PC). The trivalent bispecific antibody TF12 (anti-TROP2×anti-HSG [histamine-succinyl-glycine]) has shown to effectively target PC. In this study, the efficacy of pretargeted radioimmunotherapy (PRIT) with multiple cycles of TF12 and 177Lu-labeled diHSG-peptide (IMP288) in mice with s.c. PC3 tumors was investigated and compared with that of conventional RIT with 177Lu-labeled anti-TROP-2 mAb hRS7. Methods: The potential of one, two, and three cycles of PRIT using the TF12 pretargeted 177Lu-IMP288 (41 MBq per cycle) was determined in mice with s.c. PC3 tumors, and compared with the efficacy and toxicity of RIT with 177Lu-hRS7 dosed at the maximum tolerated dose (11 MBq). Results: PRIT of two and three cycles showed significantly higher median survival (>150 days) compared with PRIT of one cycle of TF12 and 177Lu-IMP288 (111 days, p<0.001) or the controls (76 days, p<0.0001). All mice treated with the mAb 177Lu-hRS7 survived at the end of the experiment (150 days), compared with 80% in the mice that were treated with three cycles of PRIT and 70% in the group that received two cycles of PRIT. Clinically significant hematologic toxicity was found only in the groups that received either three cycles of PRIT (p<0.0009) or RIT (p<0.0001). Conclusions: TROP-2-expressing PC can be targeted efficiently with TF12 and radiolabeled IMP288. 177Lu-IMP288 accumulated rapidly in the tumors. PRIT of multiple cycles inhibited the growth of s.c. PC3 tumors. Clinically relevant hematological toxicity was observed in the group that received three cycles of PRIT; however, conventional RIT with the parent mAb 177Lu-hRS7 was at least as effective with similar toxicity. PMID:25226447

  14. Metastatic Neuroendocrine Tumor with Extensive Bone Marrow Involvement at Diagnosis: Evaluation of Response and Hematological Toxicity Profile of PRRT with (177)Lu-DOTATATE.

    PubMed

    Basu, Sandip; Ranade, Rohit; Thapa, Pradeep

    2016-01-01

    The aim of this study was to evaluate the response and hematological toxicity in peptide receptor radionuclide therapy (PRRT) with lutetium ((177)Lu)-DOTA-octreotate (DOTATATE) in metastatic neuroendocrine tumor (NET) with extensive bone marrow metastasis at the initial diagnosis. A retrospective evaluation was undertaken for this purpose: Patients with NET with extensive diffuse bone marrow involvement at diagnosis who had received at least three cycles of PRRT with (177)Lu-DOTATATE were considered for the analysis. The selected patients were analyzed for the following: (i) Patient and lesional characteristics, (ii) associated metastatic burden, (iii) hematological parameters at diagnosis and during the course of therapy, (iv) response to PRRT (using a 3-parameter assessment: Symptomatic including Karnofsky/Lansky performance score, biochemical finding, and scan finding), (v) dual tracer imaging features [with somatostatin receptor imaging (SRI) and fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT)]. Based on the visual grading, tracer uptake in somatostatin receptor (SSTR)-positive bone marrow lesions were graded by a 4-point scale into four categories (0-III) in comparison with the hepatic uptake on the scan: 0 - no uptake; I - clear focus but less than liver uptake; II - equal to liver uptake; and III - higher than liver uptake]. Hematological toxicity was evaluated using National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 score. A total of five patients (age range: 26-62 years; three males and two females) with diffuse bone marrow involvement at the diagnosis was encountered following analysis of the entire patient population of 250 patients. Based on the site of the primary, three had thoracic NET (two patients bronchial carcinoid and one pulmonary NET) and two gastroenteropancreatic NET (one in the duodenum and one patient of unknown primary with liver metastasis). Associated sites

  15. Metastatic Neuroendocrine Tumor with Extensive Bone Marrow Involvement at Diagnosis: Evaluation of Response and Hematological Toxicity Profile of PRRT with 177Lu-DOTATATE

    PubMed Central

    Basu, Sandip; Ranade, Rohit; Thapa, Pradeep

    2016-01-01

    The aim of this study was to evaluate the response and hematological toxicity in peptide receptor radionuclide therapy (PRRT) with lutetium (177Lu)-DOTA-octreotate (DOTATATE) in metastatic neuroendocrine tumor (NET) with extensive bone marrow metastasis at the initial diagnosis. A retrospective evaluation was undertaken for this purpose: Patients with NET with extensive diffuse bone marrow involvement at diagnosis who had received at least three cycles of PRRT with 177Lu-DOTATATE were considered for the analysis. The selected patients were analyzed for the following: (i) Patient and lesional characteristics, (ii) associated metastatic burden, (iii) hematological parameters at diagnosis and during the course of therapy, (iv) response to PRRT (using a 3-parameter assessment: Symptomatic including Karnofsky/Lansky performance score, biochemical finding, and scan finding), (v) dual tracer imaging features [with somatostatin receptor imaging (SRI) and fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT)]. Based on the visual grading, tracer uptake in somatostatin receptor (SSTR)-positive bone marrow lesions were graded by a 4-point scale into four categories (0-III) in comparison with the hepatic uptake on the scan: 0 - no uptake; I - clear focus but less than liver uptake; II - equal to liver uptake; and III - higher than liver uptake]. Hematological toxicity was evaluated using National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 score. A total of five patients (age range: 26-62 years; three males and two females) with diffuse bone marrow involvement at the diagnosis was encountered following analysis of the entire patient population of 250 patients. Based on the site of the primary, three had thoracic NET (two patients bronchial carcinoid and one pulmonary NET) and two gastroenteropancreatic NET (one in the duodenum and one patient of unknown primary with liver metastasis). Associated sites of

  16. 'Reverse discordance' between 68Ga-DOTA-NOC PET/CT and 177Lu-DOTA-TATE posttherapy scan: the plausible explanations and its implications for high-dose therapy with radiolabeled somatostatin receptor analogs.

    PubMed

    Basu, Sandip; Abhyankar, Amit; Kand, Purushottam; Kumar, Rakesh; Asopa, Ramesh; Rajan, Mysore Govinda Ramakrishna; Nayak, Uday; Shimpi, Hemant; Das, Tapas; Venkatesh, Meera; Chakrabarty, Sudipta; Banerjee, Sharmila

    2011-07-01

    In this technical note, an unusual discordance between diagnostic and posttherapeutic scan resulting from the use of different somatostatin receptor ligands in two settings is described. Such observation, we believe, is multifactorial, but most importantly arises due to different receptor affinity profile of the ligands and different somatostatin receptor subtype expression in different tumors. It is important for the treating physician to be aware of this phenomenon that would aid in improving our understanding of complex ligand-receptor interactions in various somatostatin receptor-positive tumors with its possible implications for therapeutic decision making with radiolabeled somatostatin receptor analogues. PMID:21654355

  17. Radionuclide Therapy of Unresectable Tumors with AvidinOX and (90)Y-biotinDOTA: Tongue Cancer Paradigm.

    PubMed

    Albertoni, Claudio; Leoni, Barbara; Rosi, Antonio; D'Alessio, Valeria; Carollo, Valeria; Spagnoli, Luigi Giusto; van Echteld, Cees; De Santis, Rita

    2015-09-01

    Local treatment of unresectable tumors is challenging, particularly with radioactivity. Current practice relies on external beam irradiation or on a variety of medical devices for brachytherapy. Both approaches proved useful in controlling tumor growth, but are characterized by poor compliance of the patient, significant side-effects, high costs, and technological complexity, which hamper widespread use. The authors recently described a novel form of radionuclide therapy based on the oxidized form of avidin that, chemically reacting with tissue proteins, can secure radioactive biotin within the injected tissue, either when precomplexed or when taken from the blood stream after intravenous administration. AvidinOX-pretargeted (177)Lu-biotinDOTA ((177)Lu-ST2210) is currently under clinical investigation for the treatment of liver oligometastases from colorectal cancer (clinicaltrials.gov/NCT02053324). In the present work, the authors show that injected AvidinOX can link tissues of various natures such as prostate, kidney, breast, or brain and can react by contact with scraped tissues such as skin or urinary bladder. AvidinOX injected into human OSC19 tongue cancer masses orthotopically transplanted in nude mice takes up intravenously administered (90)Y-ST2210, which exerts significant antitumor activity, while preserving the integrity and functionality of the tongue. Present data confirm that AvidinOX-based radionuclide therapy is an innovative and promising approach for the local treatment of inoperable tumors. PMID:26167947

  18. Radionuclide Therapy of Unresectable Tumors with AvidinOX and 90Y-biotinDOTA: Tongue Cancer Paradigm

    PubMed Central

    Albertoni, Claudio; Leoni, Barbara; Rosi, Antonio; D'Alessio, Valeria; Carollo, Valeria; Spagnoli, Luigi Giusto; van Echteld, Cees

    2015-01-01

    Abstract Local treatment of unresectable tumors is challenging, particularly with radioactivity. Current practice relies on external beam irradiation or on a variety of medical devices for brachytherapy. Both approaches proved useful in controlling tumor growth, but are characterized by poor compliance of the patient, significant side-effects, high costs, and technological complexity, which hamper widespread use. The authors recently described a novel form of radionuclide therapy based on the oxidized form of avidin that, chemically reacting with tissue proteins, can secure radioactive biotin within the injected tissue, either when precomplexed or when taken from the blood stream after intravenous administration. AvidinOX-pretargeted 177Lu-biotinDOTA (177Lu-ST2210) is currently under clinical investigation for the treatment of liver oligometastases from colorectal cancer (clinicaltrials.gov/NCT02053324). In the present work, the authors show that injected AvidinOX can link tissues of various natures such as prostate, kidney, breast, or brain and can react by contact with scraped tissues such as skin or urinary bladder. AvidinOX injected into human OSC19 tongue cancer masses orthotopically transplanted in nude mice takes up intravenously administered 90Y-ST2210, which exerts significant antitumor activity, while preserving the integrity and functionality of the tongue. Present data confirm that AvidinOX-based radionuclide therapy is an innovative and promising approach for the local treatment of inoperable tumors. PMID:26167947

  19. 177Lu-DO3A-HSA-Z EGFR:1907: characterization as a potential radiopharmaceutical for radionuclide therapy of EGFR-expressing head and neck carcinomas.

    PubMed

    Hoppmann, Susan; Qi, Shibo; Miao, Zheng; Liu, Hongguang; Jiang, Han; Cutler, Cathy S; Bao, Ande; Cheng, Zhen

    2012-06-01

    Epidermal growth factor receptor 1 (EGFR) is an attractive target for radionuclide therapy of head and neck carcinomas. Affibody molecules against EGFR (Z(EGFR)) show excellent tumor localizations in imaging studies. However, one major drawback is that radiometal-labeled Affibody molecules display extremely high uptakes in the radiosensitive kidneys which may impact their use as radiotherapeutic agents. The purpose of this study is to further explore whether radiometal-labeled human serum albumin (HSA)-Z(EFGR) bioconjugates display desirable profiles for the use in radionuclide therapy of EGFR-positive head and neck carcinomas. The Z(EFGR) analog, Ac-Cys-Z(EGFR:1907), was site-specifically conjugated with HSA. The resulting bioconjugate 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A)-HSA-Z(EGFR:1907) was then radiolabeled with either (64)Cu or (177)Lu and subjected to in vitro cell uptake and internalization studies using the human oral squamous carcinoma cell line SAS. Positron emission tomography (PET), single photon emission computed tomography (SPECT), and biodistribution studies were conducted using SAS-tumor-bearing mice. Cell studies revealed a high (8.43 ± 0.55 % at 4 h) and specific (0.95 ± 0.09 % at 4 h) uptake of (177)Lu-DO3A-HSA-Z(EGFR:1907) as determined by blocking with nonradioactive Z(EGFR:1907). The internalization of (177)Lu-DO3A-HSA-Z(EGFR:1907) was verified in vitro and found to be significantly higher than that of (177)Lu-labeled Z(EFGR) at 2-24 h of incubation. PET and SPECT studies showed good tumor imaging contrasts. The biodistribution of (177)Lu-DO3A-HSA-Z(EGFR:1907) in SAS-tumor-bearing mice displayed high tumor uptake (5.1 ± 0.44 % ID/g) and liver uptake (31.5 ± 7.66 % ID/g) and moderate kidney uptake (8.5 ± 1.08 % ID/g) at 72 h after injection. (177)Lu-DO3A-HSA-Z(EGFR:1907) shows promising in vivo profiles and may be a potential radiopharmaceutical for radionuclide therapy of EGFR-expressing head and neck carcinomas

  20. Preparation and Biological Study of 68Ga-DOTA-alendronate

    PubMed Central

    Fakhari, Ashraf; Jalilian, Amir R.; Johari-Daha, Fariba; Shafiee-Ardestani, Mehdi; Khalaj, Ali

    2016-01-01

    Objective(s): In line with previous research on the development of conjugated bisphosphonate ligands as new bone-avid agents, in this study, DOTA-conjugated alendronate (DOTA-ALN) was synthesized and evaluated after labeling with gallium-68 (68Ga). Methods: DOTA-ALN was synthesized and characterized, followed by 68Ga-DOTA-ALN preparation, using DOTA-ALN and 68GaCl3 (pH: 4-5) at 92-95° C for 10 min. Stability tests, hydroxyapatite assay, partition coefficient calculation, biodistribution studies, and imaging were performed on the developed agent in normal rats. Results: The complex was prepared with high radiochemical purity (>99% as depicted by radio thin-layer chromatography; specific activity: 310-320 GBq/mmol) after solid phase purification and was stabilized for up to 90 min with a log P value of -2.91. Maximum ligand binding (65%) was observed in the presence of 50 mg of hydroxyapatite; a major portion of the activity was excreted through the kidneys. With the exception of excretory organs, gastrointestinal tract organs, including the liver, intestine, and colon, showed significant uptake; however, the bone uptake was low (<1%) at 30 min after the injection. The data were also confirmed by sequential imaging at 30-90 min following the intravenous injection. Conclusion: The high solubility and anionic properties of the complex led to major renal excretion and low hydroxyapatite uptake; therefore, the complex failed to demonstrate bone imaging behaviors. PMID:27408898

  1. Sci—Thur AM: YIS - 03: irtGPUMCD: a new GPU-calculated dosimetry code for {sup 177}Lu-octreotate radionuclide therapy of neuroendocrine tumors

    SciTech Connect

    Montégiani, Jean-François; Gaudin, Émilie; Després, Philippe; Jackson, Price A.; Beauregard, Jean-Mathieu

    2014-08-15

    In peptide receptor radionuclide therapy (PRRT), huge inter-patient variability in absorbed radiation doses per administered activity mandates the utilization of individualized dosimetry to evaluate therapeutic efficacy and toxicity. We created a reliable GPU-calculated dosimetry code (irtGPUMCD) and assessed {sup 177}Lu-octreotate renal dosimetry in eight patients (4 cycles of approximately 7.4 GBq). irtGPUMCD was derived from a brachytherapy dosimetry code (bGPUMCD), which was adapted to {sup 177}Lu PRRT dosimetry. Serial quantitative single-photon emission computed tomography (SPECT) images were obtained from three SPECT/CT acquisitions performed at 4, 24 and 72 hours after {sup 177}Lu-octreotate administration, and registered with non-rigid deformation of CT volumes, to obtain {sup 177}Lu-octreotate 4D quantitative biodistribution. Local energy deposition from the β disintegrations was assumed. Using Monte Carlo gamma photon transportation, irtGPUMCD computed dose rate at each time point. Average kidney absorbed dose was obtained from 1-cm{sup 3} VOI dose rate samples on each cortex, subjected to a biexponential curve fit. Integration of the latter time-dose rate curve yielded the renal absorbed dose. The mean renal dose per administered activity was 0.48 ± 0.13 Gy/GBq (range: 0.30–0.71 Gy/GBq). Comparison to another PRRT dosimetry code (VRAK: Voxelized Registration and Kinetics) showed fair accordance with irtGPUMCD (11.4 ± 6.8 %, range: 3.3–26.2%). These results suggest the possibility to use the irtGPUMCD code in order to personalize administered activity in PRRT. This could allow improving clinical outcomes by maximizing per-cycle tumor doses, without exceeding the tolerable renal dose.

  2. Ectopic Corticotropin-Producing Neuroendocrine Tumor of the Pancreas Treated With 177Lu DOTATATE Induction and Maintenance Peptide Receptor Radionuclide Therapy.

    PubMed

    Makis, William; McCann, Karey; Riauka, Terence A; McEwan, Alexander J B

    2016-01-01

    A 57-year-old woman diagnosed with ectopic Cushing syndrome was found to have a 111In-octreotide-avid corticotropin-producing pancreatic neuroendocrine tumor with liver metastases. She was treated with 4 induction and 4 maintenance cycles of 177Lu-DOTATATE, which normalized her serum corticotropin levels and dramatically reduced the size of the pancreatic primary and liver metastases. PMID:26359569

  3. Long-term evaluation of TiO2-based 68Ge/68Ga generators and optimized automation of [68Ga]DOTATOC radiosynthesis.

    PubMed

    Lin, Mai; Ranganathan, David; Mori, Tetsuya; Hagooly, Aviv; Rossin, Raffaella; Welch, Michael J; Lapi, Suzanne E

    2012-10-01

    Interest in using (68)Ga is rapidly increasing for clinical PET applications due to its favorable imaging characteristics and increased accessibility. The focus of this study was to provide our long-term evaluations of the two TiO(2)-based (68)Ge/(68)Ga generators and develop an optimized automation strategy to synthesize [(68)Ga]DOTATOC by using HEPES as a buffer system. This data will be useful in standardizing the evaluation of (68)Ge/(68)Ga generators and automation strategies to comply with regulatory issues for clinical use. PMID:22897970

  4. Accurate assessment of whole-body retention for PRRT with (177)Lu using paired measurements with external detectors.

    PubMed

    Liu, Boxue; de Blois, Erik; Breeman, Wouter A P; Konijnenberg, Mark W; Wolterbeek, Hubert T; Bode, Peter

    2015-01-01

    The aim of this study was to assess the accuracy of the results of whole-body measurements by comparison with the urine collection method in the PRRT with (177)Lu and furthermore to develop a more accurate method of paired measurements. Excreted samples were collected at given intervals and activities were measured by a dose calibrator. Traditionally, whole-body activities during subsequent measurements are normalized individually to the administered activity. In order to correct for the effects of the activity in the bladder during the baseline measurement before the first voiding and activity redistributions in the patient body during subsequent measurements, a series of paired measurements before and after each voiding were carried out. Time-dependent detector responses at given times were derived and time-activity retentions were then determined. Compared to the results of the urine collection, whole-body activities by traditional whole-body measurements were overestimated by ca. 14% at 1 h after administration and randomly varied from -29% to 49% at 24 h. Measurement uncertainties of whole-body activities were from ± 4% (the coverage factor k=2) at 1 h to >± 20% at 24 h by the urine collection and ± 7% by paired measurements, respectively. Whole-body activities at 1 h by paired measurements were validated using the results by measurements of the collected first urine. The new method of paired measurements has an equivalent measurement accuracy and even better during the later measurements with respect to the urine collection method and therefore can replace urine approach for assessing the time-activity remaining in the patient body. PMID:25771370

  5. Peptide receptor radionuclide therapy (PRRT) with [177Lu-DOTA0,Tyr3]octreotate in combination with RAD001 treatment: further investigations on tumor metastasis and response in the rat pancreatic CA20948 tumor model

    PubMed Central

    2014-01-01

    Background Previously, we reported on the unexpected development of distant metastases in the subcutaneous rat pancreas CA20948 tumor model after 4.5 weeks of treatment with RAD001-only or in combination with [177Lu-DOTA0,Tyr3]octreotate (177Lu-DOTATATE) (Cancer Res. 73:12-8, 2013). Moreover, the combination therapy was less effective compared to 177Lu-DOTATATE-only. In the current study, we address the following questions: (1) Why was the combination therapy less effective? Is 177Lu-DOTATATE tumor uptake affected by pretreatment with RAD001? (2) Could sudden cessation of RAD001 therapy cause the development of distant metastases? (3) Is 177Lu-DOTATATE an effective treatment option for these metastases? Methods Lewis rats (HanHsd or SsNHsd substrain with a slight difference in immune response) bearing subcutaneous CA20948 tumors were treated with either 125 or 275 MBq 177Lu-DOTATATE, RAD001, or their combination. RAD001 was given twice a week for 4.5 or 12 weeks, whereas 177Lu-DOTATATE was given as a single injection. When combined, RAD001 was started either 3 days prior to or 3 days post administration of 177Lu-DOTATATE. SPECT/CT was performed to quantify 177Lu-DOTATATE tumor uptake. Where indicated, primary tumors were surgically removed when tumor size is >6,000 mm3 to enable monitoring for possible metastasis. If metastases were suspected, an 111In-DTPA-octreotide SPECT/CT scan was performed. Seven rats with metastases were treated with 400 MBq 177Lu-DOTATATE. Results Lu-DOTATATE tumor uptake was not significantly affected by RAD001 pretreatment. The occurrence of metastases after RAD001 treatment was not dose dependent in the dose range tested, nor was it related to the duration of RAD001 treatment. In the experiment in which the LEW/SsNsd substrain was used, only 12.5% of RAD001-treated rats showed complete response (CR), compared to 50% tumor regression in the control group. Re-treatment with a high dose of 177Lu-DOTATATE resulted in CR in only two

  6. Comparison between 68Ga-bombesin (68Ga-BZH3) and the cRGD tetramer 68Ga-RGD4 studies in an experimental nude rat model with a neuroendocrine pancreatic tumor cell line

    PubMed Central

    2011-01-01

    Objectives Receptor scintigraphy gains more interest for diagnosis and treatment of tumors, in particular for neuroendocrine tumors (NET). We used a pan-Bombesin analog, the peptide DOTA-PEG2-[D-tyr6, β-Ala11, Thi13, Nle14] BN(6-14) amide (BZH3). BZH3 binds to at least three receptor subtypes: the BB1 (Neuromedin B), BB2 (Gastrin-releasing peptide, GRP), and BB3. Imaging of ανβ3 integrin expression playing an important role in angiogenesis and metastasis was accomplished with a 68Ga-RGD tetramer. The purpose of this study was to investigate the kinetics and to compare both tracers in an experimental NET cell line. Methods This study comprised nine nude rats inoculated with the pancreatic tumor cell line AR42J. Dynamic positron emission tomography (PET) scans using 68Ga-BZH3 and 68Ga-RGD tetramer were performed (68Ga-RGD tetramer: n = 4, 68Ga-BZH3: n = 5). Standardized uptake values (SUVs) were calculated, and a two-tissue compartmental learning-machine model (calculation of K1 - k4 vessel density (VB) and receptor binding potential (RBP)) as well as a non-compartmental model based on the fractal dimension was used for quantitative analysis of both tracers. Multivariate analysis was used to evaluate the kinetic data. Results The PET kinetic parameters showed significant differences when individual parameters were compared between groups. Significant differences were found in FD, VB, K1, and RBP (p = 0.0275, 0.05, 0.05, and 0.0275 respectively). The 56- to 60-min SUV for 68Ga-BZH3, with a range of 0.86 to 1.29 (median, 1.19) was higher than the corresponding value for the 68Ga-RGD tetramer, with a range of 0.78 to 1.31 (median, 0.99). Furthermore, FD, VB, K1, and RBP for 68Ga-BZH3 were generally higher than the corresponding values for the 68Ga-RGD tetramer, whereas k3 was slightly higher for 68Ga-RGD tetramer. Conclusions As a parameter that reflects receptor binding, the increase of K1 for 68Ga-BZH3 indicated higher expression of bombesin receptors than that of

  7. Multimodal Somatostatin Receptor Theranostics Using [(64)Cu]Cu-/[(177)Lu]Lu-DOTA-(Tyr(3))octreotate and AN-238 in a Mouse Pheochromocytoma Model.

    PubMed

    Ullrich, Martin; Bergmann, Ralf; Peitzsch, Mirko; Zenker, Erik F; Cartellieri, Marc; Bachmann, Michael; Ehrhart-Bornstein, Monika; Block, Norman L; Schally, Andrew V; Eisenhofer, Graeme; Bornstein, Stefan R; Pietzsch, Jens; Ziegler, Christian G

    2016-01-01

    Pheochromocytomas and extra-adrenal paragangliomas (PHEO/PGLs) are rare catecholamine-producing chromaffin cell tumors. For metastatic disease, no effective therapy is available. Overexpression of somatostatin type 2 receptors (SSTR2) in PHEO/PGLs promotes interest in applying therapies using somatostatin analogs linked to radionuclides and/or cytotoxic compounds, such as [(177)Lu]Lu-DOTA-(Tyr(3))octreotate (DOTATATE) and AN-238. Systematic evaluation of such therapies for the treatment of PHEO/PGLs requires sophisticated animal models. In this study, the mouse pheochromocytoma (MPC)-mCherry allograft model showed high tumor densities of murine SSTR2 (mSSTR2) and high tumor uptake of [(64)Cu]Cu-DOTATATE. Using tumor sections, we assessed mSSTR2-specific binding of DOTATATE, AN-238, and somatostatin-14. Therapeutic studies showed substantial reduction of tumor growth and tumor-related renal monoamine excretion in tumor-bearing mice after treatment with [(177)Lu]Lu-DOTATATE compared to AN-238 and doxorubicin. Analyses did not show agonist-dependent receptor downregulation after single mSSTR2-targeting therapies. This study demonstrates that the MPC-mCherry model is a uniquely powerful tool for the preclinical evaluation of SSTR2-targeting theranostic applications in vivo. Our findings highlight the therapeutic potential of somatostatin analogs, especially of [(177)Lu]Lu-DOTATATE, for the treatment of metastatic PHEO/PGLs. Repeated treatment cycles, fractionated combinations of SSTR2-targeting radionuclide and cytotoxic therapies, and other adjuvant compounds addressing additional mechanisms may further enhance therapeutic outcome. PMID:27022413

  8. Multimodal Somatostatin Receptor Theranostics Using [64Cu]Cu-/[177Lu]Lu-DOTA-(Tyr3)octreotate and AN-238 in a Mouse Pheochromocytoma Model

    PubMed Central

    Ullrich, Martin; Bergmann, Ralf; Peitzsch, Mirko; Zenker, Erik F.; Cartellieri, Marc; Bachmann, Michael; Ehrhart-Bornstein, Monika; Block, Norman L.; Schally, Andrew V.; Eisenhofer, Graeme; Bornstein, Stefan R.; Pietzsch, Jens; Ziegler, Christian G.

    2016-01-01

    Pheochromocytomas and extra-adrenal paragangliomas (PHEO/PGLs) are rare catecholamine-producing chromaffin cell tumors. For metastatic disease, no effective therapy is available. Overexpression of somatostatin type 2 receptors (SSTR2) in PHEO/PGLs promotes interest in applying therapies using somatostatin analogs linked to radionuclides and/or cytotoxic compounds, such as [177Lu]Lu-DOTA-(Tyr3)octreotate (DOTATATE) and AN-238. Systematic evaluation of such therapies for the treatment of PHEO/PGLs requires sophisticated animal models. In this study, the mouse pheochromocytoma (MPC)-mCherry allograft model showed high tumor densities of murine SSTR2 (mSSTR2) and high tumor uptake of [64Cu]Cu-DOTATATE. Using tumor sections, we assessed mSSTR2-specific binding of DOTATATE, AN-238, and somatostatin-14. Therapeutic studies showed substantial reduction of tumor growth and tumor-related renal monoamine excretion in tumor-bearing mice after treatment with [177Lu]Lu-DOTATATE compared to AN-238 and doxorubicin. Analyses did not show agonist-dependent receptor downregulation after single mSSTR2-targeting therapies. This study demonstrates that the MPC-mCherry model is a uniquely powerful tool for the preclinical evaluation of SSTR2-targeting theranostic applications in vivo. Our findings highlight the therapeutic potential of somatostatin analogs, especially of [177Lu]Lu-DOTATATE, for the treatment of metastatic PHEO/PGLs. Repeated treatment cycles, fractionated combinations of SSTR2-targeting radionuclide and cytotoxic therapies, and other adjuvant compounds addressing additional mechanisms may further enhance therapeutic outcome. PMID:27022413

  9. Inhomogeneous activity distribution of 177Lu-DOTA0-Tyr3-octreotate and effects on somatostatin receptor expression in human carcinoid GOT1 tumors in nude mice.

    PubMed

    Oddstig, Jenny; Bernhardt, Peter; Lizana, Helena; Nilsson, Ola; Ahlman, Håkan; Kölby, Lars; Forssell-Aronsson, Eva

    2012-02-01

    The aim of this study was to investigate the activity distribution in neouroendocrine tumors after diagnostic, or therapeutic, amounts of [(177)Lu-DOTA(0)-Tyr(3)]-octreotate and to investigate how the activity distribution influences the absorbed dose. Furthermore, the activity distribution of a second administration of radiolabeled octreotate was studied. Nude mice with subcutaneously grown human midgut carcinoid (GOT1) were injected intravenously with different amounts of (177)Lu-octreotate. At different time points thereafter (4 h to 13 days), a second injection of [(111)In-DOTA(0)-Tyr(3)]-octreotate was given to estimate the somatostatin receptor (sstr) expression. The activity distribution in the tumors was then determined. Monte Carlo simulations with PENELOPE were performed for dosimetry. Fifty-one out of 58 investigated tumors showed a lower activity concentration in the peripheral part than in the central part of the tumor. The amount of activity injected, or time after administration, did neither influence the relative activity nor the sstr distribution in the tumor. After an initial down-regulation (at 4-24 h), there was an up-regulation of sstr (1.5-2 times, at 7-14 days). Monte Carlo simulations demonstrated an inhomogeneous absorbed dose distribution in the tumor using (177)Lu, with twice as high absorbed dose centrally than peripherally. The high activity concentration centrally and the up-regulation of sstr demonstrated will facilitate fractionated therapy using radiolabeled somatostatin analogues if similar results will be obtained also in patients. The inhomogeneous activity distribution in the tumor has to be taken into account when the absorbed dose distribution in tumor is calculated. PMID:22108870

  10. Metastatic Insulinoma Pancreatic Neuroendocrine Tumor Treated With 177Lu-DOTATATE Induction and Maintenance Peptide Receptor Radionuclide Therapy: A Suggested Protocol.

    PubMed

    Makis, William; McCann, Karey; McEwan, Alexander J B

    2016-01-01

    A 70-year-old woman presented with frequent episodes of hypoglycemia. Imaging revealed a 6-cm pancreatic mass with several liver lesions. The pancreatic mass was resected and confirmed to be a well-differentiated insulinoma. Surgery improved but did not resolve her hypoglycemic episodes, and she was referred for peptide receptor radionuclide therapy with 177Lu-DOTATATE to treat her residual disease. A modified protocol with a continuous IV dextrose infusion was used, and the treatments were well tolerated. After 4 induction and 2 maintenance treatments, her hypoglycemic symptoms resolved completely and her disease stabilized. She has been progression free for 24 months. PMID:26562579

  11. (68) Ga-labeled Ciprofloxacin Conjugates as Radiotracers for Targeting Bacterial Infection.

    PubMed

    Satpati, Drishty; Arjun, Chanda; Krishnamohan, Repaka; Samuel, Grace; Banerjee, Sharmila

    2016-05-01

    With an aim of developing a bacteria-specific molecular imaging agent, ciprofloxacin has been modified with a propylamine spacer and linked to two common bifunctional chelators, p-SCN-Bz-DOTA and p-SCN-Bz-NOTA. The two ciprofloxacin conjugates, CP-PA-SCN-Bz-DOTA (1) and CP-PA-SCN-Bz-NOTA (2), were radiolabeled with (68)Ga in >90% radiochemical yield and were moderately stable in vitro for 4 h. The efficacy of (68)Ga-1 and (68)Ga-2 has been investigated in vitro in Staphylococcus aureus cells where bacterial binding of the radiotracers (0.9-1.0% for (68)Ga-1 and 1.6-2.3% for (68)Ga-2) could not be blocked in the presence of excess amount of unlabeled ciprofloxacin. However, uptake of radiotracers in live bacterial cells was significantly higher (p < 0.01) than that in non-viable bacterial cells. Bacterial infection targeting efficacy of (68)Ga-1 and (68)Ga-2 was tested in vivo in rats where the infected muscle-to-inflamed muscle ((68)Ga-1: 2 ± 0.2, (68)Ga-2: 3 ± 0.5) and infected muscle-to-normal muscle ratios ((68)Ga-1: 3 ± 0.4, (68)Ga-2: 6.6 ± 0.8) were found to improve at 120 min p.i. Fast blood clearance and renal excretion was observed for both the radiotracers. The two (68)Ga-labeled infection targeting radiotracers could discriminate between bacterial infection and inflammation in vivo and are worthy of further detailed investigation as infection imaging agents at the clinical level. PMID:26647765

  12. Preparation and Quality Control of 68Ga-Citrate for PET Applications

    PubMed Central

    Aghanejad, Ayuob; Jalilian, Amir Reza; Ardaneh, Khosro; Bolourinovin, Fatemeh; Yousefnia, Hassan; Samani, Ali Bahrami

    2015-01-01

    Objective(s): In nuclear medicine studies, gallium-68 (8Ga) citrate has been recently known as a suitable infection agent in positron emission tomography (PET). In this study, by applying an in-house produced 68Ge/68Ga generator, a simple technique for the synthesis and quality control of 68Ga-citrate was introduced; followed by preliminary animal studies. Methods: 68GaCl3 eluted from the generator was studied in terms of quality control factors including radiochemical purity (assessed by HPLC and RTLC), chemical purity (assessed by ICP-EOS), radionuclide purity (evaluated by HPGe), and breakthrough. 68Ga-citrate was prepared from eluted 68GaCl3 and sodium citrate under various reaction conditions. Stability of the complex was evaluated in human serum for 2 h at 370C, followed by biodistribution studies in rats for 120 min. Results: 68Ga-citrate was prepared with acceptable radiochemical purity (>97 ITLC and >98% HPLC), specific activity (4-6 GBq/mM), chemical purity (Sn, Fe<0.3 ppm and Zn<0.2 ppm) within 15 min at 500C. The biodistribution of 68Ga-citrate was consistent with former reports up to 120 minutes. Conclusion: This study demonstrated the possible in-house preparation and quality control of 68Ga-citrate, using a commercially available 68Ge/68Ga generator for PET imaging throughout the country. PMID:27408889

  13. Biological comparison of 149Pm-, 166Ho-, and 177Lu-DOTA-biotin pretargeted by CC49 scFv-streptavidin fusion protein in xenograft-bearing nude mice.

    PubMed

    Lewis, Michael R; Zhang, Jiuli; Jia, Fang; Owen, Nellie K; Cutler, Cathy S; Embree, Mary F; Schultz, Jody; Theodore, Louis J; Ketring, Alan R; Jurisson, Silvia S; Axworthy, Donald B

    2004-02-01

    The radiolanthanides (149)Pm, (166)Ho, and (177)Lu possess a range of half-lives and alpha(-) beta(-) energies for targeted radiotherapy of cancer. (149)Pm-, (166)Ho-, and (177)Lu-DOTA-biotin were pretargeted to LS174T colorectal tumors in nude mice with CC49 scFvSA antibody-streptavidin fusion protein. Tumor uptakes of (149)Pm (22.9% ID/g), (166)Ho (30.2% ID/g), and (177)Lu (35.4% ID/g) peaked at 1-4 h. Rapid blood disappearance was accompanied by urinary excretion of 59-66% ID within 1 h. Biodistributions of these agents show promise for pretargeted radioimmunotherapy of cancer. PMID:15013487

  14. Formation of medical radioisotopes {sup 111}In, {sup 117m}Sn, {sup 124}Sb, and {sup 177}Lu in photonuclear reactions

    SciTech Connect

    Danagulyan, A. S.; Hovhannisyan, G. H. Bakhshiyan, T. M.; Avagyan, R. H.; Avetisyan, A. E.; Kerobyan, I. A.; Dallakyan, R. K.

    2015-06-15

    The possibility of the photonuclear production of radioisotopes {sup 111}In, {sup 117m}Sn, {sup 124}Sb, and {sup 177}Lu is discussed. Reaction yields were measured by the gamma-activation method. The enriched tin isotopes {sup 112,} {sup 118}Sn and Te and HfO{sub 2} of natural isotopic composition were used as targets. The targets were irradiated at the linear electron accelerator of Alikhanian National Science Laboratory (Yerevan) at the energy of 40 MeV. The experimental results obtained in this way reveal that the yield and purity of radioisotopes {sup 111}In and {sup 117}mSn are acceptable for their production via photonuclear reactions. Reactions proceeding on targets from Te and HfO{sub 2} of natural isotopic composition and leading to the formation of {sup 124}Sb and {sup 177}Lu have small yields and are hardly appropriate for the photoproduction of these radioisotopes even in the case of enriched targets.

  15. Mono(pyridine-N-oxide) DOTA analog and its G1/G4-PAMAM dendrimer conjugates labeled with 177Lu: radiolabeling and biodistribution studies.

    PubMed

    Laznickova, A; Biricova, V; Laznicek, M; Hermann, P

    2014-02-01

    (177)Lu radiolabeling of the first (G1-) or fourth (G4-) generation polyaminoamide (PAMAM) dendrimer conjugates with DOTA-like bifunctional chelator with one methylenepyridine-N-oxide pendant arm (DO3A-py(NO-C)) stability of the radiolabeled species and their pharmacokinetic characteristics were evaluated in preclinical experiments. The results showed that the G1- and G4-dendrimer conjugates, modified in average with 7.5 or 57 DO3A-py(NO-C) chelating units, respectively, can also be labeled with (177)Lu with a high specific activity and radiochemical purity even at 37 °C. The radiolabeled species were stable for at least 24h. Distribution profile of G1-dendrimer conjugate in organs and tissues of rats was more favorable than that of G4 one. On the other hand, the later dendrimer conjugate bears a substantially higher number of metal chelators per molecule enabling binding of a considerably larger number of radiometals. Our results indicate that an employment of dendrimer-chelate conjugates with bound radiometals might represent a prospective way for radiolabeling of biologically active target-specific macromolecules to obtain markedly high specific activity. PMID:24333746

  16. Microwave-supported preparation of (68)Ga bioconjugates with high specific radioactivity.

    PubMed

    Velikyan, I; Beyer, G J; Långström, B

    2004-01-01

    The generator-produced positron-emitting (68)Ga (T(1/2) = 68 min) is of potential interest for clinical PET. (68)Ga as a metallic cation is suitable for complexation reactions with chelators, naked or conjugated, with peptides or other macromolecules. Large (68)Ga generator eluate volumes, metal traces from the generator column material, or reaction reagents, however, disturb a fast, reliable, and quantitative labeling procedure. In this paper we describe a simple technique, based on anion exchange, aiming first, to increase the (68)Ga concentration, second to purify it from competing impurities, and third to obtain a fast and quantitative (68)Ga-labeled peptide conjugate that can be applied in humans without further purification. Within 5 min one can obtain from the original 6 mL generator eluate a 200 microL (68)Ga preparation (volume reduction by a factor 30) that is suitable for direct and quantitative labeling of peptide conjugates. DOTATOC (DOTA-D-Phe(1)-Tyr(3)-octreotide, DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) was used as a test tracer for comparing the labeling properties of the different (68)Ga preparations. In combination with microwave heating, peptide conjugates of 0.5-1 nmol quantities could be labeled within 10 min with the full (68)Ga activity of a generator. Further purification of the (68)Ga-labeled peptide conjugate was no longer required since the nuclide incorporation was quantitative. The specific radioactivity (with respect to the peptide) was improved by a factor approximately 100 compared to the previously applied techniques using the original generator eluate. The commercial (68)Ge/(68)Ga generator from Obninsk in combination with this system for purification and concentration with an integrated microwave-supported labeling technology resulted in a kitlike technology for (68)Ga-tracer production. The first automated prototype using this technology is being tested. PMID:15149183

  17. Overview and perspectives on automation strategies in (68)Ga radiopharmaceutical preparations.

    PubMed

    Boschi, Stefano; Malizia, Claudio; Lodi, Filippo

    2013-01-01

    The renaissance of (68)Ga radiopharmacy has led to great advances in automation technology. The availability of a highly efficient, reliable, long-lived (68)Ge/(68)Ga generator system along with a well-established coordination chemistry based on bifunctional chelating agents have been the bases of this development in (68)Ga radiopharmacy. Syntheses of (68)Ga peptides were originally performed by manual or semiautomated systems, but increasing clinical demand, radioprotection, and regulatory issues have driven extensive automation of their production process. Several automated systems, based on different post-processing of the (68)Ga generator eluate, on different engineering, and on fixed tubing or disposable cassette approaches, have been developed and are discussed in this chapter. Since automatic systems for preparation of radiopharmaceuticals should comply with qualification and validation protocols established by regulations such as current Good Manufacturing Practices (cGMP) and local regulations, some regulatory issues and the more relevant qualification protocols are also discussed. PMID:22918752

  18. Investigating the Effect of Ligand Amount and Injected Therapeutic Activity: A Simulation Study for 177Lu-Labeled PSMA-Targeting Peptides.

    PubMed

    Kletting, Peter; Schuchardt, Christiane; Kulkarni, Harshad R; Shahinfar, Mostafa; Singh, Aviral; Glatting, Gerhard; Baum, Richard P; Beer, Ambros J

    2016-01-01

    In molecular radiotherapy with 177Lu-labeled prostate specific membrane antigen (PSMA) peptides, kidney and/or salivary glands doses limit the activity which can be administered. The aim of this work was to investigate the effect of the ligand amount and injected activity on the tumor-to-normal tissue biologically effective dose (BED) ratio for 177Lu-labeled PSMA peptides. For this retrospective study, a recently developed physiologically based pharmacokinetic model was adapted for PSMA targeting peptides. General physiological parameters were taken from the literature. Individual parameters were fitted to planar gamma camera measurements (177Lu-PSMA I&T) of five patients with metastasizing prostate cancer. Based on the estimated parameters, the pharmacokinetics of tumor, salivary glands, kidneys, total body and red marrow was simulated and time-integrated activity coefficients were calculated for different peptide amounts. Based on these simulations, the absorbed doses and BEDs for normal tissue and tumor were calculated for all activities leading to a maximal tolerable kidney BED of 10 Gy2.5/cycle, a maximal salivary gland absorbed dose of 7.5 Gy/cycle and a maximal red marrow BED of 0.25 Gy15/cycle. The fits yielded coefficients of determination > 0.85, acceptable relative standard errors and low parameter correlations. All estimated parameters were in a physiologically reasonable range. The amounts (for 25-29 nmol) and pertaining activities leading to a maximal tumor dose, considering the defined maximal tolerable doses to organs of risk, were calculated to be 272±253 nmol (452±420 μg) and 7.3±5.1 GBq. Using the actually injected amount (235±155 μg) and the same maximal tolerable doses, the potential improvement for the tumor BED was 1-3 fold. The results suggest that currently given amounts for therapy are in the appropriate order of magnitude for many lesions. However, for lesions with high binding site density or lower perfusion, optimizing the peptide

  19. Dosimetric evaluation of 153Sm-EDTMP, 177Lu-EDTMP and 166Ho-EDTMP for systemic radiation therapy: Influence of type and energy of radiation and half-life of radionuclides

    NASA Astrophysics Data System (ADS)

    Ranjbar, Hassan; Ghannadi-Maragheh, Mohammad; Bahrami-Samani, Ali; Beiki, Davood

    2015-03-01

    In radiopharmaceutical therapy, delivered doses to critical organs must be below a certain threshold therefore internal radiation dosimetry of radiopharmaceuticals is essential. Advantages and disadvantages of radionuclides with different characteristics were evaluated for selection of appropriate radionuclide. The Monte Carlo MCNPX simulation program was used to obtain radial dose and cumulative dose of 153Sm, 177Lu and 166Ho used in radiotherapy of bone metastases. A cylindrical geometry with constant density materials was supposed for simulation of femur bone. The radius of bone marrow, bone, and surrounding soft tissue was considered 0.6 cm, 1.3 cm and 4 cm, respectively. It was assumed that the radionuclides were uniformly distributed throughout the tumor. "continuous energy spectrum" of beta particle was used instead of mean beta energy. Our simulations show that absorbed dose in target organ (bone) is greater than other organs and 166Ho gives a higher dose to the critical organ of bone marrow than either 153Sm or 177Lu. Absorbed dose versus time demonstrate faster dose delivery for the short half-life radionuclides (153Sm and 166Ho). These results are in good agreement with clinical observations which show a pain relief within 1 week after intravenous administration of 153Sm-EDTMP, whereas it occurs within 2 week in the case of 177Lu-EDTMP. According to the results, combination of different radionuclides with different characteristics such as 153Sm-EDTMP and 177Lu-EDTMP could be more advantageous to patients with painful bone metastasis.

  20. Induction of Anti-Tumor Immune Responses by Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE in a Murine Model of a Human Neuroendocrine Tumor

    PubMed Central

    Wu, Yin; Pfeifer, Andreas Klaus; Myschetzky, Rebecca; Garbyal, Rajendra Singh; Rasmussen, Palle; Knigge, Ulrich; Bzorek, Michael; Kristensen, Michael Holmsgaard; Kjaer, Andreas

    2013-01-01

    Peptide receptor radionuclide therapy (PRRT) is a relatively new mode of internally targeted radiotherapy currently in clinical trials. In PRRT, ionizing radioisotopes conjugated to somatostatin analogues are targeted to neuroendocrine tumors (NETs) via somatostatin receptors. Despite promising clinical results, very little is known about the mechanism of tumor control. By using NCI-H727 cells in an in vivo murine xenograft model of human NETs, we showed that 177Lu-DOTATATE PRRT led to increased infiltration of CD86+ antigen presenting cells into tumor tissue. We also found that following treatment with PRRT, there was significantly increased tumor infiltration by CD49b+/FasL+ NK cells potentially capable of tumor killing. Further investigation into the immunomodulatory effects of PRRT will be essential in improving treatment efficacy. PMID:26824927

  1. An approach for conjugation of 177Lu- DOTA-SCN- Rituximab (BioSim) & its evaluation for radioimmunotherapy of relapsed & refractory B-cell non Hodgkins lymphoma patients

    PubMed Central

    Thakral, Parul; Singla, Suhas; Yadav, Madhav Prasad; Vasisht, Atul; Sharma, Atul; Gupta, Santosh Kumar; Bal, C.S.; Snehlata; Malhotra, Arun

    2014-01-01

    Background & objectives: The prerequisite of radioimmunotherapy is stable binding of a radionuclide to monoclonal antibodies, which are specific to the tumour-associated antigen. Most B-cell lymphomas express CD20 antigen on the surface of the tumour cells, making it a suitable target for therapeutic radioactive monoclonal antibodies. In the present study, the immunoconjugate of biosimilar Rituximab (Reditux™) and macrocyclic chelator, p-SCN-Bz-DOTA, was prepared and radiolabelled with Lutetium-177 followed by quality control procedures. Methods: Rituximab(BioSim) was desalted with sodium bicarbonate (0.1M, pH 9.0) and incubated with DOTA-SCN (1:50). The effectiveness of the conjugation was evaluated by determining the number of chelators per antibody molecule. This conjugate was radiolabelled with Lutetium-177 and purified using PD10 column. The quality control parameters like pH, clarity, radiochemical purity, in vitro stability and sterility were studied. Immunoreactivity of 177Lu-DOTA-Rituximab (BioSim) was assessed using RAMOS cells. The radioimmunoconjugate (RIC) after stringent quality assurance was injected in three patients and the biodistribution profile was analysed. Results: An average of 4.25 ± 1.04 p-SCN-Bz-DOTA molecules could be randomly conjugated to a single molecule of Rituximab (BioSim). The radiochemical purity of the labelled antibody was > 95 per cent with preserved affinity for CD20 antigen. The final preparation was stable up to about 120 h when tested under different conditions. A favourable biodistribution profile was observed with liver showing the maximum uptake of the RIC. Interpretation & conclusions: A favourable radiochemical purity, stability and biodistribution of the radiolabelled immunoconjugate indicate that clinical trials for evaluation of toxicity and efficacy of 177Lu-DOTA-antiCD20 antibody-Rituximab (BioSim) in patients of relapsed and refractory non Hodgkin's lymphoma can be considered. PMID:24927340

  2. (68)Ga-Bivalent Polypegylated Styrylpyridine Conjugates for Imaging Aβ Plaques in Cerebral Amyloid Angiopathy.

    PubMed

    Zha, Zhihao; Song, Jin; Choi, Seok Rye; Wu, Zehui; Ploessl, Karl; Smith, Megan; Kung, Hank

    2016-05-18

    Aβ plaques deposited on blood vessels are associated with cerebral amyloid angiopathy (CAA). In an effort to selectively map these Aβ plaques, we are reporting a new series of (68)Ga labeled styrylpyridine derivatives with high molecular weights. In vitro binding to Aβ plaques in post-mortem Alzheimer's disease (AD) brain tissue showed that these (68)Ga labeled bivalent styrylpyridines displayed good affinities and specificity (Ki < 30 nM). In vitro autoradiography using post-mortem AD brain sections showed specific binding of these (68)Ga complexes to Aβ plaques. Biodistribution studies in normal mice showed very low initial brain uptakes (<0.3% dose/g) indicating a low blood-brain barrier (BBB) penetration. The preliminary results suggest that (68)Ga labeled bivalent styrylpyridines may be promising candidates as PET imaging radiotracers for detecting CAA. PMID:27045547

  3. Investigation of the production of (68)Ga using pre-equilibrium models.

    PubMed

    Baldik, Rıdvan; Dombayci, Ayten

    2016-07-01

    In this study, some nuclear reactions for the production of (68)Ga radioisotope are investigated using pre-equilibrium nuclear reaction models. For this aim, by the pre-equilibrium reaction mechanisms, the excitation functions and emission spectra of some nuclear reactions for the production of (68)Ga radioisotope are calculated. These calculations are performed in the ALICE/ASH and the TALYS 1.6 codes. The obtained results have been discussed and compared with the available experimental results. PMID:27108069

  4. Incidental Detection of Follicular Thyroid Carcinoma in 68Ga-PSMA PET/CT Imaging.

    PubMed

    Sager, Sait; Vatankulu, Betül; Uslu, Lebriz; Sönmezoglu, Kerim

    2016-09-01

    Prostate-specific membrane antigen (PSMA) is a type II transmembrane protein. It has been shown to be expressed in various solid malignant neoplasms. We report a case of a prostate cancer patient who underwent (68)Ga-PSMA PET/CT imaging. There is a large thyroid nodule in the right thyroid gland, which had intense PSMA accumulation. Follicular thyroid lesions can be seen on (68)Ga-PSMA PET/CT imaging. PMID:26966127

  5. (68)Ga-radiopharmaceuticals for PET imaging of infection and inflammation.

    PubMed

    Kumar, Vijay; Boddeti, Dilip K

    2013-01-01

    Infection imaging has been challenging over the past four decades, which provided an excellent playing field for researchers working in this area, and till date the quest continues to find an ideal imaging agent. Labelled leukocytes were first developed in the 1970s for imaging infection lesions such as osteomyelitis, cellulitis, diabetic foot, Crohn's disease, inflammatory bowel disease, fever of unknown origin, etc. Subsequently labelled antibiotics such as (99m)Tc-labelled ciprofloxacin have emerged for directly identifying live bacterial infections. From the early 1970s through the mid-1980s,( 67)Ga-Citrate was the prime radionuclide for imaging of inflammation and infection of musculoskeletal origin. Although (68)Ga-PET was described in 1960s for tumour imaging, recent reports described (68)Ga-Citrate and (68)Ga-transferrin as possible agents for PET-imaging of infection due to successful application of (67)Ga-Citrate SPECT in the past, despite its limitations. It is important to establish a faster imaging method for (68)Ga, as its half-life is 68 min compared to 78.3 hrs for (67)Ga. Preparation of (68)Ga-Citrate and (68)Ga-transferrin is described, with very high yield and high radiochemical purity (RCP), which is ideally suited for routine clinical studies. Biodistribution of (68)Ga-Citrate-PET images were characterised with high blood pool, high liver and bone (growth plate) uptake with low soft-tissue activity. (68)Ga-Citrate or (68)Ga-transferrin was able to detect infected lesions in rats within 5-10 min post injection but a focal intense uptake at the lesion (SUV(max)) was visualized only at 30 min, which increased for up to 6 hrs post injection with concomitant decrease in the cardiac blood pool activity. The liver and bowel activity decreased after 90 min then stabilised. In the patient studies, infection lesions were detected within 30 min post injection of (68)Ga-Citrate. Cardiac blood pool and liver activities decreased during the period of study

  6. 68Ga-PRGD2 PET/CT in the Evaluation of Glioma: A Prospective Study

    PubMed Central

    2015-01-01

    Integrin αvβ3 is overexpressed in both neovasculature and glioma cells. We aimed to evaluate 68gallium-BNOTA-PRGD2 (68Ga-PRGD2) as a new reagent for noninvasive integrin αvβ3 imaging in glioma patients. With informed consent, 12 patients with suspicious brain glioma, as diagnosed by enhanced magnetic resonance imaging (MRI) scanning, were enrolled to undergo 68Ga-PRGD2 PET/CT and 18F-FDG PET/CT scans before surgery. The preoperative images were compared and correlated with the pathologically determined WHO grade. Next, the expression of integrin αvβ3, CD34, and Ki-67 were determined by immunohistochemical staining of the resected brain tumor tissue. Our findings demonstrated that 68Ga-PRGD2 specifically accumulated in the brain tumors that were rich of integrin αvβ3 and other neovasculature markers, but not in the brain parenchyma other than the choroid plexus. Therefore, 68Ga-PRGD2 PET/CT was able to evaluate the glioma demarcation more specifically than 18F-FDG PET/CT. The maximum standardized uptake values (SUVmax) of 68Ga-PRGD2, rather than those of 18F-FDG, were significantly correlated with the glioma grading. The maximum tumor-to-brain ratios (TBRmax) of both tracers were significantly correlated with glioma grading, whereas 68Ga-PRGD2 seemed to be more superior to 18F-FDG in differentiating high-grade glioma (HGG) from low-grade glioma (LGG). Moreover, 68Ga-PRGD2 PET/CT showed different accumulation patterns for HGG of WHO grades III and IV. This is the first noninvasive integrin imaging study, to the best of our knowledge, conducted in preoperative patients with different grades of glioma, and it preliminarily indicated the effectiveness of this novel method for evaluating glioma grading and demarcation. PMID:25093246

  7. (68)Ga-Pentixafor-PET/CT for Imaging of Chemokine Receptor 4 Expression in Glioblastoma.

    PubMed

    Lapa, Constantin; Lückerath, Katharina; Kleinlein, Irene; Monoranu, Camelia Maria; Linsenmann, Thomas; Kessler, Almuth F; Rudelius, Martina; Kropf, Saskia; Buck, Andreas K; Ernestus, Ralf-Ingo; Wester, Hans-Jürgen; Löhr, Mario; Herrmann, Ken

    2016-01-01

    Chemokine receptor-4 (CXCR4) has been reported to be overexpressed in glioblastoma (GBM) and to be associated with poor survival. This study investigated the feasibility of non-invasive CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using the radiolabelled chemokine receptor ligand (68)Ga-Pentixafor. 15 patients with clinical suspicion on primary or recurrent glioblastoma (13 primary, 2 recurrent tumors) underwent (68)Ga-Pentixafor-PET/CT for assessment of CXCR4 expression prior to surgery. O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) PET/CT images were available in 11/15 cases and were compared visually and semi-quantitatively (SUVmax, SUVmean). Tumor-to-background ratios (TBR) were calculated for both PET probes. (68)Ga-Pentixafor-PET/CT results were also compared to histological CXCR4 expression on neuronavigated surgical samples. (68)Ga-Pentixafor-PET/CT was visually positive in 13/15 cases with SUVmean and SUVmax of 3.0±1.5 and 3.9±2.0 respectively. Respective values for (18)F-FET were 4.4±2.0 (SUVmean) and 5.3±2.3 (SUVmax). TBR for SUVmean and SUVmax were higher for (68)Ga-Pentixafor than for (18)F-FET (SUVmean 154.0±90.7 vs. 4.1±1.3; SUVmax 70.3±44.0 and 3.8±1.2, p<0.01), respectively. Histological analysis confirmed CXCR4 expression in tumor areas with high (68)Ga-Pentixafor uptake; regions of the same tumor without apparent (68)Ga-Pentixafor uptake showed no or low receptor expression. In this pilot study, (68)Ga-Pentixafor retention has been observed in the vast majority of glioblastoma lesions and served as readout for non-invasive determination of CXCR4 expression. Given the paramount importance of the CXCR4/SDF-1 axis in tumor biology, (68)Ga-Pentixafor-PET/CT might prove a useful tool for sensitive, non-invasive in-vivo quantification of CXCR4 as well as selection of patients who might benefit from CXCR4-directed therapy. PMID:26909116

  8. 68Ga-Pentixafor-PET/CT for Imaging of Chemokine Receptor 4 Expression in Glioblastoma

    PubMed Central

    Lapa, Constantin; Lückerath, Katharina; Kleinlein, Irene; Monoranu, Camelia Maria; Linsenmann, Thomas; Kessler, Almuth F.; Rudelius, Martina; Kropf, Saskia; Buck, Andreas K.; Ernestus, Ralf-Ingo; Wester, Hans-Jürgen; Löhr, Mario; Herrmann, Ken

    2016-01-01

    Chemokine receptor-4 (CXCR4) has been reported to be overexpressed in glioblastoma (GBM) and to be associated with poor survival. This study investigated the feasibility of non-invasive CXCR4-directed imaging with positron emission tomography/computed tomography (PET/CT) using the radiolabelled chemokine receptor ligand 68Ga-Pentixafor. 15 patients with clinical suspicion on primary or recurrent glioblastoma (13 primary, 2 recurrent tumors) underwent 68Ga-Pentixafor-PET/CT for assessment of CXCR4 expression prior to surgery. O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) PET/CT images were available in 11/15 cases and were compared visually and semi-quantitatively (SUVmax, SUVmean). Tumor-to-background ratios (TBR) were calculated for both PET probes. 68Ga-Pentixafor-PET/CT results were also compared to histological CXCR4 expression on neuronavigated surgical samples. 68Ga-Pentixafor-PET/CT was visually positive in 13/15 cases with SUVmean and SUVmax of 3.0±1.5 and 3.9±2.0 respectively. Respective values for 18F-FET were 4.4±2.0 (SUVmean) and 5.3±2.3 (SUVmax). TBR for SUVmean and SUVmax were higher for 68Ga-Pentixafor than for 18F-FET (SUVmean 154.0±90.7 vs. 4.1±1.3; SUVmax 70.3±44.0 and 3.8±1.2, p<0.01), respectively. Histological analysis confirmed CXCR4 expression in tumor areas with high 68Ga-Pentixafor uptake; regions of the same tumor without apparent 68Ga-Pentixafor uptake showed no or low receptor expression. In this pilot study, 68Ga-Pentixafor retention has been observed in the vast majority of glioblastoma lesions and served as readout for non-invasive determination of CXCR4 expression. Given the paramount importance of the CXCR4/SDF-1 axis in tumor biology, 68Ga-Pentixafor-PET/CT might prove a useful tool for sensitive, non-invasive in-vivo quantification of CXCR4 as well as selection of patients who might benefit from CXCR4-directed therapy. PMID:26909116

  9. (18)F- and (68)Ga-Labeled Neurotensin Peptides for PET Imaging of Neurotensin Receptor 1.

    PubMed

    Maschauer, Simone; Einsiedel, Jürgen; Hübner, Harald; Gmeiner, Peter; Prante, Olaf

    2016-07-14

    The neurotensin (NT) receptor-1 (NTS1) is overexpressed in a variety of carcinomas and is therefore an interesting target for imaging with positron emission tomography (PET). The aim of this study was the development of new NT derivatives based on the metabolically stable peptide sequence NLys-Lys-Pro-Tyr-Tle-Leu suitable for PET imaging. The NT peptides were synthesized by solid-phase supported peptide synthesis and elongated with respective chelators (NODA-GA, DOTA) for (68)Ga-labeling or propargylglycine for (18)F-labeling via copper-catalyzed azide-alkyne cycloaddition. Receptor affinities of the peptides for NTS1 were in the range of 19-110 nM. Biodistribution studies using HT29 tumor-bearing mice showed highest tumor uptake for [(68)Ga]6 and [(68)Ga]8 and specific binding in small-animal PET studies. The tumor uptake of (68)Ga-labeled peptides in vivo significantly correlated with the in vitro Ki values for NTS1. [(68)Ga]8 displayed an excellent tumor-to-background ratio and could therefore be considered as an appropriate molecular probe for NTS1 imaging by PET. PMID:27336295

  10. Angiogenesis Imaging Using (68)Ga-RGD PET/CT: Therapeutic Implications.

    PubMed

    Eo, Jae Seon; Jeong, Jae Min

    2016-09-01

    Angiogenesis imaging is important for diagnostic and therapeutic treatment of various malignant and nonmalignant diseases. The Arg-Gly-Asp (RGD) sequence has been known to bind with the αvβ3 integrin that is expressed on the surface of angiogenic blood vessels or tumor cells. Thus, various radiolabeled derivatives of RGD peptides have been developed for angiogenesis imaging. Among the various radionuclides, (68)Ga was the most widely studied for RGD peptide imaging because of its excellent nuclear physical properties, easy-to-label chemical properties, and cost-effectiveness owing to the availability of a (68)Ge-(68)Ga generator. Thus, various (68)Ga-labeled RGD derivatives have been developed and applied for preclinical and clinical studies. Clinical trials were performed for both malignant and nonmalignant diseases. Breast cancer, glioma, and lung cancer were malignant, and myocardial infarction, atherosclerosis, and moyamoya disease were nonmalignant among the investigated diseases. Further, these (68)Ga-labeled RGD derivatives could be applied to assess the effects of antiangiogenic treatment or theragnosis or both, of cancers. In conclusion, the angiogenesis imaging technology using (68)Ga-labeled RGD derivatives might be useful for the development of new therapeutic assessments, and for diagnostic and theragnostic applications. PMID:27553467

  11. Therapeutic response and side effects of repeated radioligand therapy with 177Lu-PSMA-DKFZ-617 of castrate-resistant metastatic prostate cancer

    PubMed Central

    Ahmadzadehfar, Hojjat; Eppard, Elisabeth; Kürpig, Stefan; Fimmers, Rolf; Yordanova, Anna; Schlenkhoff, Carl Diedrich; Gärtner, Florian; Rogenhofer, Sebastian; Essler, Markus

    2016-01-01

    Prostate-specific membrane antigen (PSMA) is highly expressed on prostate epithelial cells and strongly up-regulated in prostate cancer (PC), making it an optimal target for the treatment of metastasized PC. Radioligand therapy (RLT) with 177Lu-PSMA-DKFZ-617 (Lu-PSMA) is a targeted therapy for metastatic PC. In this study, we retrospectively analyzed the side effects and the response rate of 24 hormone and/or chemorefractory PC patients with a mean age of 75.2 years (range: 64–82) with distant metastases and progressive disease according to the PSA level, who were treated with Lu-PSMA. Median PSA was 522 ng/ml (range: 17–2360). Forty-six cycles of Lu-PSMA were performed. Of the 24 patients, 22 received two cycles. Eight weeks after the first cycle of Lu-PSMA therapy 79.1% experienced a decline in PSA level. Eight weeks after the second cycle of Lu-PSMA therapy 68.2% experienced a decline in PSA relative to the baseline value. Apart from two cases of grade 3 anemia, there was no relevant hemato- or nephrotoxicity (grade 3 or 4). These results confirmed that Lu-PSMA is a safe treatment option for metastatic PC patients and has a low toxicity profile. A positive response to therapy in terms of decline in PSA occurs in about 70% of patients. PMID:26871285

  12. Favorable Response of Metastatic Merkel Cell Carcinoma to Targeted 177Lu-DOTATATE Therapy: Will PRRT Evolve to Become an Important Approach in Receptor-Positive Cases?

    PubMed

    Basu, Sandip; Ranade, Rohit

    2016-06-01

    This report illustrates an excellent partial response of Merkel cell carcinoma with multiple bilobar hepatic metastases to a single cycle of peptide receptor radionuclide therapy (PRRT) with (177)Lu-DOTATATE. This response, coupled with minimal side effects, warrants consideration of this therapy early in the disease course (rather than at an advanced stage after failure of other therapies) if the metastatic lesions exhibit adequate tracer avidity on somatostatin receptor-based imaging. Our patient showed progression of systemic disease after having undergone a second surgery and adjuvant radiotherapy to the head and neck, as well as chemotherapy, and hence was considered a candidate for PRRT. In a pretreatment study, the metastatic lesions demonstrated avidity to both somatostatin receptors and (18)F-FDG. Three months after the first cycle of treatment, when the patient was being evaluated for a second cycle, both imaging parameters showed evidence of a partial response that included nearly complete resolution of the two previously seen lesions. In view of the relatively good tolerability, minimal side effects, and targeted nature of the treatment, PRRT may evolve to become the first-line therapy for metastatic Merkel cell carcinoma and should be examined further in a larger number of patients. PMID:26471333

  13. Synthesis and biological evaluation of a novel (177)Lu-DOTA-[Gly(3)-cyclized(Dap(4), (d)-Phe(7), Asp(10))-Arg(11)]α-MSH(3-13) analogue for melanocortin-1 receptor-positive tumor targeting.

    PubMed

    Lim, Jae Cheong; Hong, Young Don; Kim, Jin Ju; Choi, Sang Mu; Baek, Hye Suk; Choi, Sun-Ju

    2012-10-01

    In this study, a novel α-melanocyte stimulating hormone (α-MSH) analogue 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) coupled [Gly(3)-cyclized(Dap(4), (d)-Phe(7), Asp(10))-Arg(11)]α-MSH(3-13) (DOTA-GMSH) for melanocortin-1 receptor (MC-1R) targeting was newly synthesized, radiolabeled with (177)Lu, and in vitro and in vivo characterized. (177)Lu-labeled peptides were prepared with a high radiolabeling yield (>98%), and its Log p value was -2.89. No degradation was observed not only by serum incubation at 37°C for 7 days but also by an HPLC analysis of radioactive metabolites in urine. A cell binding assay revealed that an inhibitory concentration of 50% (IC(50)) of the peptide was 3.80 nM. The tumor-to-blood ratio, which was 14.27 at 2 hours p.i., was increased to 56.37 at 24 hours p.i., which means that the radiolabeled peptide was highly accumulated in a tumor and was rapidly cleared from the blood pool. We, therefore, conclude that (177)Lu-DOTA-GMSH has promising characteristics for application in nuclear medicine, namely for the diagnosis of MC-1R over-expressing tumors. PMID:22831553

  14. 68Ga-PET radiopharmacy: A generator-based alternative to 18F-radiopharmacy.

    PubMed

    Maecke, H R; André, J P

    2007-01-01

    Positron emission tomography (PET) is becoming a dominating method in the field of molecular imaging. Most commonly used radionuclides are accelerator produced 11C and 18F. An alternative method to label biomolecules is the use of metallic positron emitters; among them 68Ga is the most promising as it can be produced from a generator system consisting of an inorganic or organic matrix immobilizing the parent radionuclide 68Ge. Germanium-68 has a long half-life of 271 days which allows the production of long-lived, potentially very cost-effective generator systems. A commercial generator from Obninsk, Russia, is available which uses TiO2 as an inorganic matrix to immobilize 68Ge in the oxidation state IV+. 68Ge(IV) is chemically sufficiently different to allow efficient separation from 68Ga(III). Ga3+ is redox-inert; its coordination chemistry is dominated by its hard acid character. A variety of mono- and bifunctional chelators were developed which allow immobilization of 68Ga3+ and convenient coupling to biomolecules. Especially peptides targeting G-protein coupled receptors overexpressed on human tumour cells have been studied preclinically and in patient studies showing high and specific tumour uptake and specific localization. 68Ga-radiopharmacy may indeed be an alternative to 18F-based radiopharmacy. Freeze-dried, kit-formulated precursors along with the generator may be provided, similar to the 99Mo/99mTc-based radiopharmacy, still the mainstay of nuclear medicine. PMID:17172157

  15. Design of CGMP Production of 18F- and 68Ga-Radiopharmaceuticals

    PubMed Central

    Chu, Pei-Chun; Chao, Hao-Yu; Shieh, Wei-Chen; Chen, Chuck C.

    2014-01-01

    Objective. Radiopharmaceutical production process must adhere to current good manufacturing process (CGMP) compliance to ensure the quality of precursor, prodrug (active pharmaceutical ingredient, API), and the final drug product that meet acceptance criteria. We aimed to develop an automated system for production of CGMP grade of PET radiopharmaceuticals. Methods. The hardware and software of the automated synthesizer that fit in the hot cell under cGMP requirement were developed. Examples of production yield and purity for 68Ga-DOTATATE and 18F-FDG at CGMP facility were optimized. Analytical assays and acceptance criteria for cGMP grade of 68Ga-DOTATATE and 18F-FDG were established. Results. CGMP facility for the production of PET radiopharmaceuticals has been established. Radio-TLC and HPLC analyses of 68Ga-DOTATATE and 18F-FDG showed that the radiochemical purity was 92% and 96%, respectively. The products were sterile and pyrogenic-free. Conclusion. CGMP compliance of radiopharmaceuticals has been reviewed. 68Ga-DOTATATE and 18F-FDG were synthesized with high radiochemical yield under CGMP process. PMID:25276810

  16. (68)Ga PET Ventilation and Perfusion Lung Imaging-Current Status and Future Challenges.

    PubMed

    Bailey, Dale L; Eslick, Enid M; Schembri, Geoffrey P; Roach, Paul J

    2016-09-01

    Gallium-68 ((68)Ga) is a positron-emitting radionuclide suitable for positron emission tomography (PET) imaging that has a number of convenient features-it has a physical half life of 68 minutes, it is generator produced at the PET facility and needs no local cyclotron, and being a radiometal is able to be chelated to a number of useful molecules for diagnostic imaging with PET. (68)Ga has recently been investigated as a radiotracer for ventilation and perfusion (V/Q) lung imaging. It is relatively easy to produce both V/Q radiopharmaceuticals labeled with (68)Ga for PET studies, it offers higher spatial resolution than equivalent SPECT studies, the short half life allows for multiple (repeated) scans on the same day, and low amounts of radiotracer can be used thus limiting the radiation dose to the subject. In the usual clinical setting requiring a V/Q scan, that of suspected pulmonary embolism, the role of (68)Ga V/Q PET may be limited from a logistical perspective, however, in nonacute applications such as lung function evaluation, radiotherapy treatment planning, and respiratory physiology investigations it would appear to be an ideal modality to employ. PMID:27553468

  17. Preclinical Study on GRPR-Targeted (68)Ga-Probes for PET Imaging of Prostate Cancer.

    PubMed

    Sun, Yao; Ma, Xiaowei; Zhang, Zhe; Sun, Ziyan; Loft, Mathias; Ding, Bingbing; Liu, Changhao; Xu, Liying; Yang, Meng; Jiang, Yuxin; Liu, Jianfeng; Xiao, Yuling; Cheng, Zhen; Hong, Xuechuan

    2016-08-17

    Gastrin-releasing peptide receptor (GRPR) targeted positron emission tomography (PET) is a highly promising approach for imaging of prostate cancer (PCa) in small animal models and patients. Developing a GRPR-targeted PET probe with excellent in vivo performance such as high tumor uptake, high contrast, and optimal pharmacokinetics is still very challenging. Herein, a novel bombesin (BBN) analogue (named SCH1) based on JMV594 peptide modified with an 8-amino octanoic acid spacer (AOC) was thus designed and conjugated with the metal chelator 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA). The resulting NODAGA-SCH1 was then radiolabeled with (68)Ga and evaluated for PET imaging of PCa. Compared with (68)Ga-NODAGA-JMV594 probe, (68)Ga-NODAGA-SCH1 exhibited excellent PET/CT imaging properties on PC-3 tumor-bearing nude mice, such as high tumor uptake (5.80 ± 0.42 vs 3.78 ± 0.28%ID/g, 2 h) and high tumor/muscle contrast (16.6 ± 1.50 vs 8.42 ± 0.61%ID/g, 2 h). Importantly, biodistribution data indicated a relatively similar accumulation of (68)Ga-NODAGA-SCH1 was observed in the liver (4.21 ± 0.42%ID/g) and kidney (3.41 ± 0.46%ID/g) suggesting that the clearance is through both the kidney and the liver. Overall, (68)Ga-NODAGA-SCH1 showed promising in vivo properties and is a promising candidate for translation into clinical PET-imaging of PCa patients. PMID:27399868

  18. [Manufacture and Utilization of a Low-level Radioactive 68Ge/68Ga Generator in a Radiochemistry Laboratory Course].

    PubMed

    Washiyama, Kohshin; Amano, Ryohei; Nozaki, Tadashi; Ogawa, Koji; Nagatsu, Kotaro; Sakama, Minoru; Ido, Tatuo; Yamaguchi, Hiroshi

    2015-10-01

    The low-level radioactivity of a (68)Ge/(68)Ga generator is a suitable tool for measuring radioactive growth and decay after (68)Ga milking due to their desirable nuclear decay properties, such as the EC decay of (68)Ge with no γ-ray emission andthe β(+) decay of (68)Ga with a weak γ-ray emission. To experience andund erstandrad ioactive equilibrium during a university laboratory course, we surveyedandtestedthe production of a small amount of (68)Ge and set up educational programs to manufacture a (68)Ge/(68)Ga generator for measuring the growth andd ecay of (68)Ga. The irradiation of natGa with 25 μA of a 30 MeV proton beam from a cyclotron for 4 h yields ca. 111 MBq of (68)Ge, which was sufficient to supply to several universities. For use as the adsorbent of the generator column, particles of hydrated tin (VI) oxide were prepared from precipitated tin hydroxide gel. Repeated elution of (68)Ga from the handmade (68)Ge/(68)Ga generator gave constant amounts of (68)Ga with acceptable breakthrough of (68)Ge. The feedback from the student's experience with the (68)Ge/(68)Ga generator was evaluatedby annual questionnaire surveys, which were given to all students taking the course every year from 2012 to 2014. It has been made clear that more than half of the students were interested in the (68)Ge/(68)Ga generator program, andthis interest increasedfrom 54.9%in 2012 to 78.6%in 2014. A low-level radioactive (68)Ge/(68)Ga generator is thus expectedto be a suitable experimental tool for demonstrating the phenomenon of radioactivity to students in an intriguing way. PMID:26490232

  19. Synthesis and biological evaluation of (68) Ga-labeled Pteroyl-Lys conjugates for folate receptor-targeted tumor imaging.

    PubMed

    Zhang, Xuran; Yu, Qian; He, Yingfang; Zhang, Chun; Zhu, Hua; Yang, Zhi; Lu, Jie

    2016-07-01

    In order to develop novel (68) Ga-labeled PET tracers for folate receptor imaging, two DOTA-conjugated Pteroyl-Lys derivatives, Pteroyl-Lys-DOTA and Pteroyl-Lys-DAV-DOTA, were designed, synthesized and radiolabeled with (68) Ga. Biological evaluations of the two radiotracers were performed with FR-positive KB cell line and athymic nude mice bearing KB tumors. Both (68) Ga-DOTA-Lys-Pteroyl and (68) Ga-DOTA-DAV-Lys-Pteroyl exhibited receptor specific binding in KB cells in vitro. The tumor uptake values of (68) Ga-DOTA-Lys-Pteroyl and (68) Ga-DOTA-DAV-Lys-Pteroy were 10.06 ± 0.59%ID/g and 11.05 ± 0.60%ID/g at 2 h post-injection, respectively. Flank KB tumor was clearly visualized with (68) Ga-DOTA-DAV-Lys-Pteroyl by Micro-PET imaging at 2 h post-injection, suggesting the feasibility of using (68) Ga-labeled Pteroyl-Lys conjugates as a novel class of FR targeted probes. PMID:27320312

  20. Radiosynovectomy of Painful Synovitis of Knee Joints Due to Rheumatoid Arthritis by Intra-Articular Administration of (177)Lu-Labeled Hydroxyapatite Particulates: First Human Study and Initial Indian Experience.

    PubMed

    Shinto, Ajit S; Kamaleshwaran, K K; Chakraborty, Sudipta; Vyshakh, K; Thirumalaisamy, S G; Karthik, S; Nagaprabhu, V N; Vimalnath, K V; Das, Tapas; Banerjee, Sharmila

    2015-01-01

    The aim of this study is to assess the effectiveness of Radiosynovectomy (RSV) using (177)Lu-labeled hydroxyapatite ((177)Lu-HA) in the treatment of painful synovitis and recurrent joint effusion of knee joints in rheumatoid arthritis (RA). Ten patients, diagnosed with RA and suffering from chronic painful resistant synovitis of the knee joints were referred for RSV. The joints were treated with 333 ± 46 MBq of (177)Lu-HA particles administered intra-articularly. Monitoring of activity distribution was performed by static imaging of knee joint and whole-body gamma imaging. The patients were evaluated clinically before RSV and at 6 months after the treatment by considering the pain improvement from baseline values in terms of a 100-point visual analog scale (VAS), the improvement of knee flexibility and the pain remission during the night. RSV response was classified as poor (VAS < 25), fair (VAS ≥ 25-50), good (VAS ≥ 50-75) and excellent (VAS ≥ 75), with excellent and good results considered to be success, while fair and poor as failure and also by range of motion. Three phase bone scan (BS) was repeated after 6 months and changes in the second phase of BS3 were assessed visually, using a four-degree scale and in the third phase, semiquantitatively with J/B ratio to see the response. Biochemical analysis of C-reactive protein (CRP) and fibrinogen was repeated after 48 h, 4 and 24 weeks. In all 10 patients, no leakage of administered activity to nontarget organs was visible in the whole-body scan. Static scans of the joint at 1 month revealed complete retention of (177)Lu-HA in the joints. All patients showed decreased joint swelling and pains, resulting in increased joint motion after 6 months. The percentage of VAS improvement from baseline values was 79.5 ± 20.0% 6 months after RS and found to be significantly related to patients' age (P = 0.01) and duration of the disease (P = 0.03). Knees with Steinbrocker's Grades 0 and I responded better than those

  1. Radiosynovectomy of Painful Synovitis of Knee Joints Due to Rheumatoid Arthritis by Intra-Articular Administration of 177Lu-Labeled Hydroxyapatite Particulates: First Human Study and Initial Indian Experience

    PubMed Central

    Shinto, Ajit S.; Kamaleshwaran, K. K.; Chakraborty, Sudipta; Vyshakh, K.; Thirumalaisamy, S. G.; Karthik, S.; Nagaprabhu, V. N.; Vimalnath, K. V.; Das, Tapas; Banerjee, Sharmila

    2015-01-01

    The aim of this study is to assess the effectiveness of Radiosynovectomy (RSV) using 177Lu-labeled hydroxyapatite (177Lu-HA) in the treatment of painful synovitis and recurrent joint effusion of knee joints in rheumatoid arthritis (RA). Ten patients, diagnosed with RA and suffering from chronic painful resistant synovitis of the knee joints were referred for RSV. The joints were treated with 333 ± 46 MBq of 177Lu-HA particles administered intra-articularly. Monitoring of activity distribution was performed by static imaging of knee joint and whole-body gamma imaging. The patients were evaluated clinically before RSV and at 6 months after the treatment by considering the pain improvement from baseline values in terms of a 100-point visual analog scale (VAS), the improvement of knee flexibility and the pain remission during the night. RSV response was classified as poor (VAS < 25), fair (VAS ≥ 25-50), good (VAS ≥ 50-75) and excellent (VAS ≥ 75), with excellent and good results considered to be success, while fair and poor as failure and also by range of motion. Three phase bone scan (BS) was repeated after 6 months and changes in the second phase of BS3 were assessed visually, using a four-degree scale and in the third phase, semiquantitatively with J/B ratio to see the response. Biochemical analysis of C-reactive protein (CRP) and fibrinogen was repeated after 48 h, 4 and 24 weeks. In all 10 patients, no leakage of administered activity to nontarget organs was visible in the whole-body scan. Static scans of the joint at 1 month revealed complete retention of 177Lu-HA in the joints. All patients showed decreased joint swelling and pains, resulting in increased joint motion after 6 months. The percentage of VAS improvement from baseline values was 79.5 ± 20.0% 6 months after RS and found to be significantly related to patients' age (P = 0.01) and duration of the disease (P = 0.03). Knees with Steinbrocker's Grades 0 and I responded better than those with more

  2. Evaluation of the 1077 keV γ-ray emission probability from 68Ga decay

    NASA Astrophysics Data System (ADS)

    Huang, Xiao-Long; Jiang, Li-Yang; Chen, Xiong-Jun; Chen, Guo-Chang

    2014-04-01

    68Ga decays to the excited states of 68Zn through the electron capture decay mode. New recommended values for the emission probability of 1077 keV γ-ray given by the ENSDF and DDEP databases all use data from absolute measurements. In 2011, JIANG Li-Yang deduced a new value for 1077 keV γ-ray emission probability by measuring the 69Ga(n,2n) 68Ga reaction cross section. The new value is about 20% lower than values obtained from previous absolute measurements and evaluations. In this paper, the discrepancies among the measurements and evaluations are analyzed carefully and the new values are re-recommended. Our recommended value for the emission probability of 1077 keV γ-ray is (2.72±0.16)%.

  3. Measurement of blood-brain barrier permeability with positron emission tomography and (68Ga)EDTA

    SciTech Connect

    Kessler, R.M.; Goble, J.C.; Bird, J.H.; Girton, M.E.; Doppman, J.L.; Rapoport, S.I.; Barranger, J.A.

    1984-09-01

    Positron emission tomography (PET) was employed to examine time-dependent changes in blood-brain barrier (BBB) permeability to (68Ga)ethylenediaminetetraacetate (EDTA) in the rhesus monkey, following reversible barrier opening by intracarotid infusion of a hypertonic mannitol solution. The PET technique, when combined with measurements of plasma radioactivity, provided a quantitative measure of the cerebrovascular permeability-area product (PA) at different times following mannitol infusion. Hypertonic mannitol treatment reversibly increased PA to (68Ga)EDTA more than 10-fold; much of the barrier effect was over by 10 min after mannitol treatment. The results show that PET can be used to measure transient changes in BBB integrity in specific brain regions, under in vivo, noninvasive conditions.

  4. Scaling animal to human biodistribution of the radiopharmaceutical [68Ga]Ga-PSMA-HBED-CC

    NASA Astrophysics Data System (ADS)

    Parra, Pamela Ochoa; Veloza, Stella

    2016-07-01

    The radiotracer called 68Ga-labelled Glu-urea-Lys(Ahx)-HBED-CC ([68Ga]Ga-PSMA-HBED-CC) is a novel radiophar-maceutical for the detection of prostate cancer lesions by positron emission tomography (PET) imaging. Setting up a cost-effective manual synthesis of this radiotracer and making its clinical translation in Colombia will require two important elements: the evaluation of the procedure to yield a consistent product, meeting standards of radio-chemical purity and low toxicity and then, the evaluation of the radiation dosimetry. In this paper a protocol to extrapolate the biokinetic model made in normal mice to humans by using the computer software for internal dose assessment OLINDA/EXM® is presented as an accurate and standardized method for the calculation of radiation dosimetry estimates.

  5. Mini-PEG spacering of VAP-1-targeting 68Ga-DOTAVAP-P1 peptide improves PET imaging of inflammation

    PubMed Central

    2011-01-01

    Background Vascular adhesion protein-1 (VAP-1) is an adhesion molecule that plays a key role in recruiting leucocytes into sites of inflammation. We have previously shown that 68Gallium-labelled VAP-1-targeting peptide (68Ga-DOTAVAP-P1) is a positron emission tomography (PET) imaging agent, capable of visualising inflammation in rats, but disadvantaged by its short metabolic half-life and rapid clearance. We hypothesised that prolonging the metabolic half-life of 68Ga-DOTAVAP-P1 could further improve its imaging characteristics. In this study, we evaluated a new analogue of 68Ga-DOTAVAP-P1 modified with a mini-polyethylene glycol (PEG) spacer (68Ga-DOTAVAP-PEG-P1) for in vivo imaging of inflammation. Methods Whole-body distribution kinetics and visualisation of inflammation in a rat model by the peptides 68Ga-DOTAVAP-P1 and 68Ga-DOTAVAP-PEG-P1 were evaluated in vivo by dynamic PET imaging and ex vivo by measuring the radioactivity of excised tissues. In addition, plasma samples were analysed by radio-HPLC for the in vivo stability of the peptides. Results The peptide with the mini-PEG spacer showed slower renal excretion but similar liver uptake as the original peptide. At 60 min after injection, the standardised uptake value of the inflammation site was 0.33 ± 0.07 for 68Ga-DOTAVAP-P1 and 0.53 ± 0.01 for 68Ga-DOTAVAP-PEG-P1 by PET. In addition, inflammation-to-muscle ratios were 6.7 ± 1.3 and 7.3 ± 2.1 for 68Ga-DOTAVAP-P1 and 68Ga-DOTAVAP-PEG-P1, respectively. The proportion of unchanged peptide in circulation at 60 min after injection was significantly higher for 68Ga-DOTAVAP-PEG-P1 (76%) than for 68Ga-DOTAVAP-P1 (19%). Conclusion The eight-carbon mini-PEG spacer prolonged the metabolic half-life of the 68Ga-DOTAVAP-P1 peptide, leading to higher target-to-background ratios and improved in vivo PET imaging of inflammation. PMID:22214508

  6. Experience in production of (68)Ga-DOTA-NOC for clinical use under an Expanded Access IND.

    PubMed

    Green, Mark A; Mathias, Carla J; Fletcher, James W

    2016-10-01

    [(68)Ga]Ga-DOTA-NOC was produced under an Expanded Access IND for 174 clinical PET/CT studies to evaluate patients with neuroendocrine tumors. Production employed either the TiO2-based Eckert & Ziegler (EZAG) (68)Ge/(68)Ga-generator (with fractionated elution), or the SiO2-based ITG (68)Ge/(68)Ga-generator. In both cases, [(68)Ga]Ga-DOTA-NOC was reliably produced, without pre-synthesis purification of the(68)Ga generator eluate, using readily-implemented manual synthesis procedures. [(68)Ga]Ga-DOTA-NOC radiochemical purity averaged 99.2±0.4%. Administered (68)Ga dose averaged 181±22 MBq, and administered peptide mass averaged 43.2±5.2µg (n=47) and 23.9±5.7µg (n=127), respectively, using the EZAG and ITG generators. At dose expiration, (68)Ge breakthrough in the final product averaged 2.7×10(-7)% and 5.4×10(-5%) using the EZAG and ITG generators, respectively. PMID:27501136

  7. (68)Ga-labeled 3PRGD2 for dual PET and Cerenkov luminescence imaging of orthotopic human glioblastoma.

    PubMed

    Fan, Di; Zhang, Xin; Zhong, Lijun; Liu, Xujie; Sun, Yi; Zhao, Huiyun; Jia, Bing; Liu, Zhaofei; Zhu, Zhaohui; Shi, Jiyun; Wang, Fan

    2015-06-17

    β-Emitters can produce Cerenkov radiation that is detectable by Cerenkov luminescence imaging (CLI), allowing the combination of PET and CLI with one radiotracer for both tumor diagnosis and visual guidance during surgery. Recently, the clinical feasibility of CLI with the established therapeutic reagent Na(131)I and the PET tracer (18)F-FDG was demonstrated. (68)Ga possesses a higher Cerenkov light output than (18)F and (131)I, which would result in higher sensitivity for CLI and improve the outcome of CLI in clinical applications. However, the research on (68)Ga-based tumor-specific tracers for CLI is limited. In this study, we examined the use of (68)Ga-radiolabeled DOTA-3PRGD2 ((68)Ga-3PRGD2) for dual PET and CLI of orthotopic U87MG human glioblastoma. For this purpose, the Cerenkov efficiencies of (68)Ga and (18)F were measured with the IVIS Spectrum system (PerkinElmer, USA). The CLI signal intensity of (68)Ga was 15 times stronger than that of (18)F. PET and CLI of (68)Ga-3PRGD2 were performed in U87MG human glioblastoma xenografts. Both PET and CLI revealed a remarkable accumulation of (68)Ga-3PRGD2 in the U87MG human glioblastoma xenografts at 1 h p.i. with an extremely low background in the brain when compared with (18)F-FDG. Furthermore, (68)Ga-3PRGD2 was used for dual PET and CLI of orthotopic human glioblastoma. The orthotopic human glioblastoma was clearly visualized by both imaging modalities. In addition, the biodistribution of (68)Ga-3PRGD2 was assessed in normal mice to estimate the radiation dosimetry. The whole-body effective dose is 20.1 ± 3.3 μSv/MBq, which is equal to 3.7 mSv per whole-body PET scan with a 5 mCi injection dose. Thus, (68)Ga-3PRGD2 involves less radiation exposure in patients when compared with (18)F-FDG (7.0 mSv). The use of (68)Ga-3PRGD2 in dual PET and CLI shows great promise for tumor diagnosis and image-guided surgery. PMID:25853280

  8. Unusual widespread metastatic subcutaneous lesions in a patient with ileal carcinoid evidenced by 68Ga-DOTATOC PET/CT.

    PubMed

    Caobelli, Federico; Pizzocaro, Claudio; Quartuccio, Natale; Guerra, Ugo Paolo

    2014-04-01

    68Ga-DOTATOC PET/CT has been widely validated in diagnosis and follow-up of carcinoid. A 47-year-old woman with ileal carcinoid underwent a 68Ga-DOTATOC PET/CT for restaging purposes. Images showed extensive liver involvement and also a widespread metastatic subcutaneous metastases in the right chest wall and in the right laterocervical region. The presence of multiple soft-tissue metastases, as described in our case and imaged with 68Ga-DOTATOC, represents a very rare clinical entity. PMID:24561684

  9. AMD3100: A Versatile Platform for CXCR4 Targeting (68)Ga-Based Radiopharmaceuticals.

    PubMed

    Poty, Sophie; Gourni, Eleni; Désogère, Pauline; Boschetti, Frédéric; Goze, Christine; Maecke, Helmut R; Denat, Franck

    2016-03-16

    CXCR4 is a G protein-coupled receptor (GPCR), which is overexpressed in numerous diseases, particularly in multiple cancers. Therefore, this receptor represents a valuable target for imaging and therapeutic purposes. Among the different approaches, which were developed for CXCR4 imaging, a CXCR4 antagonist biscyclam system (AMD3100, also called Mozobil), currently used in the clinic for the mobilization of hematopoietic stem cells, was radiolabeled with different radiometals such as (62)Zn, (64)Cu, (67)Ga, or (99m)Tc. However, cyclam is not an ideal chelator for most of these radiometals, and could lead to the release of the radionuclide in vivo. In the current study, a new family of CXCR4 imaging agents is presented, in which AMD3100 is used as a carrier for specific delivery of an imaging reporter, i.e., a (68)Ga complex for PET imaging. AMD3100 was functionalized on the phenyl moiety with different linkers, either ethylenediamine or diamino-polyethylene glycol 3 (PEG3). The resulting AMD3100 analogues were further coupled with two different chelators, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) or 1,4,7-triazacyclononane-1-glutaric acid-4,7-acetic acid (NODAGA). Five potential CXCR4 targeting agents were obtained. The derived AMD3100-based ligands were labeled with (68)Ga, highlighting the influence of the spacer nature on the (68)Ga-labeling yield. The lipophilic character of the different systems was also investigated, as well as their affinity for the CXCR4 receptor. The most promising compound was further evaluated in vivo in H69 tumor xenografts by biodistribution and PET imaging studies, validating the proof of principle of our concept. PMID:26886512

  10. Simultaneous {sup 68}Ga-DOTATOC-PET/MRI for IMRT Treatment Planning for Meningioma: First Experience

    SciTech Connect

    Thorwarth, Daniela; Henke, Guido; Mueller, Arndt-Christian; Reimold, Matthias; Beyer, Thomas; Boss, Andreas; Kolb, Armin; Pichler, Bernd; Pfannenberg, Christina

    2011-09-01

    Purpose: To evaluate intensity-modulated radiotherapy (IMRT) treatment planning based on simultaneous positron-emission tomography and magnetic resonance imaging (PET/MRI) of meningioma. Methods and Materials: A meningioma patient was examined prior to radiotherapy with dedicated planning computed tomography (CT), MRI, PET/CT with gallium-68-labeled DOTATOC ({sup 68}Ga-DOTATOC), and simultaneous {sup 68}Ga-DOTATOC-PET/MRI. The first gross target volume (GTV) was defined based on a combination of separate MR and {sup 68}Ga-DOTATOC-PET/CT imaging (GTV{sub PET/CT+MR}). Then, the simultaneous PET/MR images were used to delineate a second GTV (GTV{sub PET/MR}) by following exactly the same delineation strategy. After an isotropic expansion of those volumes by a 4-mm safety margin, the resulting planning target volumes (PTVs) were compared by calculating the intersection volume and the relative complements. A cross-evaluation of IMRT plans was performed, where the treatment plan created for the PTV{sub PET/CT+MR} was applied to the PET/MR-based PTV{sub PET/MR}. Results: Generally, target volumes for IMRT treatment planning did not differ between MRI plus {sup 68}Ga-DOTATOC-PET/CT and simultaneous PET/MR imaging. Only in certain regions of the GTV were differences observed. The overall volume of the PET/MR-based PTV was approximately the same as that obtained from PET/CT data. A small region of infiltrative tumor growth next to the main tumor mass was better visualized with combined PET/MR due to smaller PET voxel sizes and improved recovery. An IMRT treatment plan was optimized for the PTV{sub PET/CT+MR}. The evaluation of this plan with respect to the PTV{sub PET/MR} showed parts of the target volume that would not have received the full radiation dose after delineation of the tumor, based on simultaneous PET/MR. Conclusion: This case showed that differences in target volumes delineated on the basis of separate MR and PET/CT and simultaneous PET/MR may be observed that

  11. Exploring new frontiers in molecular imaging: Emergence of 68Ga PET/CT

    PubMed Central

    Tan, Eik Hock; Goh, Soon Whatt

    2010-01-01

    Since US Food and Drug Administration approval of 18-fluorodeoxyglucose as a positron tracer, and the development of hybrid positron emission tomography/computed tomography machines, there has been a great increase in clinical application and progress in the field of nuclear molecular imaging. However, not underestimating the value of 18F, there are known limitations in the use of this cyclotron-produced positron tracer. We hence turn our focus to an emerging positron tracer, 68Ga, and examine the advantages, current clinical uses and potential future applications of this radioisotope. PMID:21160919

  12. Preclinical Comparative Study of (68)Ga-Labeled DOTA, NOTA, and HBED-CC Chelated Radiotracers for Targeting PSMA.

    PubMed

    Ray Banerjee, Sangeeta; Chen, Zhengping; Pullambhatla, Mrudula; Lisok, Ala; Chen, Jian; Mease, Ronnie C; Pomper, Martin G

    2016-06-15

    (68)Ga-labeled, low-molecular-weight imaging agents that target the prostate-specific membrane antigen (PSMA) are increasingly used clinically to detect prostate and other cancers with positron emission tomography (PET). The goal of this study was to compare the pharmacokinetics of three PSMA-targeted radiotracers: (68)Ga-1, using DOTA-monoamide as the chelating agent; (68)Ga-2, containing the macrocyclic chelating agent p-SCN-Bn-NOTA; and (68)Ga-DKFZ-PSMA-11, currently in clinical trials, which uses the acyclic chelating agent, HBED-CC. The PSMA-targeting scaffold for all three agents utilized a similar Glu-urea-Lys-linker construct. Each radiotracer enabled visualization of PSMA+ PC3 PIP tumor, kidney, and urinary bladder as early as 15 min post-injection using small animal PET/computed tomography (PET/CT). (68)Ga-2 demonstrated the fastest rate of clearance from all tissues in this series and displayed higher uptake in PSMA+ PC3 PIP tumor compared to (68)Ga-1 at 1 h post-injection. There was no significant difference in PSMA+ PC3 PIP tumor uptake for the three agents at 2 and 3 h post-injection. (68)Ga-DKFZ-PSMA-11 demonstrated the highest uptake and retention in normal tissues, including kidney, blood, spleen, and salivary glands and PSMA-negative PC3 flu tumors up to 3 h post-injection. In this preclinical evaluation (68)Ga-2 had the most advantageous characteristics for PSMA-targeted PET imaging. PMID:27076393

  13. Role of (68)Ga-DOTATATE PET/CT in patients with multiple endocrine neoplasia type 1 (MEN1).

    PubMed

    Lastoria, Secondo; Marciello, Francesca; Faggiano, Antongiulio; Aloj, Luigi; Caracò, Corradina; Aurilio, Michela; D'Ambrosio, Laura; Di Gennaro, Francesca; Ramundo, Valeria; Camera, Luigi; De Luca, Leonardo; Fonti, Rosa; Napolitano, Vincenzo; Colao, Annamaria

    2016-06-01

    Multiple endocrine neoplasia type 1 (MEN1) is a hereditary syndrome predisposing to many endocrine and neuroendocrine tumors (NET). Conventional imaging (CI) cannot provide satisfactory results for all the different types of MEN1-related tumors. Objective of this prospective observational study was to evaluate the role of (68)Ga-DOTATATE PET/CT in MEN1 compared to CI. Diagnostic performance of (68)Ga-DOTATATE PET/CT for the detection of NET was evaluated as well as the prognostic role of SUVmax. Eighteen patients with genetically confirmed MEN1 were evaluated by (68)Ga-DOTATATE PET/CT, endoscopic ultrasounds, multidetector-row computed tomography, magnetic resonance imaging, and hormone/markers serum measurements. Four MEN1-related tumor sites (pancreas, pituitary, parathyroids, adrenals) were considered. Sensitivity and specificity of (68)Ga-DOTATATE PET/CT for the detection of NET were calculated. There was (68)Ga-DOTATATE PET/CT uptake in 11/11 patients with pancreatic lesions, in 9/12 with pituitary adenoma, in 5/15 with parathyroid enlargements, and in 5/7 with adrenal lesions. (68)Ga-DOTATATE PET/CT showed sensitivity and specificity of 100 and 100 % in pancreas, 75 and 83 % in pituitary, 28 and 100 % in parathyroids, and 62.5 and 100 % in adrenals, respectively. Compared with CI, no significant difference in sensitivity for pancreas, pituitary, and adrenals was found, while CI had a better sensitivity for parathyroids (p = 0.002). On the ROC analysis, progression of pancreatic lesions was significantly associated to SUVmax <12.3 (p < 0.05). (68)Ga-DOTATATE PET/CT is greatly helpful in the work-up of MEN1 providing a panoramic view of MEN1-related lesions. There is also a prognostic role of (68)Ga-PET in patients with MEN1-pancreatic lesions. PMID:26242621

  14. Use of 65Zn as a tracer for the assessment of purification in the 68Ga-DOTANOC synthesis.

    PubMed

    Lucconi, G; Cicoria, G; Pancaldi, D; Lodi, F; Malizia, C; Fanti, S; Boschi, S; Marengo, M

    2013-10-01

    In the last years (68)Ga has got into the focus of researchers and clinicians especially for radio-labeling of biomolecules; an important characteristic of this positron emitting isotope is its availability via the (68)Ge/(68)Ga generator system: the long-lived (68)Ge (t1/2=270.8 d) produces the short-lived (68)Ga (t1/2=67.63 min) which decays to stable (68)Zn. (68)Ge breakthrough compromises (68)Ga radionuclidic purity, while (68)Zn might affect the specific activity of the radiopharmaceutical. In this paper we investigated the weight of these impurities in (68)Ga-DOTANOC synthesis. (65)Zn (t1/2=244.26d; decay mode: EC 98.3%, β(+) 1.7%) was used as a radiotracer of stable (68)Zn; samples of the purification columns, wastes and product were recovered and measured with a calibrated HPGe gamma-ray spectrometry system. The results showed that (68)Zn competes with (68)Ga in labeling DOTANOC with a (95±2)% labeling yield; they also proved the effectiveness of the STRATA X-C cationic post-processing of the generator eluate in lowering the amount of this impurity to less than 1%. Moreover this approach, along with the purification of the final product through a STRATA X cartridge, effectively removes (68)Ge breakthrough providing a (68)Ga-DOTANOC radionuclidic purity of (99.9999986±0.0000006)%, superior to 99.9% required by the Pharmacopoeia Monograph on (68)Ga Edotreotide injection. PMID:23816878

  15. Investigations on the Ga(III) Complex of EOB-DTPA and Its 68Ga Radiolabeled Analogue.

    PubMed

    Greiser, Julia; Niksch, Tobias; Weigand, Wolfgang; Freesmeyer, Martin

    2016-01-01

    We demonstrate a method for the isolation of EOB-DTPA (3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(ethoxybenzyl)-undecanedioic acid) from its Gd(III) complex and protocols for the preparation of its novel non-radioactive, i.e., natural Ga(III) as well as radioactive (68)Ga complex. The ligand as well as the Ga(III) complex were characterized by nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry and elemental analysis. (68)Ga was obtained by a standard elution method from a (68)Ge/(68)Ga generator. Experiments to evaluate the (68)Ga-labeling efficiency of EOB-DTPA at pH 3.8-4.0 were performed. Established analysis techniques radio TLC (thin layer chromatography) and radio HPLC (high performance liquid chromatography) were used to determine the radiochemical purity of the tracer. As a first investigation of the (68)Ga tracers' lipophilicity the n-octanol/water distribution coefficient of (68)Ga species present in a pH 7.4 solution was determined by an extraction method. In vitro stability measurements of the tracer in various media at physiological pH were performed, revealing different rates of decomposition. PMID:27584545

  16. Standardization of 68Ge/68Ga Using Three Liquid Scintillation Counting Based Methods

    PubMed Central

    Zimmerman, B. E.; Cessna, J. T.; Fitzgerald, R.

    2008-01-01

    A solution containing 68Ge in equilibrium with its daughter, 68Ga, has been standardized for the first time at the National Institute of Standards and Technology (NIST) using 3 liquid scintillation-based techniques: live-timed 4πβ -γ anticoincidence (LTAC) counting, the Triple-to-Double Coincidence Ratio (TDCR) method, and 3H-standard efficiency tracing with the CIEMAT1/NIST (CNET) method. The LTAC technique is much less dependent on level scheme data and model-dependent parameters and was thus able to provide a reference activity concentration value for the master solution with a combined standard uncertainty of about 0.3 %. The other two methods gave activity concentration values with respective differences from the reference value of +1.2 % and −1.5 %, which were still within the experimental uncertainties. Measurements made on the NIST “4π”γ secondary standard ionization chamber allowed for the determination of calibration factors for that instrument, allowing future calibrations to be made for 68Ge/68Ga without the need for a primary measurement. The ability to produce standardized solutions of 68Ge presents opportunities for the development of a number of NIST-traceable calibration sources with very low (<1 %) relative standard uncertainties that can be used in diagnostic medical imaging. PMID:27096126

  17. Tumor imaging with novel radiogallium (67/68Ga) labeled agents

    NASA Astrophysics Data System (ADS)

    Kulkarni, P. V.; Antich, P. P.; Constantinescu, A.; Ranney, D. F.; Fernando, J. L.; Xiong, R.; Oz, O.; Parkey, R. W.

    1997-02-01

    Gallium-67 (t1/2: 78 h) has played an important role in tumor imaging. It is produced in a cyclotron and is commercially available for routine clinical use. 68Ga (t1/2: 68 min), a positron emitter, suitable for positron emission tomographic (PET) imaging, is obtained from a generator with long lived parent 68Ge (t1/2: 288 d). Radiogallium has been used mostly, as gallium citrate in imaging studies. Recently, receptor specific agents labeled with gallium have been developed. These include, agents to image somatostatin and folate receptors. We have shown that a new class of agents based on glycosaminoglycoans (GLYCOS) target a variety of tumors. Gallium labeled deferroxamine (DF) bound to sulfated glycosaminoglycans has the ability to rapidly target and permeate a wide variety of solid animal tumors and also undergo rapid blood clearance almost exclusively by the renal route. We have been able to image (within 5 min to 1 hr), prostate adenocarcinoma (AT-1 tumor) grown in surgically prepared pedicles of Copenhagen male rats and breast tumor in pedicles of Fisher female rats. 67Ga labeled agent was used in single photon imaging mode and 68Ga labeled agent was used in PET mode with a small animal PET imaging device built in our laboratory with plastic scintillating optical fibers.

  18. Preclinical Evaluation of 68Ga-DOTA-Minigastrin for the Detection of Cholecystokinin-2/Gastrin Receptor–Positive Tumors

    PubMed Central

    Brom, Maarten; Joosten, Lieke; Laverman, Peter; Oyen, Wim J.G.; Béhé, Martin; Gotthardt, Martin; Boerman, Otto C.

    2011-01-01

    In comparison to somatostatin receptor scintigraphy, gastrin receptor scintigraphy using 111In-DTPA-minigastrin (MG0) showed added value in diagnosing neuroendocrine tumors. We investigated whether the 68Ga-labeled gastrin analogue DOTA-MG0 is suited for positron emission tomography (PET), which could improve image quality. Targeting of cholecystokinin-2 (CCK2)/gastrin receptor–positive tumor cells with DOTA-MG0 labeled with either 111In or 68Ga in vitro was investigated using the AR42J rat tumor cell line. Biodistribution was examined in BALB/c nude mice with a subcutaneous AR42J tumor. In vivo PET imaging was performed using a preclinical PET–computed tomographic scanner. DOTA-MG0 showed high receptor affinity in vitro. Biodistribution studies revealed high tumor uptake of 68Ga-DOTA-MG0: 4.4 ± 1.3 %ID/g at 1 hour postinjection. Coadministration of an excess unlabeled peptide blocked the tumor uptake (0.7 ± 0.1 %ID/g), indicating CCK2/gastrin receptor–mediated uptake (p = .0005). The biodistribution of 68Ga-DOTA-MG0 was similar to that of 111In-DOTA-MG0. Subcutaneous and intraperitoneal tumors were clearly visualized by small-animal PET imaging with 5 MBq 68Ga-DOTA-MG0. 111In- and 68Ga-labeled DOTA-MG0 specifically accumulate in CCK2/gastrin receptor–positive AR42J tumors with similar biodistribution apart from the kidneys. AR42J tumors were clearly visualized by microPET. Therefore, 68Ga-DOTA-MG0 is a promising tracer for PET imaging of CCK2/gastrin receptor–positive tumors in humans. PMID:21439259

  19. Gastrin-releasing Peptide Receptor Imaging in Breast Cancer Using the Receptor Antagonist 68Ga-RM2 And PET

    PubMed Central

    Stoykow, Christian; Erbes, Thalia; Maecke, Helmut R; Bulla, Stefan; Bartholomä, Mark; Mayer, Sebastian; Drendel, Vanessa; Bronsert, Peter; Werner, Martin; Gitsch, Gerald; Weber, Wolfgang A; Stickeler, Elmar; Meyer, Philipp T

    2016-01-01

    Introduction: The gastrin-releasing peptide receptor (GRPR) is overexpressed in breast cancer. The present study evaluates GRPR imaging as a novel imaging modality in breast cancer by employing positron emission tomography (PET) and the GRPR antagonist 68Ga-RM2. Methods: Fifteen female patients with biopsy confirmed primary breast carcinoma (3 bilateral tumors; median clinical stage IIB) underwent 68Ga-RM2-PET/CT for pretreatment staging. In vivo tumor uptake of 68Ga-RM2 was correlated with estrogen (ER) and progesterone (PR) receptor expression, HER2/neu status and MIB-1 proliferation index in breast core biopsy specimens. Results: 13/18 tumors demonstrated strongly increased 68Ga-RM2 uptake compared to normal breast tissue (defined as PET-positive). All PET-positive primary tumors were ER- and PR-positive (13/13) in contrast to only 1/5 PET-negative tumors. Mean SUVMAX of ER-positive tumors was 10.6±6.0 compared to 2.3±1.0 in ER-negative tumors (p=0.016). In a multivariate analysis including ER, PR, HER2/neu and MIB-1, only ER expression predicted 68Ga-RM2 uptake (model: r2=0.55, p=0.025). Normal breast tissue showed inter- and intraindividually variable, moderate GRPR binding (SUVMAX 2.3±1.0), while physiological uptake of other organs was considerably less except pancreas. Of note, 68Ga-RM2-PET/CT detected internal mammary lymph nodes with high 68Ga-RM2 uptake (n=8), a contralateral axillary lymph node metastasis (verified by biopsy) and bone metastases (n=1; not detected by bone scan and CT). Conclusion: Our study demonstrates that 68Ga-RM2-PET/CT is a promising imaging method in ER-positive breast cancer. In vivo GRPR binding assessed by 68Ga-RM2-PET/CT correlated with ER expression in primary tumors of untreated patients. PMID:27446498

  20. [68Ga]Pentixafor-PET/CT for imaging of chemokine receptor 4 expression in small cell lung cancer - initial experience

    PubMed Central

    Rudelius, Martina; Schmid, Jan-Stefan; Schoene, Alexander; Schirbel, Andreas; Samnick, Samuel; Pelzer, Theo; Buck, Andreas K.; Kropf, Saskia; Wester, Hans-Jürgen; Herrmann, Ken

    2016-01-01

    Chemokine receptor CXCR4 is a key factor for tumor growth and metastasis in several types of human cancer. This study investigated the feasibility of CXCR4-directed imaging of small cell lung cancer (SCLC) with positron emission tomography/computed tomography (PET/CT) using the radiolabelled chemokine ligand [68Ga]Pentixafor. 10 patients with primarily diagnosed (n=3) or pre-treated (n=7) SCLC (n=9) or large cell neuroendocrine carcinoma of the lung (LCNEC, n=1) underwent [68Ga]Pentixafor-PET/CT. 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG, n=6) and/or somatostatin receptor (SSTR)-directed PET/CT with [68Ga]DOTATOC (n=5) and immunohistochemistry (n=10) served as standards of reference. CXCR4-PET was positive in 8/10 patients and revealed more lesions with significantly higher tumor-to-background ratios than SSTR-PET. Two patients who were positive on [18F]FDG-PET were missed by CXCR4-PET, in the remainder [68Ga]Pentixafor detected an equal (n=2) or higher (n=2) number of lesions. CXCR4 expression of tumor lesions could be confirmed by immunohistochemistry. Non-invasive imaging of CXCR4 expression in SCLC is feasible. [68Ga]Pentixafor as a novel PET tracer might serve as readout for confirmation of CXCR4 expression as prerequisite for potential CXCR4-directed treatment including receptor-radio(drug)peptide therapy. PMID:26843617

  1. May bone-targeted radionuclide therapy overcome PRRT-refractory osseous disease in NET? A pilot report on 188Re-HEDP treatment in progressive bone metastases after 177Lu-octreotate

    PubMed Central

    Sabet, Amir; Khalaf, Feras; Mahjoob, Soha; Al-Zreiqat, Abdullah; Biersack, Hans-Jürgen; Ezziddin, Samer

    2014-01-01

    Bone metastases (BM) of gastroenteropancreatic neuroendocrine tumours (GEP-NET) can be effectively controlled by peptide receptor radionuclide therapy (PRRT). Eventually, however, BM may become refractory and determine survival. We aimed to assess the clinical benefit of bone-targeted radionuclide therapy (BTRT) in this subgroup of patients failing PRRT. A small cohort of n=6 patients with progressive BM failing PRRT with 177Lu-octreotate (mean cumulative activity, 46.7 GBq) were treated with a total of 11 cycles BTRT using 2.6-3.3 GBq 188Re-HEDP per cycle and a median cumulative activity of 5.9 GBq. Pain palliation was quantified applying the visual analogue scale (VAS). The mean VAS decreased from 6.6 (range 5-8) to 3.7 (range 2-7). Five patients experienced partial resolution of bone pain (≥ 2 steps reduction on the VAS for at least 2 weeks) and one patient had no significant improvement. Flare phenomena occurred in 2 patients and lasted for 2-3 days. Tumor response consisted of stable disease in 2 and progressive disease in 4 patients. No regression of bone metastases has been observed. The median overall survival was 5 months (range 2-9). Relevant myelosuppression (grade 3-4; self-limited with no interventions or hospitalization), occurred 4-6 weeks post-treatment, and after 2 (18.1%) administrations or in 1 (16.7%) patient. No other relevant toxicities or treatment-related death was observed. 188Re-HEDP may be safely applied in patients with bone metastatic GEP-NET previously treated with 177Lu-octreotate. While acceptable pain relief may be expected, no tumor-regression or long-term disease stabilization with apparent survival benefit has been observed. This disputes the use of BTRT as salvage anti-tumor therapy in PRRT-refractory neuroendocrine bone metastases. PMID:24380048

  2. Biological evaluation of (177)Lu-labeled DOTA-Ala(SO3H)-Aminooctanoyl-Gln-Trp-Ala-Val-N methyl Gly-His-Statine-Leu-NH2 for gastrin-releasing peptide receptor-positive prostate tumor targeting.

    PubMed

    Lim, Jae Cheong; Cho, Eun Ha; Kim, Jin Joo; Choi, Sang Mu; Lee, So young; Nam, Sung Soo; Park, Ul Jae; Park, Soo Hyun

    2015-02-01

    Bombesin binds with selectivity and high affinity to a Gastrin-releasing peptide receptor (GRPR), which is highly overexpressed in prostate cancer cells. The present study describes the in vitro and in vivo biological characteristics of DOTA-Ala(SO3H)-Aminooctanoyl-Gln-Trp-Ala-Val-N methyl Gly-His-Statine-Leu-NH2 (DOTA-sBBNA), an antagonist analogue of bombesin peptide for the targeting of GRPR. DOTA-sBBNA was synthesized and labeled with (177)Lu as previously published. A saturation assay on PC-3 human prostate cancer cells revealed that the Kd value of the radiolabeled peptide was 1.88 nM with a maximum binding capacity (Bmax) of 289.3 fmol/10(6) cells. The radio-peptide slowly internalized, and 24.4±0.5% of the total binding was internalized in 4hr. Biodistribution studies were conducted in healthy and PC-3 xenografted balb/c mice, which showed high uptake and retention of tumor-associated radioactivity in PC-3 xenografted mice. The tumor-to-blood ratio was 126.02±9.36 at 1.5hr p.i., and was increased to 216.33±61.58 at 24hr p.i., which means that the radiolabeled peptide was highly accumulated in a tumor and rapidly cleared from the blood pool. The GRPR is also over-expressed in Korean prostate cancer patients. These results suggest that this (177)Lu-labeled peptide has promising characteristics for application in nuclear medicine, namely for the diagnosis and treatment of GRPR over-expressing prostate tumors. PMID:25457455

  3. (68)Ga-PSMA ligand PET/CT in patients with prostate cancer: How we review and report.

    PubMed

    Rauscher, Isabel; Maurer, Tobias; Fendler, Wolfgang P; Sommer, Wieland H; Schwaiger, Markus; Eiber, Matthias

    2016-01-01

    Recently, positron emission tomography (PET) imaging using PSMA-ligands has gained high attention as a promising new radiotracer in patients with prostate cancer (PC). Several studies promise accurate staging of primary prostate cancer and restaging after biochemical recurrence with (68)Ga-PSMA ligand Positron emission tomography/computed tomography (PET/CT). However, prospective trials and clinical guidelines for this new technique are still missing. Therefore, we summarized our experience with (68)Ga-PSMA ligand PET/CT examinations in patients with primary PC and biochemical recurrence. It focuses on the technical and logistical aspects of (68)Ga-PSMA ligand PET/CT examination as well as on the specific background for image reading discussing also potential pitfalls. Further, it includes relevant issues on free-text as well as structured reporting used in daily clinical routine. PMID:27277843

  4. Evaluation of 68Ga-labeled MG7 antibody: a targeted probe for PET/CT imaging of gastric cancer.

    PubMed

    Xu, Bing; Li, Xiaowei; Yin, Jipeng; Liang, Cong; Liu, Lijuan; Qiu, Zhaoyan; Yao, Liping; Nie, Yongzhan; Wang, Jing; Wu, Kaichun

    2015-01-01

    MG7-Ag, a specific gastric cancer-associated antigen, can be used to non-invasively monitor gastric cancer by molecular imaging with positron emission tomography/computed tomography (PET/CT). In this study, we prepared and evaluated a (68)Ga-labeled MG7 antibody as a molecular probe for nanoPET/CT imaging of gastric cancer in a BGC-823 tumor xenografted mouse model. Macrocyclic chelator 1,4,7-triazacyclononane-N,N0,N00-triacetic acid (NOTA)-conjugated MG7 antibody was synthesized and radiolabeled with (68)Ga (t1/2 = 67.71 min). Then, (68)Ga-NOTA-MG7 was tested using in vitro cytological studies, in vivo nanoPET/CT and Cerenkov imaging studies as well as ex vivo biodistribution and histology studies. The in vitro experiments demonstrated that (68)Ga-NOTA-MG7 has an excellent radiolabeling efficiency of approximately 99% without purification, and it is stable in serum after 120 min of incubation. Cell uptake and retention studies confirmed that (68)Ga-NOTA-MG7 has good binding affinity and tumor cell retention. For the nanoPET imaging study, the predominant uptake of (68)Ga-NOTA-MG7 was visualized in tumor, liver and kidneys. The tumor uptake reached at its peak (2.53 ± 0.28%ID/g) at 60 min pi. Cherenkov imaging also confirmed the specificity of tumor uptake. Moreover, the biodistribution results were consistent with the quantification data of nanoPET/CT imaging. Histologic analysis also demonstrated specific staining of BGC-823 tumor cell lines. PMID:25733152

  5. Evaluation of 68Ga-Labeled MG7 Antibody: A Targeted Probe for PET/CT Imaging of Gastric Cancer

    PubMed Central

    Xu, Bing; Li, Xiaowei; Yin, Jipeng; Liang, Cong; Liu, Lijuan; Qiu, Zhaoyan; Yao, Liping; Nie, Yongzhan; Wang, Jing; Wu, Kaichun

    2015-01-01

    MG7-Ag, a specific gastric cancer-associated antigen, can be used to non-invasively monitor gastric cancer by molecular imaging with positron emission tomography/computed tomography (PET/CT). In this study, we prepared and evaluated a 68Ga-labeled MG7 antibody as a molecular probe for nanoPET/CT imaging of gastric cancer in a BGC-823 tumor xenografted mouse model. Macrocyclic chelator 1,4,7-triazacyclononane-N,N0,N00-triacetic acid (NOTA)-conjugated MG7 antibody was synthesized and radiolabeled with 68Ga (t1/2 = 67.71 min). Then, 68Ga-NOTA-MG7 was tested using in vitro cytological studies, in vivo nanoPET/CT and Cerenkov imaging studies as well as ex vivo biodistribution and histology studies. The in vitro experiments demonstrated that 68Ga-NOTA-MG7 has an excellent radiolabeling efficiency of approximately 99% without purification, and it is stable in serum after 120 min of incubation. Cell uptake and retention studies confirmed that 68Ga-NOTA-MG7 has good binding affinity and tumor cell retention. For the nanoPET imaging study, the predominant uptake of 68Ga-NOTA-MG7 was visualized in tumor, liver and kidneys. The tumor uptake reached at its peak (2.53 ± 0.28%ID/g) at 60 min pi. Cherenkov imaging also confirmed the specificity of tumor uptake. Moreover, the biodistribution results were consistent with the quantification data of nanoPET/CT imaging. Histologic analysis also demonstrated specific staining of BGC-823 tumor cell lines. PMID:25733152

  6. Mechanochemical synthesis of mesoporous tin oxide: a new generation nanosorbent for (68)Ge/(68)Ga generator technology.

    PubMed

    Chakravarty, Rubel; Chakraborty, Sudipta; Shukla, Rakesh; Bahadur, Jitendra; Ram, Ramu; Mazumder, Subhasish; Dev Sarma, Haladhar; Tyagi, Avesh Kumar; Dash, Ashutosh

    2016-09-14

    The present article reports the synthesis and characterization of mesoporous tin oxide (MTO) nanoparticles by a solid-state mechanochemical route. The synthesized material was used as an advanced sorbent material for (68)Ge/(68)Ga radionuclide generator technology. Gallium-68 (t½ = 68 min) obtained from the (68)Ge/(68)Ga generator is an important diagnostic radioisotope which holds tremendous potential in the non-invasive monitoring of various diseases, including cancer, using positron emission tomography (PET). The crystallite size of the MTO nanoparticles was in the range of 6-12 nm with a large surface area of 265 ± 16 m(2) g(-1), while the mean pore radius was found to be 2.1 ± 0.6 nm. Determination of the zeta-potential of the MTO nanoparticles dispersed in solutions at different pH values aided in understanding the sorption and separation mechanisms, which were based on the surface charge developed on the nanosorbent. The sorption capacity observed under column-flow conditions was 85 ± 5 mg Ge per g of nanosorbent. A clinical-scale (68)Ge/(68)Ga generator (740 MBq) was developed using this nanosorbent. Gallium-68 could be regularly eluted from this generator over a prolonged period of 1 year with >70% elution yield and met all the requirements for clinical use. The suitability of (68)Ga obtained from it was evaluated in preclinical settings by the preparation of a (68)Ga-labeled peptide containing the arginine-glycine-aspartic acid (RGD) motif. To the best of our knowledge, this is the first report on the synthesis of MTO nanoparticles by a mechanochemical route which could be effectively utilized for the routine preparation of clinical-scale (68)Ge/(68)Ga generators. The promising results obtained in this study would facilitate greater implementation of mechanochemistry for the synthesis of nanosorbents for radionuclide generator technology since this method is simple, economical and convenient. PMID:27482930

  7. [Rectal mucosa metastasis in recurrent prostate cancer : (68)Ga-PSMA-PET/CT allows targeted salvage radiotherapy].

    PubMed

    Düwel, C; Blümel, C; Westenfelder, K; Wagner-Thiessen, E; Becker, A; Gschwend, J E; Eiber, M; Maurer, T

    2016-08-01

    This article presents for the first time a case of rectal mucosa metastasis of recurrent prostate cancer that was diagnosed with (68)Ga-PSMA PET/CT. After histological confirmation, the patient was treated with salvage radiotherapy. This case report underlines the specificity and efficacy of PSMA-based PET imaging. In case of biochemical relapse, it can be used even at low PSA levels to detect prostate cancer metastases that might also be in atypical locations. Thus, (68)Ga-PSMA PET/CT may allow new options for salvage therapy. PMID:27385310

  8. (68)Ga/DOTA- and (64)Cu/NOTA-phthalocyanine conjugates as fluorescent/PET bimodal imaging probes.

    PubMed

    Ranyuk, Elena; Lebel, Réjean; Bérubé-Lauzière, Yves; Klarskov, Klaus; Lecomte, Roger; van Lier, Johan E; Guérin, Brigitte

    2013-09-18

    In this paper, we describe the synthesis and characterization of a series of new bimodal probes combining water-soluble sulfonated zinc phthalocyanine (ZnPc) as a fluorescence imaging unit and either (68)Ga/1,4,7,10-tetraazocyclododecane-N,N'N″,N'″-tetraacetic acid (DOTA) or (64)Cu/1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) for PET imaging. The two moieties were linked through aliphatic chains of different lengths to modulate amphiphilicity. Labeling of DOTA- or NOTA-ZnPc conjugates with (68)Ga (t1/2 = 68 min) and (64)Cu (t1/2 = 12.7 h) was performed at 100 °C for 15 min with >90% efficiency for all conjugates. In vitro plasma stability assays demonstrated high stability of the (64)Cu/NOTA-ZnPc conjugate, which remained intact over a 24 h time period, and reasonably high stability of the (68)Ga/DOTA-ZnPc conjugate, which released up to 7% of free (68)Ga over a 3 h period. Based on in vitro plasma stability results, we performed biodistribution studies on two (64)Cu-labeled derivatives, which allowed us to select a single candidate for preliminary in vivo experiments. Fluorescence and PET imaging confirmed the potential of these novel conjugates to act as bimodal probes. PMID:23978056

  9. Measuring HER2-Receptor Expression In Metastatic Breast Cancer Using [68Ga]ABY-025 Affibody PET/CT

    PubMed Central

    Sörensen, Jens; Velikyan, Irina; Sandberg, Dan; Wennborg, Anders; Feldwisch, Joachim; Tolmachev, Vladimir; Orlova, Anna; Sandström, Mattias; Lubberink, Mark; Olofsson, Helena; Carlsson, Jörgen; Lindman, Henrik

    2016-01-01

    Purpose: Positron Emission Tomography (PET) imaging of HER2 expression could potentially be used to select patients for HER2-targed therapy, predict response based on uptake and be used for monitoring. In this phase I/II study the HER2-binding Affibody molecule ABY-025 was labeled with 68Ga-gallium ([68Ga]ABY-025) for PET to study effect of peptide mass, test-retest variability and correlation of quantified uptake in tumors to histopathology. Experimental design: Sixteen women with known metastatic breast cancer and on-going treatment were included and underwent FDG PET/CT to identify viable metastases. After iv injection of 212±46 MBq [68Ga]ABY-025 whole-body PET was performed at 1, 2 and 4 h. In the first 10 patients (6 with HER2-positive and 4 with HER2-negative primary tumors), [68Ga]ABY-025 PET/CT with two different doses of injected peptide was performed one week apart. In the last six patients (5 HER2-positive and 1 HER2-negative primary tumors), repeated [68Ga]ABY-025 PET were performed one week apart as a test-retest of uptake in individual lesions. Biopsies from 16 metastases in 12 patients were collected for verification of HER2 expression by immunohistochemistry and in-situ hybridization. Results: Imaging 4h after injection with high peptide content discriminated HER2-positive metastases best (p<0.01). PET SUV correlated with biopsy HER2-scores (r=0.91, p<0.001). Uptake was five times higher in HER2-positive than in HER2-negative lesions with no overlap (p=0.005). The test-retest intra-class correlation was r=0.996. [68Ga]ABY-025 PET correctly identified conversion and mixed expression of HER2 and targeted treatment was changed in 3 of the 16 patients. Conclusion: [68Ga]ABY-025 PET accurately quantifies whole-body HER2-receptor status in metastatic breast cancer. PMID:26877784

  10. 90Y-labeled monoclonal antibodies for cancer therapy.

    PubMed

    Washburn, L C; Hwa Sun, T T; Crook, J E; Byrd, B L; Carlton, J E; Hung, Y W; Steplewski, Z S

    1986-01-01

    Monoclonal antibody 17-1A, which has specificity for colorectal carcinoma, was labeled with 90Y (10-20% radiolabeling yield). Tissue distribution studies in tumor-bearing nude mice were carried out. 90Y-labeled 17-1A showed good uptake in the SW 948 colon carcinoma cell line. However, 90Y-labeled A5C3, a monoclonal antihepatitis virus antibody studied as a control, showed similar uptake in this tumor. Neither antibody was taken up well by a WM-9 melanoma. It is believed that the loss of specificity observed is due to the low specific activity of the 90Y-labeled monoclonal antibody preparations used. This hypothesis is supported by radioimmunoassay data. PMID:3793501

  11. 90Y labeled phosphorodiamidate morpholino oligomer for pretargeting radiotherapy.

    PubMed

    Liu, Guozheng; Dou, Shuping; Liu, Yuxia; Wang, Yuzhen; Rusckowski, Mary; Hnatowich, Donald J

    2011-12-21

    While (188)Re has been used successfully in mice for tumor radiotherapy by MORF/cMORF pretargeting, previous radiolabeling of the amine-derivatized cMORF with (90)Y, a longer physical half-life nuclide, was not very successful. After developing a method involving a prepurification heating step during conjugation that increases labeling efficiency and label stability, the biodistribution of (90)Y-DOTA-Bn-SCN-cMORF ((90)Y-DOTA-cMORF) was measured in normal mice and in MORF-CC49 pretargeted mice that bear LS174T tumors. Absorbed radiation doses were then estimated and compared to those estimated for (188)Re. The pharmacokinetics of the (90)Y-DOTA-cMORF in normal mice and in the pretargeted nude mice was similar to that observed previously with (99m)Tc- and (188)Re-MAG(3)-cMORFs. While the (90)Y-DOTA-cMORF cleared rapidly from normal tissues, tumor clearance was very slow and tumor radioactivity accumulation was constant for at least 7 days such that the tumor/blood (T/B) ratio increased linearly from 6 to 25 over this period. Therefore, by extrapolation, normal tissue toxicities following administration of therapeutic doses of (90)Y may be comparable to that observed for (188)Re in which the T/B increased from 5 to 20. In conclusion, radiolabeling of DOTA-cMORF with (90)Y was improved by introducing a prepurification heating step during conjugation. The (90)Y-DOTA-cMORF provided a similar T/B ratio and biodistribution to that of (188)Re-MAG(3)-cMORF and was retained well in the tumor pretargeted with MORF-CC49. Because of the longer physical half-life, the T/NT absorbed radiation dose ratios were improved in most organs and especially in blood. PMID:21985267

  12. 68Ga-DOTA-Siglec-9 PET/CT imaging of peri-implant tissue responses and staphylococcal infections

    PubMed Central

    2014-01-01

    Background Staphylococcus epidermidis (S. epidermidis) has emerged as one of the leading pathogens of biomaterial-related infections. Vascular adhesion protein-1 (VAP-1) is an inflammation-inducible endothelial molecule controlling extravasation of leukocytes. Sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) is a leukocyte ligand of VAP-1. We hypothesized that 68Ga-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugated Siglec-9 motif containing peptide (68Ga-DOTA-Siglec-9) could detect inflammatory response due to S. epidermidis peri-implant infection by positron emission tomography (PET). Methods Thirty Sprague-Dawley rats were randomized into three groups. A sterile catheter was implanted into the medullary canal of the left tibia. In groups 1 and 2, the implantation was followed by peri-implant injection of S. epidermidis or Staphylococcus aureus (S. aureus) with adjunct injections of aqueous sodium morrhuate. In group 3, sterile saline was injected instead of bacteria and no aqueous sodium morrhuate was used. At 2 weeks after operation, 68Ga-DOTA-Siglec-9 PET coupled with computed tomography (CT) was performed with the measurement of the standardized uptake value (SUV). The presence of the implant-related infection was verified by microbiological analysis, imaging with fluorescence microscope, and histology. The in vivo PET results were verified by ex vivo measurements by gamma counter. Results In group 3, the tibias with implanted sterile catheters showed an increased local uptake of 68Ga-DOTA-Siglec-9 compared with the intact contralateral bones (SUVratio +29.5%). 68Ga-DOTA-Siglec-9 PET detected inflammation induced by S. epidermidis and S. aureus catheter-related bone infections (SUVratio +58.1% and +41.7%, respectively). The tracer uptake was significantly higher in the S. epidermidis group than in group 3 without bacterial inoculation, but the difference between S. epidermidis and S. aureus groups was not statistically

  13. A 90Y labeled phosphorodiamidate morpholino oligomer for pretargeting radiotherapy

    PubMed Central

    Liu, Guozheng; Dou, Shuping; Liu, Yuxia; Wang, Yuzhen; Rusckowski, Mary; Hnatowich, Donald J

    2011-01-01

    While 188Re has been used successfully in mice for tumor radiotherapy by MORF/cMORF pretargeting, previous radiolabeling of the 18 mer amine-derivatized cMORF with 90Y, a longer physical half life nuclide, was not very successful. After developing a method involving a pre-purification heating step during conjugation that increases labeling efficiency and label stability, the biodistribution of 90Y-DOTA-Bn-SCN-cMORF was measured in normal mice and in MORF-CC49 pretargeted mice that bear LS174T tumors. Absorbed radiation doses were then estimated and compared to those estimated for 188Re. The pharmacokinetics of the 90Y-DOTA-cMORF in normal mice and in the pretargeted nude mice was similar to that observed previously with 99mTc- and 188Re-MAG3-cMORFs. While the 90Y-DOTA-cMORF cleared rapidly from normal tissues, tumor clearance was very slow and tumor radioactivity accumulation was constant for at least 7 days such that the tumor/blood (T/B) ratio increased linearly from 6 to 25 over this period. Therefore by extrapolation, normal tissue toxicities following administration of therapeutic doses of 90Y may be comparable to that observed for 188Re in which the T/B increased from 5 to 20. In conclusion, radiolabeling of DOTA-cMORF with 90Y was improved by introducing a prepurification heating step during conjugation. The 90Y-DOTA-cMORF provided a similar T/B ratio and biodistribution to that of 188Re-MAG3-cMORF and retained well in the tumor pretargeted with MORF-CC49. Because of the longer physical half life, the T/NT absorbed radiation dose ratios were improved in most organs and especially in blood. PMID:21985267

  14. (68)Ga-DOTANOC PET/CT detection of multiple extracranial localizations in a patient with anaplastic meningioma.

    PubMed

    Golemi, A; Ambrosini, A; Cecchi, P; Ruiu, A; Chondrogiannis, S; Farsad, M; Rubello, D

    2015-01-01

    We report herein a case of a 65-year-old male with intracranial recurrence of atypical meningioma initially treated with a combination of surgical resection and gamma knife radiotherapy. Afterwards, he underwent a (68)Ga-DOTANOC PET/CT scan in order to evaluate the feasibility of peptide receptor radionuclide therapy (PRRT). The scan identified multiple pulmonary, pleural and lymph node localizations. Histological diagnosis was consistent with intracranial atypical meningioma with diffuse metastatic spread. In our case, we have shown that meningioma with extracranial locations may present high uptake of somatostatin receptor analogues. Among other radionuclides, we believe that (68)Ga-DOTANOC PET/CT may be particularly useful for staging, detection of recurrence, evaluation of disease extension and alternative therapeutic approaches. PMID:25890891

  15. Selecting patients for treatment with 90Y ibritumomab tiuxetan (Zevalin).

    PubMed

    Gregory, Stephanie A

    2003-12-01

    Yttrium 90 ibritumomab tiuxetan (Zevalin; Biogen Idec Inc, Cambridge, MA) was the first radioimmunotherapeutic agent approved by the US Food and Drug Administration. It is indicated for treating patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma, including patients with rituximab-refractory follicular non-Hodgkin's lymphoma. Proper patient selection is essential for optimizing the efficacy and safety of treatment with (90)Y ibritumomab tiuxetan. It may be advisable to use (90)Y ibritumomab tiuxetan relatively early in a patient's course of treatment because overall and complete response rates, and the estimated median duration of response, are higher among patients who have had fewer median prior antineoplastic regimens than among those who have had a greater median number of such regimens. Furthermore, the myeloablative effect of multiple courses of chemotherapy can preclude the later use of (90)Y ibritumomab tiuxetan. In contrast, other therapies, including chemotherapy and rituximab, can be used safely and successfully after (90)Y ibritumomab tiuxetan without concerns about increased hematologic toxicity from the previous radioimmunotherapy. The main adverse event associated with (90)Y ibritumomab tiuxetan therapy is hematologic toxicity and, as a result, only patients with adequate bone marrow reserves and less than 25% lymphoma marrow involvement should currently be considered for clinical therapy. PMID:14710399

  16. 90 Y-ibritumomab tiuxetan: a nearly forgotten opportunity

    PubMed Central

    Mondello, Patrizia; Cuzzocrea, Salvatore; Navarra, Michele; Mian, Michael

    2016-01-01

    Y-ibritumomab tiuxetan (90Y-IT) combines the benefits of a monoclonal antibody with the efficacy of radiation in the treatment of B-cell non-Hodgkin lymphoma (NHL), a remarkably radiosensitive hematologic malignancy. 90Y-IT activity has been well established in the indolent setting, being approved in front-line treatment of follicular lymphoma (FL) patients as well as salvage therapy. However, no advantage in OS was observed with respect to standard treatment. Promising data are available also for aggressive B-cell lymphoma. In particular, the addition of RIT to short-course first line chemotherapy enables reduction of chemotherapy while maintaining cure rates in elderly, untreated diffuse large B-cell lymphoma (DLBCL) patients. Furthermore, 90Y-IT improves response rate and outcomes of relapsed/refractory DLBCL patients, eligible and ineligible for autologous stem cell transplantation (ASCT). Clinical results have shown a role of 90Y-IT even in mantle cell lymphoma (MCL). RIT might improve responses and treat minimal residual disease when used as consolidation after first-line chemotherapy in MCL. Moreover, 90Y-IT has demonstrated its efficacy in combination with high-dose chemotherapies as conditioning regimen for ASCT, with evidence suggesting the ability to overcome chemotherapy resistance. Herein, we review the available evidence for this approved drug and examine the recently published and ongoing trials for potential novel indication in aggressive B-cell NHL. PMID:26657116

  17. 90 Y-ibritumomab tiuxetan: a nearly forgotten opportunityr.

    PubMed

    Mondello, Patrizia; Cuzzocrea, Salvatore; Navarra, Michele; Mian, Michael

    2016-02-16

    Y-ibritumomab tiuxetan (90Y-IT) combines the benefits of a monoclonal antibody with the efficacy of radiation in the treatment of B-cell non-Hodgkin lymphoma (NHL), a remarkably radiosensitive hematologic malignancy. 90Y-IT activity has been well established in the indolent setting, being approved in front-line treatment of follicular lymphoma (FL) patients as well as salvage therapy. However, no advantage in OS was observed with respect to standard treatment. Promising data are available also for aggressive B-cell lymphoma. In particular, the addition of RIT to short-course first line chemotherapy enables reduction of chemotherapy while maintaining cure rates in elderly, untreated diffuse large B-cell lymphoma (DLBCL) patients. Furthermore, 90Y-IT improves response rate and outcomes of relapsed/refractory DLBCL patients, eligible and ineligible for autologous stem cell transplantation (ASCT). Clinical results have shown a role of 90Y-IT even in mantle cell lymphoma (MCL). RIT might improve responses and treat minimal residual disease when used as consolidation after first-line chemotherapy in MCL. Moreover, 90Y-IT has demonstrated its efficacy in combination with high-dose chemotherapies as conditioning regimen for ASCT, with evidence suggesting the ability to overcome chemotherapy resistance. Herein, we review the available evidence for this approved drug and examine the recently published and ongoing trials for potential novel indication in aggressive B-cell NHL. PMID:26657116

  18. Radiolabeling optimization and characterization of (68)Ga labeled DOTA-polyamido-amine dendrimer conjugate - Animal biodistribution and PET imaging results.

    PubMed

    Ghai, Aanchal; Singh, Baljinder; Panwar Hazari, Puja; Schultz, Michael K; Parmar, Ambika; Kumar, Pardeep; Sharma, Sarika; Dhawan, Devinder; Kumar Mishra, Anil

    2015-11-01

    The present study describes the optimization of (68)Ga radiolabeling with PAMAM dendrimer-DOTA conjugate. A conjugate (PAMAM-DOTA) concentration of 11.69µM, provided best radiolabeling efficiency of more than 93.0% at pH 4.0, incubation time of 30.0min and reaction temperature ranging between 90 and 100°C. The decay corrected radiochemical yield was found to be 79.4±0.01%. The radiolabeled preparation ([(68)Ga]-DOTA-PAMAM-D) remained stable (radiolabeling efficiency of 96.0%) at room temperature and in serum for up to 4-h. The plasma protein binding was observed to be 21.0%. After intravenous administration, 50.0% of the tracer cleared from the blood circulation by 30-min and less than 1.0% of the injected activity remained in blood by 1.0h. The animal biodistribution studies demonstrated that the tracer excretes through the kidneys and about 0.33% of the %ID/g accumulated in the tumor at 1h post injection. The animal organ's biodistribution data was supported by animal PET imaging showing good 'non-specific' tracer uptake in tumor and excretion is primarily through kidneys. Additionally, DOTA-PAMAM-D conjugation with αVβ3 receptors targeting peptides and drug loading on the dendrimers may improve the specificity of the (68)Ga labeled product for imaging and treating angiogenesis respectively. PMID:26232562

  19. 68GaTHM2BED: a potential generator-produced tracer of myocardial perfusion for positron emission tomography.

    PubMed

    Madsen, S L; Welch, M J; Motekaitis, R J; Martell, A E

    1992-05-01

    THM2BED [N,N,N',N'-tetrakis-(2-hydroxy-3,5-dimethylbenzyl)ethylenediamine] is a new hexadentate ligand which has been synthesized and complexed with gallium isotopes. A conditional stability constant of 22.3 and a pM value of 20.7 have been determined for GaTHM2BED at physiological pH. Hexachelated and pentachelated complexes of GaTHM2BED have been isolated via preparatory HPLC and evaluated individually. The hexachelated isomer of 68GaTHM2BED clears slowly from the myocardium of rats and at 1 h post-injection the heart-to-blood ratio is 1.65. The data ratio indicates that this radiotracer may be capable of measuring blood flow in the heart. The ability of 68GaTHM2BED to delineate myocardial tissue in a dog has been evaluated and good images were obtained using hexachelated 68GaTHM2BED. There is evidence that this complex penetrates the blood-brain barrier. PMID:1526808

  20. Monte Carlo dosimetry of a new 90Y brachytherapy source

    PubMed Central

    Junxiang, Wu; Shihu, You; Jing, Huang; Fengxiang, Long; Chengkai, Wang; Zhangwen, Wu; Qing, Hou

    2015-01-01

    Purpose In this study, we attempted to obtain full dosimetric data for a new 90Y brachytherapy source developed by the College of Chemistry (Sichuan University) for use in high-dose-rate after-loading systems. Material and methods The dosimetric data for this new source were used as required by the dose calculation formalisms proposed by the AAPM Task Group 60 and Task Group 149. The active core length of the new 90Y source was increased to 4.7 mm compared to the value of 2.5 mm for the old 90Sr/90Y source. The Monte Carlo simulation toolkit Geant4 was used to calculate these parameters. The source was located in a 30-cm-radius theoretical sphere water phantom. Results The dosimetric data included the reference absorbed dose rate, the radial dose function in the range of 1.0 to 8.0 mm in the longitudinal axis, and the anisotropy function with a θ in the range of 0° to 90° at 5° intervals and an r in the range of 1.0 to 8.0 mm in 0.2-mm intervals. The reference absorbed dose rate for the new 90Y source was determined to be equal to 1.6608 ± 0.0008 cGy s–1 mCi–1, compared to the values of 0.9063 ± 0.0005 cGy s–1 mCi–1 that were calculated for the old 90Sr/90Y source. A polynomial function was also obtained for the radial dose function by curve fitting. Conclusions Dosimetric data are provided for the new 90Y brachytherapy source. These data are meant to be used commercially in after-loading system. PMID:26622247

  1. Preparation & in vitro evaluation of 90Y-DOTA-rituximab

    PubMed Central

    Kameswaran, Mythili; Pandey, Usha; Dash, Ashutosh; Samuel, Grace; Venkatesh, Meera

    2016-01-01

    Background & objectives: Radioimmunotherapy is extensively being used for the treatment of non-Hodgkin's lymphoma (NHL). Use of rituximab, a chimeric anti-CD20 antibody directed against the CD20 antigen in combination with suitable beta emitters is expected to result in good treatment response by its cross-fire and bystander effects. The present work involves the conjugation of p-isothiocyanatobenzyl DOTA (p-SCN-Bn-DOTA) to rituximab, its radiolabelling with 90Y and in vitro and in vivo evaluation to determine its potential as a radioimmunotherapeutic agent. Methods: Rituximab was conjugated with p-SCN-Bn-DOTA at 1:1 antibody: DOTA molar ratio. The number of DOTA molecules linked to one molecule of rituximab was determined by radioassay and spectroscopic assay. Radiolabelling of rituximab with 90Y was carried out and its in vitro stability was evaluated. In vitro cell binding studies were carried out in Raji cells expressing CD20 antigen. Biodistribution studies were carried out in normal Swiss mice. Results: Using both radioassay and spectroscopic method, it was determined that about five molecules of DOTA were linked to rituximab. Radiolabelling of the rituximab conjugate with 90Y and subsequent purification on PD-10 column gave a product with radiochemical purity (RCP) > 98 per cent which was retained at > 90 per cent up to 72 h when stored at 37°C. In vitro cell binding experiments of 90Y-DOTA-rituximab with Raji cells exhibited specific binding of 20.7 ± 0.1 per cent with 90Y-DOTA-rituximab which reduced to 15.5 ± 0.2 per cent when incubated with cold rituximab. The equilibrium constant Kd for 90Y-DOTA-Rituximab was determined to be 3.38 nM. Radiolabelled antibody showed clearance via hepatobiliary and renal routes and activity in tibia was found to be quite low indicating in vivo stability of 90Y-DOTA-rituximab. Interpretation & conclusions: p-SCN-Bn-DOTA was conjugated with rituximab and radiolabelling with 90Y was carried out. In vitro studies carried

  2. A new 68Ge/68Ga generator system using an organic polymer containing N-methylglucamine groups as adsorbent for 68Ge.

    PubMed

    Nakayama, M; Haratake, M; Ono, M; Koiso, T; Harada, K; Nakayama, H; Yahara, S; Ohmomo, Y; Arano, Y

    2003-01-01

    A macroporous styrene-divinylbenzene copolymer containing N-methylglucamine groups was selected for a new 68Ge/68Ga generator system. This resin packed into a column effectively adsorbed the parent nuclide 68Ge. The daughter 68Ga was eluted from the resin with a solution of a low-affinity gallium chelating ligand such as citric or phosphoric acid. The 68Ge leakage was less than 0.0004% of the 68Ge adsorbed on the resin. By simple mixing of transferrin and desferoxamine conjugated HSA and IgG with the eluate from the column, 68Ga-labeling was completed in high yield. PMID:12485657

  3. A Monte Carlo approach to small-scale dosimetry of solid tumour microvasculature for nuclear medicine therapies with (223)Ra-, (131)I-, (177)Lu- and (111)In-labelled radiopharmaceuticals.

    PubMed

    Amato, Ernesto; Leotta, Salvatore; Italiano, Antonio; Baldari, Sergio

    2015-07-01

    The small-scale dosimetry of radionuclides in solid-tumours is directly related to the intra-tumoral distribution of the administered radiopharmaceutical, which is affected by its egress from the vasculature and dispersion within the tumour. The aim of the present study was to evaluate the combined dosimetric effects of radiopharmaceutical distribution and range of the emitted radiation in a model of tumour microvasculature. We developed a computational model of solid-tumour microenvironment around a blood capillary vessel, and we simulated the transport of radiation emitted by (223)Ra, (111)In, (131)I and (177)Lu using the GEANT4 Monte Carlo. For each nuclide, several models of radiopharmaceutical dispersion throughout the capillary vessel were considered. Radial dose profiles around the capillary vessel, the Initial Radioactivity (IR) necessary to deposit 100 Gy of dose at the edge of the viable tumour-cell region, the Endothelial Cell Mean Dose (ECMD) and the Tumour Edge Mean Dose (TEMD), i.e. the mean dose imparted at the 250-μm layer of tissue, were computed. The results for beta and Auger emitters demonstrate that the photon dose is about three to four orders of magnitude lower than that deposited by electrons. For (223)Ra, the beta emissions of its progeny deliver a dose about three orders of magnitude lower than that delivered by the alpha emissions. Such results may help to characterize the dose inhomogeneities in solid tumour therapies with radiopharmaceuticals, taking into account the interplay between drug distribution from vasculature and range of ionizing radiations. PMID:25979209

  4. Splenic scintigraphy for further differentiation of unclear (68) Ga-DOTATOC-PET/CT findings: Strengths and limitations.

    PubMed

    Werner, Christoph; Winkens, Thomas; Freesmeyer, Martin

    2016-06-01

    Splenic scintigraphy has been described to be a powerful tool in unclear (68 ) Ga-DOTATOC-PET/CT findings, allowing differentiation between somatostatin receptor (Sst)-positive tissue deriving from neuroendocrine tumour (NET) and functioning splenic tissue. However, our own experiences sometimes show a lack of identification on splenic scintigraphy, especially in small lesions, leading to uncertainties regarding the safe identification of NET or splenic tissue. Here, we report on 10 cases with (68) Ga-DOTATOC-PET/CT and (99m) Tc-heat-denaturated red blood cell (HDRBC) scintigraphy and we illustrate the strengths and limitations of (99m) Tc-HDRBC scintigraphy in this context. PMID:27188232

  5. Pheochromocytoma presenting with remote bony recurrence twenty years after initial surgery: detection with 68Ga-DOTANOC PET/CT.

    PubMed

    Parida, Girish Kumar; Dhull, Varun Singh; Sharma, Punit; Bal, Chandrasekhar; Kumar, Rakesh

    2014-04-01

    Pheochromocytomas are rare tumors which can be malignant in 10% of cases. We present the case of a 75-year-old woman who presented with headache and palpitation for 1 year. She had a past history of right adrenalectomy for pheochromocytoma 20 years back. In between, the patient was asymptomatic. Twenty-four-hour urinary vanillylmandelic acid was raised. Noncontrast CT and ultrasound of abdomen were unremarkable. The patient underwent 68Ga-DOTANOC PET/CT that showed metastasis to left ilium, which was confirmed on biopsy. PMID:23640231

  6. (68)Ga-DOTATOC PET and gene expression profile in patients with neuroendocrine carcinomas: strong correlation between PET tracer uptake and gene expression of somatostatin receptor subtype 2.

    PubMed

    Olsen, Ingrid H; Langer, Seppo W; Federspiel, Birgitte H; Oxbøl, Jytte; Loft, Annika; Berthelsen, Anne Kiil; Mortensen, Jann; Oturai, Peter; Knigge, Ulrich; Kjær, Andreas

    2016-01-01

    Somatostatin receptor expression on both protein and gene expression level was compared with in vivo (68)Ga-DOTATOC PET/CT in patients with neuroendocrine carcinomas (NEC). Twenty-one patients with verified NEC who underwent a (68)Ga-DOTATOC PET/CT between November 2012 and May 2014, were retrospectively included. By real-time polymerase chain reaction, we quantitatively determined the gene expression of several genes and compared with (68)Ga-DOTATOC PET uptake. By immunohistochemistry we qualitatively studied the expression of assorted proteins in NEC. The median age at diagnosis was 68 years (range 41-84) years. All patients had WHO performance status 0-1. Median Ki67 index was 50% (range 20-100%). Gene expression of somatostatin receptor subtype (SSTR) 2 and Ki67 were both positively correlated to the (68)Ga-DOTATOC uptake (r=0.89; p<0.0001 and r=0.5; p=0.021, respectively). Furthermore, SSTR2 and SSTR5 gene expression were strongly and positively correlated (r=0.57; p=0.006). This study as the first verifies a positive and close correlation of (68)Ga-DOTATOC uptake and gene expression of SSTR2 in NEC. SSTR2 gene expression has a stronger correlation to (68)Ga-DOTATOC uptake than SSTR5. In addition, the results indicate that the gene expression levels of SSTR2 and SSTR5 at large follow one another. PMID:27069766

  7. The Synthesis and Evaluations of the 68Ga-Lissamine Rhodamine B (LRB) as a New Radiotracer for Imaging Tumors by Positron Emission Tomography

    PubMed Central

    Li, Xuena; Yin, Yafu; Du, Bulin; Li, Na; Li, Yaming

    2016-01-01

    Purpose. The aim of this study is to synthesize and evaluate 68Ga-labeled Lissamine Rhodamine B (LRB) as a new radiotracer for imaging MDA-MB-231 and MCF-7 cells induced tumor mice by positron emission tomography (PET). Methods. Firstly, we performed the radio synthesis and microPET imaging of 68Ga(DOTA-LRB) in athymic nude mice bearing MDA-MB-231 and MCF-7 human breast cancer xenografts. Additionally, the evaluations of 18F-fluorodeoxyglucose (FDG), as a glucose metabolism radiotracer for imaging tumors in the same xenografts, have been conducted as a comparison. Results. The radiochemical purity of 68Ga(DOTA-LRB) was >95%. MicroPET dynamic imaging revealed that the uptake of 68Ga(DOTA-LRB) was mainly in normal organs, such as kidney, heart, liver, and brain and mainly excreted from kidney. The MDA-MB-231 and MCF-7 tumors were not clearly visible in PET images at 5, 15, 30, 40, 50, and 60 min after injection of 68Ga(DOTA-LRB). The tumor uptake values of 18F-FDG were 3.79 ± 0.57 and 1.93 ± 0.48%ID/g in MDA-MB-231 and MCF-7 tumor xenografts, respectively. Conclusions. 68Ga(DOTA-LRB) can be easily synthesized with high radiochemical purity and stability; however, it may be not an ideal PET radiotracer for imaging of MDR-positive tumors. PMID:26949707

  8. 68Ga-DOTATOC PET and gene expression profile in patients with neuroendocrine carcinomas: strong correlation between PET tracer uptake and gene expression of somatostatin receptor subtype 2

    PubMed Central

    Olsen, Ingrid H; Langer, Seppo W; Federspiel, Birgitte H; Oxbøl, Jytte; Loft, Annika; Berthelsen, Anne Kiil; Mortensen, Jann; Oturai, Peter; Knigge, Ulrich; Kjær, Andreas

    2016-01-01

    Somatostatin receptor expression on both protein and gene expression level was compared with in vivo 68Ga-DOTATOC PET/CT in patients with neuroendocrine carcinomas (NEC). Twenty-one patients with verified NEC who underwent a 68Ga-DOTATOC PET/CT between November 2012 and May 2014, were retrospectively included. By real-time polymerase chain reaction, we quantitatively determined the gene expression of several genes and compared with 68Ga-DOTATOC PET uptake. By immunohistochemistry we qualitatively studied the expression of assorted proteins in NEC. The median age at diagnosis was 68 years (range 41-84) years. All patients had WHO performance status 0-1. Median Ki67 index was 50% (range 20-100%). Gene expression of somatostatin receptor subtype (SSTR) 2 and Ki67 were both positively correlated to the 68Ga-DOTATOC uptake (r=0.89; p<0.0001 and r=0.5; p=0.021, respectively). Furthermore, SSTR2 and SSTR5 gene expression were strongly and positively correlated (r=0.57; p=0.006). This study as the first verifies a positive and close correlation of 68Ga-DOTATOC uptake and gene expression of SSTR2 in NEC. SSTR2 gene expression has a stronger correlation to 68Ga-DOTATOC uptake than SSTR5. In addition, the results indicate that the gene expression levels of SSTR2 and SSTR5 at large follow one another. PMID:27069766

  9. Good manufacturing practice production of [68Ga]Ga-ABY-025 for HER2 specific breast cancer imaging

    PubMed Central

    Velikyan, Irina; Wennborg, Anders; Feldwisch, Joachim; Lindman, Henrik; Carlsson, Jörgen; Sörensen, Jens

    2016-01-01

    Therapies targeting human epidermal growth factor receptor type 2 (HER2) have revolutionized breast cancer treatment, but require invasive biopsies and rigorous histopathology for optimal patient stratification. A non-invasive and quantitative diagnostic method such as positron emission tomography (PET) for the pre-therapeutic determination of the presence and density of the HER2 would significantly improve patient management efficacy and treatment cost. The essential part of the PET methodology is the production of the radiopharmaceutical in compliance with good manufacturing practice (GMP). The use of generator produced positron emitting 68Ga radionuclide would provide worldwide accessibility of the agent. GMP compliant, reliable and highly reproducible production of [68Ga]Ga-ABY-025 with control over the product peptide concentration and amount of radioactivity was accomplished within one hour. Two radiopharmaceuticals were developed differing in the total peptide content and were validated independently. The specific radioactivity could be kept similar throughout the study, and it was 6-fold higher for the low peptide content radiopharmaceutical. Intrapatient comparison of the two peptide doses allowed imaging optimization. The high peptide content decreased the uptake in healthy tissue, in particular liver, improving image contrast. The later imaging time points enhanced the contrast. The combination of high peptide content radiopharmaceutical and whole-body imaging at 2 hours post injection appeared to be optimal for routine clinical use. PMID:27186441

  10. 68Ga-complex lipophilicity and the targeting property of a urea-based PSMA inhibitor for PET imaging.

    PubMed

    Eder, Matthias; Schäfer, Martin; Bauder-Wüst, Ulrike; Hull, William-Edmund; Wängler, Carmen; Mier, Walter; Haberkorn, Uwe; Eisenhut, Michael

    2012-04-18

    Urea-based inhibitors of the prostate-specific membrane antigen (PSMA) represent low-molecular-weight pepidomimetics showing the ability to image PSMA-expressing prostate tumors. The highly efficient, acyclic Ga(III) chelator N,N'-bis [2-hydroxy-5-(carboxyethyl)benzyl] ethylenediamine-N,N'- diacetic acid (HBED-CC) was introduced as a lipophilic side chain into the hydrophilic pharmacophore Glu-NH-CO-NH-Lys which was found favorable to interact with the PSMA "active binding site". This report describes the syntheses, in vitro binding analyses, and biodistribution data of the radiogallium labeled PSMA inhibitor Glu-NH-CO-NH-Lys(Ahx)-HBED-CC in comparison to the corresponding DOTA conjugate. The binding properties were analyzed using competitive cell binding and enzyme-based assays followed by internalization experiments. Compared to the DOTA-conjugate, the HBED-CC derivative showed reduced unspecific binding and considerable higher specific internalization in LNCaP cells. The (68)Ga complex of the HBED-CC ligand exhibited higher specificity for PSMA expressing tumor cells resulting in improved in vivo properties. (68)Ga labeled Glu-NH-CO-NH-Lys(Ahx)-HBED-CC showed fast blood and organ clearances, low liver accumulation, and high specific uptake in PSMA expressing organs and tumor. It could be demonstrated that the PET-imaging property of a urea-based PSMA inhibitor could significantly be improved with HBED-CC. PMID:22369515

  11. (67/68)Ga-labeling agent that liberates (67/68)Ga-NOTA-methionine by lysosomal proteolysis of parental low molecular weight polypeptides to reduce renal radioactivity levels.

    PubMed

    Uehara, Tomoya; Rokugawa, Takemi; Kinoshita, Mai; Nemoto, Souki; Fransisco Lazaro, Guerra Gomez; Hanaoka, Hirofumi; Arano, Yasushi

    2014-11-19

    The renal localization of gallium-67 or gallium-68 ((67/68)Ga)-labeled low molecular weight (LMW) probes such as peptides and antibody fragments constitutes a problem in targeted imaging. Wu et al. previously showed that (67)Ga-labeled S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (SCN-Bz-NOTA)-conjugated methionine ((67)Ga-NOTA-Met) was rapidly excreted from the kidney in urine following lysosomal proteolysis of the parental (67)Ga-NOTA-Bz-SCN-disulfide-stabilized Fv fragment (Bioconjugate Chem., (1997) 8, 365-369). In the present study, a new (67/68)Ga-labeling reagent for LMW probes that liberates (67/68)Ga-NOTA-Met was designed, synthesized, and evaluated using longer-lived (67)Ga in order to reduce renal radioactivity levels. We employed a methionine-isoleucine (MI) dipeptide bond as the cleavable linkage. The amine residue of MI was coupled with SCN-Bz-NOTA for (67)Ga-labeling, while the carboxylic acid residue of MI was derivatized to maleimide for antibody conjugation in order to synthesize NOTA-MI-Mal. A Fab fragment of the anti-Her2 antibody was thiolated with iminothiolane, and NOTA-MI-Mal was conjugated with the antibody fragment by maleimide-thiol chemistry. The Fab fragment was also conjugated with SCN-Bz-NOTA (NOTA-Fab) for comparison. (67)Ga-NOTA-MI-Fab was obtained at radiochemical yields of over 95% and was stable in murine serum for 24 h. In the biodistribution study using normal mice, (67)Ga-NOTA-MI-Fab registered significantly lower renal radioactivity levels from 1 to 6 h postinjection than those of (67)Ga-NOTA-Fab. An analysis of urine samples obtained 6 h after the injection of (67)Ga-NOTA-MI-Fab showed that the majority of radioactivity was excreted as (67)Ga-NOTA-Met. In the biodistribution study using tumor-bearing mice, the tumor to kidney ratios of (67)Ga-NOTA-MI-Fab were 4 times higher (6 h postinjection) than those of (67)Ga-NOTA-Fab. Although further studies including the structure of radiometabolites and

  12. 68Ga-DOTATATE positron emission tomography/computed tomography scan in the detection of bone metastases in pediatric neuroendocrine tumors

    PubMed Central

    Goel, Reema; Shukla, Jaya; Bansal, Deepak; Sodhi, Kushaljit; Bhattacharya, Anish; Marwaha, Ram Kumar; Mittal, Bhagwant Rai

    2014-01-01

    Aim: The aim of this study is to evaluate the role of 68Ga-DOTATATE positron emission tomography/computed tomography (PET/CT) scan for the detection of bone metastases in pediatric neuroendocrine tumors (NETs) and to compare it with CT scan. Materials and Methods: A total of 30 patients (18 were males and 12 were females; age range: 1-18 years; mean age 7.6 years) with histologically confirmed NETs referred to our department were retrospectively analyzed. All patients underwent 68Ga-DOTATATE PET/CT scan at the time of diagnosis for primary staging. Contrast enhanced CT (CECT) performed at the time of PET scan acquisition was used for comparison with PET data. Imaging results were analyzed on a per-patient and on a per-lesion basis. Clinical follow-up of all patients and repeat PET/CT imaging (n = 10) was taken as the reference standard. Results: Out of the 30 patients, 17 had no evidence of bone metastases on any imaging modality or on clinical follow-up while the rest of 13 patients showed evidence of bone metastases (nine showing positivity both on 68Ga-DOTATATE PET and CT scan while four showing positivity only on 68Ga-DOTATATE PET). Compared with CT scan, 68Ga-DOTATATE PET detected bone metastases at a significantly higher rate (P = 0.0039). On a per lesion analysis, out of a total of 225 lesions detected by 68Ga-DOTATATE PET, only 84 lesions could be detected by CT scan. Conclusion: 68Ga-DOTATATE PET/CT scan is more useful than CECT scan for the early detection of bone metastases in pediatric NETs. PMID:24591776

  13. In vitro autoradiography of carcinoembryonic antigen in tissue from patients with colorectal cancer using multifunctional antibody TF2 and 67/68Ga-labeled haptens by pretargeting

    PubMed Central

    Hall, Håkan; Velikyan, Irina; Blom, Elisabeth; Ulin, Johan; Monazzam, Azita; Påhlman, Lars; Micke, Patrick; Wanders, Alkwin; McBride, William; Goldenberg, David M.; Långström, Bengt

    2012-01-01

    The carcinoembryonic antigen (CEA) was visualized in vitro in tissue from patients with colorectal cancer with trivalent bispecific antibody TF2 and two hapten molecules, [67/68Ga]Ga-IMP461 and [67/68Ga]Ga-IMP485 by means of pretargeting. Colorectal cancer tissue samples obtained from surgery at Uppsala University Hospital, were frozen fresh and cryosectioned. The two hapten molecules comprising 1,4,7-triazacyclononanetriacetic acid chelate moiety (NOTA) were labeled with 67Ga or 68Ga. The autoradiography was conducted by incubating the tissue samples with the bispecific antibody TF2, followed by washing and incubation with one of the radiolabeled hapten molecules. After washing, drying and exposure to phosphor imager plates, the autoradiograms were analyzed and compared to standard histochemistry (hematoxylin-eosin). Pronounced binding was found in the tissue from colorectal cancer using the bispecific antibody TF2 and either of the haptens [67/68Ga]Ga-IMP461 and [67/68Ga]Ga-IMP485. Distinct binding was also detected in the epithelium of most samples of neighboring tissue, taken at a minimum of 10 cm from the site of the tumor. It is concluded that pretargeting CEA with the bispecific antibody TF2 followed by the addition of 67/68Ga-labeled hapten is extremely sensitive for visualizing this marker for colorectal cancer. This methodology is therefore a very specific complement to other histochemical techniques in the diagnosis of biopsies or in samples taken from surgery. Use of the pretargeting technique in vivo may also be an advance in diagnosing patients with colorectal cancer, either using 67Ga and SPECT or 68Ga and PET. PMID:23133809

  14. Affinity of (nat/68)Ga-Labelled Curcumin and Curcuminoid Complexes for β-Amyloid Plaques: Towards the Development of New Metal-Curcumin Based Radiotracers.

    PubMed

    Rubagotti, Sara; Croci, Stefania; Ferrari, Erika; Iori, Michele; Capponi, Pier C; Lorenzini, Luca; Calzà, Laura; Versari, Annibale; Asti, Mattia

    2016-01-01

    Curcumin derivatives labelled with fluorine-18 or technetium-99m have recently shown their potential as diagnostic tools for Alzheimer's disease. Nevertheless, no study by exploiting the labelling with gallium-68 has been performed so far, in spite of its suitable properties (positron emitter, generator produced radionuclide). Herein, an evaluation of the affinity for synthetic β-amyloid fibrils and for amyloid plaques of three (nat/68)Ga-labelled curcumin analogues, namely curcumin curcumin (CUR), bis-dehydroxy-curcumin (bDHC) and diacetyl-curcumin (DAC), was performed. Affinity and specificity were tested in vitro on amyloid synthetic fibrils by using gallium-68 labelled compounds. Post-mortem brain cryosections from Tg2576 mice were used for the ex vivo visualization of amyloid plaques. The affinity of (68)Ga(CUR)₂⁺, (68)Ga(DAC)₂⁺, and (68)Ga(bDHC)₂⁺ for synthetic β-amyloid fibrils was moderate and their uptake could be observed in vitro. On the other hand, amyloid plaques could not be visualized on brain sections of Tg2576 mice after injection, probably due to the low stability of the complexes in vivo and of a hampered passage through the blood-brain barrier. Like curcumin, all (nat/68)Ga-curcuminoid complexes maintain a high affinity for β-amyloid plaques. However, structural modifications are still needed to improve their applicability as radiotracers in vivo. PMID:27608011

  15. Unusual Presentation of Bladder Paraganglioma: Comparison of 131I MIBG SPECT/CT and 68Ga DOTANOC PET/CT

    PubMed Central

    Jain, Tarun Kumar; Basher, Rajender Kumar; Gupta, Nitin; Shukla, Jaya; Singh, Shrawan Kumar; Mittal, Bhagwant Rai

    2016-01-01

    Extraadrenal chromaffin cell-related tumors or paragangliomas are rare, especially in the bladder, accounting for less than 1% of cases. We report a 16-year-old boy who presented with hematuria and paroxysmal headache and was found to have a prostatic growth infiltrating the urinary bladder on anatomical imaging. Iodine-131 (131I) metaiodobenzylguanidine (MIBG) whole-body scanning and subsequently gallium-68 (68Ga) DOTANOC positron emission tomography/computed tomography (PET/CT) were performed. The MIBG scan revealed a non-tracer-avid soft-tissue mass, while DOTANOC PET/CT revealed a tracer-avid primary soft-tissue mass involving the urinary bladder and prostate with metastasis to the iliac lymph nodes. He underwent surgical management; histopathology of the surgical specimen revealed a bladder paraganglioma, whereas the prostate was found to be free of tumor. PMID:26912984

  16. 90Y-Edotreotide for Metastatic Carcinoid Refractory to Octreotide

    PubMed Central

    Bushnell, David L.; O'Dorisio, Thomas M.; O'Dorisio, M. Sue; Menda, Yusuf; Hicks, Rodney J.; Van Cutsem, Eric; Baulieu, Jean-Louis; Borson-Chazot, Francoise; Anthony, Lowell; Benson, Al B.; Oberg, Kjell; Grossman, Ashley B.; Connolly, Mary; Bouterfa, Hakim; Li, Yong; Kacena, Katherine A.; LaFrance, Norman; Pauwels, Stanislas A.

    2010-01-01

    Purpose Metastatic carcinoid is an incurable malignancy whose symptoms, such as diarrhea and flushing, can be debilitating and occasionally life-threatening. Although symptom relief is available with octreotide, the disease eventually becomes refractory to octreotide, leaving no proven treatment options. The goal of this study was to evaluate the clinical effect of using 90Y-edotreotide to treat symptomatic patients with carcinoid tumors. Patients and Methods Patients enrolled had metastatic carcinoid, at least one sign/symptom refractory to octreotide, and at least one measurable lesion. Study treatment consisted of three cycles of 4.4 GBq (120 mCi) 90Y-edotreotide each, once every 6 weeks. Results Ninety patients were enrolled in the study. Using Southwest Oncology Group tumor response criteria, 67 (74.%) of 90 patients (95% CI, 65.4% to 83.4%) were objectively stable or responded. A statistically significant linear trend toward improvement was demonstrated across all 12 symptoms assessed. Median progression-free survival was significantly greater (P = .03) for the 38 patients who had durable diarrhea improvement than the 18 patients who did not (18.2 v 7.9 months, respectively). Adverse events (AEs) were reported in 96.7% (87 of 90) of patients. These AEs consisted primarily of reversible GI events (76 of 90), which could be caused in part by concomitant administration of amino acid solution given to reduce radiation exposure to the kidneys. There was one case each of grade 3 oliguria and grade 4 renal failure, each lasting 6 days. Conclusion 90Y-edotreotide treatment improved symptoms associated with malignant carcinoid among subjects with no treatment alternatives. Treatment was well-tolerated and had an acceptable expected AE profile. PMID:20194865

  17. Resin {sup 90}Y microsphere activity measurements for liver brachytherapy

    SciTech Connect

    Dezarn, William A.; Kennedy, Andrew S.

    2007-06-15

    The measurement of the radioactivity administered to the patient is one of the major components of {sup 90}Y microsphere liver brachytherapy. The activity of {sup 90}Y microspheres in a glass delivery vial was measured in a dose calibrator. The calibration value to use for {sup 90}Y in the dose calibrator was verified using an activity calibration standard provided by the microsphere manufacturer. This method allowed for the determination of a consistent, reproducible local activity standard. Additional measurements were made to determine some of the factors that could affect activity measurement. The axial response of the dose calibrator was determined by the ratio of activity measurements at the bottom and center of the dose calibrator. The axial response was 0.964 for a glass shipping vial, 1.001 for a glass V-vial, and 0.988 for a polycarbonate V-vial. Comparisons between activity measurements in the dose calibrator and those using a radiation survey meter were found to agree within 10%. It was determined that the dose calibrator method was superior to the survey meter method because the former allowed better defined measurement geometry and traceability of the activity standard back to the manufacturer. Part of the preparation of resin {sup 90}Y microspheres for patient delivery is to draw out a predetermined activity from a shipping vial and place it into a V-vial for delivery to the patient. If the drawn activity was placed in a glass V-vial, the activity measured in the dose calibrator with a glass V-vial was 4% higher than the drawn activity from the shipping vial standard. If the drawn activity was placed in a polycarbonate V-vial, the activity measured in the dose calibrator with a polycarbonate V-vial activity was 20% higher than the drawn activity from the shipping vial standard. Careful characterization of the local activity measurement standard is recommended instead of simply accepting the calibration value of the dose calibrator manufacturer.

  18. Growth hormone-secreting macroadenoma of the pituitary gland successfully treated with the radiolabeled somatostatin analog (90)Y-DOTATATE: case report.

    PubMed

    Waligórska-Stachura, Joanna; Gut, Paweł; Sawicka-Gutaj, Nadia; Liebert, Włodzimierz; Gryczyńska, Maria; Baszko-Błaszyk, Daria; Blanco-Gangoo, Al Ricardo; Ruchała, Marek

    2016-08-01

    Pituitary tumors causing acromegaly are usually macroadenomas at the time of diagnosis, and they can grow aggressively, infiltrating surrounding tissues. Difficulty in achieving complete tumor removal at surgery can lead toward a strong tendency for recurrence, making it necessary to consider a means of treatment other than those currently used such as somatostatin analogs (SSAs), growth hormone (GH) receptor antagonist, surgical removal, and radiotherapy. The purpose of this paper is to describe a patient diagnosed with an aggressive, giant GH-secreting tumor refractory to medical therapy but ultimately treated with the radiolabeled somatostatin analog (90)Y-DOTATATE. A 26-year-old male with an invasive macroadenoma of the pituitary gland (5.6 × 2.5 × 3.6 cm) and biochemically confirmed acromegaly underwent 2 partial tumor resections: the first used the transsphenoidal approach and the second used the transcranial method. The patient received SSAs pre- and postoperatively. Because of the progression in pituitary tumor size, he underwent classic irradiation of the tumor (50 Gy). One and a half years later, the patient presented with clinically and biochemically active disease, and the tumor size was still 52 mm in diameter (height). Two neurosurgeons disqualified him from further surgical procedures. After confirming the presence of somatostatin receptors in the pituitary tumor by using (68)Ga-DOTATATE PET/CT, we treated the patient 4 times with an SSA bound with (90)Y-DOTATATE. After this treatment, the patient attained partial biochemical remission and a reduction in the tumor mass for the first time. Treatment with an SSA bound with (90)Y-DOTATATE may be a promising option for some aggressive GH-secreting pituitary adenomas when other methods have failed. PMID:26636388

  19. Examination of blood-brain barrier permeability in dementia of the Alzheimer type with (68Ga)EDTA and positron emission tomography

    SciTech Connect

    Schlageter, N.L.; Carson, R.E.; Rapoport, S.I.

    1987-02-01

    Positron emission tomography with (/sup 68/Ga)ethylenediaminetetraacetic acid ((/sup 68/Ga)EDTA) was used to examine the integrity of the blood-brain barrier (BBB) in five patients with dementia of the Alzheimer type and in five healthy age-matched controls. Within a scanning time of 90 min, there was no evidence that measurable intravascular tracer entered the brain in either the dementia or the control group. An upper limit for the cerebrovascular permeability-surface area product of (68Ga)EDTA was estimated as 2 X 10(-6) s-1 in both groups. The results provide no evidence for breakdown of the BBB in patients with dementia of the Alzheimer type.

  20. Molecular Imaging of Chemokine Receptor CXCR4 in Non-Small Cell Lung Cancer Using 68Ga-Pentixafor PET/CT: Comparison With 18F-FDG.

    PubMed

    Derlin, Thorsten; Jonigk, Danny; Bauersachs, Johann; Bengel, Frank M

    2016-04-01

    We report the case of a 62-year-old woman with a history of ST-elevation myocardial infarction who underwent 68Ga-Pentixafor PET/CT for characterization of postinfarct myocardial inflammation. 68Ga-Pentixafor PET/CT incidentally demonstrated marked CXCR4 expression in a space-occupying lesion in the right upper lobe. Corresponding 18F-FDG PET/CT showed increased metabolism, and subsequent biopsy revealed non-small cell lung cancer. Immunohistochemistry confirmed that CXCR4 was highly expressed on tumor cells. 68Ga-Pentixafor is a novel CXCR4-targeted probe for PET imaging of CXCR4-positive tumors and holds promise for tumor staging and prognostic stratification. CXCR4-targeted radionuclide therapy represents a therapy option in metastasized diseases. PMID:26756098

  1. 68Ga-DOTATATE-PET/CT positive metastatic lymph node in a 69-year-old woman with Merkel cell carcinoma.

    PubMed

    Schneider, Christina; Schlaak, Max; Bludau, Marc; Markiefka, Birgid; Schmidt, Matthias C

    2012-11-01

    We report the case of a 69-year-old woman with a Merkel cell carcinoma (MCC) in whom subsequent lymph node metastasis was first diagnosed by 68Ga-Dotatate-PET/CT followed by histopathological confirmation. MCC is an extraordinarily rare and aggressive neuroendocrine tumor of dermal origin with a high rate of postoperative recurrence. Owing to its rarity, the diagnosis of MCC remains a significant challenge. In our case, 68Ga-Dotatate-PET/CT proved clinically useful for diagnosing the lymph node metastasis of a MCC. PMID:22996252

  2. Peptide Receptor Radionuclide Therapy (PRRT) of Medullary and Nonmedullary Thyroid Cancer Using Radiolabeled Somatostatin Analogues.

    PubMed

    Salavati, Ali; Puranik, Ameya; Kulkarni, Harshad R; Budiawan, Hendra; Baum, Richard P

    2016-05-01

    As therapeutic options in advanced medullary and non-iodine avid differentiated (nonmedullary) thyroid cancers are limited and associated with significant toxicity, targeting of somatostatin receptors (SSTRs) for internal radiation therapy provides a promising option. Theranostics (therapy and diagnosis) using radiolabeled somatostatin analogues has proved to be a milestone in the management of SSTR-expressing tumors. Peptide receptor radionuclide therapy using (177)Lu-labeled or (90)Y-labeled somatostatin analogues may have a significant role in the management of medullary and nonmedullary thyroid cancers in those patients where PET/CT with (68)Ga-labeled somatostatin analogues demonstrates significant SSTR expression. PMID:27067502

  3. Patient selection for personalized peptide receptor radionuclide therapy using Ga-68 somatostatin receptor PET/CT.

    PubMed

    Kulkarni, Harshad R; Baum, Richard P

    2014-01-01

    Neuroendocrine tumors are malignant solid tumors originating from neuroendocrine cells dispersed throughout the body. Differentiated neuroendocrine tumors overexpress somatostatin receptors (SSTRs), which enable the diagnosis using radiolabeled somatostatin analogues. Internalization and retention within the tumor cell are important for peptide receptor radionuclide therapy using the same peptide. The use of the same DOTA-peptide for SSTR PET/CT using (68)Ga and for peptide receptor radionuclide therapy using therapeutic radionuclides like (177)Lu and (90)Y offers a unique theranostic advantage. PMID:25029937

  4. New Tris(hydroxypyridinone) Bifunctional Chelators Containing Isothiocyanate Groups Provide a Versatile Platform for Rapid One-Step Labeling and PET Imaging with 68Ga3+

    PubMed Central

    2015-01-01

    Two new bifunctional tris(hydroxypyridinone) (THP) chelators designed specifically for rapid labeling with 68Ga have been synthesized, each with pendant isothiocyanate groups and three 1,6-dimethyl-3-hydroxypyridin-4-one groups. Both compounds have been conjugated with the primary amine group of a cyclic integrin targeting peptide, RGD. Each conjugate can be radiolabeled and formulated by treatment with generator-produced 68Ga3+ in over 95% radiochemical yield under ambient conditions in less than 5 min, with specific activities of 60–80 MBq nmol–1. Competitive binding assays and in vivo biodistribution in mice bearing U87MG tumors demonstrate that the new 68Ga3+-labeled THP peptide conjugates retain affinity for the αvβ3 integrin receptor, clear within 1–2 h from circulation, and undergo receptor-mediated tumor uptake in vivo. We conclude that bifunctional THP chelators can be used for simple, efficient labeling of 68Ga biomolecules under mild conditions suitable for peptides and proteins. PMID:26286399

  5. Synthesis and characterization of (68)Ga-labeled curcumin and curcuminoid complexes as potential radiotracers for imaging of cancer and Alzheimer's disease.

    PubMed

    Asti, Mattia; Ferrari, Erika; Croci, Stefania; Atti, Giulia; Rubagotti, Sara; Iori, Michele; Capponi, Pier C; Zerbini, Alessandro; Saladini, Monica; Versari, Annibale

    2014-05-19

    Curcumin (CUR) and curcuminoids complexes labeled with fluorine-18 or technetium-99m have recently shown their potential as diagnostic tools for Alzheimer's disease. Gallium-68 is a positron-emitting, generator-produced radionuclide, and its properties can be exploited in situ in medical facilities without a cyclotron. Moreover, CUR showed a higher uptake in tumor cells compared to normal cells, suggesting potential diagnostic applications in this field. In spite of this, no studies using labeled CUR have been performed in this direction, so far. Herein, (68)Ga-labeled complexes with CUR and two curcuminoids, namely diacetyl-curcumin (DAC) and bis(dehydroxy)curcumin (bDHC), were synthesized and characterized by means of experimental and theoretical approaches. Moreover, a first evaluation of their affinity to synthetic β-amyloid fibrils and uptake by A549 lung cancer cells was performed to show the potential application of these new labeled curcuminoids in these diagnostic fields. The radiotracers were prepared by reacting (68)Ga(3+) obtained from a (68)Ge/(68)Ga generator with 1 mg/mL curcuminoids solutions. Reaction parameters (precursor amount, reaction temperature, and pH) were optimized to obtain high and reproducible radiochemical yield and purity. Stoichiometry and formation of the curcuminoid complexes were investigated by matrix-assisted laser desorption ionization time-of-flight mass spectrometry, NMR, ultraviolet-visible, and fluorescence spectroscopy on the equivalent (nat)Ga-curcuminoids (nat = natural) complexes, and their structure was computed by theoretical density functional theory calculations. The analyses evidenced that CUR, DAC, and bDHC were predominantly in the keto-enol form and attested to Ga(L)2(+) species formation. Identity of the (68)Ga(L)2(+) complexes was confirmed by coelution with the equivalent (nat)Ga(L)2(+) complexes in ultrahigh-performance liquid chromatography analyses.(68)Ga(CUR)2(+), (68)Ga(DAC)2(+), and (68)Ga(bDHC)2

  6. Angiogenesis PET Tracer Uptake (68Ga-NODAGA-E[(cRGDyK)]2) in Induced Myocardial Infarction in Minipigs

    PubMed Central

    Rasmussen, Thomas; Follin, Bjarke; Kastrup, Jens; Brandt-Larsen, Malene; Madsen, Jacob; Emil Christensen, Thomas; Pharao Hammelev, Karsten; Hasbak, Philip; Kjær, Andreas

    2016-01-01

    Angiogenesis is part of the healing process following an ischemic injury and is vital for the post-ischemic repair of the myocardium. Therefore, it is of particular interest to be able to noninvasively monitor angiogenesis. This might, not only permit risk stratification of patients following myocardial infarction, but could also facilitate development and improvement of new therapies directed towards stimulation of the angiogenic response. During angiogenesis endothelial cells must adhere to one another to form new microvessels. αvβ3 integrin has been found to be highly expressed in activated endothelial cells and has been identified as a critical modulator of angiogenesis. 68Ga-NODAGA-E[c(RGDyK)]2 (RGD) has recently been developed by us as an angiogenesis positron-emission-tomography (PET) ligand targeted towards αvβ3 integrin. In the present study, we induced myocardial infarction in Göttingen minipigs. Successful infarction was documented by 82Rubidium-dipyridamole stress PET and computed tomography. RGD uptake was demonstrated in the infarcted myocardium one week and one month after induction of infarction by RGD-PET. In conclusion, we demonstrated angiogenesis by noninvasive imaging using RGD-PET in minipigs hearts, which resemble human hearts. The perspectives are very intriguing and might permit the evaluation of new treatment strategies targeted towards increasing the angiogenetic response, e.g., stem-cell treatment. PMID:27322329

  7. Angiogenesis PET Tracer Uptake ((68)Ga-NODAGA-E[(cRGDyK)]₂) in Induced Myocardial Infarction in Minipigs.

    PubMed

    Rasmussen, Thomas; Follin, Bjarke; Kastrup, Jens; Brandt-Larsen, Malene; Madsen, Jacob; Emil Christensen, Thomas; Pharao Hammelev, Karsten; Hasbak, Philip; Kjær, Andreas

    2016-01-01

    Angiogenesis is part of the healing process following an ischemic injury and is vital for the post-ischemic repair of the myocardium. Therefore, it is of particular interest to be able to noninvasively monitor angiogenesis. This might, not only permit risk stratification of patients following myocardial infarction, but could also facilitate development and improvement of new therapies directed towards stimulation of the angiogenic response. During angiogenesis endothelial cells must adhere to one another to form new microvessels. αvβ₃ integrin has been found to be highly expressed in activated endothelial cells and has been identified as a critical modulator of angiogenesis. (68)Ga-NODAGA-E[c(RGDyK)]₂ (RGD) has recently been developed by us as an angiogenesis positron-emission-tomography (PET) ligand targeted towards αvβ₃ integrin. In the present study, we induced myocardial infarction in Göttingen minipigs. Successful infarction was documented by (82)Rubidium-dipyridamole stress PET and computed tomography. RGD uptake was demonstrated in the infarcted myocardium one week and one month after induction of infarction by RGD-PET. In conclusion, we demonstrated angiogenesis by noninvasive imaging using RGD-PET in minipigs hearts, which resemble human hearts. The perspectives are very intriguing and might permit the evaluation of new treatment strategies targeted towards increasing the angiogenetic response, e.g., stem-cell treatment. PMID:27322329

  8. Comparison of 68Ga-DOTANOC PET/CT and contrast-enhanced CT in localisation of tumours in ectopic ACTH syndrome

    PubMed Central

    Jadhav, Swati S; Lila, Anurag R; Kasaliwal, Rajeev; Khare, Shruti; Yerawar, Chaitanya G; Hira, Priya; Phadke, Uday; Shah, Hina; Lele, Vikram R; Malhotra, Gaurav; Bandgar, Tushar; Shah, Nalini S

    2016-01-01

    Background Localising ectopic adrenocorticotrophic hormone (ACTH) syndrome (EAS) tumour source is challenging. Somatostatin receptor-based PET imaging has shown promising results, but the data is limited to case reports and small case series. We reviewed here the performance of 68Ga-DOTANOC positron emission tomography (PET)/computed tomography (CT) and contrast-enhanced CT (CECT) in our cohort of 12 consecutive EAS patients. Materials and methods Retrospective data analysis of 12 consecutive patients of EAS presenting to a single tertiary care centre in a period between January 2013 and December 2014 was done. CECT and 68Ga-DOTANOC PET/CT were reported (blinded) by an experienced radiologist and a nuclear medicine physician, respectively. The performance of CECT and 68Ga-DOTANOC PET/CT was compared. Results Tumours could be localised in 11 out of 12 patients at initial presentation (overt cases), whereas in one patient, tumour remained occult. Thirteen lesions were identified in 11 patients as EAS source (true positives). CECT localised 12 out of these 13 lesions (sensitivity 92.3%) and identified five false-positive lesions (positive predictive value (PPV) 70.5%). Compared with false-positive lesions, true-positive lesions had greater mean contrast enhancement at 60s (33.2 vs 5.6 Hounsfield units (HU)). 68Ga-DOTANOC PET/CT was able to identify 9 out of 13 lesions (sensitivity 69.2%) and reported no false-positive lesions (PPV 100%). Conclusion CECT remains the first-line investigation in localisation of EAS. The contrast enhancement pattern on CECT can further aid in characterisation of the lesions. 68Ga-DOTANOC PET/CT can be added to CECT, to enhance positive prediction of the suggestive lesions. PMID:27006371

  9. Feasibility of 68Ga-labeled Siglec-9 peptide for the imaging of acute lung inflammation: a pilot study in a porcine model of acute respiratory distress syndrome

    PubMed Central

    Retamal, Jaime; Sörensen, Jens; Lubberink, Mark; Suarez-Sipmann, Fernando; Borges, João Batista; Feinstein, Ricardo; Jalkanen, Sirpa; Antoni, Gunnar; Hedenstierna, Göran; Roivainen, Anne; Larsson, Anders; Velikyan, Irina

    2016-01-01

    There is an unmet need for noninvasive, specific and quantitative imaging of inherent inflammatory activity. Vascular adhesion protein-1 (VAP-1) translocates to the luminal surface of endothelial cells upon inflammatory challenge. We hypothesized that in a porcine model of acute respiratory distress syndrome (ARDS), positron emission tomography (PET) with sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) based imaging agent targeting VAP-1 would allow quantification of regional pulmonary inflammation. ARDS was induced by lung lavages and injurious mechanical ventilation. Hemodynamics, respiratory system compliance (Crs) and blood gases were monitored. Dynamic examination using [15O]water PET-CT (10 min) was followed by dynamic (90 min) and whole-body examination using VAP-1 targeting 68Ga-labeled 1,4,7,10-tetraaza cyclododecane-1,4,7-tris-acetic acid-10-ethylene glycol-conjugated Siglec-9 motif peptide ([68Ga]Ga-DOTA-Siglec-9). The animals received an anti-VAP-1 antibody for post-mortem immunohistochemistry assay of VAP-1 receptors. Tissue samples were collected post-mortem for the radioactivity uptake, histology and immunohistochemistry assessment. Marked reduction of oxygenation and Crs, and higher degree of inflammation were observed in ARDS animals. [68Ga]Ga-DOTA-Siglec-9 PET showed significant uptake in lungs, kidneys and urinary bladder. Normalization of the net uptake rate (Ki) for the tissue perfusion resulted in 4-fold higher uptake rate of [68Ga]Ga-DOTA-Siglec-9 in the ARDS lungs. Immunohistochemistry showed positive VAP-1 signal in the injured lungs. Detection of pulmonary inflammation associated with a porcine model of ARDS was possible with [68Ga]Ga-DOTA-Siglec-9 PET when using kinetic modeling and normalization for tissue perfusion. PMID:27069763

  10. Feasibility of (68)Ga-labeled Siglec-9 peptide for the imaging of acute lung inflammation: a pilot study in a porcine model of acute respiratory distress syndrome.

    PubMed

    Retamal, Jaime; Sörensen, Jens; Lubberink, Mark; Suarez-Sipmann, Fernando; Borges, João Batista; Feinstein, Ricardo; Jalkanen, Sirpa; Antoni, Gunnar; Hedenstierna, Göran; Roivainen, Anne; Larsson, Anders; Velikyan, Irina

    2016-01-01

    There is an unmet need for noninvasive, specific and quantitative imaging of inherent inflammatory activity. Vascular adhesion protein-1 (VAP-1) translocates to the luminal surface of endothelial cells upon inflammatory challenge. We hypothesized that in a porcine model of acute respiratory distress syndrome (ARDS), positron emission tomography (PET) with sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) based imaging agent targeting VAP-1 would allow quantification of regional pulmonary inflammation. ARDS was induced by lung lavages and injurious mechanical ventilation. Hemodynamics, respiratory system compliance (Crs) and blood gases were monitored. Dynamic examination using [(15)O]water PET-CT (10 min) was followed by dynamic (90 min) and whole-body examination using VAP-1 targeting (68)Ga-labeled 1,4,7,10-tetraaza cyclododecane-1,4,7-tris-acetic acid-10-ethylene glycol-conjugated Siglec-9 motif peptide ([(68)Ga]Ga-DOTA-Siglec-9). The animals received an anti-VAP-1 antibody for post-mortem immunohistochemistry assay of VAP-1 receptors. Tissue samples were collected post-mortem for the radioactivity uptake, histology and immunohistochemistry assessment. Marked reduction of oxygenation and Crs, and higher degree of inflammation were observed in ARDS animals. [(68)Ga]Ga-DOTA-Siglec-9 PET showed significant uptake in lungs, kidneys and urinary bladder. Normalization of the net uptake rate (Ki) for the tissue perfusion resulted in 4-fold higher uptake rate of [(68)Ga]Ga-DOTA-Siglec-9 in the ARDS lungs. Immunohistochemistry showed positive VAP-1 signal in the injured lungs. Detection of pulmonary inflammation associated with a porcine model of ARDS was possible with [(68)Ga]Ga-DOTA-Siglec-9 PET when using kinetic modeling and normalization for tissue perfusion. PMID:27069763

  11. Feasibility of Multiple Examinations Using 68Ga-Labelled Collagelin Analogues: Organ Distribution in Rat for Extrapolation to Human Organ and Whole-Body Radiation Dosimetry

    PubMed Central

    Velikyan, Irina; Rosenström, Ulrika; Bulenga, Thomas N.; Eriksson, Olof; Antoni, Gunnar

    2016-01-01

    Objectives: Fibrosis is involved in many chronic diseases. It affects the functionality of vital organs, such as liver, lung, heart and kidney. Two novel imaging agents for positron emission tomography (PET) imaging of fibrosis have previously pre-clinically demonstrated promising target binding and organ distribution characteristics. However, the relevant disease monitoring in the clinical setup would require multiple repetitive examinations per year. Thus, it is of paramount importance to investigate the absorbed doses and total effective doses and thus, the potential maximum number of examinations per year. Methods: Two cyclic peptide (c[CPGRVMHGLHLGDDEGPC]) analogues coupled via an ethylene glycol linker (EG2) to either 2-(4,7-bis(2-(tert-butoxy)-2-oxoethyl)-1,4,7-triazonan-1-yl)acetic acid (NO2A-Col) or 4-(4,7-bis(2-(tert-butoxy)-2-oxoethyl)-1,4,7-triazacyclononan-1-yl)-5-(tert-butoxy)-5-oxopentanoic acid (NODAGA-Col) were labelled with 68Ga. The resulting agents, [68Ga]Ga-NO2A-Col and [68Ga]Ga-NODAGA-Col, were administered in the tail vein of male and female Sprague–Dawley rats (N = 24). An ex vivo organ distribution study was performed at the 5-, 10-, 20-, 40-, 60- and 120-min time points. The resulting data were extrapolated for the estimation of human organ and total body absorbed and total effective doses using Organ Level Internal Dose Assessment Code software (OLINDA/EXM 1.1) assuming a similar organ distribution pattern between the species. Time-integrated radioactivity in each organ was calculated by trapezoidal integration followed by a single-exponential fit to the data points extrapolated to infinity. The resulting values were used for the residence time calculation. Results: Ex vivo organ distribution data revealed fast blood clearance and washout from most of the organs. Although the highest organ absorbed dose was found for kidneys (0.1 mGy/MBq), this organ was not the dose-limiting one and would allow for the administration of over 1460 MBq

  12. The use of 99mTc-HYNIC-TOC and 18F-FDG PET/CT in the evaluation of duodenal neuroendocrine tumor with atypical and extensive metastasis responding dramatically to a single fraction of PRRT with 177Lu-DOTATATE.

    PubMed

    Basu, Sandip; Abhyankar, Amit

    2014-12-01

    This report describes a case of extensive diffuse bone marrow involvement with bilateral breast metastases from duodenal neuroendocrine tumor giving rise to a superscan-like appearance on somatostatin receptor-targeted (99m)Tc-hydrazinonicotinamide-TOC scintigraphy. The metastatic lesions demonstrated partial concordance with (18)F-FDG PET/CT findings, signifying varying tumor biology and heterogeneity among metastatic lesions in the same individual, as illustrated with a dual-tracer approach. There was a dramatic symptomatic and biochemical response and better health-related quality of life with a single fraction of peptide receptor radionuclide therapy with (177)Lu-DOTATATE, and radiologically there was stable disease at that point. PMID:25190735

  13. Contribution of {sup 68}Ga-DOTATOC PET/CT to Target Volume Delineation of Skull Base Meningiomas Treated With Stereotactic Radiation Therapy

    SciTech Connect

    Graf, Reinhold; Nyuyki, Fonyuy; Steffen, Ingo G.; Michel, Roger; Fahdt, Daniel; Wust, Peter; Brenner, Winfried; Budach, Volker; Wurm, Reinhard; Plotkin, Michail

    2013-01-01

    Purpose: To investigate the potential impact of {sup 68}Ga-DOTATOC positron emission tomography ({sup 68}Ga-DOTATOC-PET) in addition to magnetic resonance imaging (MRI) and computed tomography (CT) for retrospectively assessing the gross tumor volume (GTV) delineation of meningiomas of the skull base in patients treated with fractionated stereotactic radiation therapy (FSRT). Methods and Materials: The study population consisted of 48 patients with 54 skull base meningiomas, previously treated with FSRT. After scans were coregistered, the GTVs were first delineated with MRI and CT data (GTV{sub MRI/CT}) and then by PET (GTV{sub PET}) data. The overlapping regions of both datasets resulted in the GTV{sub common}, which was enlarged to the GTV{sub final} by adding volumes defined by only one of the complementary modalities (GTV{sub MRI/CT-added} or GTV{sub PET-added}). We then evaluated the contribution of conventional imaging modalities (MRI, CT) and {sup 68}Ga-DOTATOC-PET to the GTV{sub final}, which was used for planning purposes. Results: Forty-eight of the 54 skull base lesions in 45 patients showed increased {sup 68}Ga-DOTATOC uptake and were further analyzed. The mean GTV{sub MRI/CT} and GTV{sub PET} were approximately 21 cm{sup 3} and 25 cm{sup 3}, with a common volume of approximately 15 cm{sup 3}. PET contributed a mean additional GTV of approximately 1.5 cm{sup 3} to the common volume (16% {+-} 34% of the GTV{sub common}). Approximately 4.5 cm{sup 3} of the GTV{sub MRI/CT} was excluded from the contribution to the common volume. The resulting mean GTV{sub final} was significantly smaller than both the GTV{sub MRI/CT} and the GTV{sub PET}. Compared with the initial GTV{sub MRI/CT}, the addition of {sup 68}Ga-DOTATOC-PET resulted in more than 10% modification of the size of the GTV{sub final} in 32 (67%) meningiomas Conclusions: {sup 68}Ga-DOTATOC-PET/CT seems to improve the target volume delineation in skull base meningiomas, often leading to a reduction of

  14. Application of 68Ga-PRGD2 PET/CT for αvβ3-integrin Imaging of Myocardial Infarction and Stroke

    PubMed Central

    Sun, Yi; Zeng, Yong; Zhu, Yicheng; Feng, Feng; Xu, Weihai; Wu, Chenxi; Xing, Bing; Zhang, Weihong; Wu, Peiling; Cui, Liying; Wang, Renzhi; Li, Fang; Chen, Xiaoyuan; Zhu, Zhaohui

    2014-01-01

    Purpose: Ischemic vascular diseases, including myocardial infarction (MI) and stroke, have been found to be associated with elevated expression of αvβ3-integrin, which provides a promising target for semi-quantitative monitoring of the disease. For the first time, we employed 68Ga-S-2-(isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid-PEG3-E[c(RGDyK)]2 (68Ga-PRGD2) to evaluate the αvβ3-integrin-related repair in post-MI and post-stroke patients via positron emission tomography/computed tomography (PET/CT). Methods: With Institutional Review Board approval, 23 MI patients (3 days-2 years post-MI) and 16 stroke patients (3 days-13 years post-stroke) were recruited. After giving informed consent, each patient underwent a cardiac or brain PET/CT scan 30 min after the intravenous injection of 68Ga-PRGD2 in a dose of approximately 1.85 MBq (0.05 mCi) per kilogram body weight. Two stroke patients underwent repeat scans three months after the event. Results: Patchy 68Ga-PRGD2 uptake occurred in or around the ischemic regions in 20/23 MI patients and punctate multifocal uptake occurred in 8/16 stroke patients. The peak standardized uptake values (pSUVs) in MI were 1.94 ± 0.48 (mean ± SD; range, 0.62-2.69), significantly higher than those in stroke (mean ± SD, 0.46 ± 0.29; range, 0.15-0.93; P < 0.001). Higher 68Ga-PRGD2 uptake was observed in the patients 1-3 weeks after the initial onset of the MI/stroke event. The uptake levels were significantly correlated with the diameter of the diseases (r = 0.748, P = 0.001 for MI and r = 0.835, P = 0.003 for stroke). Smaller or older lesions displayed no uptake. Conclusions: 68Ga-PRGD2 uptake was observed around the ischemic region in both MI and stroke patients, which was correlated with the disease phase and severity. The different image patterns and uptake levels in MI and stroke patients warrant further investigations. PMID:24955139

  15. [68Ga]-DOTATATE PET/CT in the localization of head and neck paragangliomas compared to other functional imaging modalities and CT/MRI

    PubMed Central

    Janssen, Ingo; Taieb, David; Patronas, Nicholas J.; Millo, Corina M.; Adams, Karen; Nambuba, Joan; Chen, Clara C.; Herscovitch, Peter; Sadowski, Samira M.; Fojo, Antonio T.; Buchmann, Inga; Kebebew, Electron; Pacak, Karel

    2015-01-01

    Pheochromocytomas/paragangliomas (PHEOs/PGLs) overexpress somatostatin receptors (SSTRs) and recent studies have already shown excellent results in the localization of sympathetic succinate dehydrogenase complex, subunit B (SDHB) mutation-related metastatic PHEOs/PGLs using [(68Ga)-DOTA0,Tyr3]Octreotate ([68Ga]-DOTATATE) positron emission tomography/computed tomography (PET/CT). Therefore, the goal of our study was to assess the clinical utility of this functional imaging modality in parasympathetic head and neck paragangliomas (HNPGLs) compared to anatomical imaging with CT/MRI and other functional imaging modalities, including [18F]-fluorohydroyphenylalanine ([18F]-FDOPA) PET/CT, currently the gold standard in the functional imaging of HNPGLs. Methods [68Ga]-DOTATATE PET/CT was prospectively performed in 20 patients with HNPGLs. All patients also underwent [18F]-FDOPA PET/CT, [18F]-fluoro-2-deoxy-D-glucose ([18F]-FDG) PET/CT, and CT/MRI, with 18 patients also receiving [18F]-fluorodopamine ([18F]-FDA) PET/CT. [18F]-FDOPA PET/CT and CT/MRI served as the imaging comparators. Results Thirty-eight lesions in 20 patients were detected, with [18F]-FDOPA PET/CT identifying 37 of 38 (37/38) and CT/MRI identifying 22 of 38 lesions (22/38, p<0.01). All 38 and additional 7 lesions (p=0.016) were detected on [68Ga]-DOTATATE PET/CT. Significantly fewer lesions were identified by [18F]-FDG PET/CT (24/38, p<0.01) and [18F]-FDA PET/CT (10/34, p<0.01). Conclusion [68Ga]-DOTATATE PET/CT identified more lesions than the other imaging modalities. Due to the results of the present study, including the increasing availability and use of DOTA-analogs in the therapy of neuroendocrine tumors, we expect that [68Ga]-DOTATATE PET/CT will become the preferred functional imaging modality for HNPGLs in the near future. PMID:26564322

  16. Improved target volume definition for fractionated stereotactic radiotherapy in patients with intracranial meningiomas by correlation of CT, MRI, and [{sup 68}Ga]-DOTATOC-PET

    SciTech Connect

    Milker-Zabel, Stefanie . E-mail: stefanie_milker-zabel@med.uni-heidelberg.de; Zabel-du Bois, Angelika; Henze, Marcus; Huber, Peter; Schulz-Ertner, Daniela; Hoess, Angelika; Haberkorn, Uwe; Debus, Juergen

    2006-05-01

    Purpose: To evaluate the influence of {sup 68}-Ga-labeled DOTA ( )-D-Phe ({sup 1})-Tyr ({sup 3})-Octreotide positron emission tomography ([{sup 68}Ga]-DOTATOC-PET) for target definition for fractionated stereotactic radiotherapy (FSRT) as a complementary modality to computed tomography (CT) and magnetic resonance imaging (MRI). Because meningiomas show a high expression of somatostatin receptor subtype 2, somatostatin analogs such as DOTATOC offer the possibility of receptor-targeted imaging. Patients and Methods: Twenty-six patients received stereotactic CT, MRI, and [{sup 68}Ga]-DOTATOC-PET as part of their treatment planning. Histology was: World Health Organization (WHO) Grade 1 61.5%, WHO Grade 2 7.7%, WHO Grade 3 3.9%, and undetermined 26.9%. Six patients received radiotherapy as primary treatment, 2 after subtotal resection; 17 patients were treated for recurrent disease. Dynamic PET scans were acquired before radiotherapy over 60 min after intravenous injection of 156 {+-} 29 MBq [{sup 68}Ga]-DOTATOC. These PET images were imported in the planning software for FSRT. Planning target volume (PTV)-I outlined on CT and contrast-enhanced MRI was compared with PTV-II outlined on PET. PTV-III was defined with CT, MRI, and PET and was actually used for radiotherapy treatment. Results: PTV-III was smaller than PTV-I in 9 patients, the same size in 7 patients, and larger in 10 patients. Median PTV-I was 49.6 cc, median PTV-III was 57.2 cc. In all patients [{sup 68}Ga]-DOTATOC-PET delivered additional information concerning tumor extension. PTV-III was significantly modified based on DOTATOC-PET data in 19 patients. In 1 patient no tumor was exactly identified on CT/MRI but was visible on PET. Conclusion: These data demonstrate that [{sup 68}Ga]-DOTATOC-PET improves target definition for FSRT in patients with intracranial meningiomas. Radiation targeting with fused DOTATOC-PET, CT, and MRI resulted in significant alterations in target definition in 73%.

  17. Assessment of blood flow with (68)Ga-DOTA PET in experimental inflammation: a validation study using (15)O-water.

    PubMed

    Autio, Anu; Saraste, Antti; Kudomi, Nobuyuki; Saanijoki, Tiina; Johansson, Jarkko; Liljenbäck, Heidi; Tarkia, Miikka; Oikonen, Vesa; Sipilä, Hannu T; Roivainen, Anne

    2014-01-01

    Increased blood flow and vascular permeability are key events in inflammation. Based on the fact that Gadolinium-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (Gd-DOTA) is commonly used in magnetic resonance (MR) imaging of blood flow (perfusion), we evaluated the feasibility of its Gallium-68 labeled DOTA analog ((68)Ga-DOTA) for positron emission tomography (PET) imaging of blood flow in experimental inflammation. Adult, male Sprague-Dawley rats with turpentine oil induced sterile skin/muscle inflammation were anesthetized with isoflurane, and imaged under rest and adenosine-induced hyperemia by means of dynamic 2-min Oxygen-15 labeled water (H2 (15)O) and 30-min (68)Ga-DOTA PET. For the quantification of PET data, regions of interest (ROIs) were defined in the focus of inflammation, healthy muscle, myocardium and heart left ventricle. Radioactivity concentration in the ROIs versus time after injection was determined for both tracers and blood flow was calculated using image-derived input. According to the H2 (15)O PET, blood flow was 0.69 ± 0.15 ml/min/g for inflammation and 0.15 ± 0.03 ml/min/g for muscle during rest. The blood flow remained unchanged during adenosine-induced hyperemia 0.67 ± 0.11 and 0.12 ± 0.03 ml/min/g for inflammation and muscle, respectively, indicating that adenosine has little effect on blood flow in peripheral tissues in rats. High focal uptake of (68)Ga-DOTA was seen at the site of inflammation throughout the 30-min PET imaging. According to the (68)Ga-DOTA PET, blood flow measured as the blood-to-tissue transport rate (K1) was 0.60 ± 0.07 ml/min/g for inflammation and 0.14 ± 0.06 ml/min/g for muscle during rest and 0.63 ± 0.08 ml/min/g for inflammation and 0.09 ± 0.04 ml/min/g for muscle during adenosine-induced hyperemia. The H2 (15)O-based blood flow and (68)Ga-DOTA-based K1 values correlated well (r = 0.94, P < 0.0001). These results show that (68)Ga-DOTA PET imaging is useful for the quantification of

  18. Assessment of blood flow with 68Ga-DOTA PET in experimental inflammation: a validation study using 15O-water

    PubMed Central

    Autio, Anu; Saraste, Antti; Kudomi, Nobuyuki; Saanijoki, Tiina; Johansson, Jarkko; Liljenbäck, Heidi; Tarkia, Miikka; Oikonen, Vesa; Sipilä, Hannu T; Roivainen, Anne

    2014-01-01

    Increased blood flow and vascular permeability are key events in inflammation. Based on the fact that Gadolinium-1,4,7,10-tetraazacyclododecane-N,N‘,N‘‘,N‘‘‘-tetraacetic acid (Gd-DOTA) is commonly used in magnetic resonance (MR) imaging of blood flow (perfusion), we evaluated the feasibility of its Gallium-68 labeled DOTA analog (68Ga-DOTA) for positron emission tomography (PET) imaging of blood flow in experimental inflammation. Adult, male Sprague-Dawley rats with turpentine oil induced sterile skin/muscle inflammation were anesthetized with isoflurane, and imaged under rest and adenosine-induced hyperemia by means of dynamic 2-min Oxygen-15 labeled water (H2 15O) and 30-min 68Ga-DOTA PET. For the quantification of PET data, regions of interest (ROIs) were defined in the focus of inflammation, healthy muscle, myocardium and heart left ventricle. Radioactivity concentration in the ROIs versus time after injection was determined for both tracers and blood flow was calculated using image-derived input. According to the H2 15O PET, blood flow was 0.69 ± 0.15 ml/min/g for inflammation and 0.15 ± 0.03 ml/min/g for muscle during rest. The blood flow remained unchanged during adenosine-induced hyperemia 0.67 ± 0.11 and 0.12 ± 0.03 ml/min/g for inflammation and muscle, respectively, indicating that adenosine has little effect on blood flow in peripheral tissues in rats. High focal uptake of 68Ga-DOTA was seen at the site of inflammation throughout the 30-min PET imaging. According to the 68Ga-DOTA PET, blood flow measured as the blood-to-tissue transport rate (K1) was 0.60 ± 0.07 ml/min/g for inflammation and 0.14 ± 0.06 ml/min/g for muscle during rest and 0.63 ± 0.08 ml/min/g for inflammation and 0.09 ± 0.04 ml/min/g for muscle during adenosine-induced hyperemia. The H2 15O-based blood flow and 68Ga-DOTA-based K1 values correlated well (r = 0.94, P < 0.0001). These results show that 68Ga-DOTA PET imaging is useful for the quantification of increased

  19. Hanford isotope project strategic business analysis yttrium-90 (Y-90)

    SciTech Connect

    1995-10-01

    The purpose of this analysis is to address the short-term direction for the Hanford yttrium-90 (Y-90) project. Hanford is the sole DOE producer of Y-90, and is the largest repository for its source in this country. The production of Y-90 is part of the DOE Isotope Production and Distribution (IP and D) mission. The Y-90 is ``milked`` from strontium-90 (Sr-90), a byproduct of the previous Hanford missions. The use of Sr-90 to produce Y-90 could help reduce the amount of waste material processed and the related costs incurred by the clean-up mission, while providing medical and economic benefits. The cost of producing Y-90 is being subsidized by DOE-IP and D due to its use for research, and resultant low production level. It is possible that the sales of Y-90 could produce full cost recovery within two to three years, at two curies per week. Preliminary projections place the demand at between 20,000 and 50,000 curies per year within the next ten years, assuming FDA approval of one or more of the current therapies now in clinical trials. This level of production would incentivize private firms to commercialize the operation, and allow the government to recover some of its sunk costs. There are a number of potential barriers to the success of the Y-90 project, outside the control of the Hanford Site. The key issues include: efficacy, Food and Drug Administration (FDA) approval and medical community acceptance. There are at least three other sources for Y-90 available to the US users, but they appear to have limited resources to produce the isotope. Several companies have communicated interest in entering into agreements with Hanford for the processing and distribution of Y-90, including some of the major pharmaceutical firms in this country.

  20. (64)Cu- and (68)Ga-Based PET Imaging of Folate Receptor-Positive Tumors: Development and Evaluation of an Albumin-Binding NODAGA-Folate.

    PubMed

    Farkas, Renáta; Siwowska, Klaudia; Ametamey, Simon M; Schibli, Roger; van der Meulen, Nicholas P; Müller, Cristina

    2016-06-01

    A number of folate-based radioconjugates have been synthesized and evaluated for nuclear imaging purposes of folate receptor (FR)-positive tumors and potential therapeutic application. A common shortcoming of radiofolates is, however, a significant accumulation of radioactivity in the kidneys. This situation has been faced by modifying the folate conjugate with an albumin-binding entity to increase the circulation time of the radiofolate, which led to significantly improved tumor-to-kidney ratios. The aim of this study was to develop an albumin-binding folate conjugate with a NODAGA-chelator (rf42) for labeling with (64)Cu and (68)Ga, allowing application for PET imaging. The folate conjugate rf42 was synthesized in 8 steps, with an overall yield of 5%. Radiolabeling with (64)Cu and (68)Ga was carried out at room temperature within 10 min resulting in (64)Cu-rf42 and (68)Ga-rf42 with >95% radiochemical purity. (64)Cu-rf42 and (68)Ga-rf42 were stable (>95% intact) in phosphate-buffered saline over more than 4 half-lives of the corresponding radionuclide. In vitro, the plasma protein-bound fraction of (64)Cu-rf42 and (68)Ga-rf42 was determined to be >96%. Cell experiments proved FR-specific uptake of both radiofolates, as it was reduced to <1% when KB tumor cells were coincubated with excess folic acid. In vivo, high accumulation of (64)Cu-rf42 and (68)Ga-rf42 was found in KB tumors of mice (14.52 ± 0.99% IA/g and 11.92 ± 1.68% IA/g, respectively) at 4 h after injection. The tumor-to-kidney ratios were in the range of 0.43-0.55 over the first 4 h of investigation. At later time points (up to 72 h p.i. of (64)Cu-rf42) the tumor-to-kidney ratio increased to 0.73. High-quality PET/CT images were obtained 2 h after injection of (64)Cu-rf42 and (68)Ga-rf42, respectively, allowing distinct visualization of tumors and kidneys. Comparison of PET/CT images obtained with (64)Cu-rf42 and a (64)Cu-labeled DOTA-folate conjugate (cm10) clearly proved the superiority of NODAGA

  1. Diffuse bone metastases on (68)Ga-PSMA PET-CT in a patient with prostate cancer and normal bone scan.

    PubMed

    Lavalaye, J; Kaldeway, P; van Melick, H H E

    2016-07-01

    A 75-year-old patient was diagnosed with a Gleason 9 prostate carcinoma. His PSA level was 50.4 ng/ml. Routine bone scintigraphy was negative for metastasis (a). Due to the high tumour grading and relatively high PSA level, (68)Ga-PSMA PET-CT was ordered to rule out distant metastases. This scan showed numerous skeletal lesions with high tracer accumulation as sign of diffuse osseous metastases (b). On low-dose CT there were no signs of sclerosis (c). (68)Ga-PSMA PET-CT also showed high uptake in the prostate and in para-iliac and para-aortal lymph nodes, without lymph node enlargement. No bone biopsy was obtained to confirm the metastases. Due to this result, the treatment plan was changed to systemic therapy, instead of local therapy. PMID:27121692

  2. Radiolabeling of DOTA-like conjugated peptides with generator-produced (68)Ga and using NaCl-based cationic elution method.

    PubMed

    Mueller, Dirk; Breeman, Wouter A P; Klette, Ingo; Gottschaldt, Michael; Odparlik, Andreas; Baehre, Manfred; Tworowska, Izabela; Schultz, Michael K

    2016-06-01

    Gallium-68 ((68)Ga) is a generator-produced radionuclide with a short half-life (t½ = 68 min) that is particularly well suited for molecular imaging by positron emission tomography (PET). Methods have been developed to synthesize (68)Ga-labeled imaging agents possessing certain drawbacks, such as longer synthesis time because of a required final purification step, the use of organic solvents or concentrated hydrochloric acid (HCl). In our manuscript, we provide a detailed protocol for the use of an advantageous sodium chloride (NaCl)-based method for radiolabeling of chelator-modified peptides for molecular imaging. By working in a lead-shielded hot-cell system,(68)Ga(3+) of the generator eluate is trapped on a cation exchanger cartridge (100 mg, ∼8 mm long and 5 mm diameter) and then eluted with acidified 5 M NaCl solution directly into a sodium acetate-buffered solution containing a DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) or DOTA-like chelator-modified peptide. The main advantages of this procedure are the high efficiency and the absence of organic solvents. It can be applied to a variety of peptides, which are stable in 1 M NaCl solution at a pH value of 3-4 during reaction. After labeling, neutralization, sterile filtration and quality control (instant thin-layer chromatography (iTLC), HPLC and pH), the radiopharmaceutical can be directly administered to patients, without determination of organic solvents, which reduces the overall synthesis-to-release time. This procedure has been adapted easily to automated synthesis modules, which leads to a rapid preparation of (68)Ga radiopharmaceuticals (12-16 min). PMID:27172166

  3. In vivo monitoring of parathyroid hormone treatment after myocardial infarction in mice with [68Ga]annexin A5 and [18F]fluorodeoxyglucose positron emission tomography.

    PubMed

    Lehner, Sebastian; Todica, Andrei; Vanchev, Yordan; Uebleis, Christopher; Wang, Hao; Herrler, Tanja; Wängler, Carmen; Cumming, Paul; Böning, Guido; Franz, Wolfgang M; Bartenstein, Peter; Hacker, Marcus; Brunner, Stefan

    2014-01-01

    [68Ga]Annexin A5 positron emission tomography (PET) reveals the externalization of phosphatidylserine as a surrogate marker for apoptosis. We tested this technique for therapy monitoring in a murine model of myocardial infarction (MI) including parathyroid hormone (PTH) treatment. MI was induced in mice, and they were assigned to the saline or the PTH group. On day 2, they received [68Ga]annexin A5 PET or histofluorescence TUNEL staining. Mice had 2-deoxy-2-[18F]fluoro-d-glucose (FDG)-PET examinations on days 6 and 30 for calculation of the left ventricular ejection fraction and infarct area. [68Ga]Annexin A5 uptake was 7.4 ± 1.3 %ID/g within the infarction for the controls and 4.5 ± 1.9 %ID/g for the PTH group (p  =  .013). TUNEL staining revealed significantly more apoptotic cells in the infarct area on day 2 in the controls (64 ± 9%) compared to the treatment group (52 ± 4%; p  =  .045). FDG-PET revealed a significant decrease in infarct size in the treatment group and an increase in the controls. Examinations of left ventricular ejection fraction on days 6 and 30 did not reveal treatment effects. [68Ga]Annexin A5 PET can detect the effects of PTH treatment as a marker of apoptosis 2 days after MI; ex vivo examination confirmed significant rescue of myocardiocytes. FDG-PET showed a small but significant reduction in infarct size but no functional improvement. PMID:25249170

  4. Synthesis, 68Ga-Radiolabeling, and Preliminary In Vivo Assessment of a Depsipeptide-Derived Compound as a Potential PET/CT Infection Imaging Agent

    PubMed Central

    Mokaleng, Botshelo B.; Ebenhan, Thomas; Ramesh, Suhas; Govender, Thavendran; Kruger, Hendrik G.; Hazari, Puja P.; Mishra, Anil K.; Marjanovic-Painter, Biljana; Zeevaart, Jan R.; Sathekge, Mike M.

    2015-01-01

    Noninvasive imaging is a powerful tool for early diagnosis and monitoring of various disease processes, such as infections. An alarming shortage of infection-selective radiopharmaceuticals exists for overcoming the diagnostic limitations with unspecific tracers such as 67/68Ga-citrate or 18F-FDG. We report here TBIA101, an antimicrobial peptide derivative that was conjugated to DOTA and radiolabeled with 68Ga for a subsequent in vitro assessment and in vivo infection imaging using Escherichia coli-bearing mice by targeting bacterial lipopolysaccharides with PET/CT. Following DOTA-conjugation, the compound was verified for its cytotoxic and bacterial binding behaviour and compound stability, followed by 68Gallium-radiolabeling. µPET/CT using 68Ga-DOTA-TBIA101 was employed to detect muscular E. coli-infection in BALB/c mice, as warranted by the in vitro results. 68Ga-DOTA-TBIA101-PET detected E. coli-infected muscle tissue (SUV = 1.3–2.4) > noninfected thighs (P = 0.322) > forearm muscles (P = 0.092) > background (P = 0.021) in the same animal. Normalization of the infected thigh muscle to reference tissue showed a ratio of 3.0 ± 0.8 and a ratio of 2.3 ± 0.6 compared to the identical healthy tissue. The majority of the activity was cleared by renal excretion. The latter findings warrant further preclinical imaging studies of greater depth, as the DOTA-conjugation did not compromise the TBIA101's capacity as targeting vector. PMID:25699267

  5. Synthesis, 68Ga-radiolabeling, and preliminary in vivo assessment of a depsipeptide-derived compound as a potential PET/CT infection imaging agent.

    PubMed

    Mokaleng, Botshelo B; Ebenhan, Thomas; Ramesh, Suhas; Govender, Thavendran; Kruger, Hendrik G; Parboosing, Raveen; Hazari, Puja P; Mishra, Anil K; Marjanovic-Painter, Biljana; Zeevaart, Jan R; Sathekge, Mike M

    2015-01-01

    Noninvasive imaging is a powerful tool for early diagnosis and monitoring of various disease processes, such as infections. An alarming shortage of infection-selective radiopharmaceuticals exists for overcoming the diagnostic limitations with unspecific tracers such as (67/68)Ga-citrate or (18)F-FDG. We report here TBIA101, an antimicrobial peptide derivative that was conjugated to DOTA and radiolabeled with (68)Ga for a subsequent in vitro assessment and in vivo infection imaging using Escherichia coli-bearing mice by targeting bacterial lipopolysaccharides with PET/CT. Following DOTA-conjugation, the compound was verified for its cytotoxic and bacterial binding behaviour and compound stability, followed by (68)Gallium-radiolabeling. µPET/CT using (68)Ga-DOTA-TBIA101 was employed to detect muscular E. coli-infection in BALB/c mice, as warranted by the in vitro results. (68)Ga-DOTA-TBIA101-PET detected E. coli-infected muscle tissue (SUV = 1.3-2.4) > noninfected thighs (P = 0.322) > forearm muscles (P = 0.092) > background (P = 0.021) in the same animal. Normalization of the infected thigh muscle to reference tissue showed a ratio of 3.0 ± 0.8 and a ratio of 2.3 ± 0.6 compared to the identical healthy tissue. The majority of the activity was cleared by renal excretion. The latter findings warrant further preclinical imaging studies of greater depth, as the DOTA-conjugation did not compromise the TBIA101's capacity as targeting vector. PMID:25699267

  6. Synthesis and in Vivo Biological Evaluation of (68)Ga-Labeled Carbonic Anhydrase IX Targeting Small Molecules for Positron Emission Tomography.

    PubMed

    Sneddon, Deborah; Niemans, Raymon; Bauwens, Matthias; Yaromina, Ala; van Kuijk, Simon J A; Lieuwes, Natasja G; Biemans, Rianne; Pooters, Ivo; Pellegrini, Paul A; Lengkeek, Nigel A; Greguric, Ivan; Tonissen, Kathryn F; Supuran, Claudiu T; Lambin, Philippe; Dubois, Ludwig; Poulsen, Sally-Ann

    2016-07-14

    Tumor hypoxia contributes resistance to chemo- and radiotherapy, while oxygenated tumors are sensitive to these treatments. The indirect detection of hypoxic tumors is possible by targeting carbonic anhydrase IX (CA IX), an enzyme overexpressed in hypoxic tumors, with sulfonamide-based imaging agents. In this study, we present the design and synthesis of novel gallium-radiolabeled small-molecule sulfonamides targeting CA IX. The compounds display favorable in vivo pharmacokinetics and stability. We demonstrate that our lead compound, [(68)Ga]-2, discriminates CA IX-expressing tumors in vivo in a mouse xenograft model using positron emission tomography (PET). This compound shows specific tumor accumulation and low uptake in blood and clears intact to the urine. These findings were reproduced in a second study using PET/computed tomography. Small molecules investigated to date utilizing (68)Ga for preclinical CA IX imaging are scarce, and this is one of the first effective (68)Ga compounds reported for PET imaging of CA IX. PMID:27322137

  7. Superiority of [68Ga]-DOTATATE PET/CT to other functional imaging modalities in the localization of SDHB-associated metastatic pheochromocytoma and paraganglioma

    PubMed Central

    Janssen, Ingo; Blanchet, Elise M.; Adams, Karen; Chen, Clara C.; Millo, Corina M.; Herscovitch, Peter; Taieb, David; Kebebew, Electron; Lehnert, Hendrik; Fojo, Antonio T.; Pacak, Karel

    2015-01-01

    Purpose Patients with succinate dehydrogenase subunit B (SDHB) mutation-related pheochromocytoma/paraganglioma (PHEO/PGL) are at a higher risk for metastatic disease than other hereditary PHEOs/PGLs. Current therapeutic approaches are limited but the best outcomes are based on the early and proper detection of as many lesions as possible. Because PHEOs/PGLs overexpress somatostatin receptor 2 (SSTR2), the goal of our study was to assess the clinical utility of [68Ga]-DOTA(0)-Tyr(3)-octreotate ([68Ga]-DOTATATE) positron emission tomography/computed tomography (PET/CT) and to evaluate its diagnostic utility in comparison to the currently recommended functional imaging modalities [18F]-fluorodopamine ([18F]-FDA), [18F]-fluorodihydroxyphenylalanine ([18F]-FDOPA), [18F]-fluoro-2-deoxy-D-glucose ([18F]-FDG) PET/CT as well as CT/magnetic resonance imaging (MRI). Experimental Design [68Ga]-DOTATATE PET/CT was prospectively performed in 17 patients with SDHB-related metastatic PHEOs/PGLs. All patients also underwent [18F]-FDG PET/CT and CT/MRI with 16 of the 17 patients also receiving [18F]-FDOPA and [18F]-FDA PET/CT scans. Detection rates of metastatic lesions were compared between all these functional imaging studies. A composite synthesis of all used functional and anatomical imaging studies served as the imaging comparator. Results [68Ga]-DOTATATE PET/CT demonstrated a lesion-based detection rate of 98.6% (95% confidence interval (CI) 96.5% to 99.5%), [18F]-FDG, [18F]-FDOPA, [18F]-FDA PET/CT, and CT/MRI showed detection rates of 85.8% (CI 81.3% to 89.4%) (p<0.01), 61.4% (CI 55.6% to 66.9%) (p<0.01), 51.9% (CI 46.1% to 57.7%) (p<0.01), and 84.8% (CI 80.0% to 88.5%) (p<0.01), respectively. Conclusions [68Ga]-DOTATATE PET/CT showed a significantly superior detection rate compared to all other functional and anatomical imaging modalities and may represent the preferred future imaging modality in the evaluation of SDHB-related metastatic PHEO/PGL. PMID:25873086

  8. Positron emission tomography study on pancreatic somatostatin receptors in normal and diabetic rats with {sup 68}Ga-DOTA-octreotide: A potential PET tracer for beta cell mass measurement

    SciTech Connect

    Sako, Takeo; Hasegawa, Koki; Nishimura, Mie; Kanayama, Yousuke; Wada, Yasuhiro; Hayashinaka, Emi; Cui, Yilong; Kataoka, Yosky; Senda, Michio; Watanabe, Yasuyoshi

    2013-12-06

    Highlights: •PET images showed high uptake of {sup 68}Ga-DOTA-octreotide in the normal pancreas. •{sup 68}Ga-DOTA-octreotide specifically binds to somatostatin receptors in the pancreas. •The pancreatic uptake of {sup 68}Ga-DOTA-octreotide was decreased in the diabetic rats. •{sup 68}Ga-DOTA-octreotide could be a candidate PET probe to measure the beta cell mass. -- Abstract: Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, and the loss or dysfunction of pancreatic beta cells has been reported before the appearance of clinical symptoms and hyperglycemia. To evaluate beta cell mass (BCM) for improving the detection and treatment of DM at earlier stages, we focused on somatostatin receptors that are highly expressed in the pancreatic beta cells, and developed a positron emission tomography (PET) probe derived from octreotide, a metabolically stable somatostatin analog. Octreotide was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), a chelating agent, and labeled with {sup 68}Gallium ({sup 68}Ga). After intravenous injection of {sup 68}Ga-DOTA-octreotide, a 90-min emission scan of the abdomen was performed in normal and DM model rats. The PET studies showed that {sup 68}Ga-DOTA-octreotide radioactivity was highly accumulated in the pancreas of normal rats and that the pancreatic accumulation was significantly reduced in the rats administered with an excess amount of unlabeled octreotide or after treatment with streptozotocin, which was used for the chemical induction of DM in rats. These results were in good agreement with the ex vivo biodistribution data. These results indicated that the pancreatic accumulation of {sup 68}Ga-DOTA-octreotide represented specific binding to the somatostatin receptors and reflected BCM. Therefore, PET imaging with {sup 68}Ga-DOTA-octreotide could be a potential tool for evaluating BCM.

  9. 90Sr content in 90Y-labeled SIR-spheres and Zevalin.

    PubMed

    Metyko, John; Erwin, William; Poston, John; Jimenez, Sandra

    2014-11-01

    Three different 90Y internally administered radionuclide therapies are currently used in both standard-of-care and clinical trial procedures atMD Anderson Cancer Center. TheraSphere and SIR-Spheres therapies utilize 90Y-labeled microspheres, while Zevalin is an 90Y-labeled radioimmunotherapeutic agent. Several publications have indicated radionuclidic impurities resulting from 90Y production methods. The 90Y in SIR-Spheres and Zevalin are produced from a 90Sr/90Y generator, which leaves measurable quantities of 90Sr in the final product. TheraSphere 90Y is produced in a nuclear reactor which results in a large number of impurities, most notably 88Y and 91Y. Product information sheets reference these impurities with specific limits given. These limits represent a tiny fraction of the total product activity, and in the case of TheraSphere and SIR-Spheres gamma-emitting impurities, this has been verified in the literature. An analysis of 90Sr impurities in SIR-Spheres and Zevalin is presented in this paper. Impurity quantities were found to be within the vendors’ documented limits. PMID:25272027

  10. 68Ga-HBED-CC-PSMA PET/CT Versus Histopathology in Primary Localized Prostate Cancer: A Voxel-Wise Comparison

    PubMed Central

    Zamboglou, Constantinos; Schiller, Florian; Fechter, Tobias; Wieser, Gesche; Jilg, Cordula Annette; Chirindel, Alin; Salman, Nasr; Drendel, Vanessa; Werner, Martin; Mix, Michael; Meyer, Philipp Tobias; Grosu, Anca Ligia

    2016-01-01

    Purpose: We performed a voxel-wise comparison of 68Ga-HBED-CC-PSMA PET/CT with prostate histopathology to evaluate the performance of 68Ga-HBED-CC-PSMA for the detection and delineation of primary prostate cancer (PCa). Methodology: Nine patients with histopathological proven primary PCa underwent 68Ga-HBED-CC-PSMA PET/CT followed by radical prostatectomy. Resected prostates were scanned by ex-vivo CT in a special localizer and histopathologically prepared. Histopathological information was matched to ex-vivo CT. PCa volume (PCa-histo) and non-PCa tissue in the prostate (NPCa-histo) were processed to obtain a PCa-model, which was adjusted to PET-resolution (histo-PET). Each histo-PET was coregistered to in-vivo PSMA-PET/CT data. Results: Analysis of spatial overlap between histo-PET and PSMA PET revealed highly significant correlations (p < 10-5) in nine patients and moderate to high coefficients of determination (R²) from 42 to 82 % with an average of 60 ± 14 % in eight patients (in one patient R2 = 7 %). Mean SUVmean in PCa-histo and NPCa-histo was 5.6 ± 6.1 and 3.3 ± 2.5 (p = 0.012). Voxel-wise receiver-operating characteristic (ROC) analyses comparing the prediction by PSMA-PET with the non-smoothed tumor distribution from histopathology yielded an average area under the curve of 0.83 ± 0.12. Absolute and relative SUV (normalized to SUVmax) thresholds for achieving at least 90 % sensitivity were 3.19 ± 3.35 and 0.28 ± 0.09, respectively. Conclusions: Voxel-wise analyses revealed good correlations of 68Ga-HBED-CC-PSMA PET/CT and histopathology in eight out of nine patients. Thus, PSMA-PET allows a reliable detection and delineation of PCa as basis for PET-guided focal therapies. PMID:27446496

  11. Peptide receptor radionuclide therapy with 90Y-DOTATATE/90Y-DOTATOC in patients with progressive metastatic neuroendocrine tumours: assessment of response, survival and toxicity

    PubMed Central

    Vinjamuri, S; Gilbert, T M; Banks, M; McKane, G; Maltby, P; Poston, G; Weissman, H; Palmer, D H; Vora, J; Pritchard, D M; Cuthbertson, D J

    2013-01-01

    Background: Peptide receptor radionuclide therapy (PRRT) is an established treatment for patients with metastatic neuroendocrine tumours (NETs), although which factors are associated with an improved overall survival (OS) remains unclear. The primary aim of this study is to determine to what extent a radiological response to 90Y-DOTATOC/90Y-DOTATATE PRRT is associated with an improved OS. The association of biochemical and clinical response to OS were assessed as secondary outcome measures. Methods: A retrospective analysis was conducted on 57 patients: radiological response was classified using RECIST criteria, biochemical response was classified using WHO criteria and clinical response was assessed subjectively. Responses were recorded as positive response (PR), stable disease (SD) or progressive disease (PD), and survival analysed. Results: Radiological response was achieved in 71.5% (24.5% PR, 47% SD) and was associated with a greater OS (51 and 56 months, respectively), compared with PD (18 months). A biochemical or clinical response post PRRT were not associated with a statistically significant improvement in OS. However, when combined with radiological response a survival benefit was observed according to the number of outcomes (radiological, biochemical, clinical), in which a response was observed. Mild haematological toxicity was common, renal toxicity was rare. Conclusion: In patients with progressive metastatic NETs receiving 90Y-DOTATOC/90Y-DOTATATE PRRT, a radiological response with either a PR or a SD post therapy confers a significant OS benefit. PMID:23492685

  12. Evaluation of carrier added and no carrier added 90Y-EDTMP as bone seeking therapeutic radiopharmaceutical.

    PubMed

    Khalid, Muhammad; Bokhari, Tanveer Hussain; Ahmad, Mushtaq; Bhatti, Haq Nawaz; Iqbal, Munawar; Ghaffar, Abdul; Qadir, Muhammad Imran

    2014-07-01

    The optimum conditions to label ethylenediaminetetramethylene phosphonate (EDTMP) compound with (90)y as a potential candidate for bone metastases therapy were investigated. Yttrium-90 is a pure β-emitter and can be obtained by (89)y (n,γ) (90)y nuclear reaction in a reactor or from an in-house generator system ((90)sr(90)y). The preparation of (90)Y-EDTMPis described using (90)y, which was obtained from neutron irradiation of y2o3 as well as from a laboratory scale organic resin-based (90)sr--(90)y generator. Because of the radiolabeling yield of 90Y-EDTMP on ligand/metal molar ratio, incubation time and ph was evaluated. Under optimum parameters, the radiolabeling yields of (90)Y-EDTMP were <95% for no-carrier-added as well as carrier-added (90)y. The biodistribution of no-carrier-added and carrier-added (90)Y-EDTMP complexes in rats was identical. The results indicate that (90)y (carrier-added)-edtmp is also an effective bone pain palliation agent because of its rapid blood clearance, greater uptake in bones and little absorption in soft tissues. PMID:25015445

  13. Administered activity and outcomes of glass versus resin 90Y microsphere radioembolization in patients with colorectal liver metastases

    PubMed Central

    Nasr, Elie C.; Kunam, Vamsi K.; Bullen, Jennifer A.; Purysko, Andrei S.

    2016-01-01

    Background Given the differences in size, specific activity, and dosing methods for glass yttrium-90 microspheres (90Y-glass) and resin 90Y microspheres (90Y-resin), these therapies may expose the liver to different amounts of radiation, thereby affecting their efficacy and tolerability. We aimed to compare the prescribed activity of 90Y-glass and 90Y-resin for real-world patients undergoing selective internal radiation therapy (SIRT) for liver-dominant metastatic colorectal cancer (mCRC) and to assess efficacy and safety outcomes in these patients. Methods We examined the records of 28 consecutive patients with unresectable colorectal liver metastases treated with SIRT between June 2008 and May 2011 at our institution. Using baseline CT and MR images, we calculated a projected activity as if we had used the other product and compared it to the actual prescribed activity of 90Y-glass and 90Y-resin for each SIRT treatment per manufacturer guidelines. Progression and adverse events were evaluated at follow up visits. Survival was analyzed by the Kaplan-Meier method. Results For 90Y-glass treatments with a mean prescribed 90Y activity of 1.77 GBq, the mean projected 90Y-resin activity was 0.84 GBq. For 90Y-resin treatments with a mean prescribed 90Y activity of 1.05 GBq, the mean projected 90Y-glass activity was 2.48 GBq. The median survival was 9.3 months versus 18.2 months for 90Y-glass and 90Y-resin, respectively (P=0.292). During the second year after SIRT, the hazard ratio of death for patients treated with 90Y-glass versus 90Y-resin was 4.0 (95% CI: 1.3, 12.3; P=0.017). No significant difference in progression, adverse events or liver toxicity was observed. Conclusions Using manufacturer recommended guidelines, 90Y-resin delivers significantly less activity than 90Y-glass to patients with liver-dominant mCRC undergoing SIRT with no significant difference in adverse events and a trend toward improved survival. PMID:27563442

  14. Monte Carlo simulation of PET and SPECT imaging of {sup 90}Y

    SciTech Connect

    Takahashi, Akihiko Sasaki, Masayuki; Himuro, Kazuhiko; Yamashita, Yasuo; Komiya, Isao; Baba, Shingo

    2015-04-15

    Purpose: Yittrium-90 ({sup 90}Y) is traditionally thought of as a pure beta emitter, and is used in targeted radionuclide therapy, with imaging performed using bremsstrahlung single-photon emission computed tomography (SPECT). However, because {sup 90}Y also emits positrons through internal pair production with a very small branching ratio, positron emission tomography (PET) imaging is also available. Because of the insufficient image quality of {sup 90}Y bremsstrahlung SPECT, PET imaging has been suggested as an alternative. In this paper, the authors present the Monte Carlo-based simulation–reconstruction framework for {sup 90}Y to comprehensively analyze the PET and SPECT imaging techniques and to quantitatively consider the disadvantages associated with them. Methods: Our PET and SPECT simulation modules were developed using Monte Carlo simulation of Electrons and Photons (MCEP), developed by Dr. S. Uehara. PET code (MCEP-PET) generates a sinogram, and reconstructs the tomography image using a time-of-flight ordered subset expectation maximization (TOF-OSEM) algorithm with attenuation compensation. To evaluate MCEP-PET, simulated results of {sup 18}F PET imaging were compared with the experimental results. The results confirmed that MCEP-PET can simulate the experimental results very well. The SPECT code (MCEP-SPECT) models the collimator and NaI detector system, and generates the projection images and projection data. To save the computational time, the authors adopt the prerecorded {sup 90}Y bremsstrahlung photon data calculated by MCEP. The projection data are also reconstructed using the OSEM algorithm. The authors simulated PET and SPECT images of a water phantom containing six hot spheres filled with different concentrations of {sup 90}Y without background activity. The amount of activity was 163 MBq, with an acquisition time of 40 min. Results: The simulated {sup 90}Y-PET image accurately simulated the experimental results. PET image is visually

  15. Use of 90Y-ibritumomab tiuxetan in non-Hodgkin's lymphoma.

    PubMed

    Marcus, Robert

    2005-02-01

    The increase in the incidence of non-Hodgkin's lymphoma (NHL) that has occurred over recent decades is expected to continue. Therapeutic options for patients with NHL have improved over the past 20 years, but almost all patients with low-grade lymphoma and approximately 50% of patients with high-grade lymphoma eventually die of their disease, regardless of the regimen used. Thus, there is a continuing need for novel therapeutic options. One such strategy is targeted radioimmunotherapy, which is an attractive approach because lymphoma cells are inherently sensitive to radiation. 90 Y-ibritumomab tiuxetan (Zevalin; Biogen Idec Inc, San Diego, CA, and Schering AG, Berlin, Germany) was the first radioimmunotherapy agent to be approved by the US Food and Drug Administration for the treatment of patients with relapsed, low-grade B-cell NHL. 90Y-ibritumomab tiuxetan comprises the murine IgG1 anti-CD20 antibody ibritumomab, covalently linked to the beta-emitter 90 Y by a chelator tiuxetan. A prospective trial comparing 90Y-ibritumomab tiuxetan with single-agent rituximab showed an overall response rate (ORR) to 90Y-ibritumomab tiuxetan of 80% (34% complete response [CR]/unconfirmed CR [CRu]) compared with 56% (20% CR/CRu) with rituximab (P = .002). Of patients achieving a CR/CRu, 32% were still in remission at 3 to 4 years of follow-up. Similar efficacy (83% ORR, 43% CR/CRu) has been reported with 90 Y-ibritumomab tiuxetan in patients with relapsed or refractory low-grade NHL with mild thrombocytopenia (platelet counts 100,000 to 149,000/mm3 ), and in patients with rituximab-refractory NHL (ORR 74% [CR 15%] compared with an ORR 32% to last rituximab treatment). Safety data compiled from patients entered into five studies have confirmed initial observations that the toxicities encountered with 90Y-ibritumomab tiuxetan therapy are mainly hematologic and transient. As part of a consolidated clinical approach to the ongoing development of 90Y-ibritumomab tiuxetan, studies are

  16. Evaluation of quantitative planar 90Y bremsstrahlung whole-body imaging

    NASA Astrophysics Data System (ADS)

    Minarik, D.; Ljungberg, M.; Segars, P.; Sjögreen Gleisner, K.

    2009-10-01

    With high-dose administration of 90Y labeled antibodies, it is possible to image 90Y without an admixture of 111In. We have earlier shown that it is possible to perform quantitative 90Y bremsstrahlung SPECT for dosimetry purposes with reasonable accuracy. However, whole-body (WB) activity quantification with the conjugate view method is not as time consuming as SPECT and has been the method of choice for dosimetry. We have investigated the possibility of using a conjugate view method where scatter-, backscatter- and septal-penetration compensations are performed by inverse filtering and attenuation correction is performed with a WB x-ray image, for total-body and organ activity quantification of 90Y. The method was evaluated using both Monte Carlo simulated scintillation camera images using realistic source distributions, and by an experimental phantom study. The method was evaluated in terms of image quality and accuracy of the activity quantification. The experimental phantom study was performed using the RSD torso phantom with 90Y activity uniformly distributed in the liver insert. A GE Discovery VH/Hawkeye system was used to acquire the image. The simulation study was performed for a realistic activity distribution in the NCAT anthropomorphic phantom where 90Y bremsstrahlung images were generated using the SIMIND MC program. Two different phantom configurations and two activity distributions were simulated. To mimic the RSD phantom experiment one simulation study was also made with 90Y activity located only in the liver. The SIMIND program was configured to resemble a GE Discovery VH/Hawkeye system. An x-ray projector program was used to generate whole-body x-ray images from the NCAT phantom for attenuation correction in the conjugate view method. Organ activities were calculated from ROIs that exactly covered the organs. Corrections for background activity, overlapping activity and source extension in the depth direction were applied on the ROI data. The total

  17. First-In-Human Study Demonstrating Tumor-Angiogenesis by PET/CT Imaging with 68Ga-NODAGA-THERANOST, a High-Affinity Peptidomimetic for αvβ3 Integrin Receptor Targeting

    PubMed Central

    Baum, Richard P.; Kulkarni, Harshad R.; Müller, Dirk; Danthi, Narasimhan; Kim, Young-Seung; Brechbiel, Martin W.

    2015-01-01

    Abstract 68Ga-NODAGA-THERANOST™ is an αvβ3 integrin antagonist and the first radiolabeled peptidomimetic to reach clinical development for targeting integrin receptors. In this first-in-human study, the feasibility of integrin receptor peptidomimetic positron emission tomography/computed tomography (PET/CT) imaging was confirmed in patients with non-small-cell lung cancer and breast cancer. Methods: Patients underwent PET/CT imaging with 68Ga NODAGA-THERANOST. PET images were analyzed qualitatively and quantitatively and compared to 2-deoxy-2-(18F) fluoro-d-glucose (18F-FDG) findings. Images were obtained 60 minutes postinjection of 300–500 MBq of 68Ga-NODAGA-THERANOST. Results: 68Ga-NODAGA-THERANOST revealed high tumor-to-background ratios (SUVmax=4.8) and uptake at neoangiogenesis sites. Reconstructed fused images distinguished cancers with high malignancy potential and enabled enhanced bone metastasis detection. 18F-FDG-positive lung and lymph node metastases did not show uptake, indicating the absence of neovascularization. Conclusions: 68Ga-NODAGA-THERANOST was found to be safe and effective, exhibiting in this study rapid blood clearance, stability, rapid renal excretion, favorable biodistribution and PK/PD, low irradiation burden (μSv/MBq/μg), and convenient radiolabeling. This radioligand might enable theranostics, that is, a combination of diagnostics followed by the appropriate therapeutics, namely antiangiogenic therapy, image-guided presurgical assessment, treatment response evaluation, prediction of pathologic response, neoadjuvant-peptidomimetic-radiochemotherapy, and personalized medicine strategies. Further clinical trials evaluating 68Ga-NODAGA-THERANOST are warranted. PMID:25945808

  18. Posttherapy radiation safety considerations in radiomicrosphere treatment with 90Y-microspheres.

    PubMed

    Gulec, Seza A; Siegel, Jeffry A

    2007-12-01

    Radiomicrosphere treatment involves the intrahepatic arterial administration of (90)Y-resin or (90)Y-glass microspheres. The microspheres are biocompatible, but not biodegradable, and little to no (90)Y leaches from the microspheres. Without any bioelimination, the beta-dose delivery is generally confined to the liver. Although U.S. Nuclear Regulatory Commission requirements permit patients treated with these microspheres to be released without the need for dose determination or patient instructions, there are important radiation safety issues that need scientific clarification. We carefully evaluated the radiation exposure mechanisms, including the bremsstrahlung radiation doses to others, for a variety of lifestyle behaviors. Dose estimates were also made for several practical and theoretic situations involving the patient's gonads, an embryo or fetus, and a nursing infant. For the infant, we evaluated the potential beta-dose that might be introduced via breast milk ingestion. The bremsstrahlung component of the decay scheme of the pure beta-emitter (90)Y has traditionally been ignored in internal and external dose calculations. Because the production of in vivo bremsstrahlung with the high-energy pure beta-particle-emitting radionuclides used for therapeutic purposes is sufficient to permit external detection and imaging, we believe that the contribution of such radiation should be considered with regard to patient release; we therefore chose to evaluate this potential external radiation hazard. In all cases, the estimated doses were very small, indicating that no patient restrictions are required for radiation safety purposes after the release of a patient who has been treated with (90)Y-microspheres. PMID:18006608

  19. MO-G-17A-06: Kernel Based Dosimetry for 90Y Microsphere Liver Therapy Using 90Y Bremsstrahlung SPECT/CT

    SciTech Connect

    Mikell, J; Siman, W; Kappadath, S; Mahvash, A; Mourtada, F

    2014-06-15

    Purpose: 90Y microsphere therapy in liver presents a situation where beta transport is dominant and the tissue is relatively homogenous. We compare voxel-based absorbed doses from a 90Y kernel to Monte Carlo (MC) using quantitative 90Y bremsstrahlung SPECT/CT as source distribution. Methods: Liver, normal liver, and tumors were delineated by an interventional radiologist using contrast-enhanced CT registered with 90Y SPECT/CT scans for 14 therapies. Right lung was segmented via region growing. The kernel was generated with 1.04 g/cc soft tissue for 4.8 mm voxel matching the SPECT. MC simulation materials included air, lung, soft tissue, and bone with varying densities. We report percent difference between kernel and MC (%Δ(K,MC)) for mean absorbed dose, D70, and V20Gy in total liver, normal liver, tumors, and right lung. We also report %Δ(K,MC) for heterogeneity metrics: coefficient of variation (COV) and D10/D90. The impact of spatial resolution (0, 10, 20 mm FWHM) and lung shunt fraction (LSF) (1,5,10,20%) on the accuracy of MC and kernel doses near the liver-lung interface was modeled in 1D. We report the distance from the interface where errors become <10% of unblurred MC as d10(side of interface, dose calculation, FWHM blurring, LSF). Results: The %Δ(K,MC) for mean, D70, and V20Gy in tumor and liver was <7% while right lung differences varied from 60–90%. The %Δ(K,MC) for COV was <4.8% for tumor and liver and <54% for the right lung. The %Δ(K,MC) for D10/D90 was <5% for 22/23 tumors. d10(liver,MC,10,1–20) awere <9mm and d10(liver,MC,20,1–20) awere <15mm; both agreed within 3mm to the kernel. d10(lung,MC,10,20), d10(lung,MC,10,1), d10(lung,MC,20,20), and d10(lung,MC,20,1) awere 6, 25, 15, and 34mm, respectively. Kernel calculations on blurred distributions in lung had errors > 10%. Conclusions: Liver and tumor voxel doses with 90Y kernel and MC agree within 7%. Large differences exist between the two methods in right lung. Research reported in this

  20. Development and evaluation of an improved quantitative 90Y bremsstrahlung SPECT method

    PubMed Central

    Rong, Xing; Du, Yong; Ljungberg, Michael; Rault, Erwann; Vandenberghe, Stefaan; Frey, Eric C.

    2012-01-01

    Purpose: Yttrium-90 (90Y) is one of the most commonly used radionuclides in targeted radionuclide therapy (TRT). Since it decays with essentially no gamma photon emissions, surrogate radionuclides (e.g., 111In) or imaging agents (e.g., 99mTc MAA) are typically used for treatment planning. It would, however, be useful to image 90Y directly in order to confirm that the distributions measured with these other radionuclides or agents are the same as for the 90Y labeled agents. As a result, there has been a great deal of interest in quantitative imaging of 90Y bremsstrahlung photons using single photon emission computed tomography (SPECT) imaging. The continuous and broad energy distribution of bremsstrahlung photons, however, imposes substantial challenges on accurate quantification of the activity distribution. The aim of this work was to develop and evaluate an improved quantitative 90Y bremsstrahlung SPECT reconstruction method appropriate for these imaging applications. Methods: Accurate modeling of image degrading factors such as object attenuation and scatter and the collimator-detector response is essential to obtain quantitatively accurate images. All of the image degrading factors are energy dependent. Thus, the authors separated the modeling of the bremsstrahlung photons into multiple categories and energy ranges. To improve the accuracy, the authors used a bremsstrahlung energy spectrum previously estimated from experimental measurements and incorporated a model of the distance between 90Y decay location and bremsstrahlung emission location into the SIMIND code used to generate the response functions and kernels used in the model. This improved Monte Carlo bremsstrahlung simulation was validated by comparison to experimentally measured projection data of a 90Y line source. The authors validated the accuracy of the forward projection model for photons in the various categories and energy ranges using the validated Monte Carlo (MC) simulation method. The

  1. Integrin αvβ3 as a Promising Target to Image Neoangiogenesis Using In-House Generator-Produced Positron Emitter (68)Ga-Labeled DOTA-Arginine-Glycine-Aspartic Acid (RGD) Ligand.

    PubMed

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

    2015-06-01

    For the growth and spread of a tumor beyond 2 mm, angiogenesis plays a crucial role, and association of various integrins with angiogenesis is evidential. The aim of the study was radiolabeling of DOTA-chelated RGD (arginine-glycine-aspartic acid) peptide with (68)Ga for PET imaging in locally advanced breast carcinoma. DOTA-RGD was incubated with (68)GaCl3, eluted in 0.05 m HCl. Elution volume, peptide amount, and reaction pH were studied. Radio-ITLC, gas chromatography, endotoxin, and sterility testing were performed. Serial (n=3) and whole-body (n=2) PET/CT imaging was done on patients post i.v. injection of 111-185 MBq of (68)Ga-DOTA-RGD. Maximum radiolabeling yield was achieved with 3 mL elution volume of 15-20 μg peptide at pH 3.5-4.0 with 10 minutes of incubation at 95°C. Product samples were sterile having 99.5% radiochemical purity with residual ethanol content and endotoxins in injectable limits. Intense radiotracer uptake was noticed in the tumor with SUVmax 15.3 at 45 minutes in serial images. Physiological radiotracer uptake was seen in the liver, spleen, ventricles, and thyroid with excretion through the kidneys. The authors concluded that (68)Ga-DOTA-RGD has the potential for imaging α,vβ3 integrin-expressing tumors. PMID:26083951

  2. [sup 90]Y-labeled antibody uptake by human tumor xenografts and the effect of systemic administration of EDTA

    SciTech Connect

    Rowlinson-Busza, G.; Snook, D.; Epenetos, A.A. )

    1994-03-30

    A human tumor xenograft model was used to compare the tumor and normal tissue uptake of a tumor-associated monoclonal antibody radiolabeled with [sup 125]I or [sup 90]Y. Nude mice bearing SC xenografts of the human colon adenocarcinoma, HT29, were injected with a mixture of [sup 125]I- and [sup 90]Y-DTPA-labeled AUA1 monoclonal antibody, which recognizes an antigen expressed on the surface of the tumor cells. In addition, the effect of systemic ethylenediaminetetraacetic acid (EDTA) administration on [sup 90]Y-labeled antibody clearance, tumor uptake of antibody and bone accumulation of [sup 90]Y was studied in a nude mouse model of intraperitoneal cancer. Both the absolute amount (%id[center dot]g[sup -1]) and the tumor:normal tissue ratios were superior for the [sup 90]Y-labeled antibody, compared with the iodinated antibody, with the notable exception of bone. These results suggest that [sup 90]Y is a preferable isotope to iodine for radioimmunotherapy of solid masses, but that myelotoxicity due to bone uptake of released [sup 90]Y will limit the radiation dose which can be given when DTPA is used to chelate the [sup 90]Y. The [sup 90]Y-labeled antibody showed similar serum stability in vitro in the presence or absence of EDTA after incubation for up to 48 h. In vivo, urine excretion of [sup 90]Y was significantly enhanced in mice receiving daily injections of 20 mg EDTA for 3 days, commencing 2 h after intraperitoneal antibody administration, compared with control mice. There was no significant difference in the tumor uptake of [sup 90]Y-labeled antibody in EDTA-treated and control mice at any time-point up to 9 days postinjection. However, the bone levels of [sup 90]Y were significantly reduced in EDTA-treated mice at all times from 1 to 9 days. Based on these results, it should be possible to increase the amount of [sup 90]Y-labeled antibody administered, by chelating the released [sup 90]Y with systemic EDTA to facilitate its excretion. 50 refs., 5 figs.

  3. Comparison of (90)Y activity measurements in nuclear medicine in Germany.

    PubMed

    Kossert, Karsten; Bokeloh, Karen; Ehlers, Marion; Nähle, Ole; Scheibe, Olaf; Schwarz, Uwe; Thieme, Klaus

    2016-03-01

    In 2014, PTB and the company Eckert & Ziegler organized a national comparison exercise to determine the activity of a (90)Y solution. One aim of the comparison was to assess the measurement capability of hospitals and medical practices in Germany. P6-type vials were filled with aliquots of a radioactive (90)Y solution and then sent to 19 participants who were asked to measure the activity in the ampoules as well as in their own standard geometry using syringes. Most of the submitted results have a deviation of less than ±10% from the PTB reference activity when measured in the P6-type vials. The spread is somewhat larger when measured in a syringe geometry. The comparison revealed that some participants have difficulties in applying decay corrections and only a few participants were capable of estimating realistic measurement uncertainties. PMID:26597654

  4. Disproof of solar influence on the decay rates of 90Sr/90 Y

    NASA Astrophysics Data System (ADS)

    Kossert, Karsten; Nähle, Ole J.

    2015-09-01

    A custom-built liquid scintillation counter was used for long-term measurements of 90Sr/90 Y sources. The detector system is equipped with an automated sample changer and three photomultiplier tubes, which makes the application of the triple-to-double coincidence ratio (TDCR) method possible. After decay correction, the measured decay rates were found to be stable and no annual oscillation could be observed. Thus, the findings of this work are in strong contradiction to those of Parkhomov (2011) who reported on annual oscillations when measuring 90Sr/90 Y with a Geiger-Müller counter. Sturrock et al. (2012) carried out a more detailed analysis of the experimental data from Parkhomov and claimed to have found correlations between the decay rates and processes inside the Sun. These findings are questionable, since they are based on inappropriate experimental data as is demonstrated in this work. A frequency analysis of our activity data does not show any significant periodicity.

  5. A Comparison of Techniques for 90Y PET/CT Image-Based Dosimetry Following Radioembolization with Resin Microspheres

    PubMed Central

    Pasciak, Alexander S.; Bourgeois, Austin C.; Bradley, Yong C.

    2014-01-01

    90Y PET/CT following radioembolization has recently been established as a viable diagnostic tool, capable of producing images that are both quantitative and have superior image quality than alternative 90Y imaging modalities. Because radioembolization is assumed to be a permanent implant, it is possible to convert quantitative 90Y PET image sets into data representative of spatial committed absorbed-dose. Multiple authors have performed this transformation using dose-point kernel (DPK) convolution to account for the transport of the high-energy 90Y β-particles. This article explores a technique called the Local Deposition Method (LDM), an alternative to DPK convolution for 90Y image-based dosimetry. The LDM assumes that the kinetic energy from each 90Y β-particle is deposited locally, within the voxel where the decay occurred. Using the combined analysis of phantoms scanned using 90Y PET/CT and ideal mathematical phantoms, an accuracy comparison of DPK convolution and the LDM has been performed. Based on the presented analysis, DPK convolution provides no detectible accuracy benefit over the LDM for 90Y PET-based dosimetry. For PET systems with 90Y resolution poorer than 3.25 mm at full-width and half-max using a small voxel size, the LDM may produce a dosimetric solution that is more accurate than DPK convolution under ideal conditions; however, image noise can obscure some of the perceived benefit. As voxel size increases and resolution decreases, differences between the LDM and DPK convolution are reduced. The LDM method of post-radioembolization dosimetry has the advantage of not requiring additional post-processing. The provided conversion factors can be used to determine committed absorbed-dose using conventional PET image analysis tools. The LDM is a recommended option for routine post-radioembolization 90Y dosimetry based on PET/CT imaging. PMID:24904832

  6. Position for site-specific attachment of a DOTA chelator to synthetic affibody molecules has a different influence on the targeting properties of 68Ga- compared to 111in-labeled conjugates.

    PubMed

    Honarvar, Hadis; Strand, Joanna; Perols, Anna; Orlova, Anna; Selvaraju, Ram Kumar; Eriksson Karlström, Amelie; Tolmachev, Vladimir

    2014-01-01

    Affibody molecules, small (7 kDa) scaffold proteins, are a promising class of probes for radionuclide molecular imaging. Radiolabeling of Affibody molecules with the positron-emitting nuclide 68Ga would permit the use of positron emission tomography (PET), providing better resolution, sensitivity, and quantification accuracy than single-photon emission computed tomography (SPECT). The synthetic anti-HER2 ZHER2:S1 Affibody molecule was conjugated with DOTA at the N-terminus, in the middle of helix 3, or at the C-terminus. The biodistribution of 68Ga- and 111In-labeled Affibody molecules was directly compared in NMRI nu/nu mice bearing SKOV3 xenografts. The position of the chelator strongly influenced the biodistribution of the tracers, and the influence was more pronounced for 68Ga-labeled Affibody molecules than for the 111In-labeled counterparts. The best 68Ga-labeled variant was 68Ga-[DOTA-A1]-ZHER2:S1, which provided a tumor uptake of 13 ± 1 %ID/g and a tumor to blood ratio of 39 ± 12 at 2 hours after injection. 111In-[DOTA-A1]-ZHER2:S1 and 111In-[DOTA-K58]-ZHER2:S1 were equally good at this time point, providing a tumor uptake of 15 to 16 %ID/g and a tumor to blood ratio in the range of 60 to 80. In conclusion, the selection of the best position for a chelator in Affibody molecules can be used for optimization of their imaging properties. This may be important for the development of Affibody-based and other protein-based imaging probes. PMID:25249017

  7. Multimodality imaging following 90Y radioembolization: a comprehensive review and pictorial essay.

    PubMed

    Atassi, Bassel; Bangash, Affaan K; Bahrani, Ammar; Pizzi, Giuseppi; Lewandowski, Robert J; Ryu, Robert K; Sato, Kent T; Gates, Vanessa L; Mulcahy, Mary F; Kulik, Laura; Miller, Frank; Yaghmai, Vahid; Murthy, Ravi; Larson, Andrew; Omary, Reed A; Salem, Riad

    2008-01-01

    Radioembolization with yttrium 90 (90Y) microspheres represents an emerging transarterial therapy for the treatment of liver malignancies that continues to generate interest in the medical community. The classic indication of treatment response is a reduction in tumor size; however, parenchymal changes (eg, necrosis, lack of enhancement, specific findings at positron emission tomography and functional magnetic resonance imaging) and other benign findings (pleural effusions, perivascular edema, contralateral hypertrophy, ring enhancement, perihepatic fluid, fibrosis) may occur following treatment, requiring proper image interpretation. With classic imaging findings and surrogates (time to progression, duration of response, disease-free interval), response rates range from 20% to 80% in patients treated for hepatocellular carcinoma or metastatic disease to the liver. Complications of 90Y radioembolization include cholecystitis, abscess, and bilomas and should be recognized early in the imaging follow-up of these patients. Radiologists who are involved in the posttreatment assessment of patients undergoing 90Y radioembolization should be familiar with the imaging findings and potential imaging pitfalls associated with this therapy. PMID:18203932

  8. Increased 177Lu-DOTATATE uptake in Paget disease.

    PubMed

    Minutoli, Fabio; Sindoni, Alessandro; Cardile, Davide; Pecorella, Giorgio Restifo; Baldari, Sergio

    2013-10-01

    A 45-year-old female patient was referred for peptide receptor radionuclide therapy of liver metastases of neuroendocrine origin; the patient had undergone 2 years earlier surgical resection of a grade 2 neuroendocrine neoplasm of ampulla of Vater infiltrating the duodenal submucosa and muscular layers and the neighboring pancreatic tissue. Post-therapy whole-body scan performed to evaluate in vivo radiopharmaceutical distribution confirmed high accumulation in liver lesions and revealed increased uptake in the hip bone. Bone scan and corresponding CT images demonstrated changes of Paget disease in the same district. PMID:23877528

  9. Thymoma treated with 177Lu DOTATATE induction and maintenance PRRT.

    PubMed

    Makis, William; McCann, Karey; McEwan, Alexander J B

    2015-05-01

    A 47-year-old man presented with a recurrent thymoma World Health Organization type A of the anterior chest wall with pleural metastases after failing chemotherapy. The tumor was positive on In-octreotide, and he was referred for peptide receptor radionuclide therapy (PRRT) with Lu DOTATATE. He received 4 induction and 2 maintenance Lu DOTATATE treatments (total dose, 1000 mCi) and reported significant improvement in symptoms. Before the seventh treatment, mild progression was diagnosed on CT, and PRRT was terminated. The use of induction and maintenance Lu DOTATATE PRRT therapy in the management of thymoma warrants further research. PMID:25783505

  10. Treatment of Advanced Pancreatic Carcinoma with 90Y-Clivatuzumab Tetraxetan: A Phase I Single-Dose Escalation Trial

    PubMed Central

    Gulec, Seza A.; Cohen, Steven J.; Pennington, Kenneth L.; Zuckier, Lionel S.; Hauke, Ralph J.; Horne, Heather; Wegener, William A.; Teoh, Nick; Gold, David V.; Sharkey, Robert M.; Goldenberg, David M.

    2014-01-01

    Purpose Humanized antibody hPAM4 specifically binds a mucin glycoprotein expressed in pancreatic adenocarcinomas. This phase I study evaluated a single dose of 90Y-clivatuzumab tetraxetan (90Y-labeled hPAM4) in patients with advanced pancreatic cancer. Experimental Design Twenty-one patients (4 stage III; 17 stage IV) received 111In-hPAM4 for imaging and serum sampling before 90Y-hPAM4. Study procedures evaluated adverse events, safety laboratories, computed tomography (CT) scans, biomarkers, pharmacokinetics, radiation dosimetry, and immunogenicity (HAHA). Results 111In-hPAM4 showed normal biodistribution with radiation dose estimates to red marrow and solid organs acceptable for radioimmunotherapy and with tumor targeting in 12 patients. One patient withdrew before 90Y-hPAM4; otherwise, 20 patients received 90Y doses of 15 (n = 7), 20 (n = 9), and 25 mCi/m2 (n = 4). Treatment was well tolerated; the only significant drug-related toxicities were (NCI CTC v.3) grade 3 to 4 neutropenia and thrombocytopenia increasing with 90Y dose. There were no bleeding events or serious infections, and most cytopenias recovered to grade 1 within 12 weeks. Three patients at 25 mCi/m2 encountered dose-limiting toxicity with grade 4 cytopenias more than 7 days, establishing 20 mCi/m2 as the maximal tolerated 90Y dose. Two patients developed HAHA of uncertain clinical significance. Most patients progressed rapidly and with CA19-9 levels increasing within 1 month of therapy, but 7 remained progression-free by CT for 1.5 to 5.6 months, including 3 achieving transient partial responses (32%–52% tumor diameter shrinkage). Conclusion 90Y-Clivatuzumab tetraxetan was well tolerated with manageable hematologic toxicity at the maximal tolerated 90Y dose, and is a potential new therapeutic for advanced pancreatic cancer. PMID:21527562

  11. "Click"-cyclized (68)Ga-labeled peptides for molecular imaging and therapy: synthesis and preliminary in vitro and in vivo evaluation in a melanoma model system.

    PubMed

    Martin, Molly E; Sue O'Dorisio, M; Leverich, Whitney M; Kloepping, Kyle C; Walsh, Susan A; Schultz, Michael K

    2013-01-01

    Cyclization techniques are used often to impart higher in vivo stability and binding affinity to peptide targeting vectors for molecular imaging and therapy. The two most often used techniques to impart these qualities are lactam bridge construction and disulfide bond formation. While these techniques have been demonstrated to be effective, orthogonal protection/deprotection steps can limit achievable product yields. In the work described in this chapter, new α-melanocyte stimulating hormone (α-MSH) peptide analogs were synthesized and cyclized by copper-catalyzed terminal azide-alkyne cycloaddition "click" chemistry techniques. The α-MSH peptide and its cognate receptor (melanocortin receptor subtype 1, MC1R) represent a well-characterized model system to examine the effect of the triazole linkage for peptide cyclization on receptor binding in vitro and in vivo. Four new DOTA-conjugated α-MSH analogs were cyclized and evaluated by in vitro competitive binding assays, serum stability testing, and in vivo imaging by positron emission tomography (PET) of tumor-bearing mice. These new DOTA-conjugated click-cyclized analogs exhibited selective high binding affinity (<2 nM) for MC1R on melanoma cells in vitro, high stability in human serum, and produced high-contrast PET/CT images of tumor xenografts. (68)Ga-labeled DOTA bioconjugates displayed rapid pharmacokinetics with receptor-mediated tumor accumulation of up to 16 ± 5% ID/g. The results indicate that the triazole ring is an effective bioisosteric replacement for the standard lactam bridge assemblage for peptide cyclization. Radiolabeling results confirm that Cu catalyst is sufficiently removed prior to DOTA chelator addition to enable insertion of radio metals or stable metals for molecular imaging and therapy. Thus, these click-chemistry-cyclized variants show promise as agents for melanocortin receptor-targeted imaging and radionuclide therapy. PMID:22918759

  12. A Sr-90/Y-90 field calibrator for performance testing of beta-gamma survey instruments

    SciTech Connect

    Olsher, R.H.; Haynie, J.S.

    1988-01-01

    ANSI and regulatory agency guidelines prescribe periodic performance tests for radiation protection instrumentation. Reference readings should be obtained for one point on each scale or decade normally used. A small and lightweight calibrator has been developed that facilitates field testing of beta-gamma survey instruments. The calibrator uses a 45 microcurie Sr-90/Y-90 beta source with a filter wheel to generate variable dose rates in the range from 4 to 400 mrad/hr. Thus, several ranges may be checked by dialing in appropriate filters. The design, use, and typical applications of the calibrator are described.

  13. Treatment of cystic craniopharyngioma with 90Y-Colloid. Four clinical cases.

    PubMed

    Sabaté-Llobera, A; Rojas-Camacho, J G; Mora Salvadó, J; Acebes Martín, J J; Rodríguez-Gasén, A; Ramal Leiva, D; Martín-Comín, J

    2013-01-01

    Craniopharyngioma is a histologically benign and frequently cystic intracranial tumor. It may present aggressive behavior due to compression from nearby structures. Its therapeutic management is complicated because although surgery is the usual treatment of choice, it is not exempt of high morbidity and mortality and frequent tumor recurrence. In craniopharyngiomas with a significant cystic component,internal irradiation with radioactive isotopes is a therapeutic alternative to conventional treatments. We present the cases of four patients with cystic craniopharyngiomas who were treated with intracystic administration of 90Y-colloid, and their evolution after the treatment. PMID:23291161

  14. PET optimization for improved assessment and accurate quantification of {sup 90}Y-microsphere biodistribution after radioembolization

    SciTech Connect

    Martí-Climent, Josep M. Prieto, Elena; Elosúa, César; Rodríguez-Fraile, Macarena; Domínguez-Prado, Inés; Vigil, Carmen; García-Velloso, María J.; Arbizu, Javier; Peñuelas, Iván; Richter, José A.

    2014-09-15

    Purpose: {sup 90}Y-microspheres are widely used for the radioembolization of metastatic liver cancer or hepatocellular carcinoma and there is a growing interest for imaging {sup 90}Y-microspheres with PET. The aim of this study is to evaluate the performance of a current generation PET/CT scanner for {sup 90}Y imaging and to optimize the PET protocol to improve the assessment and the quantification of {sup 90}Y-microsphere biodistribution after radioembolization. Methods: Data were acquired on a Biograph mCT-TrueV scanner with time of flight (TOF) and point spread function (PSF) modeling. Spatial resolution was measured with a{sup 90}Y point source. Sensitivity was evaluated using the NEMA 70 cm line source filled with {sup 90}Y. To evaluate the count rate performance, {sup 90}Y vials with activity ranging from 3.64 to 0.035 GBq were measured in the center of the field of view (CFOV). The energy spectrum was evaluated. Image quality with different reconstructions was studied using the Jaszczak phantom containing six hollow spheres (diameters: 31.3, 28.1, 21.8, 16.1, 13.3, and 10.5 mm), filled with a 207 kBq/ml {sup 90}Y concentration and a 5:1 sphere-to-background ratio. Acquisition time was adjusted to simulate the quality of a realistic clinical PET acquisition of a patient treated with SIR-Spheres{sup ®}. The developed methodology was applied to ten patients after SIR-Spheres{sup ®} treatment acquiring a 10 min per bed PET. Results: The energy spectrum showed the{sup 90}Y bremsstrahlung radiation. The {sup 90}Y transverse resolution, with filtered backprojection reconstruction, was 4.5 mm in the CFOV and degraded to 5.0 mm at 10 cm off-axis. {sup 90}Y absolute sensitivity was 0.40 kcps/MBq in the center of the field of view. Tendency of true and random rates as a function of the {sup 90}Y activity could be accurately described using linear and quadratic models, respectively. Phantom studies demonstrated that, due to low count statistics in {sup 90}Y PET

  15. Cerenkov luminescence imaging of αv β6 integrin expressing tumors using (90) Y-labeled peptides.

    PubMed

    Satpati, Drishty; Hausner, Sven H; Bauer, Nadine; Sutcliffe, Julie L

    2014-07-01

    Cerenkov luminescence imaging (CLI) is an emerging preclinical molecular imaging modality that tracks the radiation emitted in the visible spectrum by fast moving charged decay products of radionuclides. The aim of this study was in vitro and in vivo evaluation of the two radiotracers, (90) Y-DOTA-PEG28 -A20FMDV2 ((90) Y-1) and (90) Y-DOTA-Ahx-A20FMDV2 ((90) Y-2) (>99% radiochemical purity, 3.7 GBq/µmol specific activity) for noninvasive assessment of tumors expressing the integrin αv β6 and their future use in tumor targeted radiotherapy. Cell binding and internalization in αv β6 -positive cells was (90) Y-1: 10.1 ± 0.8%, 50.3 ± 2.1%; (90) Y-2: 22.4 ± 1.7%, 44.7 ± 1.5% with <5% binding to αv β6 -negative control cells. Biodistribution studies showed maximum αv β6 -positive tumor uptake of the radiotracers at 1-h post injection (p.i.) ((90) Y-1: 0.64 ± 0.15% ID/g; (90) Y-2: 0.34 ± 0.11% ID/g) with high renal uptake (>25% ID/g at 24 h). Because of the lower tumor uptake and high radioactivity accumulation in kidneys (that could not be reduced by pre-administration of either lysine or furosemide), the luminescence signal from the αv β6 -positive tumor was not clearly detectable in CLI images. The studies suggest that CLI is useful for indicating major organ uptake for both radiotracers; however, it reaches its limitation when there is low signal-to-noise ratio. PMID:25042833

  16. Comparison of autologous 111In-leukocytes, 18F-FDG, 11C-methionine, 11C-PK11195 and 68Ga-citrate for diagnostic nuclear imaging in a juvenile porcine haematogenous staphylococcus aureus osteomyelitis model

    PubMed Central

    Nielsen, Ole L; Afzelius, Pia; Bender, Dirk; Schønheyder, Henrik C; Leifsson, Páll S; Nielsen, Karin M; Larsen, Jytte O; Jensen, Svend B; Alstrup, Aage KO

    2015-01-01

    The aim of this study was to compare 111In-labeled leukocyte single-photon emission computed tomography (SPECT) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) to PET with tracers that potentially could improve detection of osteomyelitis. We chose 11C-methionine, 11C-PK11195 and 68Ga-citrate and validated their diagnostic utility in a porcine haematogenous osteomyelitis model. Four juvenile 14-15 weeks old female pigs were scanned seven days after intra-arterial inoculation in the right femoral artery with a porcine strain of Staphylococcus aureus using a sequential scan protocol with 18F-FDG, 68Ga-citrate, 11C-methionine, 11C-PK11195, 99mTc-Nanocoll and 111In-labelled autologous leukocytes. This was followed by necropsy of the pigs and gross pathology, histopathology and microbial examination. The pigs developed a total of five osteomyelitis lesions, five lesions characterized as abscesses/cellulitis, arthritis in three joints and five enlarged lymph nodes. None of the tracers accumulated in joints with arthritis. By comparing the 10 infectious lesions, 18F-FDG accumulated in nine, 111In-leukocytes in eight, 11C-methionine in six, 68Ga-citrate in four and 11C-PK11195 accumulated in only one lesion. Overall, 18F-FDG PET was superior to 111In-leukocyte SPECT in marking infectious and proliferative, i.e. hyperplastic, lesions. However, leukocyte SPECT was performed as early scans, approximately 6 h after injection of the leukocytes, to match the requirements of the 18 h long scan protocol. 11C-methionine and possibly 68Ga-citrate may be useful for diagnosis of soft issue lesions. PMID:25973338

  17. Comparison of autologous (111)In-leukocytes, (18)F-FDG, (11)C-methionine, (11)C-PK11195 and (68)Ga-citrate for diagnostic nuclear imaging in a juvenile porcine haematogenous staphylococcus aureus osteomyelitis model.

    PubMed

    Nielsen, Ole L; Afzelius, Pia; Bender, Dirk; Schønheyder, Henrik C; Leifsson, Páll S; Nielsen, Karin M; Larsen, Jytte O; Jensen, Svend B; Alstrup, Aage Ko

    2015-01-01

    The aim of this study was to compare (111)In-labeled leukocyte single-photon emission computed tomography (SPECT) and (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) to PET with tracers that potentially could improve detection of osteomyelitis. We chose (11)C-methionine, (11)C-PK11195 and (68)Ga-citrate and validated their diagnostic utility in a porcine haematogenous osteomyelitis model. Four juvenile 14-15 weeks old female pigs were scanned seven days after intra-arterial inoculation in the right femoral artery with a porcine strain of Staphylococcus aureus using a sequential scan protocol with (18)F-FDG, (68)Ga-citrate, (11)C-methionine, (11)C-PK11195, (99m)Tc-Nanocoll and (111)In-labelled autologous leukocytes. This was followed by necropsy of the pigs and gross pathology, histopathology and microbial examination. The pigs developed a total of five osteomyelitis lesions, five lesions characterized as abscesses/cellulitis, arthritis in three joints and five enlarged lymph nodes. None of the tracers accumulated in joints with arthritis. By comparing the 10 infectious lesions, (18)F-FDG accumulated in nine, (111)In-leukocytes in eight, (11)C-methionine in six, (68)Ga-citrate in four and (11)C-PK11195 accumulated in only one lesion. Overall, (18)F-FDG PET was superior to (111)In-leukocyte SPECT in marking infectious and proliferative, i.e. hyperplastic, lesions. However, leukocyte SPECT was performed as early scans, approximately 6 h after injection of the leukocytes, to match the requirements of the 18 h long scan protocol. (11)C-methionine and possibly (68)Ga-citrate may be useful for diagnosis of soft issue lesions. PMID:25973338

  18. Production of large quantities of 90Y by ion-exchange chromatography using an organic resin and a chelating agent.

    PubMed

    Castillo, Abmel Xiques; Pérez-Malo, Marylaine; Isaac-Olivé, Keila; Mukhallalati, Heyam; González, Edgar Casanova; Berdeguez, Mirta Torres; Díaz, Néstor Cornejo

    2010-11-01

    The performance of a system composed of an organic cation exchanger (Dowex 50Wx8) and a chelating agent (EDTA) previously described for the successful production of (90)Y via a (90)Sr/(90)Y generator is assessed under dynamic conditions. In an attempt to overcome the established limitation of ion-exchange resins for the separation of subcurie quantities of activity, (90)Y is repeatedly isolated from an 11.8-GBq (320 mCi) (90)Sr cow using a three-column tandem arrangement. The high recovery and radionuclidic purity obtained for (90)Y and the parameters of the separation (time, eluant concentration, pH and flow rate range) strongly suggest that Ci quantities of (90)Y can be handled satisfactorily by the ion-exchange method. No replacement or treatment of the cow, low waste generation and (90)Sr losses less than 0.1% after each run were observed during the present study which, in combination with the low cost of this resin, may result in an attractive alternate method for the production of large quantities of (90)Y. PMID:21055624

  19. Accuracy and Utility of Deformable Image Registration in {sup 68}Ga 4D PET/CT Assessment of Pulmonary Perfusion Changes During and After Lung Radiation Therapy

    SciTech Connect

    Hardcastle, Nicholas; Hofman, Michael S.; Hicks, Rodney J.; Callahan, Jason; Kron, Tomas; MacManus, Michael P.; Ball, David L.; Jackson, Price; Siva, Shankar

    2015-09-01

    Purpose: Measuring changes in lung perfusion resulting from radiation therapy dose requires registration of the functional imaging to the radiation therapy treatment planning scan. This study investigates registration accuracy and utility for positron emission tomography (PET)/computed tomography (CT) perfusion imaging in radiation therapy for non–small cell lung cancer. Methods: {sup 68}Ga 4-dimensional PET/CT ventilation-perfusion imaging was performed before, during, and after radiation therapy for 5 patients. Rigid registration and deformable image registration (DIR) using B-splines and Demons algorithms was performed with the CT data to obtain a deformation map between the functional images and planning CT. Contour propagation accuracy and correspondence of anatomic features were used to assess registration accuracy. Wilcoxon signed-rank test was used to determine statistical significance. Changes in lung perfusion resulting from radiation therapy dose were calculated for each registration method for each patient and averaged over all patients. Results: With B-splines/Demons DIR, median distance to agreement between lung contours reduced modestly by 0.9/1.1 mm, 1.3/1.6 mm, and 1.3/1.6 mm for pretreatment, midtreatment, and posttreatment (P<.01 for all), and median Dice score between lung contours improved by 0.04/0.04, 0.05/0.05, and 0.05/0.05 for pretreatment, midtreatment, and posttreatment (P<.001 for all). Distance between anatomic features reduced with DIR by median 2.5 mm and 2.8 for pretreatment and midtreatment time points, respectively (P=.001) and 1.4 mm for posttreatment (P>.2). Poorer posttreatment results were likely caused by posttreatment pneumonitis and tumor regression. Up to 80% standardized uptake value loss in perfusion scans was observed. There was limited change in the loss in lung perfusion between registration methods; however, Demons resulted in larger interpatient variation compared with rigid and B-splines registration

  20. Efficacy and safety of 90Y ibritumomab tiuxetan (Zevalin) radioimmunotherapy for non-Hodgkin's lymphoma.

    PubMed

    Witzig, Thomas E

    2003-12-01

    Radioimmunotherapy, an emerging treatment option for certain patients with non-Hodgkin's lymphoma (NHL), enables the targeting of cytotoxic radiation to tumor cells with minimal irradiation of normal cells. Yttrium 90 ibritumomab tiuxetan (Zevalin; Biogen Idec Inc, Cambridge, MA) was approved in February 2002 for the treatment of patients with relapsed or refractory low-grade, follicular, or transformed B-cell NHL, including patients with rituximab-refractory NHL. Yttrium 90 ibritumomab tiuxetan is an effective treatment with a consistent overall response rate of 73% to 83%. It has a good safety profile and is generally well tolerated in the indicated population. The results of clinical trials show that (90)Y ibritumomab tiuxetan can be used effectively and safely in many patients with NHL, including those with mild thrombocytopenia and those with disease that is refractory to rituximab, without the adverse events associated with conventional chemotherapy and external beam radiation therapy. The use of (90)Y ibritumomab tiuxetan does not preclude subsequent therapy with other conventional treatment options. PMID:14710398

  1. [Determination of 90 Sr in milk by solvent extraction of 90Y (author's transl)].

    PubMed

    Mitsuhashi, T; Sakanoue, M

    1977-10-01

    In order to replace the conventional method using violent fuming nitric acid, a new method for the determination of 90 Sr in milk has been developed by using the solvent extraction with bis (2-ethylhexyl) phosphoric acid (HDEHP). The daughter nuclide 90Y in a radiochemical equilibrium with its parent 90Sr was extracted with 2:1 HDEHP-toluene from the acid solution (1M HCL) of milk ash sample prepared by dry-ashing. After stripping with 8M HCL, 90Y, together with stable yttrium added as carrier, was precipated as oxalate to prepare beta-counting source. The radiochemical purity was confirmed by decay curve. The decontamination of strontium was checked by applying non-dispersive fluorescence X-ray analysis using 133Ba as irradiating source. Bone samples of cow were also analyzed by the same method and the results were compared with those obtained by other methods. The duplicate crosschecking analyses of finely ground bone samples were carried out to examine the effectiveness of this method. This simple new method was found to be very effective for the routine analysis of 90Sr in these samples. PMID:579456

  2. Dosimetry of [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 in rodents, pigs, non-human primates and human - repeated scanning in human is possible

    PubMed Central

    Selvaraju, Ram Kumar; Bulenga, Thomas N; Espes, Daniel; Lubberink, Mark; Sörensen, Jens; Eriksson, Barbro; Estrada, Sergio; Velikyan, Irina; Eriksson, Olof

    2015-01-01

    Quantitative PET imaging with [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 has potential use in diabetes and cancer. However, the radiation dose to the kidneys has been a concern for the possibility of repeated imaging studies in humans. Therefore, we investigated the dosimetry of [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 based on the biodistribution data in rats, pigs, non-human primates (NHP) and a human.Organ distribution of [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 in rats (Male Lewis; n=12; 30, 60, and 80 min) was measured ex vivo. The dynamic uptake of [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 in the abdomen was assessed by PET/CT scanning of pigs (male; n = 4, 0-60 min), NHP (Female; cynomolgus; n=3; 0-90 min), and human (female; n=1; 0-40, 100, 120 min).The organ distribution data in each species were extrapolated to those of a human, assuming similar distribution between the species. Residence times were assessed by trapezoidal approximation of the kinetic data. Organ doses (mGy/MBq) and the whole body effective dose (mSv/MBq), was extrapolated by using the OLINDA/EXM 1.1 software. The extrapolated human whole body effective dose was 0.017 ± 0.004 (rats), 0.014 ± 0.004 (pigs), 0.017 ± 0.004 (NHP), and 0.016 (human) mSv/MBq. The absorbed dose to the kidneys was limiting:0.33 ± 0.06 (rats), 0.28±0.05 (pigs), 0.65 ± 0.11 (NHP), and 0.28 (human) mGy/MBq, which corresponded to the maximum yearly administered amounts of 455 (rat), 536 (pig), 231 (NHP), and 536 (human) MBq before reaching the yearly kidney limiting dose of 150 mGy. More than 200 MBq of [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 can be administered yearly in a human, allowing for repeated (2-4 times) scanning. This potentially enables longitudinal clinical PET imaging studies of the GLP-1R in the pancreas, transplanted islets, or insulinoma. PMID:26069859

  3. Theranostic Applications of Lutetium-177 in Radionuclide Therapy.

    PubMed

    Das, Tapas; Banerjee, Sharmila

    2016-01-01

    Lutetium-177 has been widely discussed as a radioisotope of choice for targeted radionuclide therapy. The simultaneous emission of imageable gamma photons [208 keV (11%) and 113 keV (6.4%)] along with particulate β(-) emission [β(max) = 497 keV] makes it a theranostically desirable radioisotope. In the present article, the possibility of using two 177Lu-based agents viz. 177Lu-EDTMP and 177Lu-DOTATATE for theranostic applications in metastatic bone pain palliation (MBPP) and peptide receptor radionuclide therapy (PRRT), have been explored. In the case of 177Lu-EDTMP, the whole-body images obtained are compared with those recorded using 99mTc-MDP in the same patient. On the other hand, pre-therapy images acquired with 177Lu-DOTA-TATE are compared with similar images obtained with standard agents, such as 99mTc-HYNIC-TOC (SPECT) and 68Ga-DOTA-TOC (PET) in the same patient. The advantage of the long physical half-life (T1/2) of 177Lu has been utilized in mapping the pharmacokinetics of two additional agents, 177Lu-labeled hydroxyapatite (HA) in radiation synovectomy of knee joints and 177Lu-HA for therapy of hepatocellular carcinoma. Results of these multiple studies conclusively document the potential of 177Lu as a theranostic radioisotope. PMID:25771364

  4. Validating and improving CT ventilation imaging by correlating with ventilation 4D-PET/CT using {sup 68}Ga-labeled nanoparticles

    SciTech Connect

    Kipritidis, John Keall, Paul J.; Siva, Shankar; Hofman, Michael S.; Callahan, Jason; Hicks, Rodney J.

    2014-01-15

    Purpose: CT ventilation imaging is a novel functional lung imaging modality based on deformable image registration. The authors present the first validation study of CT ventilation using positron emission tomography with{sup 68}Ga-labeled nanoparticles (PET-Galligas). The authors quantify this agreement for different CT ventilation metrics and PET reconstruction parameters. Methods: PET-Galligas ventilation scans were acquired for 12 lung cancer patients using a four-dimensional (4D) PET/CT scanner. CT ventilation images were then produced by applying B-spline deformable image registration between the respiratory correlated phases of the 4D-CT. The authors test four ventilation metrics, two existing and two modified. The two existing metrics model mechanical ventilation (alveolar air-flow) based on Hounsfield unit (HU) change (V{sub HU}) or Jacobian determinant of deformation (V{sub Jac}). The two modified metrics incorporate a voxel-wise tissue-density scaling (ρV{sub HU} and ρV{sub Jac}) and were hypothesized to better model the physiological ventilation. In order to assess the impact of PET image quality, comparisons were performed using both standard and respiratory-gated PET images with the former exhibiting better signal. Different median filtering kernels (σ{sub m} = 0 or 3 mm) were also applied to all images. As in previous studies, similarity metrics included the Spearman correlation coefficient r within the segmented lung volumes, and Dice coefficient d{sub 20} for the (0 − 20)th functional percentile volumes. Results: The best agreement between CT and PET ventilation was obtained comparing standard PET images to the density-scaled HU metric (ρV{sub HU}) with σ{sub m} = 3 mm. This leads to correlation values in the ranges 0.22 ⩽ r ⩽ 0.76 and 0.38 ⩽ d{sub 20} ⩽ 0.68, with r{sup ¯}=0.42±0.16 and d{sup ¯}{sub 20}=0.52±0.09 averaged over the 12 patients. Compared to Jacobian-based metrics, HU-based metrics lead to statistically significant

  5. Prediction of tumor response to experimental radioimmunotherapy with {sup 90}Y in nude mice

    SciTech Connect

    Dillehay, L.E.; Mayer, R.; Zhang, Y.G.

    1995-09-30

    The purpose of this investigation was to identify those factors that predict variability in tumor response to {sup 90}Y-radioimmunotherapy based on measurement of incorporated activity and physical dimensions of individual tumors and to apply the concept of effective dose to radioimmunotherapy. Human colon carcinoma xenografts growing in nude mice were treated with anti-CEA antibodies labeled with {sup 90}Y directly or through a bispecific antibody/labeled hapten system. Tumor response was measured as the delay in growth to eight times the treatment volume. Noninvasive activity (based on bremsstrahlung radiation) and dimension measurements were made in these animals at several times after label injection. The following parameters were compared for their ability to predict individual tumor response: (a) injected activity, (b) injected activity times a factor based on average uptake as a function of volume, (c) in vivo activity per volume measured in each animal at a single time, (d) the integral over time of in vivo activity per volume in each animal, and (e) the minimum dose for each animal in a uniformly active ellipsoid whose total activity and dimensions varied over time the same as the tumor. After correcting for differences in injected activity, two parameters account for much of the variability in tumor response. One of these is the general trend of larger tumors to take up less activity per volume. Additional variability can be accounted for by the in vivo activity per volume measurements. The minimum dose as introduced here is likely to be useful in estimating the biologically effective dose delivered by each treatment. 27 refs., 5 figs., 1 tab.

  6. External Beam Radiotherapy Followed by {sup 90}Y Ibritumomab Tiuxetan in Relapsed or Refractory Bulky Follicular Lymphoma

    SciTech Connect

    Burdick, Michael J.; Neumann, Donald; Pohlman, Brad; Reddy, Chandana A.; Tendulkar, Rahul D.; Macklis, Roger

    2011-03-15

    Purpose: We combined external beam radiotherapy (EBRT) with yttrium-90 ibritumomab tiuxetan ({sup 90}Y-IT) in an attempt to improve therapeutic response in patients with relapsed or refractory bulky follicular lymphoma (RRBFL). Methods and Materials: Between February 2006 and September 2007, 11 patients with RRBFL were treated with EBRT followed by {sup 90}Y-IT. Bulky disease (BD) was defined as >5 cm. EBRT was delivered to BD as 2,400 cGy in eight fractions using computed tomography (CT)-based planning. BD was contoured as the gross tumor volume. A planning margin of 1 to 2 cm was added depending on anatomical location. After recovery of complete blood counts (CBC), {sup 90}Y-IT was administered at a dose of 0.3 or 0.4 mCi/kg depending on platelet counts. Hematologic toxicity was monitored through weekly CBC. Response was measured by positron emission tomography/CT or CT 3-4 months after {sup 90}Y-IT. Results: Only 2 patients required prolonged breaks between EBRT and {sup 90}Y-IT. The median time after {sup 90}Y-IT for platelets to recover to >100,000/ml was 55 days (range, 41-128 days). Platelet counts for 1 patient, who had received 4 previous chemotherapy regimens, never reached 100,000/ml. The complete and overall responses to combined therapy as measured 3-4 months after {sup 90}Y-IT were 64%. No patients relapsed within the EBRT field. With a median follow-up of 36.1 months, 6 patients have relapsed, 2 of whom have died. Median progression-free survival was 17.5 months. Conclusions: In contrast to prior failure analysis data for RRBFL patients treated with {sup 90}Y-IT alone, a brief course of EBRT prevented relapse in sites of BD. EBRT used to pretreat bulky sites may improve clinical outcomes and potentially extend survival when combined with {sup 90}Y-IT.

  7. Three dosimetry models of lipoma arborescens treated by {sup 90}Y synovectomy

    SciTech Connect

    O’Doherty, Jim; Clauss, Ralf; Scuffham, James; Khan, Aman; Petitguillaume, Alice; Desbrée, Aurélie

    2014-05-15

    Purpose: Lipoma arborescens (LA) is a benign intra-articular lipomatous proliferation of the synovial membrane. This extremely rare condition has previously been treated by intra-articular{sup 90}Y radiosynoviorthesis but dosimetry literature on this form of radionuclide therapy is nonexistent. The authors detail methodology for successful treatment of LA and provide for the first time estimates of radiation dosimetry. The authors also analyze the biodistribution of the radiopharmaceutical over the course of the patient's treatment through sequential imaging. Methods: A patient with bilateral LA underwent intracavity injection of{sup 90}Y citrate colloid to the right and left knee joint spaces (181 and 198 MBq, respectively). SPECT/CT datasets were acquired over 9 days to quantify the biodistribution and kinetics of the radiopharmaceutical. Radiation dosimetry was performed using the MIRD schema (through OLINDA software), a custom voxel-based method, and a direct Monte Carlo calculation (OEDIPE). Results: Follow-up MRI showed marked reduction in LA size in both knees. Mean absorbed doses to the LA were 21.2 ± 0.8 and 42.9 ± 2.3 Gy using OLINDA, 8.1 ± 0.3 and 16.7 ± 0.5 Gy using voxel based methodology, and 8.2 ± 0.3 and 15.7 ± 0.5 Gy for OEDIPE in the right and left LA, respectively. Distribution of the radiopharmaceutical within the joint space alters over the imaging period, with less than 1% of the remaining activity having moved posteriorly in the knee cavity. No uptake was detected outside of the joint space after assessment with whole-body scintigraphy. Conclusions: An activity of approximately 185 MBq successfully relieved clinical symptoms of LA. There was good correlation between direct Monte Carlo and voxel based techniques, but OLINDA was shown to overestimate the absorbed dose to the tumor. Accurate dosimetry may help select an activity more tailored to the specific size and location of the LA.

  8. Post-mortem considerations of Yttrium-90 90Y microsphere therapy procedures.

    PubMed

    Nelson, Kevin; Vause, Paul E; Koropova, Polina

    2008-11-01

    Yttrium-90 (Y) microspheres, either in the form of resin beads or glass, are currently used to treat unresectable hepatocellular cancer. It has been discovered that long-lived contaminants, principally Eu and Eu, can be found in the waste generated by this procedure. Recently, at our medical facility, an elevated count rate was discovered on a deceased patient scheduled to have an autopsy and who had undergone Y microsphere therapy nearly 5 months previously. Regulatory issues arose when the family of the patient requested that the body of the deceased be cremated. In this particular instance the exposure rate from the body was below regulatory concern; however, the potential contamination and exposure from these long-lived contaminants cannot be ignored for individuals working in the autopsy room, funeral home embalming area, and crematorium. Information provided to potential patients in pamphlet form from the manufacturer failed to identify the existence of long-lived contaminants and possible difficulties associated with cremation. To ensure potential Y microsphere patients and family members are aware of the possible existence of long-lived contaminants, a patient consent and notification form has been developed. The proper disposal of residual material associated with these procedures, i.e., long-lived radioactive contaminants in explanted organs, pose additional difficulties. Further education of medical staff and funeral home directors with crematoriums is necessary. Close cooperation with the regulatory authority was instrumental in resolving this situation. PMID:18849708

  9. (90)Y microspheres prepared by sol-gel method, promising medical material for radioembolization of liver malignancies.

    PubMed

    Łada, Wiesława; Iller, Edward; Wawszczak, Danuta; Konior, Marcin; Dziel, Tomasz

    2016-10-01

    A new technology for the production of radiopharmaceutical (90)Y microspheres in the form of spherical yttrium oxide grains obtained by sol-gel method has been described. The authors present and discuss the results of investigations performed in the development of new production technology of yttrium microspheres and determination of their physic-chemical properties. The final product has the structure of spherical yttrium oxide grains with a diameter 25-100μm, is stable and free from contaminants. Irradiation of 20mg samples of grains with diameter of 20-50μm in the thermal neutron flux of 1.7×10(14)cm(-2)s(-1) at the core of MARIA research nuclear reactor allowed to obtain microspheres labelled with the (90)Y isotope on the way of the nuclear reaction (89)Y(n, ɤ)(90)Y. Specific activity of irradiated microspheres has been determined by application of absolute triple to double coincidence ratio method (TDCR) and has been evaluated at 190MBq/mg Y. (90)Y microspheres prepared by the proposed technique can be regarded as a promising medical material for radioembolization of liver malignancies. PMID:27287162

  10. Dosimetric comparison of {sup 90}Y, {sup 32}P, and {sup 186}Re radiocolloids in craniopharyngioma treatments

    SciTech Connect

    Sadeghi, Mahdi; Karimi, Elham; Hosseini, S. Hamed

    2009-11-15

    Purpose: In the radionuclide treatment of some forms of brain tumors such as craniopharyngiomas, the selection of the appropriate radionuclide for therapy is a key element in treatment planning. The aim was to study the influence by considering the beta-emitter radionuclide dose rate in an intracranial cyst. Methods: Dosimetry was performed using the MCNP4C radiation transport code. Analytical dosimetry was additionally performed using the Loevinger and the Berger formulas in the MATLAB software. Each result was compared under identical conditions. The advantages and disadvantages of using {sup 90}Y versus {sup 32}P and {sup 186}Re were investigated. Results: The dose rate at the inner surface of the cyst wall was estimated to be 400 mGy/h for a 1 MBq/ml concentration of {sup 90}Y. Under identical conditions of treatment, the corresponding dose rates were 300 mGy/h for {sup 32}P and 160 mGy/h for {sup 186}Re. For a well-defined cyst radius and identical wall thickness, higher dose rates resulted for {sup 90}Y. Conclusions: To achieve the same radiological burden, the required amount of physical activity of injectable solution is lower for {sup 32}P. This is found to be a consequence of both the radionuclide physical half-life and the pattern of energy deposition from the emitted radiation. According to the half-life and dose-rate results, {sup 90}Y would be a good substitute for {sup 32}P.

  11. 90Y-Labeled Anti-ROBO1 Monoclonal Antibody Exhibits Antitumor Activity against Small Cell Lung Cancer Xenografts

    PubMed Central

    Fujiwara, Kentaro; Koyama, Keitaro; Suga, Kosuke; Ikemura, Masako; Saito, Yasutaka; Hino, Akihiro; Iwanari, Hiroko; Kusano-Arai, Osamu; Mitsui, Kenichi; Kasahara, Hiroyuki; Fukayama, Masashi; Kodama, Tatsuhiko; Hamakubo, Takao; Momose, Toshimitsu

    2015-01-01

    Introduction ROBO1 is a membrane protein that contributes to tumor metastasis and angiogenesis. We previously reported that 90Y-labeled anti-ROBO1 monoclonal antibody (90Y-anti-ROBO1 IgG) showed an antitumor effect against ROBO1-positive tumors. In this study, we performed a biodistribution study and radioimmunotherapy (RIT) against ROBO1-positive small cell lung cancer (SCLC) models. Methods For the biodistribution study, 111In-labeled anti-ROBO1 monoclonal antibody (111In-anti-ROBO1 IgG) was injected into ROBO1-positive SCLC xenograft mice via the tail vein. To evaluate antitumor effects, an RIT study was performed, and SCLC xenograft mice were treated with 90Y-anti-ROBO1 IgG. Tumor volume and body weight were periodically measured throughout the experiments. The tumors and organs of mice were then collected, and a pathological analysis was carried out. Results As a result of the biodistribution study, we observed tumor uptake of 111In-anti-ROBO1 IgG. The liver, kidney, spleen, and lung showed comparably high accumulation of 111In-labeled anti-ROBO1. In the RIT study, 90Y-anti-ROBO1 IgG significantly reduced tumor volume compared with baseline. Pathological analyses of tumors revealed coagulation necrosis and fatal degeneration of tumor cells, significant reduction in the number of Ki-67-positive cells, and an increase in the number of apoptotic cells. A transient reduction of hematopoietic cells was observed in the spleen, sternum, and femur. Conclusions These results suggest that RIT with 90Y-anti-ROBO1 IgG is a promising treatment for ROBO1-positive SCLC. PMID:26017283

  12. Diagnostic Utility of PET CT in Thymic Tumours with Emphasis on 68Ga-DOTATATE PET CT in Thymic Neuroendocrine Tumour - Experience at a Tertiary Level Hospital in India

    PubMed Central

    Shanthly, Nylla; Oommen, Regi

    2014-01-01

    Introduction:18 Fluorine-fluoro-2-deoxyglucose positron emis–sion tomography/computed tomography (18F- FDG-PET/CT) is of importance in assessing high-risk thymoma and thymic carcinomas. Detection of advanced thymoma versus thymic carcinoma by routine cross sectional anatomical imaging such as computed tomography (CT), magnetic resonance imaging (MRI) often poses a diagnostic dilemma. In this case series we observed the utility of FDG uptake to predict advanced thymoma and distinguish thymoma from thymic cancer. Materials and Methods: We reviewed 18F- FDG-PET/CT scans of 12 patients (8 males, 4 females); age 24-60yrs with thymic epithelial malignancy from January 2011 to May 2013. FDG activity in lesions was quantified using maximum standardised uptake value (SUVmax) and correlated with Masaoka staging and WHO classification. All patients fasted 4 hr prior to 18F-FDG PET/CT. Images from vertex to mid-thigh were acquired 60min post injection of 3.7 -4.7 MBq/kg (Mega Becquerel)/kilogram of18F-FDG and SUV max of each tumour was measured. One patient underwent DOTATATE scan, received 138MBq of 68Gallium (68Ga)-DOTATATE injection IV and imaging was done after 60 min. Results: Higher FDG uptake of SUVmax 7.35 was seen in type B3 thymoma. FDG uptake was higher in thymic carcinoma (20.45 in primary and 17.46 in the node) or neuroendocrine differentiation (NED) than in patients with thymomas (ranged 7.35 - 3.02). No significant association was observed between higher focal FDG uptake and advanced-stage disease in thymoma. In NED 68Ga - DOTATATE imaging identified more lesions than in FDG. Conclusion: PET CT is a valuable diagnostic tool in evaluation of thymic tumours, to assess in initial workup, for treatment response and for prognostication. 68Ga-DOTATATE PET/CT is beneficial in assessing neuroendocrine thymic tumours. Focal FDG uptake cannot predict advanced thymoma but is helpful in distinguishing thymoma from thymic carcinoma, or the more aggressive thymoma B3. PMID

  13. A review of 3D image-based dosimetry, technical considerations and emerging perspectives in 90Y microsphere therapy

    PubMed Central

    O’ Doherty, Jim

    2016-01-01

    Yttrium-90 radioembolization (90Y-RE) is a well-established therapy for the treatment of hepatocellular carcinoma (HCC) and also of metastatic liver deposits from other malignancies. Nuclear Medicine and Cath Lab diagnostic imaging takes a pivotal role in the success of the treatment, and in order to fully exploit the efficacy of the technique and provide reliable quantitative dosimetry that are related to clinical endpoints in the era of personalized medicine, technical challenges in imaging need to be overcome. In this paper, the extensive literature of current 90Y-RE techniques and challenges facing it in terms of quantification and dosimetry are reviewed, with a focus on the current generation of 3D dosimetry techniques. Finally, new emerging techniques are reviewed which seek to overcome these challenges, such as high-resolution imaging, novel surgical procedures and the use of other radiopharmaceuticals for therapy and pre-therapeutic planning. PMID:27182449

  14. Hepatectomy After Yttrium-90 (Y90) Radioembolization-Induced Liver Fibrosis.

    PubMed

    Maker, Ajay V; August, Carey; Maker, Vijay K; Weisenberg, Elliot

    2016-04-01

    An obese 55-year-old woman with nonalcoholic fatty liver disease presented 7 years after resection of a T3N1 ileal carcinoid tumor with an elevated chromogranin A, multifocal metastatic disease to the liver, and carcinoid syndrome. She underwent right hepatic artery yttrium-90 (Y90) radioembolization, followed a month later by selective Y90 treatment to segment IV. She then presented to our clinic 10 months later, remaining symptomatic with flushing, diarrhea, anxiety, myalgia, pain, and persistent night sweats despite Sandostatin administration. At least 11 tumors were identified in the right lobe of the liver and three in segment IV on liver-specific imaging. These lesions were stable over a year with no new lesions. At exploration, there was marked hypertrophy of the left lateral segment due to the yttrium-90 treatment of segments IV-VIII, corresponding with preoperative volumetrics predicting a functional liver remnant (FLR) of 40% after extended right hepatectomy. The right lobe and segment IV were fibrotic, hard, and visibly damaged. The gland had a thick, fibrotic capsule, and the parenchyma was dense, inflexible, and difficult to dissect, consistent with the previously reported morbidity of these operations. Extended right hepatectomy was performed. Final pathology demonstrated 15 foci of metastatic well-differentiated neuroendocrine carcinoma that were negative for necrosis, as was expected given her continued symptoms despite radioembolization. Numerous amorphous spheres, frequently in clusters, were present in segments IV-VIII in vessels and approximating tumors consistent with prior Y90 radioembolization. The patient had an uneventful post-operative recovery and remains symptom free on follow-up. Treatment options for metastatic tumors to the liver have increased in recent years and currently include radioembolization in selected patients. Surgical cytoreduction and complete metastasectomy continue to offer improvement in symptoms, quality of life, and

  15. Safety of {sup 90}Y Radioembolization in Patients Who Have Undergone Previous External Beam Radiation Therapy

    SciTech Connect

    Lam, Marnix G.E.H.; Abdelmaksoud, Mohamed H.K.; Chang, Daniel T.; Eclov, Neville C.; Chung, Melody P.; Koong, Albert C.; Louie, John D.; Sze, Daniel Y.

    2013-10-01

    Purpose: Previous external beam radiation therapy (EBRT) is theoretically contraindicated for yttrium-90 ({sup 90}Y) radioembolization (RE) because the liver has a lifetime tolerance to radiation before becoming vulnerable to radiation-induced liver disease. We analyzed the safety of RE as salvage treatment in patients who had previously undergone EBRT. Methods and Materials: Between June 2004 and December 2010, a total of 31 patients who had previously undergone EBRT were treated with RE. Three-dimensional treatment planning with dose–volume histogram (DVH) analysis of the liver was used to calculate the EBRT liver dose. Liver-related toxicities including RE-induced liver disease (REILD) were reviewed and classified according to Common Terminology Criteria for Adverse Events version 4.02. Results: The mean EBRT and RE liver doses were 4.40 Gy (range, 0-23.13 Gy) and 57.9 Gy (range, 27.0-125.9 Gy), respectively. Patients who experienced hepatotoxicity (≥grade2; n=12) had higher EBRT mean liver doses (7.96 ± 8.55 Gy vs 1.62 ± 3.39 Gy; P=.037), the only independent predictor in multivariate analysis. DVH analysis showed that the fraction of liver exposed to ≥30 Gy (V30) was the strongest predictor of hepatotoxicity (10.14% ± 12.75% vs 0.84% ± 3.24%; P=.006). All patients with V30 >13% experienced hepatotoxicity. Fatal REILD (n=2) occurred at the 2 highest EBRT mean liver doses (20.9 Gy and 23.1 Gy) but also at the highest cumulative liver doses (91.8 Gy and 149 Gy). Conclusions: Prior exposure of the liver to EBRT may lead to increased liver toxicity after RE treatment, depending on fractional liver exposure and dose level. The V30 was the strongest predictor of toxicity. RE appears to be safe for the treatment of hepatic malignancies only in patients who have had limited hepatic exposure to prior EBRT.

  16. Development of anthropomorphic hand phantoms for personal dosimetry in 90Y-Zevalin preparation and patient delivering.

    PubMed

    Ciolini, R; d'Errico, F; Traino, A C; Paternostro, E; Laganà, A; Romei, C; Pazzagli, F; Del Gratta, A

    2014-01-01

    Anthropomorphic tissue-equivalent hand phantoms were achieved to measure the extremity dose involved in Zevalin (90)Y-labelling and patient delivering procedure for radioimmunotherapy treatment of non-Hodgkin lymphoma. The extremity doses to hands and wrists of operators were measured by using thermoluminescent detectors mounted on the developed phantoms. Measurements of chest- and lens-equivalent doses performed on a Rando phantom are also reported. PMID:23960242

  17. Inhibitory effects of 90Sr/90Y β-irradiation on alkali burn-induced corneal neovascularization in rats

    PubMed Central

    LIN, YUANQIANG; MA, QINGJIE; LIN, SHAN; ZHOU, HONGYAN; WEN, QIANG; GAO, SHI; CHENG, GUANGHUI

    2016-01-01

    The aim of the present study was to investigate the inhibitory effects of 90Sr-90Y β-irradiation in a rat model of alkali burn-induced corneal neovascularization (CNV). Alkali burn-induced CNV was induced in the right eyes of 30 female Wistar rats, which were randomly divided into the following three groups (n=10/group): i) The alkali burn control group, which received a balanced salt solution treatment; ii) group 1, which received treatment with angiogenesis inhibitors; and iii) group 2, which received 90Sr-90Y β-irradiation treatment. A further 10 female Wistar rats comprised a blank control group and received only balanced salt solution. Digital photographs of the corneas were acquired and the area of NV was calculated. In addition, the expression levels of matrix metalloproteinase (MMP)-9, vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR)-1 and VEGFR-2 in alkali-burned rat corneas were determined using western blot analysis. The results suggested that the number of new vessels and the area of CNV were significantly decreased in groups 1 and 2, as compared with the alkali burn group at each time point (P<0.05). In addition, the number of inflammatory cells and the degree of edema were decreased in groups 1 and 2, as compared with the alkali burn group, with group 2 exhibiting the most marked reduction. Western blot analysis demonstrated that the expression levels of MMP-9, VEGF, VEGFR-1 and VEGFR-2 were significantly decreased in groups 1 and 2, as compared with the alkali burn control group, with group 2 exhibiting the most significant reduction (P<0.05). The results of the present study suggested that 90Sr-90Y β-irradiation and angiogenesis inhibitor treatments were able to inhibit alkali burn-induced CNV, although 90Sr-90Y β-irradiation may be more effective. PMID:26893623

  18. Pathologic response and microdosimetry of {sup 90}Y microspheres in man: Review of four explanted whole livers

    SciTech Connect

    Kennedy, Andrew S. . E-mail: akennedy@wakerad.com; Nutting, Charles; Coldwell, Douglas; Gaiser, James; Drachenberg, Cinthia

    2004-12-01

    Introduction: Radioactive microsphere {sup 90}Y therapy is increasingly used for primary and metastatic solid tumors in the liver. We present an analysis of 4 explanted livers previously treated with {sup 90}Y microsphere agents (glass or resin). One tumor nodule was analyzed with submillimeter three-dimensional microdosimetry. Methods and materials: Four patients received hepatic artery delivery of {sup 90}Y microspheres for unresectable hepatocellular and colon cancers. Whole livers were explanted as part of lifesaving cadaveric transplant in 2 patients with hepatoma. These patients had received glass microspheres as a procedural bridge to transplant. Autopsy was performed on 2 patients with colon cancer who died of progressive metastatic disease and who had been treated with resin microspheres. Complete pathologic review was performed on each whole liver, including estimation of the response of the tumor to therapy, distribution of microspheres in the tumor and normal liver tissues, and normal-tissue radiation response. A biopsy taken from the edge of a tumor nodule was sectioned serially for three-dimensional radiation dosimetry analyses. Three-dimensional microsphere coordinates within the biopsy specimen were used to calculate dosage using a three-dimensional dose kernel. Isodose coverage of tumor and normal liver areas and total dose delivered were determined. Results: Preferential and heterogeneous deposition of microspheres was noted at the edge of tumor nodules compared with the center portion of the tumor or normal liver parenchyma. Both glass and resin microspheres delivered high cumulative doses to the tumor, which varied from 100 Gy to more than 3000 Gy. No veno-occlusive disease or widespread radiation hepatitis was seen. Conclusion: Microsphere ({sup 90}Y) therapy delivers high numbers of spheres with resulting high total doses of radiation, preferentially in the periphery of tumors. Normal liver parenchyma showed little radiation effect away from

  19. PET Imaging of Very Late Antigen-4 in Melanoma: Comparison of 68Ga- and 64Cu-Labeled NODAGA and CB-TE1A1P-LLP2A Conjugates

    PubMed Central

    Beaino, Wissam; Anderson, Carolyn J.

    2014-01-01

    Melanoma is a malignant tumor derived from epidermal melanocytes, and it is known for its aggressiveness, therapeutic resistance, and predisposition for late metastasis. Very late antigen-4 (VLA-4; also called integrin α4β1) is a transmembrane noncovalent heterodimer overexpressed in melanoma tumors that plays an important role in tumor growth, angiogenesis, and metastasis by promoting adhesion and migration of cancer cells. In this study, we evaluated 2 conjugates of a high-affinity VLA-4 peptidomimetic ligand, LLP2A, for PET/CT imaging in a subcutaneous and metastatic melanoma tumor. Methods LLP2A was conjugated to 1,4,8,11-tetraazacyclotetradecane-1-(methane phosphonic acid)-8-(methane carboxylic acid) (CB-TE1A1P) and 2-(4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl)pentanedioic acid (NODAGA) chelators for 68Ga and 64Cu labeling. The conjugates were synthesized by solid-phase peptide synthesis, purified by reversed-phase high-performance liquid chromatography, and verified by liquid chromatography mass spectrometry. Saturation and competitive binding assays with B16F10 melanoma cells determined the affinity of the compounds for VLA-4. The biodistributions of the LLP2A conjugates were evaluated in murine B16F10 subcutaneous tumor–bearing C57BL/6 mice. Melanoma metastasis was induced by intracardiac injection of B16F10 cells. PET/CT imaging was performed at 2, 4, and 24 h after injection for the 64Cu tracers and 1 h after injection for the 68Ga tracer. Results 64Cu-labeled CB-TE1A1P-PEG4-LLP2A and NODAGA-PEG4-LLP2A showed high affinity to VLA-4, with a comparable dissociation constant (0.28 vs. 0.23 nM) and receptor concentration (296 vs. 243 fmol/mg). The tumor uptake at 2 h after injection was comparable for the 2 probes, but 64Cu-CB-TE1A1P-PEG4-LLP2A trended toward higher uptake than 64Cu-NODAGA-PEG4-LLP2A (16.9 ± 2.2 vs. 13.4 ± 1.7 percentage injected dose per gram, P = 0.07). Tumor-to-muscle and tumor-to-blood ratios from biodistribution and PET/CT images

  20. Magnetically directed poly(lactic acid) [sup 90]Y-microspheres: Novel agents for targeted intracavitary radiotherapy

    SciTech Connect

    Haefeli, U.O.; Sweeney, S.M.; Beresford, B.A.; Sim, E.H.; Macklis, R.M. . Joint Center for Radiation Therapy)

    1994-08-01

    High energy [beta]-emitting radioisotopes like Yttrium-90 have a radiotoxic range of about one centimeter. For cancer treatment they must be brought near the tumor cells and kept there for as long as they are radioactive. The authors developed as carriers for the ionic form of [sup 90]Y a matrix-type polymeric drug delivery system, poly(lactic acid) (PLA) microspheres. This radiopharmaceutical could be selectively delivered to the target site after incorporating 10% Fe[sub 3]O[sub 4] which made the magnetic microspheres (MMS) responsive to an external magnetic field. Furthermore, MMS are biodegradable and slowly hydrolyze into physiologic lactic acid after the radioactivity is completely decayed. Previously prepared 10--40 [mu]m MMS were radiochemically loaded to high specific activity with [sup 90]Y at a pH of 5.7. Stability studies showed that approximately 95% of added [sup 90]Y is retained within the PLA matrix after 28 days (> 10 half-lives) at 37 C in serum, and electron microscopy showed that the microspheres retained their characteristic morphologic appearance for the same time period. Cytotoxicity studies with SK-N-SH neuroblastoma cells growing in monolayer showed that the radiocytotoxicity of the microspheres could be directed magnetically to either kill or spare specific cell populations, thus making them of great interest for targeted intracavitary tumor therapy. The authors are currently optimizing this system for use in the treatment of neoplastic meningitis.

  1. Fractionated Radioimmunotherapy With 90Y-Clivatuzumab Tetraxetan and Low-Dose Gemcitabine Is Active in Advanced Pancreatic Cancer

    PubMed Central

    Ocean, Allyson J.; Pennington, Kenneth L.; Guarino, Michael J.; Sheikh, Arif; Bekaii-Saab, Tanios; Serafini, Aldo N.; Lee, Daniel; Sung, Max W.; Gulec, Seza A.; Goldsmith, Stanley J.; Manzone, Timothy; Holt, Michael; O’Neil, Bert H.; Hall, Nathan; Montero, Alberto J.; Kauh, John; Gold, David V.; Horne, Heather; Wegener, William A.; Goldenberg, David M.

    2014-01-01

    BACKGROUND It has been demonstrated that the humanized clivatuzumab tetraxetan (hPAM4) antibody targets pancreatic ductal carcinoma selectively. After a trial of radioimmunotherapy that determined the maximum tolerated dose of single-dose yttrium-90-labeled hPAM4 (90Y-hPAM4) and produced objective responses in patients with advanced pancreatic ductal carcinoma, the authors studied fractionated radioimmunotherapy combined with low-dose gemcitabine in this disease. METHODS Thirty-eight previously untreated patients (33 patients with stage IV disease and 5 patients with stage III disease) received gemcitabine 200 mg/m2 weekly for 4 weeks with 90Y-hPAM4 given weekly in Weeks 2, 3, and 4 (cycle 1), and the same cycle was repeated in 13 patients (cycles 2–4). In the first part of the study, 19 patients received escalating weekly 90Y doses of 6.5 mCi/m2, 9.0 mCi/m2, 12.0 mCi/m2, and 15.0 mCi/m2. In the second portion, 19 additional patients received weekly doses of 9.0 mCi/m2 or 12.0 mCi/m2. RESULTS Grade 3/4 thrombocytopenia or neutropenia (according to version 3.0 of the National Cancer Institute’s Common Terminology Criteria for Adverse Events) developed in 28 of 38 patients after cycle 1 and in all retreated patients; no grade >3 nonhematologic toxicities occurred. Fractionated dosing of cycle 1 allowed almost twice the radiation dose compared with single-dose radioimmunotherapy. The maximum tolerated dose of 90Y-hPAM4 was 12.0 mCi/m2 weekly for 3 weeks for cycle 1, with ≤9.0 mCi/m2 weekly for 3 weeks for subsequent cycles, and that dose will be used in future trials. Six patients (16%) had partial responses according to computed tomography-based Response Evaluation Criteria in Solid Tumors, and 16 patients (42%) had stabilization as their best response (58% disease control). The median overall survival was 7.7 months for all 38 patients, including 11.8 months for those who received repeated cycles (46% [6 of 13 patients] ≥1 year), with improved efficacy at

  2. Treatment of lung tumor colonies with 90Y targeted to blood vessels: comparison with the alpha-particle emitter 213Bi.

    PubMed

    Kennel, S J; Stabin, M; Yoriyaz, H; Brechbiel, M; Mirzadeh, S

    1999-01-01

    An in vivo lung tumor model system for radioimmunotherapy of lung metastases was used to test the relative effectiveness of the vascular- targeted beta-particle emitter 90Y, and alpha-particle emitter, 213Bi. Yttrium-90 was shown to be stably bound by CHXa" DTPA-MAb 201B conjugates and delivered efficiently to lung tumor blood vessels. Dosimetry calculations indicated that the lung received 16.2 Gy/MBq from treatment with 90Y MAb 201B, which was a sevenfold greater absorbed dose than any other organ examined. Therapy was optimal for 90Y with 3 MBq injected. Bismuth-213 MAb 201B also delivered a similar absorbed dose (15Gy/MBq) to the lung. Yttrium-90 was found to be slightly more effective against larger tumors than 213Bi, consistent with the larger range of 2 MeV beta particles from 90Y than the 8 MeV alpha particles from 213Bi. Treatment of EMT-6 tumors growing in immunodeficient SCID mice with 90Y or 213Bi MAb 201 resulted in significant destruction of tumor colonies; however, 90Y MAb 201B was toxic for the SCID mice, inflicting acute lung damage. In another tumor model, IC-12 rat tracheal carcinoma growing in SCID mouse lungs, 90Y therapy was more effective than 213Bi at destroying lung tumors. However, 90Y MAb 201B toxicity for the lung limited any therapeutic effect. We conclude that, although vascular-targeted 90Y MAb can be an effective therapeutic agent, particularly for larger tumors, in this model system, acute damage to the lung may limit its application. PMID:10096515

  3. Hepatic Toxicity After Radioembolization of the Liver Using {sup 90}Y-Microspheres: Sequential Lobar Versus Whole Liver Approach

    SciTech Connect

    Seidensticker, Ricarda; Seidensticker, Max; Damm, Robert; Mohnike, Konrad; Schuette, Kerstin; Malfertheiner, Peter; Buskirk, Mark Van; Pech, Maciej; Amthauer, Holger; Ricke, Jens

    2012-10-15

    Purpose: {sup 90}Y-radioembolization (RE) is a promising technique for delivering high doses of radiation to liver tumors but may result in compromise of liver function. To gain further perspective, we evaluated the toxicity rates of sequential lobar versus 'whole liver' {sup 90}Y-radioembolization. Methods: Thirty-four patients with liver malignancy in noncirrhotic livers were included; {sup 90}Y-radioembolization was performed as either whole liver or sequential lobar treatment in 17 patients each. Standard clinical and liver specific laboratory parameters as well as MR imaging before treatment and at follow-up (6 and 12 weeks) after radioembolization were evaluated for toxicity using the Common Terminology Criteria for Adverse Events (CTCAE). Volumetry of the liver, tumor, and spleen and measurement of portal vein diameter also were performed. Results: Three months after whole liver RE, 14 liver-related grade 3/4 events were recorded versus 2 events after sequential lobar treatment (P < 0.05). Three patients treated with whole liver RE suffered from radioembolization-induced liver disease (REILD). Pathological increases in bilirubin at 3 months were observed for the whole liver group only (52.3 vs. 18.7 {mu}mol/l, P = 0.012). Total liver volume did not change significantly in either group, but shrinkage of the initially treated hepatic lobe with compensatory hypertrophy of the subsequently treated lobe was observed in the sequential lobar group (P < 0.05). Portal vein diameter increased significantly in whole liver-treated patients only (+17% vs. +6.6%, P = 0.043). Conclusions: Noncirrhotic patients undergoing sequential lobar radioembolization had less hepatic toxicity compared to whole liver embolization. The sequential approach should be the preferred strategy.

  4. Phase II study of (90)Y Ibritumomab tiuxetan (Zevalin) in patients with previously untreated marginal zone lymphoma.

    PubMed

    Lossos, Izidore S; Fabregas, Jesus C; Koru-Sengul, Tulay; Miao, Feng; Goodman, Deborah; Serafini, Aldo N; Hosein, Peter J; Stefanovic, Alexandra; Rosenblatt, Joseph D; Hoffman, James E

    2015-06-01

    The best upfront therapy for patients with non-gastric extranodal marginal zone lymphomas (MZLs) is not defined. We assessed the safety and efficacy of radioimmunotherapy with (90)yttrium ((90)Y) ibritumomab tiuxetan as upfront therapy in MZL (NCT00453102). A total of 16 patients were enrolled, 81% with advanced-stage disease and 44% with bulky disease. The overall response rate (ORR) at 12 weeks post-therapy was 87.5% (90% confidence interval [CI]: 65.6-97.7%), including a complete response in eight (50%), complete response unconfirmed in one (6%) and partial response in five (31%) patients. With a median follow-up of 65.6 months (range 4.0-96.5), the median progression-free survival (PFS) was 47.6 months (range 4.0-93.3) and median overall survival (OS) was not reached. The 5-year PFS was 40% (90% CI: 19.9-59.5%) and 5-year OS was 71.8% (90% CI: 46.8-86.5%). Overall, (90)Y ibritumomab tiuxetan was well tolerated and led to long-term responses and PFS rates. PMID:25315074

  5. Attenuation of bremsstrahlung from 90Sr-90Y, 147Pm and 204Tl in thick target compounds

    NASA Astrophysics Data System (ADS)

    Manjunatha, H. C.

    2014-11-01

    The external bremsstrahlung (EB) produced by beta particles such as from 90Sr-90Y, 147Pm and 204Tl in PbCl2, PbF2, Pb(NO3)2 and CdO were measured using NaI(Tl) crystal. The beta stopper technique is employed to measure the integral intensities above 100 keV energy in different absorber thicknesses. Attenuation of the external bremsstrahlung, excited by 90Sr-90Y, 147Pm and 204Tl beta-emitters in the same compounds has also been studied. The measured attenuation parameter is not constant with absorber thickness and it increases with increasing Zmod of the absorber. Whereas, the mass attenuation coefficient of gamma rays of equivalent energy is independent of the absorber thickness. This confirms that the attenuation of EB in an absorber does not conform to a single exponential law, unlike the absorption of monoenergetic gamma rays. Rather it may be a combination of a large number of exponential terms.

  6. A new approach for dose calculation in targeted radionuclide therapy (TRT) based on collapsed cone superposition: validation with (90)Y.

    PubMed

    Sanchez-Garcia, Manuel; Gardin, Isabelle; Lebtahi, Rachida; Dieudonné, Arnaud

    2014-09-01

    To speed-up the absorbed dose (AD) computation while accounting for tissue heterogeneities, a Collapsed Cone (CC) superposition algorithm was developed and validated for (90)Y. The superposition was implemented with an Energy Deposition Kernel scaled with the radiological distance, along with CC acceleration. The validation relative to Monte Carlo simulations was performed on 6 phantoms involving soft tissue, lung and bone, a radioembolisation treatment and a simulated bone metastasis treatment. As a figure of merit, the relative AD difference (ΔAD) in low gradient regions (LGR), distance to agreement (DTA) in high gradient regions and the γ(1%,1 mm) criterion were used for the phantoms. Mean organ doses and γ(3%,3 mm) were used for the patient data. For the semi-infinite sources, ΔAD in LGR was below 1%. DTA was below 0.6 mm. All profiles verified the γ(1%,1 mm) criterion. For both clinical cases, mean doses differed by less than 1% for the considered organs and all profiles verified the γ(3%,3 mm). The calculation time was below 4 min on a single processor for CC superposition and 40 h on a 40 nodes cluster for MCNP (10(8) histories). Our results show that the CC superposition is a very promising alternative to MC for (90)Y dosimetry, while significantly reducing computation time. PMID:25097006

  7. A new approach for dose calculation in targeted radionuclide therapy (TRT) based on collapsed cone superposition: validation with 90Y

    NASA Astrophysics Data System (ADS)

    Sanchez-Garcia, Manuel; Gardin, Isabelle; Lebtahi, Rachida; Dieudonné, Arnaud

    2014-09-01

    To speed-up the absorbed dose (AD) computation while accounting for tissue heterogeneities, a Collapsed Cone (CC) superposition algorithm was developed and validated for 90Y. The superposition was implemented with an Energy Deposition Kernel scaled with the radiological distance, along with CC acceleration. The validation relative to Monte Carlo simulations was performed on 6 phantoms involving soft tissue, lung and bone, a radioembolisation treatment and a simulated bone metastasis treatment. As a figure of merit, the relative AD difference (ΔAD) in low gradient regions (LGR), distance to agreement (DTA) in high gradient regions and the γ(1%,1 mm) criterion were used for the phantoms. Mean organ doses and γ(3%,3 mm) were used for the patient data. For the semi-infinite sources, ΔAD in LGR was below 1%. DTA was below 0.6 mm. All profiles verified the γ(1%,1 mm) criterion. For both clinical cases, mean doses differed by less than 1% for the considered organs and all profiles verified the γ(3%,3 mm). The calculation time was below 4 min on a single processor for CC superposition and 40 h on a 40 nodes cluster for MCNP (108 histories). Our results show that the CC superposition is a very promising alternative to MC for 90Y dosimetry, while significantly reducing computation time.

  8. Dosimetry of a (90)Y-hydroxide liquid brachytherapy treatment approach to canine osteosarcoma using PET/CT.

    PubMed

    Zhou, Jien Jie; Gonzalez, Arnulfo; Lenox, Mark W; Fossum, Theresa W; Frank, R Keith; Simon, Jaime; Stearns, Stan; Ruoff, Catherine M; Wendt, Richard E; Akabani, Gamal

    2015-03-01

    A new treatment strategy based on direct injections of (90)Y-hydroxide into the tumor bed in dogs with osteosarcoma was studied. Direct injections of the radiopharmaceutical into the tumor bed were made according to a pretreatment plan established using (18)F-FDG images. Using a special drill, cannulas were inserted going through tissue, tumor and bone. Using these cannulas, direct injections of the radiopharmaceutical were made. The in vivo biodistribution of (90)Y-hydroxide and the anatomical tumor bed were imaged using a time-of-flight (TOF) PET/CT scanner. The material properties of the tissues were estimated from corresponding CT numbers using an electron-density calibration. Radiation absorbed dose estimates were calculated using Monte Carlo methods where the biodistribution of the pharmaceutical from PET images was sampled using a collapsing 3-D rejection technique. Dose distributions in the tumor bed and surrounding tissues were calculated, showing significant heterogeneity with multiple hot spots at injection sites. Dose volume histograms showed that approximately 33.9% of bone and tumor and 70.2% of bone marrow and trabecular bone received an absorbed dose over 200Gy; approximately 3.2% of bone and tumor and 31.0% of bone marrow and trabecular bone received a total dose of over 1000Gy. PMID:25638490

  9. Large-scale purification of 90Sr from nuclear waste materials for production of 90Y, a therapeutic medical radioisotope.

    PubMed

    Wester, Dennis W; Steele, Richard T; Rinehart, Donald E; DesChane, Jaquetta R; Carson, Katharine J; Rapko, Brian M; Tenforde, Thomas S

    2003-07-01

    A major limitation on the supply of the short-lived medical isotope 90Y (t1/2 = 64 h) is the available quantity of highly purified 90Sr generator material. A radiochemical production campaign was therefore undertaken to purify 1,500 Ci of 90Sr that had been isolated from fission waste materials. A series of alkaline precipitation steps removed all detectable traces of 137Cs, alpha emitters, and uranium and transuranic elements. Technical obstacles such as the buildup of gas pressure generated upon mixing large quantities of acid with solid 90Sr carbonate were overcome through safety features incorporated into the custom-built equipment used for 90Sr purification. Methods are described for analyzing the chemical and radiochemical purity of the final product and for accurately determining by gravimetry the quantities of 90Sr immobilized on stainless steel filters for future use. PMID:12878120

  10. A computational tool for patient specific dosimetry and radiobiological modeling of selective internal radiation therapy with (90)Y microspheres.

    PubMed

    Kalantzis, Georgios; Leventouri, Theodora; Apte, Aditiya; Shang, Charles

    2015-11-01

    In recent years we have witnessed tremendous progress in selective internal radiation therapy. In clinical practice, quite often, radionuclide therapy is planned using simple models based on standard activity values or activity administered per unit body weight or surface area in spite of the admission that radiation-dose methods provide more accurate dosimetric results. To address that issue, the authors developed a Matlab-based computational software, named Patient Specific Yttrium-90 Dosimetry Toolkit (PSYDT). PSYDT was designed for patient specific voxel-based dosimetric calculations and radiobiological modeling of selective internal radiation therapy with (90)Y microspheres. The developed toolkit is composed of three dimensional dose calculations for both bremsstrahlung and beta emissions. Subsequently, radiobiological modeling is performed on a per-voxel basis and cumulative dose volume histograms (DVHs) are generated. In this report we describe the functionality and visualization features of PSYDT. PMID:26296058

  11. Radioimmunotherapy of breast cancer metastases with alpha-particle emitter 225Ac: comparing efficacy with 213Bi and 90Y.

    PubMed

    Song, Hong; Hobbs, Robert F; Vajravelu, Ravy; Huso, David L; Esaias, Caroline; Apostolidis, Christos; Morgenstern, Alfred; Sgouros, George

    2009-12-01

    alpha-Particles are suitable to treat cancer micrometastases because of their short range and very high linear energy transfer. alpha-Particle emitter (213)Bi-based radioimmunotherapy has shown efficacy in a variety of metastatic animal cancer models, such as breast, ovarian, and prostate cancers. Its clinical implementation, however, is challenging due to the limited supply of (225)Ac, high technical requirement to prepare radioimmunoconjugate with very short half-life (T(1/2) = 45.6 min) on site, and prohibitive cost. In this study, we investigated the efficacy of the alpha-particle emitter (225)Ac, parent of (213)Bi, in a mouse model of breast cancer metastases. A single administration of (225)Ac (400 nCi)-labeled anti-rat HER-2/neu monoclonal antibody (7.16.4) completely eradicated breast cancer lung micrometastases in approximately 67% of HER-2/neu transgenic mice and led to long-term survival of these mice for up to 1 year. Treatment with (225)Ac-7.16.4 is significantly more effective than (213)Bi-7.16.4 (120 microCi; median survival, 61 days; P = 0.001) and (90)Y-7.16.4 (120 microCi; median survival, 50 days; P < 0.001) as well as untreated control (median survival, 41 days; P < 0.0001). Dosimetric analysis showed that (225)Ac-treated metastases received a total dose of 9.6 Gy, significantly higher than 2.0 Gy from (213)Bi and 2.4 Gy from (90)Y. Biodistribution studies revealed that (225)Ac daughters, (221)Fr and (213)Bi, accumulated in kidneys and probably contributed to the long-term renal toxicity observed in surviving mice. These data suggest (225)Ac-labeled anti-HER-2/neu monoclonal antibody could significantly prolong survival in HER-2/neu-positive metastatic breast cancer patients. PMID:19920193

  12. Separation of carrier-free {sup 90}Y from high level waste by extraction chromatographic technique using 2-ethylhexyl-2-ethylhexyl phosphonic acid (KSM-17)

    SciTech Connect

    Achuthan, P.V.; Dhami, P.S.; Kannan, R.; Gopalakrishnan, V.; Ramanujam, A.

    2000-01-01

    An extraction chromatographic technique has been developed for the separation of carrier-free {sup 90}Y from the {sup 90}Sr present in the high level waste (HLW) of the Purex process. When a Purex HLW solution in 2--3 M HNO{sub 3} is passed through a CMPO-Chromosorb-102 (CAC) column, all the trivalent, tetravalent, and hexavalent ions are sorbed. The effluent from this experiment, after adjusting the pH to 2 with NaOH, was passed through a 2-ethylhexyl-2-ethylhexyl phosphonic acid (KSM-17)-Chromosorb-102 (KSMC) extraction chromatographic column where only {sup 90}Y was sorbed. All the other ions ({sup 90}Sr, {sup 137}Cs, {sup 125}Sb, {sup 106}Ru, {sup 106}Rh, etc.) were washed off with dilute HNO{sub 3} (pH 2), and carrier-free {sup 90}Y was eluted with 0.5 M HNO{sub 3}. This technique can yield {sup 90}Y in mCi levels in pure form for medical applications. The {sup 90}Sr can be used repeatedly after allowing for {sup 90}Y buildup.

  13. Cocktail Therapy of 177Lu-PSMA-617 and 177Lu-EDTMP in Patients With mCRPC: A Proof-of-Principle Application.

    PubMed

    Bal, Chandrasekhar; Yadav, Madhav Prasad; Ballal, Sanjana

    2016-08-01

    Prostate cancer is the second most common primary tumor affecting men worldwide. Among them, 10-20% develop castration resistant prostate cancer (CRPC). Ga-PSMA-PET/CT is an important theranostic agent for the evaluation of CRPC to assess the feasibility of treatment with Lu-PSMA-617 which is a novel therapeutic agent. Interestingly, in certain cases, we have observed non-PSMA-avid lesions despite raised sPSA levels. In this regard, we present a case of cocktail therapy applied using Lu-PSMA-617 and Lu-EDTMP therapy in a 38-year-old male CRPC patient with both soft tissue and extensive skeletal metastases. PMID:27187728

  14. 2.69-2.68 Ga granulite facies metamorphism in the Wyoming Craton revealed by Sm-Nd garnet geochronology and trace element zoning, eastern Beartooth Mountains, Montana and Wyoming, USA

    NASA Astrophysics Data System (ADS)

    Guevara, V.; Dragovic, B.; Caddick, M. J.; Baxter, E. F.

    2014-12-01

    The Beartooth Mountains in Montana and Wyoming, USA, form an extensive exposure of Archean rocks of the Wyoming Craton and are dominantly comprised of a ~2.8 Ga granitoid batholith known as the Long Lake Magmatic Complex (LLMC). Contained within the LLMC are numerous m- to km-scale enclaves of metasedimentary granulites. P-T pseudosection modeling indicates that these granulites reached peak pressure-temperature (P-T) conditions of 800 °C, 7-8 kbar. This has previously been interpreted to result from contact heating with the LLMC. However, substantial field evidence from multiple localities suggests that the texturally dominant phase of HT metamorphism in the metasediments postdates LLMC emplacement. Further, Sm-Nd garnet (grt) dates from the metasediments are in the range ~2.69-2.68 Ga ('bulk' dates incorporating crystal cores and rims), ~100 Myrs younger than LLMC emplacement (based on U-Pb zircon ages, 1). Trace element zoning in grt suggests that these dates record the age of granulite facies metamorphism. Euhedral high-Ca overgrowths in Grt from a residual pelite are coincident with a high Eu spike, interpreted to result from plagioclase breakdown during partial melting. These overgrowths are also coincident with high Sm and Nd annuli, and we thus interpret the bulk grt date (2689±4 Ma) to record timing of the late stages of grt growth during migmatisation near peak T. Coupled with major element zoning, retention of Sm and Nd zoning in euhedral grt from the leucosome of another sample suggest that its bulk date (2681±1 Ma) also represents peritectic grt growth rather than subsequent diffusion. Grt from a lithology that did not experience melting records a date of 2686±1 Ma. Together, these ages indicate that granulite facies metamorphism persisted in the area for at least ~3 Myrs (inner bounds of the 2σ dates), ~100 Myrs after batholith emplacement. Limited evidence for this later event in the plutonic rocks is consistent with their experiencing little

  15. Current status and future perspectives for yttrium-90 ((90)Y)-ibritumomab tiuxetan in stem cell transplantation for non-Hodgkin's lymphoma.

    PubMed

    Gisselbrecht, C; Bethge, W; Duarte, R F; Gianni, A M; Glass, B; Haioun, C; Martinelli, G; Nagler, A; Pettengell, R; Sureda, A; Tilly, H; Wilson, K

    2007-12-01

    Haematopoietic SCT is currently considered a therapeutic option mainly in relapsed or refractory non-Hodgkin's lymphoma (NHL) owing to high post-transplantation relapse rates and significant toxicity of conventional myeloablative conditioning for allogeneic SCT. Radiolabelled immunotherapy combines the benefits of monoclonal antibody targeting with therapeutic doses of radiation, and is a promising advance in the treatment of malignant lymphomas. It is now under investigation as a component of conditioning prior to SCT, with the aim of improving outcomes following SCT without increasing the toxicity of high-dose chemotherapy pre-transplant conditioning. An expert panel met at a European workshop in November 2006 to review the latest data on radiolabelled immunotherapy in the transplant setting, and its potential future directions, with a focus on (90)Y-ibritumomab tiuxetan. They reviewed data on the combination of standard/high/escalating dose (90)Y-ibritumomab tiuxetan with high-dose chemotherapy, and high/escalating dose (90)Y-ibritumomab tiuxetan as the sole myeloablative agent, prior to autologous SCT, and also (90)Y-ibritumomab tiuxetan as a component of reduced intensity conditioning prior to allogeneic SCT. The preliminary data are highly promising in terms of conditioning tolerability and patient outcomes following transplant; further phase II studies are now needed to consolidate these data and to investigate specific patient populations and NHL subtypes. PMID:17922042

  16. Use of radioactive substances in diagnosis and treatment of neuroendocrine tumors

    PubMed Central

    Kjaer, Andreas; Knigge, Ulrich

    2015-01-01

    Abstract Radionuclides are needed both for nuclear medicine imaging as well as for peptide-receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NET). Imaging is important in the initial diagnostic work-up and for staging NETs. In therapy planning, somatostatin receptor imaging (SRI) is used when treatment is targeted at the somatostatin receptors as with the use of somatostatin analogues or PRRT. SRI with gamma camera technique using the tracer 111In-DTPA-octreotide has for many years been the backbone of nuclear imaging of NETs. However, increasingly PET tracers for SRI are now used. 68Ga-DOTATATE, 68Ga-DOTATOC and 68Ga-DOTANOC are the three most often used PET tracers. They perform better than SPECT tracers and should be preferred. FDG-PET is well suited for visualization of most of the somatostatin receptor-negative tumors prognostic in NET patients. Also 11C-5-HTP, 18F-DOPA and 123I-MIBG may be used in NET. However, with FDG-PET and somatostatin receptor PET at hand we see limited necessity of other tracers. PRRT is an important tool in the treatment of advanced NETs causing complete or partial response in 20% and minor response or tumor stabilization in 60% with response duration of up to 3 years. Grade 3–4 kidney or bone marrow toxicity is seen in 1.5% and 9.5%, respectively, but are completely or partly reversible in most patients. 177Lu-DOTATATE seems to have less toxicity than 90Y-DOTATOC. However, until now only retrospective, non-randomized studies have been performed and the role of PRRT in treatment of NETs remains to be established. PMID:25959100

  17. Lutetium-labelled peptides for therapy of neuroendocrine tumours.

    PubMed

    Kam, B L R; Teunissen, J J M; Krenning, E P; de Herder, W W; Khan, S; van Vliet, E I; Kwekkeboom, D J

    2012-02-01

    Treatment with radiolabelled somatostatin analogues is a promising new tool in the management of patients with inoperable or metastasized neuroendocrine tumours. Symptomatic improvement may occur with (177)Lu-labelled somatostatin analogues that have been used for peptide receptor radionuclide therapy (PRRT). The results obtained with (177)Lu-[DOTA(0),Tyr(3)]octreotate (DOTATATE) are very encouraging in terms of tumour regression. Dosimetry studies with (177)Lu-DOTATATE as well as the limited side effects with additional cycles of (177)Lu-DOTATATE suggest that more cycles of (177)Lu-DOTATATE can be safely given. Also, if kidney-protective agents are used, the side effects of this therapy are few and mild and less than those from the use of (90)Y-[DOTA(0),Tyr(3)]octreotide (DOTATOC). Besides objective tumour responses, the median progression-free survival is more than 40 months. The patients' self-assessed quality of life increases significantly after treatment with (177)Lu-DOTATATE. Lastly, compared to historical controls, there is a benefit in overall survival of several years from the time of diagnosis in patients treated with (177)Lu-DOTATATE. These findings compare favourably with the limited number of alternative therapeutic approaches. If more widespread use of PRRT can be guaranteed, such therapy may well become the therapy of first choice in patients with metastasized or inoperable neuroendocrine tumours. PMID:22388631

  18. Optimization of energy window for {sup 90}Y bremsstrahlung SPECT imaging for detection tasks using the ideal observer with model-mismatch

    SciTech Connect

    Rong Xing; Ghaly, Michael; Frey, Eric C.

    2013-06-15

    Purpose: In yttrium-90 ({sup 90}Y) microsphere brachytherapy (radioembolization) of unresectable liver cancer, posttherapy {sup 90}Y bremsstrahlung single photon emission computed tomography (SPECT) has been used to document the distribution of microspheres in the patient and to help predict potential side effects. The energy window used during projection acquisition can have a significant effect on image quality. Thus, using an optimal energy window is desirable. However, there has been great variability in the choice of energy window due to the continuous and broad energy distribution of {sup 90}Y bremsstrahlung photons. The area under the receiver operating characteristic curve (AUC) for the ideal observer (IO) is a widely used figure of merit (FOM) for optimizing the imaging system for detection tasks. The IO implicitly assumes a perfect model of the image formation process. However, for {sup 90}Y bremsstrahlung SPECT there can be substantial model-mismatch (i.e., difference between the actual image formation process and the model of it assumed in reconstruction), and the amount of the model-mismatch depends on the energy window. It is thus important to account for the degradation of the observer performance due to model-mismatch in the optimization of the energy window. The purpose of this paper is to optimize the energy window for {sup 90}Y bremsstrahlung SPECT for a detection task while taking into account the effects of the model-mismatch. Methods: An observer, termed the ideal observer with model-mismatch (IO-MM), has been proposed previously to account for the effects of the model-mismatch on IO performance. In this work, the AUC for the IO-MM was used as the FOM for the optimization. To provide a clinically realistic object model and imaging simulation, the authors used a background-known-statistically and signal-known-statistically task. The background was modeled as multiple compartments in the liver with activity parameters independently following a

  19. 90Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin’s lymphoma

    PubMed Central

    Janik, John E.; Morris, John C.; O’Mahony, Deirdre; Pittaluga, Stefania; Jaffe, Elaine S.; Redon, Christophe E.; Bonner, William M.; Brechbiel, Martin W.; Paik, Chang H.; Whatley, Millie; Chen, Clara; Lee, Jae-Ho; Fleisher, Thomas A.; Brown, Maggie; White, Jeffrey D.; Stewart, Donn M.; Fioravanti, Suzanne; Lee, Cathryn C.; Goldman, Carolyn K.; Bryant, Bonita R.; Junghans, Richard P.; Carrasquillo, Jorge A.; Worthy, Tat’Yana; Corcoran, Erin; Conlon, Kevin C.; Waldmann, Thomas A.

    2015-01-01

    Despite significant advances in the treatment of Hodgkin’s lymphoma (HL), a significant proportion of patients will not respond or will subsequently relapse. We identified CD25, the IL-2 receptor alpha subunit, as a favorable target for systemic radioimmunotherapy of HL. The scientific basis for the clinical trial was that, although most normal cells with exception of Treg cells do not express CD25, it is expressed by a minority of Reed–Sternberg cells and by most polyclonal T cells rosetting around Reed–Sternberg cells. Forty-six patients with refractory and relapsed HL were evaluated with up to seven i.v. infusions of the radiolabeled anti-CD25 antibody 90Y-daclizumab. 90Y provides strong β emissions that kill tumor cells at a distance by a crossfire effect. In 46 evaluable HL patients treated with 90Y-daclizumab there were 14 complete responses and nine partial responses; 14 patients had stable disease, and nine progressed. Responses were observed both in patients whose Reed–Sternberg cells expressed CD25 and in those whose neoplastic cells were CD25− provided that associated rosetting T cells expressed CD25. As assessed using phosphorylated H2AX (γ-H2AX) as a bioindicator of the effects of radiation exposure, predominantly nonmalignant cells in the tumor microenvironment manifested DNA damage, as reflected by increased expression of γ-H2AX. Toxicities were transient bone-marrow suppression and myelodysplastic syndrome in six patients who had not been evaluated with bone-marrow karyotype analyses before therapy. In conclusion, repeated 90Y-daclizumab infusions directed predominantly toward nonmalignant T cells rosetting around Reed–Sternberg cells provided meaningful therapy for select HL patients. PMID:26438866

  20. Monte Carlo characterization of biocompatible beta-emitting 90Y glass seed incorporated with the radionuclide 153Sm as a SPECT marker for brachytherapy applications.

    PubMed

    Hadadi, Asghar; Sadeghi, Mahdi; Sardari, Dariush; Khanchi, Alireza; Shirazi, Alireza

    2013-01-01

    A glass seed consisting of the β--emitting radionuclide 90Y incorporated with radionuclide 153Sm as SPECT marker is proposed for potential application in brachytherapy in order to reduce the undesirable dose to healthy adjacent organs. The aim of this work is to determine the dosimetric characteristics, as suggested in the AAPM TG-60/TG-149 reports, for this seed using Monte Carlo simulation. Monte Carlo codes MCNP5, EGSnrc, and FLUKA were used to calculate the absorbed dose distribution around the seed. Dosimetric parameters, such as reference absorbed dose rate, radial dose function, and one-dimensional (1D) and two-dimensional (2D) anisotropy functions, were obtained. The computational results from these three codes are in agreement within 5.4% difference on average. The absorbed dose rate at the reference point was estimated to be 5.01 cGy h-1 μCi-1 and self absorption of YAS glass seed amounted to 30.51%. The results showed that, with thermal neutron bombardment of 5 hours in a typical flux, sufficient activity for applications in brachytherapy may be achieved. With a 5 mCi initial activity, the total dose of a YAS glass seed was estimated to be 1.38 Gy at 1.0 cm from the seed center. Comparing with gamma emitting seeds, the 90Y seed could reduce undesirable doses to adjacent organs, because of the rapid dose falloff of beta ray. Because of the high R90 value of 5.5 mm, fewer number of 90Y seeds will be required for an interstitial brachytherapy treatment using permanent implant, in comparison with other beta-emitting seeds. The results would be helpful in the development of the radioactive implants using 90Y glass seeds for the brachytherapy treatment. PMID:24036862

  1. Chemotherapy tolerance after radioimmunotherapy with 90Y-CC49 monoclonal antibody in patients with advanced non-small cell lung cancer: clinical effects and hematologic toxicity.

    PubMed

    Robert, Francisco; Busby, Elizabeth M; LoBuglio, Albert F

    2003-06-01

    The purpose of this retrospective analysis was to evaluate the hematologic toxicity and clinical outcome of salvage chemotherapy following (90)Y-CC49 radioimmunotherapy (RIT) in patients with non-small cell lung cancer (NSCLC). Sixteen patients from a total of 37 who were enrolled in a phase I trial of (90)Y-CC49 monoclonal therapy were treated with post-RIT salvage chemotherapy at our institution. Five patients had received chest radiation therapy prior to RIT, and seven patients had prior chemotherapy. The majority of these patients were treated with doses of (90)Y of >/= 14 mCi/m(2) (8-20 mCi/m(2)), and four of them received concurrent 96-hour taxol infusion. The maximum tolerated dose of this study was exceeded at 17 mCi/m(2), and grade 4 thrombocytopenia/neutropenia were the dose-limiting toxicities. Twelve patients received one chemotherapy regimen as salvage therapy, and four patients had more than one regimen. Four patients (25%) experienced reversible grade 4 neutropenia, but no grade 4 thrombocytopenia was observed. Five patients had stable disease. The median survival from start of salvage therapy was 5.5 months. Our data suggest that therapy with RIT did not significantly affect survival of these patients. Taking into consideration the potential clinical relevance of integration of RIT with other treatment modalities, it is important to expand this clinical experience in order to support combined modality strategies. PMID:12954119

  2. Biodistribution of the radionuclides (18)F-FDG, (11)C-methionine, (11)C-PK11195, and (68)Ga-citrate in domestic juvenile female pigs and morphological and molecular imaging of the tracers in hematogenously disseminated Staphylococcus aureus lesions.

    PubMed

    Afzelius, Pia; Nielsen, Ole L; Alstrup, Aage Ko; Bender, Dirk; Leifsson, Páll S; Jensen, Svend B; Schønheyder, Henrik C

    2016-01-01

    Approximately 5-7% of acute-care patients suffer from bacteremia. Bacteremia may give rise to bacterial spread to different tissues. Conventional imaging procedures as X-ray, Computed Tomography (CT), Magnetic Resonance Imaging (MRI), and ultrasound are often first-line imaging methods for identification and localization of infection. These methods are, however, not always successful. Early identification and localization of infection is critical for the appropriate and timely selection of therapy. The aim of this study was thus; a head to head comparison of (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) to PET with tracers that potentially could improve uncovering of infectious lesions in soft tissues. We chose (11)C-methionine, (11)C-PK11195, and (68)Ga-citrate as tracers and besides presenting their bio-distribution we validated their diagnostic utility in pigs with experimental bacterial infection. Four juvenile 14-15 weeks old female domestic pigs were scanned seven days after intra-arterial inoculation in the right femoral artery with a porcine strain of S. aureus using a sequential scanning protocol with (18)F-FDG, (11)C-methionine, (11)C-PK11195 and (68)Ga-citrate. This was followed by necropsy of the pigs consisting of gross pathology, histopathology and microbial examination. The pigs primarily developed lesions in lungs and neck muscles. (18)F-FDG had higher infection to background ratios and accumulated in most infectious foci caused by S. aureus, while (11)C-methionine and particularly (11)C-PK11195 and (68)Ga-citrate accumulated to a lesser extent in infectious foci. (18)F-FDG-uptake was seen in the areas of inflammatory cells and to a much lesser extent in reparative infiltration surrounding necrotic regions. PMID:27069765

  3. Biodistribution of the radionuclides 18F-FDG, 11C-methionine, 11C-PK11195, and 68Ga-citrate in domestic juvenile female pigs and morphological and molecular imaging of the tracers in hematogenously disseminated Staphylococcus aureus lesions

    PubMed Central

    Afzelius, Pia; Nielsen, Ole L; Alstrup, Aage KO; Bender, Dirk; Leifsson, Páll S; Jensen, Svend B; Schønheyder, Henrik C

    2016-01-01

    Approximately 5-7% of acute-care patients suffer from bacteremia. Bacteremia may give rise to bacterial spread to different tissues. Conventional imaging procedures as X-ray, Computed Tomography (CT), Magnetic Resonance Imaging (MRI), and ultrasound are often first-line imaging methods for identification and localization of infection. These methods are, however, not always successful. Early identification and localization of infection is critical for the appropriate and timely selection of therapy. The aim of this study was thus; a head to head comparison of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) to PET with tracers that potentially could improve uncovering of infectious lesions in soft tissues. We chose 11C-methionine, 11C-PK11195, and 68Ga-citrate as tracers and besides presenting their bio-distribution we validated their diagnostic utility in pigs with experimental bacterial infection. Four juvenile 14-15 weeks old female domestic pigs were scanned seven days after intra-arterial inoculation in the right femoral artery with a porcine strain of S. aureus using a sequential scanning protocol with 18F-FDG, 11C-methionine, 11C-PK11195 and 68Ga-citrate. This was followed by necropsy of the pigs consisting of gross pathology, histopathology and microbial examination. The pigs primarily developed lesions in lungs and neck muscles. 18F-FDG had higher infection to background ratios and accumulated in most infectious foci caused by S. aureus, while 11C-methionine and particularly 11C-PK11195 and 68Ga-citrate accumulated to a lesser extent in infectious foci. 18F-FDG-uptake was seen in the areas of inflammatory cells and to a much lesser extent in reparative infiltration surrounding necrotic regions. PMID:27069765

  4. Production of {sup 177}Lu, a potential radionuclide for diagnostic and therapeutic applications

    SciTech Connect

    Khandaker, Mayeen Uddin; Kassim, Hasan Abu; Haba, Hiromitsu

    2015-04-24

    {sup 177g}Lu (T{sub 1/2}=6.647d; E{sub β{sup −max}}=498.3KeV, I{sub β{sup −total}}=100%; E{sub γ} = 112.9498 keV, I{sub γ} = 6.17%; E{sub γ} = 208.3662 keV, I {sub γ} = 10.36%) is widely used in many clinical procedures due to its excellent decay characteristics. Production cross-sections of the {sup nat}Yb(d,x){sup 177g}Lu reactions have been measured from a 24-MeV deuteron energy down to the threshold by using a stacked-foil activation technique combined with high resolution γ-ray spectrometry. An overall good agreement is found with some of the earlier measurements, whereas a partial agreement is obtained with the theoretical data extracted from the TENDL-2013 library. Physical thick target yield for the {sup 177g}Lu radionuclide was deduced using the measured cross-sections. The deduced yield curves indicate that a low energy (<11 MeV) cyclotron and a highly enriched {sup 176}Yb target could be used to obtain {sup 177g}Lu with negligible impurity from {sup 177m}Lu.

  5. Medullary thyroid carcinoma (MTC) treated with 177Lu-DOTATATE PRRT: a report of two cases.

    PubMed

    Makis, William; McCann, Karey; McEwan, Alexander J B

    2015-05-01

    Two patients diagnosed with metastatic medullary thyroid carcinoma (MTC) were referred for peptide receptor radionuclide therapy (PRRT) with Lu-[DOTA,Tyr]octreotate (DOTATATE). Each patient was treated with 4 doses of Lu-DOTATATE given 2 months apart. One patient achieved stable disease for 10 months then chose to pursue surgery, and the other achieved stable disease for 9 months on imaging; however, calcitonin continued to rise. The use of Lu-DOTATATE PRRT therapy in the management of MTC warrants further research. PMID:25674858

  6. Glucagonoma Pancreatic Neuroendocrine Tumor Treated With 177Lu DOTATATE Induction and Maintenance Peptide Receptor Radionuclide Therapy.

    PubMed

    Makis, William; McCann, Karey; Riauka, Terence A; McEwan, Alexander J B

    2015-11-01

    A 56-year-old man presented with a history of 2 prior resections of a recurrent pancreatic glucagonoma in the past 4 years. Workup revealed new liver and abdominal nodal metastases with a rising serum glucagon level. He was started on peptide receptor radionuclide therapy with Lu DOTATATE, and his disease stabilized, while his glucagon levels decreased and also stabilized. After 4 induction and 2 maintenance cycles, he remains progression free for 23 months. PMID:26204206

  7. Metastatic superscan in prostate carcinoma on gallium-68-prostate-specific membrane antigen positron emission tomography/computed tomography scan

    PubMed Central

    Agarwal, Krishan Kant; Tripathi, Madhavi; Kumar, Rajeev; Bal, Chandrasekhar

    2016-01-01

    We describe the imaging features of a metastatic superscan on gallium-68 Glu-NH-CO-NH-Lys-(Ahx)-[Ga-68(HBED-CC)], abbreviated as gallium-68-prostate-specific membrane antigen (68Ga-PSMA) positron emission tomography/computed tomography (PET/CT) imaging. 68Ga-PSMA is novel radiotracer undergoing evaluation for PET/CT imaging of prostate carcinoma. This patient had a superscan of metastases on conventional bone scintigraphy and was referred for 68Ga-PSMA PET/CT to evaluate the feasibility of 177Lu-PSMA therapy. PMID:27095868

  8. Carcinoid crisis induced by receptor radionuclide therapy with 90Y-DOTATOC in a case of liver metastases from bronchial neuroendocrine tumor (atypical carcinoid).

    PubMed

    Davì, M V; Bodei, L; Francia, G; Bartolomei, M; Oliani, C; Scilanga, L; Reghellin, D; Falconi, M; Paganelli, G; Lo Cascio, V; Ferdeghini, M

    2006-06-01

    SS receptors are overexpressed in many tumors, mainly of neuroendocrine origin, thus enabling the treatment with SS analogs. The clinical experience of receptor radionuclide therapy with the new analog [90Y-DOTA0-Tyr3 ]-octreotide [90Y-DOTATOC] has been developed over the last decade and is gaining a pivotal role in the therapeutic workout of these tumors. It is well known that some procedures performed in diagnostic and therapeutic management of endocrine tumors, such as agobiopsy and hepatic chemoembolization, can be associated with the occurrence of symptoms related to the release of vasoactive amines and/or hormonal peptides from tumor cell lysis. This is the first report of a severe carcinoid crisis developed after receptor radionuclide therapy with 90Y-DOTATOC administered in a patient affected by liver metastases from bronchial neuroendocrine tumor (atypical carcinoid). Despite protection with H1 receptor antagonists, octreotide and corticosteroids, few days after the therapy the patient complained of persistent flushing of the face and upper trunk, severe labial and periocular oedema, diarrhoea and loss of appetite. These symptoms increased and required new hospitalisation. The patient received iv infusion of octreotide associated with H1 and H2 receptor antagonists and corticosteroid therapy, which induced symptom remission within few days. The case here reported confirms that radionuclide therapy is highly effective in determining early rupture of metastatic tissue and also suggests that pre-medication should be implemented before the radiopeptide administration associated with a close monitoring of the patient in the following days. PMID:16840837

  9. Pyclen Tri-n-butylphosphonate Ester as Potential Chelator for Targeted Radiotherapy: From Yttrium(III) Complexation to (90)Y Radiolabeling.

    PubMed

    Le Fur, Mariane; Beyler, Maryline; Lepareur, Nicolas; Fougère, Olivier; Platas-Iglesias, Carlos; Rousseaux, Olivier; Tripier, Raphaël

    2016-08-15

    The Y(3+) complex of PCTMB, the tri-n-butyl phosphonate ester of pyclen (3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene), was synthesized as well as its Ho(3+) and Lu(3+) analogues. X-ray diffraction analyses revealed isomorphous dimeric M2(PCTMB)2·9H2O (M = Y, Ho, Lu) structures that crystallize in the centrosymmetric P1̅ triclinic space group. (1)H NMR and UV studies in aqueous solutions indicated that Y(3+) complexation is fast, being quantitative in 167 min at pH 3.8 and in 13 min at pH 5.5 (25 °C, acetate buffer, I = 0.150 M, [Y(3+)] = [PCTMB] = 0.2 mM). (1)H NMR DOSY and photon correlation spectroscopy experiments evidenced the formation of aggregates in chloroform with a bimodal distribution that changes slightly with concentration (11-24 and 240-258 nm). The behavior of the acid-assisted dissociation of the complex of Y(3+) with PCTMB was studied under pseudo-first-order conditions, and the half-life of the [Y(PCTMB)] complex in 0.5 M HCl at 25 °C was found to be 37 min, a value that decreases to 2.6 min in 5 M HCl. The Y(3+) complex of PCTMB is thermodynamically very stable, with a stability constant of log KY-PCTMB = 19.49 and pY = 16.7 measured by potentiometry. (90)Y complexation studies revealed fast radiolabeling kinetics; optimal radiolabeling conditions were obtained for (90)Y in acetate medium, PCTMB at 10(-4) to 10(-2) M in acetate buffer pH = 4.75, 15 min at 45-60 °C. In vitro stability studies in human serum showed that [(90)Y(PCTMB)] is quite stable, with about 90% of the activity still in the form of the radiotracer at 24 h and 80% from 48 h to 72 h. A comparison with other ligands such as PCTA, DOTA, and DTPA already used for in vivo application shows that [(90)Y(PCTMB)] is an interesting lipophilic and neutral analogue of these reference chelates for therapeutic applications in aqueous and nonaqueous media. PMID:27486673

  10. A 90Y-labelled anti-ROBO1 monoclonal antibody exhibits antitumour activity against hepatocellular carcinoma xenografts during ROBO1-targeted radioimmunotherapy

    PubMed Central

    2014-01-01

    Background ROBO1 is a membrane protein that functions in axon guidance. ROBO1 contributes to tumour metastasis and angiogenesis and may have potential as a target protein of immunotherapy because ROBO1 is specifically expressed at high levels in hepatocellular carcinoma. In this study, we examined biodistribution and radioimmunotherapy (RIT) using a radioisotope-labelled anti-ROBO1 monoclonal antibody (MAb) against hepatocellular carcinoma models. Methods ROBO1-positive HepG2 human hepatocellular carcinoma xenograft nude mice were used in this study. We conjugated anti-ROBO1 MAb with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), and the conjugates were labelled with 111In and 90Y. To study biodistribution, the 111In-DOTA-anti-ROBO1 MAb was injected into HepG2 xenograft mice via the tail vein. To evaluate any antitumour effect, a RIT study was performed, and the 90Y-DOTA-anti-ROBO1 MAb was injected via the tail vein. Tumour volume, mouse weight, and blood cell count were periodically measured throughout the experiments. The tumours and organs of mice were collected, and a histopathological analysis was carried out. Results The tumour uptake of 111In-anti-ROBO1 MAb in HepG2 xenograft mice was 15.0% ± 0.69% injected dose per gram at 48 h after injection. Immunotherapy with cold-anti-ROBO1 MAb (70 μg) did not cause a significant antitumour effect. RIT with 6.7 MBq of 90Y-anti-ROBO1 MAb caused significant tumour growth suppression. Transient body weight loss and bone-marrow suppression were observed. Histopathological analyses of tumours revealed the fatal degeneration of tumour cells, significant reduction of the Ki-67 index, and an increase of the apoptosis index. Normal organs showed no significant injury, but a transient reduction of hematopoietic cells was observed in the spleen and in the sternal bone marrow. Conclusions These results suggest that RIT with 90Y-anti-ROBO1 MAb is a promising treatment for ROBO1-positive hepatocellular

  11. Treatment Parameters and Outcome in 680 Treatments of Internal Radiation With Resin {sup 90}Y-Microspheres for Unresectable Hepatic Tumors

    SciTech Connect

    Kennedy, Andrew S. McNeillie, Patrick M.S.; Dezarn, William A.; Nutting, Charles; Sangro, Bruno; Wertman, Dan; Garafalo, Michael; Liu, David; Coldwell, Douglas; Savin, Michael; Jakobs, Tobias; Rose, Steven; Warner, Richard; Carter, Dennis; Sapareto, Stephen; Nag, Subir; Gulec, Seza; Calkins, Allison; Gates, Vanessa L.; Salem, Riad

    2009-08-01

    Purpose: Radioembolization (RE) using {sup 90}Y-microspheres is an effective and safe treatment for patients with unresectable liver malignancies. Radiation-induced liver disease (RILD) is rare after RE; however, greater understanding of radiation-related factors leading to serious liver toxicity is needed. Methods and Materials: Retrospective review of radiation parameters was performed. All data pertaining to demographics, tumor, radiation, and outcomes were analyzed for significance and dependencies to develop a predictive model for RILD. Toxicity was scored using the National Cancer Institute Common Toxicity Criteria Adverse Events Version 3.0 scale. Results: A total of 515 patients (287 men; 228 women) from 14 US and 2 EU centers underwent 680 separate RE treatments with resin {sup 90}Y-microspheres in 2003-2006. Multifactorial analyses identified factors related to toxicity, including activity (GBq) Selective Internal Radiation Therapy delivered (p < 0.0001), prescribed (GBq) activity (p < 0.0001), percentage of empiric activity (GBq) delivered (p < 0.0001), number of prior liver treatments (p < 0.0008), and medical center (p < 0.0001). The RILD was diagnosed in 28 of 680 treatments (4%), with 21 of 28 cases (75%) from one center, which used the empiric method. Conclusions: There was an association between the empiric method, percentage of calculated activity delivered to the patient, and the most severe toxicity, RILD. A predictive model for RILD is not yet possible given the large variance in these data.

  12. (Depth-dose curves of the beta reference fields (147)Pm, (85)Kr and (90)Sr/(90)Y produced by the beta secondary standard BSS2.

    PubMed

    Brunzendorf, Jens

    2012-08-01

    The most common reference fields in beta dosimetry are the ISO 6980 series 1 radiation fields produced by the beta secondary standard BSS2 and its predecessor BSS. These reference fields require sealed beta radiation sources ((147)Pm, (85)Kr or (90)Sr/(90)Y) in combination with a source-specific beam-flattening filter, and are defined only at a given distance from the source. Every radiation sources shipped with the BSS2 is sold with a calibration certificate of the Physikalisch-Technische Bundesanstalt. The calibration workflow also comprises regular depth-dose measurements. This work publishes complete depth-dose curves of the series 1 sources (147)Pm, (85)Kr and (90)Sr/(90)Y in ICRU tissue up to a depth of 11 mm,when all electrons are stopped. For this purpose, the individual depth-dose curves of all BSS2 sources calibrated so far have been determined, i.e. the complete datasets of all BSS2 beta sources have been re-evaluated. It includes 191 depth-dose curves of 116 different sources comprising more than 2200 data points in total. Appropriate analytical representations of the nuclide-specific depth-dose curves are provided for the first time. PMID:22267274

  13. A dose point kernel database using GATE Monte Carlo simulation toolkit for nuclear medicine applications: Comparison with other Monte Carlo codes

    SciTech Connect

    Papadimitroulas, Panagiotis; Loudos, George; Nikiforidis, George C.; Kagadis, George C.

    2012-08-15

    , which allowed us to produce a unique DPKs dataset using GATE. The dataset contains the total DPKs for {sup 67}Ga, {sup 68}Ga, {sup 90}Y, {sup 99m}Tc, {sup 111}In, {sup 123}I, {sup 124}I, {sup 125}I, {sup 131}I, {sup 153}Sm, {sup 177}Lu {sup 186}Re, and {sup 188}Re generated in water, bone, and lung. Conclusions: In this study, the authors have checked GATE's reliability for absorbed dose calculation when transporting different kind of particles, which indicates its robustness for dosimetry applications. A novel dataset of DPKs is provided, which can be applied in patient-specific dosimetry using analytical point kernel convolution algorithms.

  14. In Vivo Stabilization of a Gastrin-Releasing Peptide Receptor Antagonist Enhances PET Imaging and Radionuclide Therapy of Prostate Cancer in Preclinical Studies

    PubMed Central

    Chatalic, Kristell L.S.; Konijnenberg, Mark; Nonnekens, Julie; de Blois, Erik; Hoeben, Sander; de Ridder, Corrina; Brunel, Luc; Fehrentz, Jean-Alain; Martinez, Jean; van Gent, Dik C.; Nock, Berthold A.; Maina, Theodosia; van Weerden, Wytske M.; de Jong, Marion

    2016-01-01

    A single tool for early detection, accurate staging, and personalized treatment of prostate cancer (PCa) would be a major breakthrough in the field of PCa. Gastrin-releasing peptide receptor (GRPR) targeting peptides are promising probes for a theranostic approach for PCa overexpressing GRPR. However, the successful application of small peptides in a theranostic approach is often hampered by their fast in vivo degradation by proteolytic enzymes, such as neutral endopeptidase (NEP). Here we show for the first time that co-injection of a NEP inhibitor (phosphoramidon (PA)) can lead to an impressive enhancement of diagnostic sensitivity and therapeutic efficacy of the theranostic 68Ga-/177Lu-JMV4168 GRPR-antagonist. Co-injection of PA (300 µg) led to stabilization of 177Lu-JMV4168 in murine peripheral blood. In PC-3 tumor-bearing mice, PA co-injection led to a two-fold increase in tumor uptake of 68Ga-/177Lu-JMV4168, 1 h after injection. In positron emission tomography (PET) imaging with 68Ga-JMV4168, PA co-injection substantially enhanced PC-3 tumor signal intensity. Radionuclide therapy with 177Lu-JMV4168 resulted in significant regression of PC-3 tumor size. Radionuclide therapy efficacy was confirmed by production of DNA double strand breaks, decreased cell proliferation and increased apoptosis. Increased survival rates were observed in mice treated with 177Lu-JMV4168 plus PA as compared to those without PA. This data shows that co-injection of the enzyme inhibitor PA greatly enhances the theranostic potential of GRPR-radioantagonists for future application in PCa patients. PMID:26722377

  15. 90Y-ibritumomab tiuxetan radiotherapy as first-line therapy for early stage low-grade B-cell lymphomas, including bulky disease.

    PubMed

    Samaniego, Felipe; Berkova, Zuzana; Romaguera, Jorge E; Fowler, Nathan; Fanale, Michelle A; Pro, Barbara; Shah, Jatin J; McLaughlin, Peter; Sehgal, Lalit; Selvaraj, Vijairam; Braun, Frank K; Mathur, Rohit; Feng, Lei; Neelapu, Sattva S; Kwak, Larry W

    2014-10-01

    (90) Y-ibritumomab-tiuxetan ((90) YIT) was used as a first-line therapy for patients with early-stage follicular lymphoma (FL) or marginal zone B-cell lymphoma (MZL). Thirty-one patients were treated, with an overall 3-month response rate of 100% (68% complete response, 29% unconfirmed complete response and 3% partial response). At a median follow-up of 56 months, ten patients (32%) had disease relapse or progression. The progression-free rates at 3 and 5 years were lower in males, patients with FL, stage II disease and non-bulky disease, although they did not reach statistical significance. Grade 3-4 neutropenia, thrombocytopenia and anaemia were 61%, 35%, and 3%, respectively. (90) YIT was well tolerated, including in those patients over 60 years old, and achieved high response rates in patients with early-stage low-grade B-cell lymphomas. Bulky disease did not adversely affect tumour response. PMID:25040450

  16. A novel method for the preparation of large-area 90Sr/90Y sources for the calibration of hand contamination monitors.

    PubMed

    Kumar, Manoj; Gandhi, Shyamala S; Chakravarty, Rubel; Nuwad, J; Udhayakumar, J; Dash, Ashutosh

    2013-09-01

    This paper describes a method for the preparation of large-area (90)Sr/(90)Y polymer film sources for the calibration of hand contamination monitors. The process consists of solvent extraction of predictable quantity of (90)Sr into an organic solvent containing di-tert-butyl-cyclohexano-18-crown-6 (DCH18C6), formation of a polymeric solution of poly(methyl methacrylate) (PMMA), pouring the (90)Sr-embedded polymer solution over a surface of a defined area followed by evaporation to create a thin film and peeling-off of the radioactive PMMA film. Quality control tests of the radioactive films were carried out to ensure nonleachability, uniform distribution of activity and stability. Sources having 5kBq±428Bq were prepared using this method and routinely used for calibration of contamination monitors. PMID:23714116

  17. Efficacy of low-dose 90Sr-90Y therapy combined with topical application of 0.5% timolol maleate solution for the treatment of superficial infantile hemangiomas

    PubMed Central

    ZHU, HONG-JIAN; LIU, QINGHONG; DENG, XIAO-LI; GUAN, YAN-XING

    2015-01-01

    The aim of the present study was to investigate the clinical efficacy and safety of low-dose 90Sr-90Y therapy combined with the topical application of 0.5% timolol maleate solution for the treatment of superficial infantile hemangiomas (IHs). A total of 72 infants with hemangiomas were allocated at random into the observation group (17 cases aged ≤3 months, 20 cases aged >3 months) or the control group (15 cases aged ≤3 months, 20 cases aged >3 months). The observation group was treated with low-dose 90Sr-90Y combined with timolol, while the control group received an identical dose of 90Sr-90Y with physiological saline. Data were collected for statistical analysis, and treatment efficacy was compared between the two groups. In the observation group, 100% (37/37) of subjects exhibited an ‘excellent’ response to the treatment, while 94.1% (16/17) of patients aged ≤3 months and 85.0% (17/20) aged >3 months were classed as being cured. In the control group, the treatment was classed as ‘effective’ in 100% (35/35) of the subjects, while the excellent response rate was 86.7% (13/15) among the infants aged ≤3 months and 75.0% (15/20) among the infants aged >3 months. The ‘cure’ rates in the control group were 66.7% (10/15) and 60.0% (12/20) for the ≤3-month- and >3-month-old subjects, respectively. The excellent response and cure rates were notably higher in the observation group than those in the control group. Comparison between the two groups revealed a χ2 value of 13.90 (P<0.01) for excellent responses in subjects aged ≤3 months, while for patients aged >3 months the χ2 value was 28.57 (P<0.01). Analysis of the cure responses gave similar results [≤3 months, χ2=23.22 (P<0.01); >3 months, χ2=15.67 (P<0.01)]. At 3–4 months after the first course of treatment, the cure rate was 33.3% (11/33) in the observation group, which was significantly higher than the rate of 18.32% (4/22) in the control group (χ2=5.92, P<0.05). No serious adverse

  18. PET/CT-Based Dosimetry in 90Y-Microsphere Selective Internal Radiation Therapy: Single Cohort Comparison With Pretreatment Planning on 99mTc-MAA Imaging and Correlation With Treatment Efficacy

    PubMed Central

    Song, Yoo Sung; Paeng, Jin Chul; Kim, Hyo-Cheol; Chung, Jin Wook; Cheon, Gi Jeong; Chung, June-Key; Lee, Dong Soo; Kang, Keon Wook

    2015-01-01

    Abstract 90Y PET/CT can be acquired after 90Y-microsphere selective radiation internal therapy (SIRT) to describe radioactivity distribution. We performed dosimetry using 90Y-microsphere PET/CT data to evaluate treatment efficacy and appropriateness of activity planning from 99mTc-MAA scan and SPECT/CT. Twenty-three patients with liver malignancy were included in the study. 99mTc-MAA was injected during planning angiography and whole body 99mTc-MAA scan and liver SPECT/CT were acquired. After SIRT using 90Y-resin microsphere, 90Y-microsphere PET/CT was acquired. A partition model (PM) using 4 compartments (tumor, intarget normal liver, out-target normal liver, and lung) was adopted, and absorbed dose to each compartment was calculated based on measurements from 99mTc-MAA SPECT/CT and 90Y-microsphere PET/CT, respectively, to be compared with each other. Progression-free survival (PFS) was evaluated in terms of tumor absorbed doses calculated by 99mTc-MAA SPECT/CT and 90Y-microsphere PET/CT results. Lung shunt fraction was overestimated on 99mTc-MAA scan compared with 90Y-microsphere PET/CT (0.060 ± 0.037 vs. 0.018 ± 0.026, P < 0.01). Tumor absorbed dose exhibited a close correlation between the results from 99mTc-MAA SPECT/CT and 90Y-microsphere PET/CT (r = 0.64, P < 0.01), although the result from 99mTc-MAA SPECT/CT was significantly lower than that from 90Y-microsphere PET/CT (135.4 ± 64.2 Gy vs. 185.0 ± 87.8 Gy, P < 0.01). Absorbed dose to in-target normal liver was overestimated on 99mTc-MAA SPECT/CT compared with PET/CT (62.6 ± 38.2 Gy vs. 45.2 ± 32.0 Gy, P = 0.02). Absorbed dose to out-target normal liver did not differ between 99mTc-MAA SPECT/CT and 90Y-microsphere PET/CT (P = 0.49). Patients with tumor absorbed dose >200 Gy on 90Y-microsphere PET/CT had longer PFS than those with tumor absorbed dose ≤200 Gy (286 ± 56 days vs. 92 ± 20 days, P = 0.046). Tumor absorbed dose calculated by 99m

  19. Long-term efficacy of (90)Y ibritumomab tiuxetan therapy in follicular non-Hodgkin lymphoma and health-related quality of life.

    PubMed

    Andrade-Campos, Marcio Miguel; Montes-Limón, Anel E; Soro-Alcubierre, Gloria; Grasa, José María; Lopez-Gómez, Luis; Baringo, Teresa; Giraldo, Pilar

    2014-12-01

    The aim of this study was to analyze the outcomes of 37 follicular lymphoma (FL) patients treated with (90)ytrium ibritumomab tiuxetan (90Y-IT), outside of clinical trial, according to protocol ISCRTN36210045, after ≥5 years follow-up to February 2014. Health-related quality of life (HRQoL) was evaluated with the SF-36, Spanish version, and compared with the general population of Spain. Patients had a mean age of 61.9 (range, 30-85) years and included 18 males. FLIPI, low: 25 (67.6 %), intermedium 9 (24.3 %), and low 3 (8.1 %). Previous therapy schedules >2: 48.6 % The median follow-up was 66 months, mean Time to Relapse (TTR) 71.3 months (58.8-83.8) median not reached. Thirty-four patients achieved complete response (91.8 %), and three no response. Mean overall survival: 82.3 months (71.6-92.9). Four patients presented with concomitant tumors (colon, breast, prostate, lung) after radioimmunotherapy, and three developed second primary neoplasms (esophagus, renal, and myelodysplastic syndrome in a relapsed patient who received fludarabine). Four of 10 deaths were related to lymphoma progression. Hematological toxicities were mild and easily managed. No patients required hospitalization. Negative scores were obtained in the physical and emotional roles items; however, the perception of general health and vitality were better than in the general population, with the best outcomes in non-relapsed patients. Radioimmunotherapy with 90Y-IT was safe and effective as long-term therapy in patients with FL. Early use of radioimmunotherapy could offer good, sustained responses with low toxicity over the long term and acceptable HRQoL. PMID:24985089

  20. 3D inpatient dose reconstruction from the PET-CT imaging of {sup 90}Y microspheres for metastatic cancer to the liver: Feasibility study

    SciTech Connect

    Fourkal, E.; Veltchev, I.; Lin, M.; Meyer, J.; Koren, S.; Doss, M.; Yu, J. Q.

    2013-08-15

    Purpose: The introduction of radioembolization with microspheres represents a significant step forward in the treatment of patients with metastatic disease to the liver. This technique uses semiempirical formulae based on body surface area or liver and target volumes to calculate the required total activity for a given patient. However, this treatment modality lacks extremely important information, which is the three-dimensional (3D) dose delivered by microspheres to different organs after their administration. The absence of this information dramatically limits the clinical efficacy of this modality, specifically the predictive power of the treatment. Therefore, the aim of this study is to develop a 3D dose calculation technique that is based on the PET imaging of the infused microspheres.Methods: The Fluka Monte Carlo code was used to calculate the voxel dose kernel for {sup 90}Y source with voxel size equal to that of the PET scan. The measured PET activity distribution was converted to total activity distribution for the subsequent convolution with the voxel dose kernel to obtain the 3D dose distribution. In addition, dose-volume histograms were generated to analyze the dose to the tumor and critical structures.Results: The 3D inpatient dose distribution can be reconstructed from the PET data of a patient scanned after the infusion of microspheres. A total of seven patients have been analyzed so far using the proposed reconstruction method. Four patients underwent treatment with SIR-Spheres for liver metastases from colorectal cancer and three patients were treated with Therasphere for hepatocellular cancer. A total of 14 target tumors were contoured on post-treatment PET-CT scans for dosimetric evaluation. Mean prescription activity was 1.7 GBq (range: 0.58–3.8 GBq). The resulting mean maximum measured dose to targets was 167 Gy (range: 71–311 Gy). Mean minimum dose to 70% of target (D70) was 68 Gy (range: 25–155 Gy). Mean minimum dose to 90% of target

  1. Anti-CD22 90Y-epratuzumab tetraxetan combined with anti-CD20 veltuzumab: a phase I study in patients with relapsed/refractory, aggressive non-Hodgkin lymphoma.

    PubMed

    Witzig, Thomas E; Tomblyn, Michael B; Misleh, Jamal G; Kio, Ebenezer A; Sharkey, Robert M; Wegener, William A; Goldenberg, David M

    2014-11-01

    A lingering criticism of radioimmunotherapy in non-Hodgkin lymphoma is the use of cold anti-CD20 antibody along with the radiolabeled anti-CD20 antibody. We instead combined radioimmunotherapy with immunotherapy targeting different B-cell antigens. We evaluated the anti-CD22 (90)Y-epratuzumab tetraxetan with the anti-CD20 veltuzumab in patients with aggressive lymphoma in whom at least one prior standard treatment had failed, but who had not undergone stem cell transplantation. Eighteen patients (median age 73 years, median of 3 prior treatments) received 200 mg/m(2) veltuzumab once-weekly for 4 weeks, with (90)Y-epratuzumab tetraxetan at planned doses in weeks 3 and 4, and (111)In-epratuzumab tetraxetan in week 2 for imaging and dosimetry. Veltuzumab effectively lowered levels of B cells in the blood prior to the radioimmunotherapy doses. No significant immunogenicity or change in pharmacokinetics of either agent occurred in combination. (111)In imaging showed tumor targeting with acceptable radiation dosimetry to normal organs. For (90)Y-epratuzumab tetraxetan, transient myelosuppression was dose-limiting with 6 mCi/m(2) (222 MBq/m(2)) × 2 being the maximal tolerated dose. Of 17 assessable patients, nine (53%) had objective responses according to the 2007 revised treatment response criteria, including three (18%) complete responses (2 relapsing after 11 and 13 months, 1 continuing to be clinically disease-free at 19 months), and six (35%) partial responses (1 relapsing after 14 months, 5 at 3 - 7 months). Responses occurred in patients with different lymphoma histologies, treated at different (90)Y dose levels, and with a predicted risk of poor outcome, most importantly including five of the six patients treated with the maximal tolerated dose (2 of whom achieved durable complete responses). In conclusion, the combination of (90)Y-epratuzumab tetraxetan and veltuzumab was well-tolerated with encouraging therapeutic activity in this difficult-to-treat population

  2. In vitro and in vivo evaluation of novel ligands for radioimmunotherapy.

    PubMed

    Chong, Hyun-Soon; Milenic, Diane E; Garmestani, Kayhan; Brady, Erik D; Arora, Hans; Pfiester, Candice; Brechbiel, Martin W

    2006-05-01

    Novel ligands cis-2,6-bis[N,N-bis(carboxymethyl)aminomethyl]-1-piperidineacetic acid (PIP-DTPA), cis-[(1R,11S)-6,9,15-Tris-carboxymethyl-3,6,9,15-tetraazabicyclo[9.3.1]pentadec-3-yl]-acetic acid (PIP-DOTA), cis-{2,7-bis-[bis-carboxymethyl-amino)-methyl]-azepan-1-yl}-acetic acid (AZEP-DTPA), [2-(4,7-bis-carboxymethyl-[1,4,7]triazacyclononan-1-yl-ethyl]-2-carbonylmethyl-amino]-tetraacetic acid (NETA) and [{4-carboxymethyl-7-[2-(carboxymethylamino)-ethyl]-perhydro-1,4,7-triazonin-1-yl}-acetic acid (NPTA) are investigated as potential chelators of 177Lu, 90Y, 212Pb and 213Bi for radioimmunotherapy (RIT). The new ligands are radiolabeled with 177Lu, 86/88/90Y, 203Pb and 205/6Bi, and in vitro stability and in vivo stability of the radiolabeled complexes are assessed in human serum and athymic mice, respectively. In vitro studies indicate that all radiolabeled complexes with the exception of 90Y-AZEP-DTPA are stable in serum for 5-11 days. All new ligands examined herein are found to tightly hold 177Lu in vivo. Piperidine-backboned DTPA (PIP-DTPA) complexes radiolabeled with all radioisotopes examined display excellent in vivo stability, that is, excretion without dissociation. The azepane-backboned DTPA derivative, AZEP-DTPA, appears ineffective in binding all but 177Lu in vivo. NETA and NPTA radiolabeled with 86Y or 177Lu exhibit rapid blood clearance and low organ uptakes. Significant accretion in the kidney, femur and/or liver is observed with 203Pb-labeled AZEP-DTPA, PIP-DOTA and NPTA. Both 203Pb-PIP-DOTA and 205/6Bi-PIP-DOTA result in moderate to high renal accumulation of radioactivity. NETA exhibits improved renal accumulation with respect to PIP-DOTA for 205/6Bi but also shows significant liver uptake. Of all ligands studied, only PIP-DTPA appears to effectively bind 203Pb and 205/6Bi in vivo. PIP-DTPA, PIP-DOTA, NETA and NPTA all show strong evidence of rapid blood clearance and low organ uptake for 177Lu and 90Y. Serum stability and in vivo biodistribution

  3. Investigation of a {sup 90}Sr/{sup 90}Y source for intra-ocular treatment of wet age-related macular degeneration

    SciTech Connect

    Holmes, Shannon M.; Micka, John A.; DeWerd, Larry A.

    2009-10-15

    Purpose: The purpose of this study is to perform an extensive investigation of an approximately 2.5 mm long {sup 90}Sr/{sup 90}Y source designed for treating wet age-related macular degeneration. Methods: As part of this investigation, a NIST-traceable absorbed dose to water calibration technique was established, and a source deployment verification test was developed. The influence of treatment cannula construction tolerance on the measurements as well as the dose delivered to the patient was investigated using the Monte Carlo code MCNP5. Variation between production cannulae was quantified experimentally using a well-type ionization chamber, and additional measurements along with Monte Carlo calculations of the collimating insert used for source deployment verification were performed to validate the model. Results: Maximum variation in the integrated target dose was seen when the source was shifted laterally within the treatment cannula. For the well chamber measurements, the observed standard deviation in ionization current for a single source placed in different reference cannulae was {+-}0.3%, with a maximum observed range of less than {+-}0.5%. Clinical cannulae in the collimating insert showed an average of 17.8%{+-}0.4% of the reference signal when sources were fully deployed compared to 18.5% predicted by Monte Carlo calculations. This discrepancy has been attributed primarily to construction of the collimator since the collimation gap was observed to be approximately 0.025-0.075 mm smaller than specified. Construction tolerance of the well chamber insert as well as position tolerance of the cannula tip were both investigated, and their influence on the predicted signal was quantified. Additional measurements along with Monte Carlo based calculations of the collimating insert with polyethylene spacers added to the setup were performed to validate the Monte Carlo model. The shimmed Monte Carlo and measured data agree to within 1%, which is a magnitude

  4. Multicenter evaluation of the safety and efficacy of radioembolization in patients with unresectable colorectal liver metastases selected as candidates for 90Y resin microspheres

    PubMed Central

    Ball, David; Cohen, Steven J.; Cohn, Michael; Coldwell, Douglas M.; Drooz, Alain; Ehrenwald, Eduardo; Kanani, Samir; Rose, Steven C.; Nutting, Charles W.; Moeslein, Fred M.; Savin, Michael A.; Schirm, Sabine; Putnam, Samuel G.; Sharma, Navesh K.; Wang, Eric A.

    2015-01-01

    Background Metastatic colorectal cancer liver metastases Outcomes after RadioEmbolization (MORE) was an investigator-initiated case-control study to assess the experience of 11 US centers who treated liver-dominant metastases from colorectal cancer (mCRC) using radioembolization [selective internal radiation therapy (SIRT)] with yttrium-90-(90Y)-labeled resin microspheres. Methods Data from 606 consecutive patients who received radioembolization between July 2002 and December 2011 were collected by an independent research organization. Adverse events (AEs) and survival were compared across lines of treatment using Fisher’s exact test and Kaplan-Meier estimates, respectively. Results Patients received a median of 2 (range, 0-6) lines of prior chemotherapy; 35.1% had limited extrahepatic metastases. Median tumor-to-liver ratio and -activity administered at first procedure were 15% and 1.17 GBq, respectively. Hospital stay was <24 hours in 97.8% cases. Common grade ≥3 AEs over 184 days follow-up were: abdominal pain (6.1%), fatigue (5.5%), hyperbilirubinemia (5.4%), ascites (3.6%) and gastrointestinal ulceration (1.7%). There was no statistical difference in AEs across treatment lines (P>0.05). Median survivals [95% confidence interval (CI)] following radioembolization as a 2nd-line, 3rd-line, or 4th-plus line were 13.0 (range, 10.5-14.6), 9.0 (range, 7.8-11.0), and 8.1 (range, 6.4-9.3) months, respectively; and significantly prolonged in patients with ECOG 0 vs. ≥1 (P=0.009). Statistically significant independent variables for survival at radioembolization were: disease stage [extrahepatic metastases, extent of liver involvement (tumor-to-treated-liver ratio)], liver function (uncontrolled ascites, albumin, alkaline phosphatase, aspartate transaminase), leukocytes, and prior chemotherapy. Conclusions Radioembolization appears to have a favorable risk/benefit profile, even among mCRC patients who had received ≥3 prior lines of chemotherapy. PMID:25830033

  5. Positive Influence of 177Lu PSMA-617 Therapy on Bone Marrow Depression Caused by Metastatic Prostate Cancer.

    PubMed

    Schlenkhoff, Carl Diedrich; Gaertner, Florian; Essler, Markus; Schmidt, Matthias; Ahmadzadehfar, Hojjat

    2016-06-01

    A 75-year-old man with castrate-resistant prostate cancer and increasing prostate-specific antigen (PSA) level developed severe bone marrow depression during Ra radionuclide therapy. Because of this, he was treated with Lu-PSMA in compassionate use for this not-yet-approved therapy. At the beginning of Lu-PSMA therapy, repeated blood transfusions (BT) were necessary. Six months after the last BT, after 3 cycles of Lu-PSMA, his blood count stabilized. He required no further BTs and his PSA level remained lowered. PMID:26909716

  6. Metastatic Prostate Cancer With Restored Hormone-Response After Radioligand Therapy With 177Lu-PSMA-617.

    PubMed

    Schlenkhoff, Carl Diedrich; Knüpfer, Eberhard; Essler, Markus; Ahmadzadehfar, Hojjat

    2016-07-01

    An 80-year-old patient with castrate-resistant prostate cancer presented to our department for PSMA imaging because of a rising prostate-specific antigen (PSA) level. The tumor was diagnosed in 2004. GnRh analog was the only treatment the patient received. Two cycles of Lu-PSMA-617 were performed with a 2-month interval in between. Ten months after finishing with 2 cycles of Lu-PSMA therapy, we noticed a continuous falling PSA level and a decreasing tumor spread in the PET/CT imaging just under the hormone therapy. PMID:26909718

  7. Cardiac metastases of neuroendocrine tumors treated with 177Lu DOTATATE peptide receptor radionuclide therapy or 131I-MIBG therapy.

    PubMed

    Makis, William; McCann, Karey; Bryanton, Mark; McEwan, Alexander J B

    2015-12-01

    Neuroendocrine tumors have a propensity to metastasize to the heart, although the reason for this remains unknown. A review of 251 neuroendocrine tumor patients treated with Lu DOTATATE peptide receptor radionuclide therapy or I-MIBG therapy at our institution since 2003 revealed 2 patients with cardiac metastases (incidence, 0.8%), one treated with Lu DOTATATE and one with I-MIBG. We present the imaging findings of these 2 patients, as well as their management and responses to therapy. PMID:26359563

  8. Peptide receptor radionuclide therapy with (177)Lu DOTATATE in a case of recurrent carotid body paraganglioma with spinal metastases.

    PubMed

    Gupta, Santosh Kumar; Singla, Suhas; Karunanithi, Sellam; Damle, Nishikant; Bal, Chandrasekhar

    2014-05-01

    Paragangliomas are rare benign neuroendocrine tumors, and 80% of all paragangliomas are either carotid body tumors or glomus jugulare tumors. We present a case of recurrent unresectable carotid body paraganglioma with nodal and T7 vertebral metastases in a 30-year-old man 6 years postsurgery detected with Ga DOTANOC PET/CT and was administered with peptide receptor radionuclide therapy using Lu DOTATATE. After 5 cycles of Lu DOTATATE (total cumulative activity of 750 mCi [27 GBq]), significant response at the primary site on Ga DOTANOC PET/CT and complete disappearance of nodal and T7 vertebral metastases were noted. PMID:24217545

  9. Liver and bone metastases from small bowel neuroendocrine tumor respond to 177Lu-DOTATATE induction and maintenance therapies.

    PubMed

    Makis, William; McCann, Karey; Buteau, Francois A; McEwan, Alexander J B

    2015-02-01

    A 73-year-old man diagnosed with small bowel neuroendocrine tumor (NET) with liver and bone metastases was treated with 4 induction cycles and 2 maintenance cycles of Lu-DOTATATE peptide receptor radionuclide therapy (PRRT). His symptoms and mobility improved significantly following induction as well as maintenance treatments, and posttherapy imaging studies showed significant improvement in metastatic liver and bone disease. Current protocols consisting of 4 induction cycles of Lu-DOTATATE only may not be sufficient to optimally treat neuroendocrine liver and bone metastases, and further research into maintenance Lu-DOTATATE therapy is warranted. PMID:25243941

  10. Anti-CD22 90Y-epratuzumab tetraxetan combined with anti-CD20 veltuzumab: a phase I study in patients with relapsed/refractory, aggressive non-Hodgkin lymphoma

    PubMed Central

    Witzig, Thomas E.; Tomblyn, Michael B.; Misleh, Jamal G.; Kio, Ebenezer A.; Sharkey, Robert M.; Wegener, William A.; Goldenberg, David M.

    2014-01-01

    A lingering criticism of radioimmunotherapy in non-Hodgkin lymphoma is the use of cold anti-CD20 antibody along with the radiolabeled anti-CD20 antibody. We instead combined radioimmunotherapy with immunotherapy targeting different B-cell antigens. We evaluated the anti-CD22 90Y-epratuzumab tetraxetan with the anti-CD20 veltuzumab in patients with aggressive lymphoma in whom at least one prior standard treatment had failed, but who had not undergone stem cell transplantation. Eighteen patients (median age 73 years, median of 3 prior treatments) received 200 mg/m2 veltuzumab once-weekly for 4 weeks, with 90Y-epratuzumab tetraxetan at planned doses in weeks 3 and 4, and 111In-epratuzumab tetraxetan in week 2 for imaging and dosimetry. Veltuzumab effectively lowered levels of B cells in the blood prior to the radioimmunotherapy doses. No significant immunogenicity or change in pharmacokinetics of either agent occurred in combination. 111In imaging showed tumor targeting with acceptable radiation dosimetry to normal organs. For 90Y-epratuzumab tetraxetan, transient myelosuppression was dose-limiting with 6 mCi/m2 (222 MBq/m2) × 2 being the maximal tolerated dose. Of 17 assessable patients, nine (53%) had objective responses according to the 2007 revised treatment response criteria, including three (18%) complete responses (2 relapsing after 11 and 13 months, 1 continuing to be clinically disease-free at 19 months), and six (35%) partial responses (1 relapsing after 14 months, 5 at 3 – 7 months). Responses occurred in patients with different lymphoma histologies, treated at different 90Y dose levels, and with a predicted risk of poor outcome, most importantly including five of the six patients treated with the maximal tolerated dose (2 of whom achieved durable complete responses). In conclusion, the combination of 90Y-epratuzumab tetraxetan and veltuzumab was well-tolerated with encouraging therapeutic activity in this difficult-to-treat population. PMID:25150258

  11. Kidney dosimetry in ¹⁷⁷Lu and ⁹⁰Y peptide receptor radionuclide therapy: influence of image timing, time-activity integration method, and risk factors.

    PubMed

    Guerriero, F; Ferrari, M E; Botta, F; Fioroni, F; Grassi, E; Versari, A; Sarnelli, A; Pacilio, M; Amato, E; Strigari, L; Bodei, L; Paganelli, G; Iori, M; Pedroli, G; Cremonesi, M

    2013-01-01

    Kidney dosimetry in (177)Lu and (90)Y PRRT requires 3 to 6 whole-body/SPECT scans to extrapolate the peptide kinetics, and it is considered time and resource consuming. We investigated the most adequate timing for imaging and time-activity interpolating curve, as well as the performance of a simplified dosimetry, by means of just 1-2 scans. Finally the influence of risk factors and of the peptide (DOTATOC versus DOTATATE) is considered. 28 patients treated at first cycle with (177)Lu DOTATATE and 30 with (177)Lu DOTATOC underwent SPECT scans at 2 and 6 hours, 1, 2, and 3 days after the radiopharmaceutical injection. Dose was calculated with our simplified method, as well as the ones most used in the clinic, that is, trapezoids, monoexponential, and biexponential functions. The same was done skipping the 6 h and the 3 d points. We found that data should be collected until 100 h for (177)Lu therapy and 70 h for (90)Y therapy, otherwise the dose calculation is strongly influenced by the curve interpolating the data and should be carefully chosen. Risk factors (hypertension, diabetes) cause a rather statistically significant 20% increase in dose (t-test, P < 0.10), with DOTATATE affecting an increase of 25% compared to DOTATOC (t-test, P < 0.05). PMID:23865075

  12. New Perspectives Offered by Nuclear Medicine for the Imaging and Therapy of Multiple Myeloma

    PubMed Central

    Mesguich, Charles; Zanotti-Fregonara, Paolo; Hindié, Elif

    2016-01-01

    The management of multiple myeloma has fundamentally changed over the years and imaging techniques able to match the therapeutic advances are now much needed. Although many patients now achieve complete response after first-line treatment, relapse is common. Therefore, it would be important to improve the initial prognostic stratification and to detect minimal residual disease after treatment. 18F-FDG-PET/CT is a useful imaging tool which has a high prognostic value at baseline evaluation and can effectively differentiate active from inactive lesions during induction treatment or after autologous stem-cell transplantation. In combination with biological data, it improves the prediction of relapse. Other PET tracers may soon enter clinical practice and overcome some of the limitations of 18F-FDG, such as the low sensitivity in detecting early bone marrow infiltration. Excellent results with 11C-Methionine are reported by Lapa and colleagues in this issue of the Journal. 11C-Methionine uptake reflects the increased protein synthesis of malignant plasmocytes and correlates well with bone marrow infiltration. Other promising PET ligands include lipid tracers, such as 11C-Choline or 11C-acetate, and some peptide tracers, such as 68Ga-Pentixafor, that targets CXCR4 (chemokine receptor-4), which is often expressed with high density by myeloma cells. Malignant plasma cells are radiosensitive and thus potentially amenable to systemic radionuclide therapy. Indeed, excellent preclinical results were obtained with radioimmunotherapy targeting CD38. Also, preliminary clinical results with peptides targeting CXCR4 (e.g. 177Lu- or 90Y-Pentixather) are encouraging. Multiple myeloma may represent a renewal of the already strong partnership between hematologists and nuclear medicine physicians. PMID:26877786

  13. New Perspectives Offered by Nuclear Medicine for the Imaging and Therapy of Multiple Myeloma.

    PubMed

    Mesguich, Charles; Zanotti-Fregonara, Paolo; Hindié, Elif

    2016-01-01

    The management of multiple myeloma has fundamentally changed over the years and imaging techniques able to match the therapeutic advances are now much needed. Although many patients now achieve complete response after first-line treatment, relapse is common. Therefore, it would be important to improve the initial prognostic stratification and to detect minimal residual disease after treatment. (18)F-FDG-PET/CT is a useful imaging tool which has a high prognostic value at baseline evaluation and can effectively differentiate active from inactive lesions during induction treatment or after autologous stem-cell transplantation. In combination with biological data, it improves the prediction of relapse. Other PET tracers may soon enter clinical practice and overcome some of the limitations of (18)F-FDG, such as the low sensitivity in detecting early bone marrow infiltration. Excellent results with (11)C-Methionine are reported by Lapa and colleagues in this issue of the Journal. (11)C-Methionine uptake reflects the increased protein synthesis of malignant plasmocytes and correlates well with bone marrow infiltration. Other promising PET ligands include lipid tracers, such as (11)C-Choline or (11)C-acetate, and some peptide tracers, such as (68)Ga-Pentixafor, that targets CXCR4 (chemokine receptor-4), which is often expressed with high density by myeloma cells. Malignant plasma cells are radiosensitive and thus potentially amenable to systemic radionuclide therapy. Indeed, excellent preclinical results were obtained with radioimmunotherapy targeting CD38. Also, preliminary clinical results with peptides targeting CXCR4 (e.g. (177)Lu- or (90)Y-Pentixather) are encouraging. Multiple myeloma may represent a renewal of the already strong partnership between hematologists and nuclear medicine physicians. PMID:26877786

  14. The use of Yttrium-90 Ibritumomab Tiuxetan (90Y-IT) as a consolidation therapy in high-risk patients with diffuse large B-cell lymphoma ineligible for autologous stem-cell transplantation

    PubMed Central

    Kisiel, Elżbieta; Sawczuk-Chabin, Joanna; Centkowski, Piotr; Knopińska-Posłuszny, Wanda; Khan, Omeir

    2015-01-01

    Aim of the study To evaluate the efficacy and safety of Yttrium-90 Ibritumomab Tiuxetan (90Y-IT) as a consolidation therapy in the management of DLBCL. Material and methods Patients with primary refractory or high-risk DLBCL (n = 18), ineligible for autologous stem-cell transplantation, were included in a retrospective study performed at three centers by the Polish Lymphoma Research Group (PLRG). All patients (mean age 61, range 35–82) either didn't achieve a complete response or didn't complete the scheduled therapy due to its complications. Response rates (CR, PR, SD, PD) according to Cheson criteria, overall survival (OS), progression-free survival (PFS) and adverse effects of radioimmunotherapy were analyzed. Results Consolidation radioimmunotherapy increased the CR rate from 38% (n = 7) to 82% (n = 15). One patient remained in PR, one patient remained in SD, while one patient remained in PD. During a median follow-up of five years, 11 patients (62%) were alive with no recurrence, 4 patients (22%) were alive with relapse while 3 patients (16%) died. There was no statistically significant difference in PFS between those in CR and those in PR before 90Y-IT. Conclusions Radioimmunotherapy is an effective consolidation therapy for high risk/refractory DLBCL patients and worthy of further investigation in prospective trials. PMID:26199570

  15. Mechanism and energetics for complexation of {sup 90}Y with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), a model for cancer radioimmunotherapy

    SciTech Connect

    Jang, Y.H.; Blanco, M.; Dasgupta, S.; Keire, D.A.; Shively, J.E.; Goddard, W.A. III

    1999-07-07

    A promising cancer therapy involves the use of the macrocyclic polyaminoacetate DOTA (1,4,6,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) attached to a tumor-targeting antibody complexed with the {beta} emitter {sup 90}Y{sup 3+}. However, incorporation of the {sup 90}Y into the DOTA conjugate is too slow. To identify the origins of this problem, ab initio quantum chemistry methods (B3LYP/:ACVP* and HF/LACVP*) were used to predict structures and energetics. The authors find that the initial complex YH{sub 2}(DOTA){sup +} is 4-coodinate (the four equivalent carboxylate oxygens), which transforms to YH(DOTA) (5-coordinate with one ring N and four carboxylate oxygens), and finally to Y(DOTA){sup {minus}}, which is 8-coordinate (four oxygens and four nitrogens). The rate-determining step is the conversion of YH(DOTA) to Y(DOTA){sup {minus}}, which was calculated to have an activation free energy (aqueous phase) of 8.4 kcal/mol, in agreement with experimental results (8.1--9.3 kcal/mol) for various metals to DOTA [Kumar, K.; Tweedle, M.F. Inorg. Chem. 1993, 32, 4193--4199; Wu, S.L.; Horrocks, W.D., Jr., Inorg. Chem. 1995, 34, 3724--2732]. On the basis of this mechanism the authors propose a modified chelate, DO3AlPr, which has calculated at a much faster rate of incorporation.

  16. Predictors of Long-Term Outcome from Intraperitoneal Radioimmunotherapy for Ovarian Cancer

    PubMed Central

    You, Zhiying; Alvarez, Ronald; Partridge, Edward; Grizzle, William; LoBuglio, Albert

    2012-01-01

    Abstract Data was analyzed from 92 patients > 5 years after intraperitoneal (IP) radionuclide therapy (RIT) with 90Y- or 177Lu-CC49 to determine prognostic factors. Patients had CC49 antibody-reactive ovarian cancer confined to the abdominal cavity after primary debulking and chemotherapy. The first 27 patients received IP 177Lu-CC49 alone; the remainder received Interferon (IFN), to increase the expression of the tumor-associated glycoprotein-72 (TAG-72) antigen, +/− IP paclitaxel (25–100 mg/m2) 2 days before RIT. Factors assessed by univariate (and some multivariate) analysis included age, race, body size, interval between initial diagnosis and RIT, interval between 2nd look surgery and RIT, 90Y versus 177Lu, MBq dose, paclitaxel dose, grade of tumor, extent of initial surgery, size of disease deposits prior to RIT, intensity of TAG reactivity, the addition of unlabeled antibody, and the development of human anti-mouse antibody and/or serum sickness after murine antibody. A statistically significant improvement in progression-free survival (p≤0.05) was noted for less bulky disease and younger age. Administration of paclitaxel plus IFN, an immune response, and use of 90Y showed a favorable nonsignificant trend. Dose escalation of radionuclide did not change risk of progression; thus, this therapy may have therapeutic efficacy at modest dose levels. PMID:22239432

  17. Short-course R-CHOP followed by 90Y-Ibritumomab tiuxetan in previously untreated high-risk elderly diffuse large B-cell lymphoma patients: 7-year long-term results

    PubMed Central

    Stefoni, V; Casadei, B; Bottelli, C; Gaidano, G; Ciochetto, C; Cabras, M G; Ansuinelli, M; Argnani, L; Broccoli, A; Gandolfi, L; Pellegrini, C; Zinzani, P L

    2016-01-01

    An update at 7 years was conceived for our multicenter phase II study in which 55 elderly high-risk untreated diffuse large B-cell lymphoma patients were treated with 90Y-ibritumomab tiuxetan after a short course of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) as long-term follow-up analyses of this combined therapeutic modality are lacking. The overall response rate to the entire regimen was 80%, including 73% (40/55) of complete response (CR) rate and 7% (4/55) of partial response rate. At the time of writing, 24/55 (43.6%) patients experienced a progression disease and 20 of 40 (50%) patients who obtained a CR are still alive in continuous CR. With a median follow-up of 7 years, the disease-free survival was 43.3% and the progression-free survival was 36.1%. The overall survival at 7.9 years was 38.9% (27 deaths mainly because of lymphoma). Two patients developed secondary hematological malignancies, an acute myeloid leukemia and a myelodysplastic syndrome, at 4 and 3 years from radioimmunotherapy, respectively. Our data confirm the feasibility, efficacy and safety of four cycles of R-CHOP followed by radioimmunotherapy consolidation even in the long term: this combination allows dispensing less chemotherapy in a frail group of patients without invalidating response quality and duration. PMID:27176801

  18. Comparison of two different types of LiF:Mg,Cu,P thermoluminescent dosimeters for detection of beta rays (beta-TLDs) from 90Sr/90Y, 85Kr and 147Pm sources.

    PubMed

    Grassi, Elisa; Sghedoni, Roberto; Piccagli, Vando; Fioroni, Federica; Borasi, Giovanni; Iori, Mauro

    2011-05-01

    Targeted radionuclide therapies in nuclear medicine departments increasingly depend on using unsealed beta radiation sources in the labeling of peptides and antibodies. Monitoring doses received by the fingers and hands during these procedures is best accomplished with TLD dosimeters that can be located at the fingertips. The present study examines the response of two TLD dosimeters (MCP-Ns and GR200A) to 90Sr/90Y, 85Kr, and 147Pm. The dosimeters were supplied by two different services, and all irradiations were performed at the PTB Institute in Germany. Each dosimetry service evaluated the dosimeters without knowledge that they had been purposefully irradiated. The accuracy and precision of the dosimeters were evaluated as a function of delivered dose, energy of beta particles and angular incidence. The results are compared to performance measures recommended by the IEC. Both dosimeter types displayed significant energy dependence. Angular dependence was moderate. Accuracy and precision as a function of dose (linearity) differed between the two systems, with the MCP-Ns being noticeably better than the GR200A. The superior precision makes the MCP-Ns much more useful for extremity dose measurements. The differences between these two dosimeter systems reinforce the need to evaluate a dosimeter carefully before using it in the daily work routine. PMID:21451322

  19. Short-course R-CHOP followed by (90)Y-Ibritumomab tiuxetan in previously untreated high-risk elderly diffuse large B-cell lymphoma patients: 7-year long-term results.

    PubMed

    Stefoni, V; Casadei, B; Bottelli, C; Gaidano, G; Ciochetto, C; Cabras, M G; Ansuinelli, M; Argnani, L; Broccoli, A; Gandolfi, L; Pellegrini, C; Zinzani, P L

    2016-01-01

    An update at 7 years was conceived for our multicenter phase II study in which 55 elderly high-risk untreated diffuse large B-cell lymphoma patients were treated with (90)Y-ibritumomab tiuxetan after a short course of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) as long-term follow-up analyses of this combined therapeutic modality are lacking. The overall response rate to the entire regimen was 80%, including 73% (40/55) of complete response (CR) rate and 7% (4/55) of partial response rate. At the time of writing, 24/55 (43.6%) patients experienced a progression disease and 20 of 40 (50%) patients who obtained a CR are still alive in continuous CR. With a median follow-up of 7 years, the disease-free survival was 43.3% and the progression-free survival was 36.1%. The overall survival at 7.9 years was 38.9% (27 deaths mainly because of lymphoma). Two patients developed secondary hematological malignancies, an acute myeloid leukemia and a myelodysplastic syndrome, at 4 and 3 years from radioimmunotherapy, respectively. Our data confirm the feasibility, efficacy and safety of four cycles of R-CHOP followed by radioimmunotherapy consolidation even in the long term: this combination allows dispensing less chemotherapy in a frail group of patients without invalidating response quality and duration. PMID:27176801

  20. Influence of total-body mass on the scaling of S-factors for patient-specific, blood-based red-marrow dosimetry

    NASA Astrophysics Data System (ADS)

    Traino, A. C.; Ferrari, M.; Cremonesi, M.; Stabin, M. G.

    2007-09-01

    To perform patient-specific, blood-based red-marrow dosimetry, dose conversion factors (the S factors in the MIRD formalism) have to be scaled by patients' organ masses. The dose to red marrow includes both self-dose and cross-irradiation contributions. Linear mass scaling for the self-irradiation term only is usually applied as a first approximation, whereas the cross-irradiation term is considered to be mass independent. Recently, the need of a mass scaling correction on both terms, not necessarily linear and dependent on the radionuclide, has been highlighted in the literature. S-factors taking into account different mass adjustments of organs are available in the OLINDA/EXM code. In this paper, a general algorithm able to fit the mass-dependent factors Srm<--tb and Srm<--rm is suggested and included in a more general equation for red-marrow dose calculation. Moreover, parameters to be considered specifically for therapeutic radionuclides such as 131I, 90Y and 177Lu are reported. The red-marrow doses calculated by the traditional and new algorithms are compared for 131I in ablation therapy (14 pts), 177Lu- (13 pts) and 90Y- (11 pts) peptide therapy for neuroendocrine tumours, and 90Y-Zevalin therapy for NHL (21 pts). The range of differences observed is as follows: -36% to -10% for 131I ablation, -22% to 5% for 177Lu-DOTATATE, -9% to 11% for 90Y-DOTATOC and -8% to 6% for 90Y-Zevalin. All differences are mostly due to the activity in the remainder of the body contributing to cross-irradiation. This paper quantifies the influence of mass scaling adjustment on usually applied therapies and shows how to derive the appropriate parameters for other radionuclides and radiopharmaceuticals.

  1. Evaluation of S-values and dose distributions for {sup 90}Y, {sup 131}I, {sup 166}Ho, and {sup 188}Re in seven lobes of the rat liver

    SciTech Connect

    Xie Tianwu; Liu Qian; Zaidi, Habib

    2012-03-15

    Purpose: Rats have been widely used in radionuclide therapy research for the treatment of hepatocellular carcinoma (HCC). This has created the need to assess rat liver absorbed radiation dose. In most dose estimation studies, the rat liver is considered as a homogeneous integrated target organ with a tissue composition assumed to be similar to that of human liver tissue. However, the rat liver is composed of several lobes having different anatomical and chemical characteristics. To assess the overall impact on rat liver dose calculation, the authors use a new voxel-based rat model with identified suborgan regions of the liver. Methods: The liver in the original cryosectional color images was manually segmented into seven individual lobes and subsequently integrated into a voxel-based computational rat model. Photon and electron particle transport was simulated using the MCNPX Monte Carlo code to calculate absorbed fractions and S-values for {sup 90}Y, {sup 131}I, {sup 166}Ho, and {sup 188}Re for the seven liver lobes. The effect of chemical composition on organ-specific absorbed dose was investigated by changing the chemical composition of the voxel filling liver material. Radionuclide-specific absorbed doses at the voxel level were further assessed for a small spherical hepatic tumor. Results: The self-absorbed dose for different liver lobes varied depending on their respective masses. A maximum difference of 3.5% was observed for the liver self-absorbed fraction between rat and human tissues for photon energies below 100 keV. {sup 166}Ho and {sup 188}Re produce a uniformly distributed high dose in the tumor and relatively low absorbed dose for surrounding tissues. Conclusions: The authors evaluated rat liver radiation doses from various radionuclides used in HCC treatments using a realistic computational rat model. This work contributes to a better understanding of all aspects influencing radiation transport in organ-specific radiation dose evaluation for

  2. Relative Biologic Effects of Low-Dose-Rate {alpha}-Emitting {sup 227}Th-Rituximab and {beta}-Emitting {sup 90}Y-Tiuexetan-Ibritumomab Versus External Beam X-Radiation

    SciTech Connect

    Dahle, Jostein Bruland, Oyvind S.; Larsen, Roy H.

    2008-09-01

    Purpose: To determine the relative biologic effects (RBE) of {alpha}-particle radiation from {sup 227}Th-rituximab and of {beta}-radiation from {sup 90}Y-tiuexetan-ibritumomab (Zevalin) compared with external beam X-radiation in the Raji lymphoma xenograft model. Methods and Materials: Radioimmunoconjugates were administered intravenously in nude mice with Raji lymphoma xenografts at different levels of activity. Absorbed dose to tumor was estimated by separate biodistribution experiments for {sup 227}Th-rituximab and Zevalin. Tumor growth was measured two to three times per week after injection or X-radiation. Treatment-induced increase in growth delay to reach tumor volumes of 500 and 1,000 mm{sup 3}, respectively, was used as an end point. Results: The absorbed radiation dose-rate in tumor was slightly more than 0.1 Gy/d for the first week following injection of {sup 227}Th-rituximab, and thereafter gradually decreased to 0.03 Gy/d at 21 days after injection. For treatment with Zevalin the maximum dose-rate in tumor was achieved already 6 h after injection (0.2 Gy/d), and thereafter decreased to 0.01 Gy/d after 7 days. The relative biologic effect was between 2.5 and 7.2 for {sup 227}Th-rituximab and between 1 and 1.3 for Zevalin. Conclusions: Both at low doses and low-dose-rates, the {sup 227}Th-rituximab treatment was more effective per absorbed radiation dose unit than the two other treatments. The considerable effect at low doses suggests that the best way to administer low-dose-rates, {alpha}-emitting radioimmunoconjugates is via multiple injections.

  3. Complete Remission of Metastatic Neuroendocrine Paragastric Carcinoma After "Neoadjuvant" Peptide Receptor Radionuclide Therapy and Surgery.

    PubMed

    Schmidt, Matthias C; Uhrhan, Klara; Fischer, Thomas; Schmitz, Stephan; Markiefka, Birgid; Drzezga, Alexander; Stippel, Dirk

    2015-08-01

    A 48-year-old man presenting with upper abdominal pain was diagnosed with neuroendocrine tumor after biopsy of a paragastric mass with multiple liver metastases. (68)Ga-DOTATATE PET/CT showed intense uptake in the paragastric tumor and in multiple liver metastases not allowing primary surgery. Two cycles with cumulative 14.6 GBq (177)Lu-DOTATATE were given resulting in a considerable improvement. Subsequent surgery resulted in a complete remission as demonstrated by (68)Ga-DOTATATE PET/CT. Usually, peptide receptor radionuclide (PRRT) therapy is considered a palliative treatment. Few patients demonstrate a very favorable response allowing resection of the primary tumor after downstaging metastatic disease burden. PMID:26053706

  4. Reversal of Severe and Refractory Humoral Hypercalcemia With 177Lu-Octreotate Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumor of the Pancreas.

    PubMed

    Iliuta, Ioan-Andrei; Beauregard, Jean-Mathieu; Couture, Félix; Douville, Pierre; Mac-Way, Fabrice

    2015-09-01

    A 48-year-old Caucasian male patient with newly diagnosed neuroendocrine tumor of the pancreas with multiple liver metastases developed severe and refractory hypercalcemia. Complementary investigations were compatible with humoral hypercalcemia with high parathyroid hormone-related peptide (PTHrP) levels. Hypercalcemia was refractory to medical treatments for more than 2 years. Serum calcium returned to normal values only after 4 cycles of peptide receptor radionuclide therapy with Lu-octreotate, with concomitant reduction of PTHrP level and tumor regression. The use of radionuclide therapy could be an option for the management of severe humoral hypercalcemia in patients with inoperable metastatic pancreatic neuroendocrine tumor. PMID:26053724

  5. Resolution of Hyperreninemia, Secondary Hyperaldosteronism, and Hypokalemia With 177Lu-DOTATATE Induction and Maintenance Peptide Receptor Radionuclide Therapy in a Patient With Pancreatic Neuroendocrine Tumor.

    PubMed

    Makis, William; McCann, Karey; Riauka, Terence A; McEwan, Alexander J B

    2015-11-01

    A 54-year-old woman presented with a history of nausea, vomiting, diarrhea, and recurrent episodes of severe hypokalemia requiring hospitalization. Imaging revealed a pancreatic mass with liver metastases, histologically confirmed to be a neuroendocrine tumor. Elevated active renin and aldosterone levels were identified, and the patient was treated with 4 induction cycles of Lu-DOTATATE, which resolved the diarrhea, nausea, and hypokalemia, and normalized the renin and aldosterone levels. After 3 additional maintenance Lu-DOTATATE treatments, the pancreatic tumor had decreased in size, was deemed operable, and was resected. She remains on maintenance Lu-DOTATATE therapy with progression-free survival of 45 months thus far. PMID:26359564

  6. (99m)Tc HYNIC-TOC imaging and 177Lu DOTA-octreotate treatment in non-iodine-concentrating dedifferentiated thyroid carcinoma metastases: an unusual alternative diagnosis.

    PubMed

    Basu, Sandip; Joshi, Amit

    2014-07-01

    The value of Tc HYNIC-TOC scintigraphy clarifying skeletal and hepatic-predominant metastatic disease in a 55-year-old woman (diagnosed earlier to have papillary carcinoma thyroid and had undergone total thyroidectomy and radioiodine ablation) is illustrated. The whole-body radioiodine scan and battery of serum tumor markers were normal. Multiple metastatic foci in the liver and skeleton were Tc HYNIC-TOC avid. Serum chromogranin A level was substantially elevated (1771.60 ng/mL). This represents an unusual alternative diagnosis signified by a highly positive scan in the setting of apparent non-iodine-concentrating metastatic disease in a patient of differentiated thyroid carcinoma. PMID:24873792

  7. 4D SPECT/CT acquisition for 3D dose calculation and dose planning in (177)Lu-peptide receptor radionuclide therapy: applications for clinical routine.

    PubMed

    Kairemo, Kalevi; Kangasmäki, Aki

    2013-01-01

    Molecular radiotherapy combines the potential of a specific tracer (vector) targeting tumor cells with local radiotoxicity. Designing a specific tumor-targeting/killing combination is a tailoring process. Radionuclides with imaging capacity serve best in the selection of the targeting molecule. The potential of targeted therapy with radiolabeled peptides has been reported in many conditions; peptide receptor radionuclide therapy (PRRT) is already part of Scandinavian guidelines for treating neuroendocrine tumors. Lu-177- and Y-90-labeled somatostatin analogs, including DOTATOC, DOTANOC, and DOTATATE, are most the commonly used and have turned out to be effective. For routine use, an efficient, rapid, and reliable dose calculation tool is needed. In this chapter we describe how serial pre- and posttherapeutic scans can be used for dose calculation and for predicting therapy doses. Our software for radionuclide dose calculation is a three-dimensional, voxel-based system. The 3D dose calculation requires coregistered SPECT image sets from several time points after infusion to reconstruct time-activity curves for each voxel. Image registration is done directly by SPECT image registration using the first time point as a target. From the time-activity curves, initial activity and total half-life maps are calculated to produce a cumulated activity map. The cumulated activity map is then convoluted with a voxel-dose kernel to obtain a 3D dose map. We performed dose calculations similarly for both therapeutic and preplanning images. Preplanning dose was extrapolated to predict therapy dose using the ratio of administered activities. Our 3D dose calculation results are also compared with those of OLINDA. Our preliminary results indicate that dose planning using pretherapeutic scanning can predict critical organ and tumor doses. In some cases, the dose planning prediction resulted in slight, and slightly dose-dependent, overestimation of final therapy dose. Real tumor dose was similar in both pretherapeutic and posttherapeutic scans using our software. The OLINDA software and our program gave similar normal organ doses, whereas tumor doses could be calculated in a more detailed manner using the 3D program. PMID:22918781

  8. Lutetium-177 DOTATATE Production with an Automated Radiopharmaceutical Synthesis System

    PubMed Central

    Aslani, Alireza; Snowdon, Graeme M; Bailey, Dale L; Schembri, Geoffrey P; Bailey, Elizabeth A; Pavlakis, Nick; Roach, Paul J

    2015-01-01

    Objective(s): Peptide Receptor Radionuclide Therapy (PRRT) with yttrium-90 (90Y) and lutetium-177 (177Lu)-labelled SST analogues are now therapy option for patients who have failed to respond to conventional medical therapy. In-house production with automated PRRT synthesis systems have clear advantages over manual methods resulting in increasing use in hospital-based radiopharmacies. We report on our one year experience with an automated radiopharmaceutical synthesis system. Methods: All syntheses were carried out using the Eckert & Ziegler Eurotope’s Modular-Lab Pharm Tracer® automated synthesis system. All materials and methods used were followed as instructed by the manufacturer of the system (Eckert & Ziegler Eurotope, Berlin, Germany). Sterile, GMP-certified, no-carrier added (NCA) 177Lu was used with GMP-certified peptide. An audit trail was also produced and saved by the system. The quality of the final product was assessed after each synthesis by ITLC-SG and HPLC methods. Results: A total of 17 [177Lu]-DOTATATE syntheses were performed between August 2013 and December 2014. The amount of radioactive [177Lu]-DOTATATE produced by each synthesis varied between 10-40 GBq and was dependant on the number of patients being treated on a given day. Thirteen individuals received a total of 37 individual treatment administrations in this period. There were no issues and failures with the system or the synthesis cassettes. The average radiochemical purity as determined by ITLC was above 99% (99.8 ± 0.05%) and the average radiochemical purity as determined by HPLC technique was above 97% (97.3 ± 1.5%) for this period. Conclusions: The automated synthesis of [177Lu]-DOTATATE using Eckert & Ziegler Eurotope’s Modular-Lab Pharm Tracer® system is a robust, convenient and high yield approach to the radiolabelling of DOTATATE peptide benefiting from the use of NCA 177Lu and almost negligible radiation exposure of the operators. PMID:27408890

  9. Radiation exposure to nuclear medicine personnel handling positron emitters from Ge-68/Ga-68 generator

    PubMed Central

    Dwivedi, Durgesh Kumar; Snehlata; Dwivedi, Alok Kumar; Lochab, Satya Pal; Kumar, Rakesh; Naswa, Niraj; Sharma, Punit; Malhotra, Arun; Bandopadhayaya, Guru Pad; Bal, Chandrashekhar; Pant, Gauri Shankar

    2011-01-01

    Objective: To measure the radiation exposure to nuclear medicine personnel during synthesis and injection to the patients of Ga-68 1,4,7,10-tetraazacyclododecane-N,N′,N″,N″′-tetraacetic acid (DOTA)-1-Nal3-octreotide (NOC)- (DOTA-NOC) using ring thermoluminescence dosimeters (TLDs). Materials and Methods: Synthesis of Ga-68 DOTA-NOC was done on a semi-automated system. Finger doses were measured during synthesis and injection of Ga-68 DOTA-NOC. The occupational workers wore TLDs at the base of ring finger of both hands. The finger doses of two radio chemists were measured during synthesis of Ga-68 DOTA-NOC while that of a physician during its injection to the patients. Results: Duration of the study was eight months and a total of 20 samples were prepared. During synthesis, the mean dose to base of left ring finger was 3.02 ± 1.01 mSv and to base of right ring finger was 1.96 ± 0.86 mSv. Mean dose to base of left ring finger was 1.26 ± 0.35 mSv while that to base of right ring finger was 1.03 ± 0.13 mSv during injection. The mean dose was observed to be higher during synthesis than injection. However, the difference was not significant (P = 0.27 and P = 0.18, respectively). Overall mean finger dose of left hand was 2.43 ± 1.21 mSv, whereas for the right hand the same was 1.65± 0.82 mSv. Conclusion: Finger doses to radio chemists during semi-automated synthesis of Ga-68 DOTA-NOC and that to the physician involved in injection of Ga-68 DOTA-NOC were found to be within permissible limits. Ring dosimeters must be worn for the safety of the nuclear medicine personnel involved in synthesis and injection of Ga-68 DOTA-NOC. PMID:22174513

  10. 68Ga DOTATATE PET/CT of Synchronous Meningioma and Prolactinoma.

    PubMed

    Basu, Sandip; Ranade, Rohit; Hazarika, Suman

    2016-03-01

    Ga DOTATATE PET/CT in noninvasive characterization of synchronous pituitary neoplasm and meningioma in a 38-year-old man is illustrated. The patient presented with an MRI-detected lobulated enhancing sellar-suprasellar mass with erosion of bony sella measuring 4.5 × 3.5 × 3.4 cm (with differential diagnosis with germ cell tumor) and a right parafalcine mass (2.7 × 2.6 cm) suggesting meningioma. Ga DOTATATE PET/CT demonstrated intense uptake in both lesions, suggesting the sellar mass to be pituitary macroadenoma. The finding of high serum prolactin and normal LH, FSH, cortisol, and testosterone levels suggested diagnosis of prolactinoma, and the patient was started on cabergoline. PMID:26462040

  11. Schwannoma Showing Avid Uptake on 68Ga-PSMA-HBED-CC PET/CT.

    PubMed

    Kanthan, Gowri L; Izard, Michael A; Emmett, Louise; Hsiao, Edward; Schembri, Geoffrey Paul

    2016-09-01

    Ga prostate-specific membrane antigen (PSMA) PET/CT is a relatively new and highly sensitive imaging modality used in staging metastatic prostate cancer. We report a case of a 65-year-old man with newly diagnosed prostate carcinoma who had a PSMA PET/CT scan for staging of his disease. A PSMA-avid right pelvic mass was identified anterior to the sacrum. Surgical removal and histopathological examination of this lesion revealed the diagnosis of schwannoma. It is important to be aware that schwannoma may also show avid uptake on PSMA PET/CT scan and may potentially lead to an incorrect diagnosis of metastatic prostate carcinoma. PMID:27405039

  12. Follicular Lymphoma Showing Avid Uptake on 68Ga PSMA-HBED-CC PET/CT.

    PubMed

    Kanthan, Gowri L; Coyle, Luke; Kneebone, Andrew; Schembri, Geoffrey Paul; Hsiao, Edward

    2016-06-01

    Ga prostate-specific membrane antigen (PSMA) PET/CT is a new imaging technique that is significantly more sensitive to prostate cancer lesions than other conventional imaging modalities. Various other benign and malignant neoplasms may also express PSMA and show uptake on PSMA PET/CT scan. We report a case of 66-year-old man who had a PSMA PET/CT scan for restaging of prostate carcinoma. A PSMA-avid left femoral lymph node was identified. Subsequent biopsy confirmed the diagnosis of follicular lymphoma. It is important to be aware of this possibility to avoid scan misinterpretation. Biopsy of any atypical or clinically unexpected lesions should be considered. PMID:26914565

  13. Widespread Metastatic Prostate Carcinoma Shown by 68Ga-PSMA PET/CT.

    PubMed

    Soydal, Cigdem; Ozkan, Elgin; Yerlikaya, Halis; Utkan, Gungor; Kucuk, Ozlem Nuriye

    2016-06-01

    We present the F-FDG and Ga prostate-specific membrane antigen PET/CT images of a 61-year-old patient with a newly diagnosed prostate carcinoma (4 + 4 Gleason score) and high serum prostate-specific antigen levels (460 ng/mL). In F-FDG PET/CT, minimal uptake was demonstrated in the prostatic mass without any accompanying pathological uptake. However, Ga prostate-specific membrane antigen PET/CT revealed multiple pathological uptake in the lung nodules, mediastinal nodes, abdominal-pelvic lymph nodes, bone lesions, and prostatic mass. PMID:26909710

  14. Desmoid Tumor Showing Intense Uptake on 68Ga PSMA-HBED-CC PET/CT.

    PubMed

    Kanthan, Gowri L; Hsiao, Edward; Kneebone, Andrew; Eade, Thomas; Schembri, Geoffrey Paul

    2016-06-01

    Ga-PSMA PET/CT is a new imaging technique that is highly sensitive to metastatic prostate cancer lesions compared with other conventional imaging modalities. We report a case of a 77-year-old man with newly diagnosed prostate carcinoma who had a PSMA PET/CT scan for staging of his disease. An intensely PSMA-avid right pelvic mass was identified abutting the cecum and terminal ileum. Surgical removal and histopathologic examination of this lesion revealed the diagnosis of a desmoid tumor. It is important to be aware that many tumors other than prostate carcinoma may also show avid uptake on PSMA PET/CT scan. PMID:26909712

  15. 68Ga Prostate-Specific Membrane Antigen Uptake in Renal Cell Cancer Lymph Node Metastases.

    PubMed

    Einspieler, Ingo; Tauber, Robert; Maurer, Tobias; Schwaiger, Markus; Eiber, Matthias

    2016-05-01

    Ga prostate-specific membrane antigen (PSMA)-HBED-CC PET/CT in a patient with a history of both prostate cancer (PC) and renal cell cancer (RCC) shows high PSMA expression in the residual right seminal vesicle suggestive of local recurrence of PC as well as suspected PSMA-positive mediastinal, retroperitoneal, and iliac lymph nodes. Regarding the latter, biopsy revealed lymph node metastases from RCC excluding PC metastases. This case exemplarily demonstrates that high PSMA expression in RCC metastases can potentially mimic PC metastases. Thus, for accurate interpretation of imaging results in PC patients with additional primary tumors, knowledge of PSMA expression of non-PC tissue is necessary. PMID:26859205

  16. 68Ga-DOTATATE Breast Uptake and Expression in Breast Milk.

    PubMed

    Forwood, Nicholas J; Kanthan, Gowri L; Bailey, Dale L; Chan, David L; Schembri, Geoffrey P

    2016-08-01

    The excretion of Ga-DOTA-Octreotate (DOTATATE) and related somatostatin analogues in breast milk has not been demonstrated. We report a case of a 34-year-old woman, 7 months postpartum and breastfeeding, who was referred for DOTATATE imaging after the diagnosis of appendiceal carcinoid and subsequent appendectomy. Prominent breast uptake was noted. A breast milk sample from the patient at 90 minutes postinjection was assayed in a gamma counter and shown to have a concentration of 5.6 Bq/g per MBq administered. The excretion of DOTATATE in breast milk is important to consider when providing radiation safety advice to breastfeeding patients. PMID:27276203

  17. Radiolabeled Somatostatin Analogue Therapy Of Gastroenteropancreatic Cancer.

    PubMed

    Bodei, Lisa; Kwekkeboom, Dik J; Kidd, Mark; Modlin, Irvin M; Krenning, Eric P

    2016-05-01

    Peptide receptor radionuclide therapy (PRRT) has been utilized for more than two decades and has been accepted as an effective therapeutic modality in the treatment of inoperable or metastatic gastroenteropancreatic neuroendocrine neoplasms (NENs) or neuroendocrine tumors (NETs). The two most commonly used radiopeptides for PRRT, (90)Y-octreotide and (177)Lu-octreotate, produce disease-control rates of 68%-94%, with progression-free survival rates that compare favorably with chemotherapy, somatostatin analogues, and newer targeted therapies. In addition, biochemical and symptomatic responses are commonly observed. In general, PRRT is well tolerated with only low to moderate toxicity in most individuals. In line with the need to place PRRT in the therapeutic sequence of gastroenteropancreatic NENs, a recently sponsored phase III randomized trial in small intestine NENs treated with (177)Lu-octreotate vs high-dose octreotide long-acting release demonstrated that (177)Lu-octreotate significantly improved progression-free survival. Other strategies that are presently being developed include combinations with targeted therapies or chemotherapy, intra-arterial PRRT, and salvage treatments. Sophisticated molecular tools need to be incorporated into the management strategy to more effectively define therapeutic efficacy and for an early identification of adverse events. The strategy of randomized controlled trials is a key issue to standardize the treatment and establish the position of PRRT in the therapeutic algorithm of NENs. PMID:27067503

  18. First-line treatment with rituximab-hyperCVAD alternating with rituximab-methotrexate-cytarabine and followed by consolidation with 90Y-ibritumomab-tiuxetan in patients with mantle cell lymphoma. Results of a multicenter, phase 2 pilot trial from the GELTAMO group

    PubMed Central

    Arranz, Reyes; García-Noblejas, Ana; Grande, Carlos; Cannata-Ortiz, Jimena; Sánchez, José J.; García-Marco, José-Antonio; Aláez, Concepción; Pérez-Calvo, Javier; Martínez-Sánchez, Pilar; Sánchez-González, Blanca; Canales, Miguel-Angel; Conde, Eulogio; Martín, Alejandro; Arranz, Eva; Terol, María-José; Salar, Antonio; Caballero, Dolores

    2013-01-01

    The prognosis for fit patients with mantle cell lymphoma has improved with intensive strategies. Currently, the role of maintenance/consolidation approaches is being tested as relapses continue to appear. In this trial we evaluated the feasibility, safety and efficacy of rituximab-hyperCVAD alternating with rituximab-methotrexate-cytarabine followed by consolidation with 90Y-ibritumomab tiuxetan. Patients received six cycles followed by a single dose of 90Y-ibritumomab tiuxetan. Thirty patients were enrolled; their median age was 59 years. Twenty-four patients finished the induction treatment, 23 achieved complete remission (77%, 95% confidence interval 60–93) and one patient had progressive disease (3%). Eighteen patients (60%), all in complete remission, received consolidation therapy. In the intent-to-treat population, failure-free, progression-free and overall survival rates at 4 years were 40% (95% confidence interval 20.4–59.6), 52% (95% confidence interval 32.4–71.6) and 81% (95% confidence interval 67.28–94.72), respectively. For patients who received consolidation, failure-free and overall survival rates were 55% (95% confidence interval 31.48–78.52) and 87% (95% confidence interval 70–100), respectively. Hematologic toxicity was significant during induction and responsible for one death (3.3%). After consolidation, grade 3–4 neutropenia and thrombocytopenia were observed in 72% and 83% of patients, with a median duration of 5 and 12 weeks, respectively. Six (20%) patients died, three due to secondary malignancies (myelodysplastic syndrome and bladder and rectum carcinomas). In conclusion, in our experience, rituximab-hyperCVAD alternated with rituximab-methotrexate-cytarabine and followed by consolidation with 90Y-ibritumomab tiuxetan was efficacious although less feasible than expected. The unacceptable toxicity observed, especially secondary malignancies, advise against the use of this strategy. Trial registration: clinical.gov identifier

  19. Comparative analysis of 11 different radioisotopes for palliative treatment of bone metastases by computational methods

    SciTech Connect

    Guerra Liberal, Francisco D. C. E-mail: adriana-tavares@msn.com; Tavares, Adriana Alexandre S. E-mail: adriana-tavares@msn.com; Tavares, João Manuel R. S.

    2014-11-01

    Purpose: Throughout the years, the palliative treatment of bone metastases using bone seeking radiotracers has been part of the therapeutic resources used in oncology, but the choice of which bone seeking agent to use is not consensual across sites and limited data are available comparing the characteristics of each radioisotope. Computational simulation is a simple and practical method to study and to compare a variety of radioisotopes for different medical applications, including the palliative treatment of bone metastases. This study aims to evaluate and compare 11 different radioisotopes currently in use or under research for the palliative treatment of bone metastases using computational methods. Methods: Computational models were used to estimate the percentage of deoxyribonucleic acid (DNA) damage (fast Monte Carlo damage algorithm), the probability of correct DNA repair (Monte Carlo excision repair algorithm), and the radiation-induced cellular effects (virtual cell radiobiology algorithm) post-irradiation with selected particles emitted by phosphorus-32 ({sup 32}P), strontium-89 ({sup 89}Sr), yttrium-90 ({sup 90}Y ), tin-117 ({sup 117m}Sn), samarium-153 ({sup 153}Sm), holmium-166 ({sup 166}Ho), thulium-170 ({sup 170}Tm), lutetium-177 ({sup 177}Lu), rhenium-186 ({sup 186}Re), rhenium-188 ({sup 188}Re), and radium-223 ({sup 223}Ra). Results: {sup 223}Ra alpha particles, {sup 177}Lu beta minus particles, and {sup 170}Tm beta minus particles induced the highest cell death of all investigated particles and radioisotopes. The cell survival fraction measured post-irradiation with beta minus particles emitted by {sup 89}Sr and {sup 153}Sm, two of the most frequently used radionuclides in the palliative treatment of bone metastases in clinical routine practice, was higher than {sup 177}Lu beta minus particles and {sup 223}Ra alpha particles. Conclusions: {sup 223}Ra and {sup 177}Lu hold the highest potential for palliative treatment of bone metastases of all

  20. The determination of the rate of conjugation immunoglobuline with bifunctional chelator

    NASA Astrophysics Data System (ADS)

    Málek, Z.; Miler, V.; Budský, F.

    2006-01-01

    The work was performed under the GACR project: "Technology of preparation of radionuclides and their labelled compounds for nuclear medicine and pharmacy with the use of the reactor LVR-15" reg. no. 104/03/0499. Imaging of cell’s antigens with the use of labelled immunoglobulines allows imaging of specific receptors on cell membrane and specific tumours. It is necessary to carry out the labelling of the immunoglobulines with radionuclides of suitable physical properties, which form cations (e.g., 111In, 90Y, 177Lu) that form very strong chelates of sufficiently high stability constant preventing the dissociation of complexes or the radionuclide under “in-vivo” conditions. The immunoglobuline must be conjugated with the bifunctional chelator (BCH), which contains both chelating unit and reactive group for binding to the immunoglobuline. In our laboratory we have conjugated human IgG and monoclonal antibody CD20 with diethylenetriamine pentaacetic acid dianhydride (cDTPAA). Radionuclides 90Y and 177Lu prepared on the LVR-15 reactor in NRI Rez were used for labelling. After conjugation and labelling the yields in relation to the amount of isotopic carrier have been determined.

  1. A preclinical simulated dataset of S-values and investigation of the impact of rescaled organ masses using the MOBY phantom.

    PubMed

    Kostou, Theodora; Papadimitroulas, Panagiotis; Loudos, George; Kagadis, George C

    2016-03-21

    Nuclear medicine and radiation therapy, although well established, are still rapidly evolving, by exploiting animal models, aiming to define precise dosimetry in molecular imaging protocols. The purpose of the present study was to create a dataset based on the MOBY phantom for the calculation of organ-to-organ S-values of commonly used radionuclides. S-values of most crucial organs were calculated using specific biodistributions with a whole-body heterogeneous source. In order to determine the impact of the varying organs' size on the S-values, and based on the fact that the anatomic properties of the organs are correlated with S-values, dosimetric calculations were performed by simulating the MOBY-version 2 model with different whole-body masses. The GATE Monte Carlo simulation toolkit was used for all simulations. Two mouse models of different body masses were developed to calculate the S-values of eight commonly used radioisotopes in nuclear imaging studies, namely (18)F, (68)Ga, (131)I, (111)In, (177)Lu, and (99m)Tc, (90)Y and (188)Re. The impact of modified mass of the source organs in S-values was investigated with (18)F, and (90)Y in five different scalings of the source organs. Based on realistic preclinical exams, three mouse models, 22, 28 and 34 g, were used as input in the GATE simulator based on realistic preclinical exams to calculate the S-values of the six radioisotopes used. Whole body activity distributions were used as the source organ. The simulation procedure was validated in terms of extracting individual organ-to-organ S-values, and consequently in calculating the new S-values using a heterogeneous activity distribution as a source. The calculation was validated with (18)F source in a 30 g mouse model. For the generation of the new S-values with heterogeneous activity sources, four organs were used for the calculation of a single S-value. The absorbed doses per organ were compared with previously published reports. The validation

  2. A preclinical simulated dataset of S-values and investigation of the impact of rescaled organ masses using the MOBY phantom

    NASA Astrophysics Data System (ADS)

    Kostou, Theodora; Papadimitroulas, Panagiotis; Loudos, George; Kagadis, George C.

    2016-03-01

    Nuclear medicine and radiation therapy, although well established, are still rapidly evolving, by exploiting animal models, aiming to define precise dosimetry in molecular imaging protocols. The purpose of the present study was to create a dataset based on the MOBY phantom for the calculation of organ-to-organ S-values of commonly used radionuclides. S-values of most crucial organs were calculated using specific biodistributions with a whole-body heterogeneous source. In order to determine the impact of the varying organs’ size on the S-values, and based on the fact that the anatomic properties of the organs are correlated with S-values, dosimetric calculations were performed by simulating the MOBY-version 2 model with different whole-body masses. The GATE Monte Carlo simulation toolkit was used for all simulations. Two mouse models of different body masses were developed to calculate the S-values of eight commonly used radioisotopes in nuclear imaging studies, namely 18F, 68Ga, 131I, 111In, 177Lu, and 99mTc, 90Y and 188Re. The impact of modified mass of the source organs in S-values was investigated with 18F, and 90Y in five different scalings of the source organs. Based on realistic preclinical exams, three mouse models, 22, 28 and 34 g, were used as input in the GATE simulator based on realistic preclinical exams to calculate the S-values of the six radioisotopes used. Whole body activity distributions were used as the source organ. The simulation procedure was validated in terms of extracting individual organ-to-organ S-values, and consequently in calculating the new S-values using a heterogeneous activity distribution as a source. The calculation was validated with 18F source in a 30 g mouse model. For the generation of the new S-values with heterogeneous activity sources, four organs were used for the calculation of a single S-value. The absorbed doses per organ were compared with previously published reports. The validation procedure of 18F indicates

  3. Linker Modification Strategies To Control the Prostate-Specific Membrane Antigen (PSMA)-Targeting and Pharmacokinetic Properties of DOTA-Conjugated PSMA Inhibitors.

    PubMed

    Benešová, Martina; Bauder-Wüst, Ulrike; Schäfer, Martin; Klika, Karel D; Mier, Walter; Haberkorn, Uwe; Kopka, Klaus; Eder, Matthias

    2016-03-10

    Since prostate-specific membrane antigen (PSMA) is up-regulated in nearly all stages of prostate cancer (PCa), PSMA can be considered as a viable diagnostic biomarker and treatment target in PCa. This project is focused on the development and evaluation of a series of compounds directed against PSMA. The modifications to the linker are designed to improve the binding potential and pharmacokinetics for theranostic application. In addition, the results help to further elucidate the structure-activity relationships (SAR) of the resulting PSMA inhibitors. Both in vitro and in vivo experiments of 18 synthesized PSMA inhibitor variants showed that systematic chemical modification of the linker has a significant impact on the tumor-targeting and pharmacokinetic properties. This approach can lead to an improved management of patients suffering from recurrent prostate cancer by the use of one radiolabeling precursor, which can be radiolabeled either with (68)Ga for diagnosis or with (177)Lu or (225)Ac for therapy. PMID:26878194

  4. Radioembolization with {sup 90}Y Microspheres: Angiographic and Technical Considerations

    SciTech Connect

    Lewandowski, Robert J.; Sato, Kent T.; Atassi, Bassel; Ryu, Robert K.; Nemcek, Albert A.; Kulik, Laura; Geschwind, Jean-Francois; Murthy, Ravi; Rilling, William; Liu, David; Bilbao, Jose Ignacio; Kennedy, Andrew S.; Omary, Reed A.; Salem, Riad

    2007-07-15

    The anatomy of the mesenteric system and the hepatic arterial bed has been demonstrated to have a high degree of variation. This is important when considering pre-surgical planning, catheterization, and trans-arterial hepatic therapies. Although anatomical variants have been well described, the characterization and understanding of regional hepatic perfusion in the context of radioembolization have not been studied with great depth. The purpose of this review is to provide a thorough discussion and detailed presentation of the angiographic and technical aspects of radioembolization. Normal vascular anatomy, commonly encountered variants, and factors involved in changes to regional perfusion in the presence of liver tumors are discussed. Furthermore, the principles described here apply to all liver-directed transarterial therapies.

  5. Radionuclide therapy in neuroendocrine tumours: a systematic review.

    PubMed

    Gulenchyn, K Y; Yao, X; Asa, S L; Singh, S; Law, C

    2012-05-01

    The purpose of this systematic review was to investigate the effects of therapeutic radiopharmaceuticals in patients with different types of advanced neuroendocrine tumour (NETs). A literature search was carried out in MEDLINE and EMBASE from January 1998 to November 2010. The Cochrane Library (to Issue 10, 2010) and the Standards and Guidelines Evidence Inventory of Cancer Guidelines, including over 1100 English-language cancer guidelines from January 2003 to June 2010, were also checked. No existing systematic reviews or clinical practice guidelines based on a systematic review or randomised controlled trials focusing on this topic were found. Twenty-four fully published articles were abstracted and summarised: 16 articles focused on five peptide receptor radionuclide therapy ((111)In-DTPAOC, (90)Y-DOTALAN, (90)Y-DOTATOC, (90)Y-DOTATATE, and (177)Lu-DOTATATE) and eight focused on (131)I-MIBG treatment. Limited evidence from a historical comparison of studies in one centre supported that (177)Lu-DOTATATE might be associated with greater clinical outcomes compared with (90)Y-DOTATOC or (111)In-DTPAOC. The severe toxicities for (177)Lu-DOTATATE included hepatic insufficiency in 0.6%, myelodysplastic syndrome in 0.8% and renal insufficiency in 0.4% of patients in this study. Insufficient evidence suggested efficacy of (131)I-MIBG in adult NET patients, but the overall tumour response rate from (131)I-MIBG was 27-75% for malignant neuroblastoma, paraganglioma or pheochromocytoma. Haematological toxicities were the main severe side-effects after (131)I-MIBG and 4% of patients developed secondary malignancies in one study. To date, peptide receptor radionuclide therapy seems to be an acceptable option and is relatively safe in adult advanced NET patients with receptor uptake positive on scintigraphy, but patients' renal function must be monitored. (131)I-MIBG may be effective for malignant neuroblastoma, paraganglioma or pheochromocytoma, but its side-effects need to be

  6. Efficacy of 68Ga-DOTATOC Positron Emission Tomography (PET) CT in Children and Young Adults With Brain Tumors

    ClinicalTrials.gov

    2016-09-07

    Acoustic Schwannoma; Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Meningioma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Choroid Plexus Tumor; Adult Craniopharyngioma; Adult Diffuse Astrocytoma; Adult Ependymoblastoma; Adult Ependymoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Grade I Meningioma; Adult Grade II Meningioma; Adult Medulloblastoma; Adult Meningeal Hemangiopericytoma; Adult Mixed Glioma; Adult Myxopapillary Ependymoma; Adult Oligodendroglioma; Adult Papillary Meningioma; Adult Pilocytic Astrocytoma; Adult Pineal Gland Astrocytoma; Adult Pineoblastoma; Adult Pineocytoma; Adult Subependymal Giant Cell Astrocytoma; Adult Subependymoma; Adult Supratentorial Primitive Neuroectodermal Tumor (PNET); Childhood Choroid Plexus Tumor; Childhood Craniopharyngioma; Childhood Ependymoblastoma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood High-grade Cerebellar Astrocytoma; Childhood High-grade Cerebral Astrocytoma; Childhood Infratentorial Ependymoma; Childhood Low-grade Cerebellar Astrocytoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Medulloepithelioma; Childhood Supratentorial Ependymoma; Meningeal Melanocytoma; Newly Diagnosed Childhood Ependymoma; Recurrent Adult Brain Tumor; Recurrent Childhood Anaplastic Astrocytoma; Recurrent Childhood Anaplastic Oligoastrocytoma; Recurrent Childhood Anaplastic Oligodendroglioma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Diffuse Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Fibrillary Astrocytoma; Recurrent Childhood Gemistocytic Astrocytoma; Recurrent Childhood Giant Cell Glioblastoma; Recurrent Childhood Glioblastoma; Recurrent Childhood Gliomatosis Cerebri; Recurrent Childhood Gliosarcoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Oligoastrocytoma; Recurrent Childhood Oligodendroglioma; Recurrent Childhood Pilocytic Astrocytoma; Recurrent Childhood Pilomyxoid Astrocytoma; Recurrent Childhood Pineoblastoma; Recurrent Childhood Pleomorphic Xanthoastrocytoma; Recurrent Childhood Protoplasmic Astrocytoma; Recurrent Childhood Subependymal Giant Cell Astrocytoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Recurrent Childhood Visual Pathway Glioma; Untreated Childhood Anaplastic Astrocytoma; Untreated Childhood Anaplastic Oligodendroglioma; Untreated Childhood Brain Stem Glioma; Untreated Childhood Cerebellar Astrocytoma; Untreated Childhood Cerebral Astrocytoma; Untreated Childhood Diffuse Astrocytoma; Untreated Childhood Fibrillary Astrocytoma; Untreated Childhood Gemistocytic Astrocytoma; Untreated Childhood Giant Cell Glioblastoma; Untreated Childhood Glioblastoma; Untreated Childhood Gliomatosis Cerebri; Untreated Childhood Gliosarcoma; Untreated Childhood Medulloblastoma; Untreated Childhood Oligoastrocytoma; Untreated Childhood Oligodendroglioma; Untreated Childhood Pilocytic Astrocytoma; Untreated Childhood Pilomyxoid Astrocytoma; Untreated Childhood Pineoblastoma; Untreated Childhood Pleomorphic Xanthoastrocytoma; Untreated Childhood Protoplasmic Astrocytoma; Untreated Childhood Subependymal Giant Cell Astrocytoma; Untreated Childhood Supratentorial Primitive Neuroectodermal Tumor; Untreated Childhood Visual Pathway and Hypothalamic Glioma; Untreated Childhood Visual Pathway Glioma

  7. Elevated 68Ga Prostate-Specific Membrane Antigen Activity in Metastatic Non-Small Cell Lung Cancer.

    PubMed

    Shetty, Deepa; Loh, Han; Bui, Chuong; Mansberg, Robert; Stevanovic, Amanda

    2016-05-01

    A 71-year-old man with a background of treated stage IIIB non-small cell lung cancer was referred for Ga prostate-specific membrane antigen (PSMA) PET/CT for staging of prostate cancer. In addition to the PSMA uptake in the known prostate malignancy, the study also demonstrated increased PSMA uptake in an enlarging left lower lobe lung mass with diffusely increased PSMA uptake in an enlarged thyroid gland and bilateral enlarged supraclavicular lymph nodes. Fine-needle aspiration biopsy of the thyroid gland and a left supraclavicular lymph node demonstrated metastatic adenocarcinoma from a primary lung cancer. PMID:26828144

  8. Metastatic Renal Cell Carcinoma in the Thyroid Gland and Pancreas Showing Uptake on 68Ga DOTATATE PET/CT Scan.

    PubMed

    Kanthan, Gowri L; Schembri, Geoffrey Paul; Samra, Jaswinder; Roach, Paul; Hsiao, Edward

    2016-07-01

    Ga DOTATATE PET/CT is an imaging technique used in the diagnosis of neuroendocrine tumors. We report a case of 66-year-old woman with a history of surgically removed renal cell carcinoma who presented for a DOTATATE PET/CT scan to characterize a newly diagnosed pancreatic lesion. DOTATATE-avid lesions were identified in the thyroid gland and pancreas. Subsequent biopsy confirmed the diagnosis of metastatic renal cell carcinoma at both sites. It is important to be aware that tumors other than neuroendocrine tumors may also show uptake on DOTATATE PET/CT scan. A biopsy may be required if lesions are identified at atypical sites. PMID:27055137

  9. Clinical Impact of 68Ga-PSMA PET/CT in a Patient With Biochemical Recurrence of Prostate Cancer.

    PubMed

    Queiroz, Marcelo A; Viana, Publio; Santos, Allan; Bastos, Diogo; Etchebehere, Elba; Cerri, Giovanni

    2016-09-01

    A 64-year-old man with history of prostate adenocarcinoma underwent radical prostatectomy in 2003. He remained with undetectable prostate-specific antigen (PSA) levels until 2014, when he then presented rising serum PSA levels and performed a Tc-MDP bone scan that was negative for metastases. In August 2015, his PSA was 4.89 ng/dL, and restaging images with pelvic MR and F-FDG PET/CT were both negative. Therefore, the patient underwent a Ga-PSMA PET/CT that showed marked tracer uptake in a single mediastinal lymph node. Histopathology demonstrated metastatic adenocarcinoma secondary to prostate cancer, altering patient management to hormone therapy instead of pelvic radiotherapy. PMID:27276202

  10. 68Ga-PSMA PET/CT Imaging and 153Sm-EDTMP Bone Pain Palliation Therapy.

    PubMed

    Sasikumar, Arun; Joy, Ajith; Nanabala, Raviteja; Pillai, M R A; Thomas, Boben

    2016-07-01

    Ga-labeled prostate-specific membrane antigen (PSMA) is a potential tool in the imaging of recurrent prostate cancer. Ga-PSMA imaging is also useful for radiotherapy planning and in targeted therapy with Lu-PSMA. A few case reports regarding the use of Ga-PSMA in nonprostate cancer malignancies are also reported. We describe the use of Ga-PSMA imaging before Sm-EDTMP bone pain palliation therapy in a 58-year-old hormone refractory prostate cancer patient with extensive bone metastases. PMID:27055142

  11. Healing Sacral Fracture Masquerading as Metastatic Bone Disease on a 68Ga-PSMA PET/CT.

    PubMed

    Gykiere, Pieterjan; Goethals, Lode; Everaert, Hendrik

    2016-07-01

    Prostate-specific membrane antigen (PSMA) is a cell surface glycoprotein, which is frequently overexpressed on prostate cancer cells. A Ga-PSMA PET/CT can be used for early detection of lymph node or bone metastases after radical prostatectomy when there is biochemical recurrence. This report describes PSMA uptake in a healing fracture masquerading as metastatic bone disease in a patient with a history of prostate adenocarcinoma. Clinicians reporting Ga-PSMA PET/CT should be aware of this potential important pitfall. PMID:27055135

  12. Detection of Sarcomatoid Lung Metastasis With 68GA-PSMA PET/CT in a Patient With Prostate Cancer.

    PubMed

    Geraldo, Llanos; Ceci, Francesco; Uprimny, Christian; Kendler, Dorota; Virgolini, Irene

    2016-05-01

    A 70-year-old man with prostate cancer (adenocarcinoma; pT3aN0Mx; GS: 4 + 4) underwent radical prostatectomy and lymph node dissection in February 2008. In December 2009, biochemical recurrence occurred and prostate-specific antigen progressively increased to 4.63 ng/mL despite local salvage radiotherapy and androgen deprivation. Ga-PSMA PET/CT showed a positive left iliac lymph node and a pathological left pulmonary lesion, which was highly positive in a subsequent F-FDG PET/CT. Lymph node resection confirmed an adenocarcinoma metastasis of the prostate cancer and lung surgery demonstrated a sarcomatoid metastasis of prostate cancer. After surgery, prostate-specific antigen decreased to 0.03 ng/mL. PMID:26859209

  13. Schmorl Nodes Can Cause Increased 68Ga DOTATATE Activity on PET/CT, Mimicking Metastasis in Patients With Neuroendocrine Malignancy.

    PubMed

    Papadakis, Georgios Z; Millo, Corina; Bagci, Ulas; Sadowski, Samira M; Stratakis, Constantine A

    2016-03-01

    Schmorl node (SN) is the herniation of the nucleus pulposus through the cartilaginous and bony endplate into the adjacent vertebral body. It is documented that SNs produce areas of moderately increased F-FDG uptake. We present a case of a patient with history of neuroendocrine tumor, who underwent Ga DOTATATE PET/CT for follow-up, showing increased focal vertebral uptake suggestive of bone metastasis. CT revealed typical findings of an SN. The presented case indicates that SNs should be considered when encountering focally increased skeletal uptake in Ga DOTATATE PET/CT studies, which can mimic metastasis in patients with history of neuroendocrine tumors. PMID:26562580

  14. Estimated human absorbed dose of ¹⁷⁷Lu-BPAMD based on mice data: Comparison with ¹⁷⁷Lu-EDTMP.

    PubMed

    Yousefnia, Hassan; Zolghadri, Samaneh; Shanehsazzadeh, Saeed

    2015-10-01

    In this work, the absorbed dose of human organs for (177)Lu-BPAMD was evaluated based on biodistribution studies into the Syrian mice by RADAR method and was compared with (177)Lu-EDTMP as the only clinically used Lu-177 bone-seeking agent. The highest absorbed dose for both (177)Lu-BPAMD and (177)Lu-EDTMP is observed on the bone surface with 8.007 and 4.802 mSv/MBq. Generally, (177)Lu-BPAMD has considerable characteristics compared with (177)Lu-EDTMP and can be considered as a promising agent for the bone pain palliation therapy. PMID:26163291

  15. Resolution of Malignant Ascites and Stabilization of Metastases in a Patient With Small Bowel Neuroendocrine Tumor With 177Lu-DOTATATE Following Progression After 17 131I-MIBG Treatments and Chemotherapy.

    PubMed

    Makis, William; McCann, Karey; Buteau, Francois A; McEwan, Alexander J B

    2015-07-01

    A 39-year-old man diagnosed with a small bowel neuroendocrine tumor metastatic to the liver, lymph nodes, and bones achieved stable disease with ¹³¹I-MIBG therapy totalling 17 treatments over 9 years (cumulative dose of 1.9 Ci). His disease progressed after the 17th ¹³¹I-MIBG treatment, and he went on to fail chemotherapy, developing severe ascites requiring up to 8 L of weekly paracentesis. He was referred for ¹⁷⁷Lu-[DOTA⁰,Tyr³]octreotate (DOTATATE) therapy, and after 4 induction cycles, his ascites resolved completely, and his metastatic disease stabilized. ¹⁷⁷Lu-DOTATATE may be useful in patients with an extensive history of radioisotope therapy with ¹³¹I-MIBG. PMID:25546192

  16. Current Status of Nuclear Medicine Practice in the Middle East.

    PubMed

    Paez, Diana; Becic, Tarik; Bhonsle, Uday; Jalilian, Amir R; Nuñez-Miller, Rodolfo; Osso, Joao Alberto

    2016-07-01

    availability of (68)Ge-(68)Ga generators is increasing and studies involving prostate-specific membrane antigen or DOTA-chelated peptides or both are performed in at least seven countries. Although therapeutic radionuclide agents are mostly imported from outside the region, this does not limit the availability of therapies with (90)Y, (153)Sm, (177)Lu, (131)I, (188)Re, and (89)Sr. Nevertheless, therapies based on alpha particle emitters are still largely not available in the region and are currently only available in Israel and Turkey. Regarding human resources, according to the data provided there are 1157 NM physicians, 1953 technologists, 586 medical physicists, and 173 radiopharmacists or radiochemists in the region. Approximately half of all available human resources are accounted for by Turkey. The region has great potential for expanding the applications of NM; this becomes especially important in view of the high prevalence of non-communicable diseases. Further increasing awareness of the clinical applications of NM in healthcare and strengthening technical and human capacities including the establishment of training programs for all professionals and disciplines in the field are recognized as key components in advancing the practice of NM in the Middle East. PMID:27237437

  17. Preclinical evaluation of multistep targeting of diasialoganglioside GD2 using a IgG-scFv bispecific antibody with high affinity for GD2 and DOTA metal complex

    PubMed Central

    Cheal, Sarah M.; Xu, Hong; Guo, Hong-fen; Zanzonico, Pat B.; Larson, Steven M.; Cheung, Nai-Kong

    2014-01-01

    Bispecific antibodies (BsAb) have proven to be useful targeting vectors for pretargeted radioimmunotherapy (PRIT). We sought to overcome key PRIT limitations such as high renal radiation exposure and immunogenicity (e.g. of streptavidin-antibody fusions), to advance clinical translation of this PRIT strategy for diasialoganglioside GD2-positive (GD2(+)) tumors. For this purpose, a IgG-scFv BsAb was engineered using the sequences for the anti-GD2 humanized monoclonal antibody hu3F8 (1) and C825, a murine scFv antibody with high affinity for the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) complexed with beta-particle emitting radiometals such as 177Lu and 90Y (2, 3). A three-step regimen including hu3F8-C825, a dextran-based clearing agent, and p-aminobenzyl-DOTA radiolabeled with 177Lu (as 177Lu-DOTA-Bn; t1/2 = 6.71 days (d)) was optimized in immunocompromised mice carrying subcutaneous (s.c.) human GD2(+) neuroblastoma (NB) xenografts. Absorbed doses for tumor and normal tissues were ∼85 cGy/MBq and ≤3.7 cGy/MBq, respectively, with therapeutic indicies (TI) of 142 for blood and 23 for kidney. A therapy study (n = 5 per group; tumor volume: 240 ± 160 mm3) with three successive PRIT cycles (total 177Lu: ∼33 MBq; tumor dose ∼3400 cGy), revealed complete tumor response in 5/5 animals, with no recurrence up to 28 d post-treatment. Tumor ablation was confirmed histologically in 4/5 mice, and normal organs showed minimal overall toxicities. All non-treated mice required sacrifice within 12 d (>1.0 cm3 tumor volume). We conclude that this novel anti-GD2 PRIT approach has sufficient TI to successfully ablate s.c. GD2(+)–NB in mice while sparing kidney and bone marrow. PMID:24944121

  18. Malignant presacral ghrelinoma with long-standing hyperghrelinaemia

    PubMed Central

    Gustafsson, Thomas; Wenzel, Ralf; Wierup, Nils; Sundler, Frank; Kulkarni, Harshad; Baum, Richard P.

    2015-01-01

    Background. A 57-year old man with low-back pain was found to have a 3 × 3 × 3 cm presacral neuroendocrine tumour (NET) with widespread metastases, mainly to the skeleton. His neoplastic disease responded well to peptide receptor radionuclide therapy (PRRT) with the radiotagged somatostatin agonist 177Lu-DOTATATE. During almost 10 years he was fit for a normal life. He succumbed to an intraspinal dissemination. Procedures. A resection of the rectum, with a non-radical excision of the adjacent NET, was made. In addition to computerized tomography (CT), receptor positron emission tomography (PET) with 68Ga-labelled somatostatin analogues was used. Observations. The NET showed the growth pattern and immunoprofile of a G2 carcinoid. A majority cell population displayed immunoreactivity to ghrelin, exceptionally with co-immunoreactivity to motilin. Somatostatin receptor scintigraphy and 68Ga-DOTATATE PET-CT demonstrated uptake in the metastatic lesions. High serum concentrations of total (desacyl-)ghrelin were found with fluctuations reflecting the severity of the symptoms. In contrast, the concentrations of active (acyl-)ghrelin were consistently low, as were those of chromogranin A (CgA). Conclusions. Neoplastically transformed ghrelin cells can release large amounts of desacyl-ghrelin, evoking an array of non-specific clinical symptoms. Despite an early dissemination to the skeleton, a ghrelinoma can be compatible with longevity after adequate radiotherapy. PMID:26095011

  19. In vivo localization of ⁹⁰Y and ¹⁷⁷Lu radioimmunoconjugates using Cerenkov luminescence imaging in a disseminated murine leukemia model.

    PubMed

    Balkin, Ethan R; Kenoyer, Aimee; Orozco, Johnnie J; Hernandez, Alexandra; Shadman, Mazyar; Fisher, Darrell R; Green, Damian J; Hylarides, Mark D; Press, Oliver W; Wilbur, D Scott; Pagel, John M

    2014-10-15

    Cerenkov radiation generated by positron-emitting radionuclides can be exploited for a molecular imaging technique known as Cerenkov luminescence imaging (CLI). Data have been limited, however, on the use of medium- to high-energy β-emitting radionuclides of interest for cancer imaging and treatment. We assessed the use of CLI as an adjunct to determine localization of radioimmunoconjugates to hematolymphoid tissues. Radiolabeled (177)Lu- or (90)Y-anti-CD45 antibody (Ab; DOTA-30F11) was administered by tail vein injection to athymic mice bearing disseminated murine myeloid leukemia, with CLI images acquired at times afterward. Gamma counting of individual organs showed preferential uptake in CD45(+) tissues with significant retention of radiolabeled Ab in sites of leukemia (spleen and bone marrow). This result was confirmed in CLI images with 1.35 × 10(5) ± 2.2 × 10(4) p/s/cm(2)/sr and 3.45 × 10(3) ± 7.0 × 10(2) p/s/cm(2)/sr for (90)Y-DOTA-30F11 and (177)Lu-DOTA-30F11, respectively, compared with undetectable signal for both radionuclides using the nonbinding control Ab. Results showed that CLI allows for in vivo visualization of localized β-emissions. Pixel intensity variability resulted from differences in absorbed doses of the associated energies of the β-emitting radionuclide. Overall, our findings offer a preclinical proof of concept for the use of CLI techniques in tandem with currently available clinical diagnostic tools. PMID:25261237

  20. H2CHXdedpa and H4CHXoctapa-chiral acyclic chelating ligands for (67/68)Ga and (111)In radiopharmaceuticals.

    PubMed

    Ramogida, Caterina F; Cawthray, Jacqueline F; Boros, Eszter; Ferreira, Cara L; Patrick, Brian O; Adam, Michael J; Orvig, Chris

    2015-02-16

    The chiral acyclic ligands H2CHXdedpa (N4O2), H2CHXdedpa-bb (N4O2), and H4CHXoctapa (N4O4) (CHX = cyclohexyl/cyclohexane, H2dedpa = 1,2-[[6-carboxy-pyridin-2-yl]-methylamino]ethane, bb = N,N'-dibenzylated, H4octapa = N,N'-bis(6-carboxy-2-pyridylmethyl)-ethylenediamine-N,N'-diacetic acid) were synthesized, complexed with Ga(III) and/or In(III), and evaluated for their potential as chelating agents in radiopharmaceutical applications. The ligands were compared to the previously studied hexadentate H2dedpa and octadentate H4octapa ligands to determine the effect adding a chiral 1R,2R-trans-cyclohexane to replace the ethylenediamine backbone would have on metal complex stability and radiolabeling kinetics. It was found that [Ga(CHXdedpa)](+) showed very similar properties to those of [Ga(dedpa)](+), with only one isomer in solution observed by NMR spectroscopy, and minimal structural changes in the solid-state X-ray structure. Like [Ga(dedpa)](+), [Ga(CHXdedpa)](+) exhibited exceptionally high thermodynamic stability constants (log KML = 28.11(8)), and the chelate retained the ability to label (67)Ga quantitatively in 10 min at room temperature at ligand concentrations of 1 × 10(-5) M. In vitro kinetic inertness assays demonstrated the [(67)Ga(CHXdedpa)](+) complex to be more stable than [(67)Ga(dedpa)](+) in a human serum competition, with 90.5% and 77.8% of (67)Ga remaining chelate-bound after 2 h, respectively. Preliminary coordination studies of H4CHXoctapa with In(III) demonstrated [In(CHXoctapa)](-) to have an equivalently high thermodynamically stable constant as [In(octapa)](-), with log KML values of 27.16(9) and 26.76(14), respectively. The [(111)In(CHXoctapa)](-) complex showed exceptionally high in vitro kinetic inertness over 120 h in human serum, comparing well with previously reported [(111)In(octapa)](-) values, and an improved stability compared to the current industry "gold standards" 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and diethylenetriaminepentaacetic acid (DTPA). Initial investigations reveal that the chiral acyclic hexadentate H2CHXdedpa and octadentate H4CHXoctapa ligands are ideal candidates for radiopharmaceutical elaboration of gallium or indium isotopes, respectively. PMID:25621728

  1. Early Response to Everolimus Therapy Detected on 68Ga-DOTATATE PET/CT in a Patient With Pancreatic Neuroendocrine Tumor.

    PubMed

    Ozkan, Elgin; Soydal, Cigdem; Ucak Semirgin, Sibel; Yapici, Oktay; Atmaca, Aysegul; Demirag, Guzin

    2016-07-01

    Everolimus is a mammalian target of rapamycin inhibitor that has been recently approved for the treatment of patients with advanced progressive pancreatic neuroendocrine tumor. Here, we present a case in which an early therapy response to everolimus was effectively demonstrated by Ga-DOTATATE PET/CT. PMID:27163457

  2. 68Ga DOTANOC PET/CT aiding in the diagnosis of von Hippel-Lindau syndrome by detecting cerebellar hemangioblastoma and adrenal pheochromocytoma.

    PubMed

    Mukherjee, Anirban; Karunanithi, Sellam; Bal, Chandrasekhar; Kumar, Rakesh

    2014-10-01

    A 35-year-old man with clinical suspicion of adrenal pheochromocytoma was evaluated using Ga DOTANOC PET/CT. PET/CT demonstrated Ga DOTANOC-avid right adrenal mass and cerebellar lesion, raising the suspicion of adrenal pheochromocytoma with cerebellar hemangioblastoma suggesting von Hippel-Lindau (VHL) syndrome. Cerebellar lesion on further evaluation with MRI was suggestive of cerebellar hemangioblastoma. Surgical resection of the adrenal mass revealed pheochromocytoma, and genetic analysis revealed mutation involving the chromosome 3p, confirming the diagnosis of VHL syndrome. Ga DOTANOC PET/CT in our patient helped in the diagnosis of VHL syndrome and changed the disease management. PMID:24999687

  3. Comparison of (18)F-FDG PET/CT and (68)Ga-DOTATATE PET/CT imaging in metastasized Merkel cell carcinoma.

    PubMed

    Epstude, Maximilian; Tornquist, Katharina; Riklin, Christian; di Lenardo, Francesca; Winterhalder, Ralph; Hug, Urs; Strobel, Klaus

    2013-04-01

    Merkel cell carcinoma (MCC) is a rare but very aggressive neuroendocrine tumor of the skin in elderly patients with higher mortality compared with melanoma. No evidence-based standardized chemotherapy exists for metastasized patients.We report the case of an 87-year-old patient with the history of resection of a large MCC of the parietal scalp planned for radiotherapy and staged with FDG PET/CT showing disseminated distant metastases. Ga-DOTATATE PET/CT revealed more extensive tumor load compared with FDG, and due to the intensive expression of somatostatin receptors the patient qualified for Y DOTATOC therapy. PMID:23429397

  4. 68Ga-PSMA-11 PET Represents the Tumoricidal Effect of 223Ra in a Patient With Castrate-Resistant Metastatic Prostate Cancer.

    PubMed

    Ahmadzadehfar, Hojjat; Schlenkhoff, Carl Diedrich; Rogenhofer, Sebastian; Yordanova, Anna; Essler, Markus

    2016-09-01

    A 64-year-old man with prostate cancer and an increasing prostate-specific antigen (PSA) level under therapy with abiraterone acetate underwent a therapy with Ra. Before the first therapy and 4 weeks after the last cycle, the patient underwent Ga-PSMA PET, which showed a clear response of bone metastases. PMID:27405025

  5. 68Ga-Labeled Anti-Prostate-Specific Membrane Antigen Peptide as Marker for Androgen Deprivation Therapy Response in Prostate Cancer.

    PubMed

    Schlenkhoff, Carl Diedrich; Gaertner, Florian; Essler, Markus; Hauser, Stefan; Ahmadzadehfar, Hojjat

    2016-05-01

    Prostate cancer was diagnosed in a 71-year-old man with an elevated prostate-specific antigen. The CT of the abdomen showed multiple para-aortal lymph nodes, and thus, a Ga anti-prostate-specific membrane antigen (PSMA-11) PET/CT was initiated, which showed, aside from the prostate cancer and multiple iliacal and para-aortal lymph node metastases, an increased tracer uptake in a lymph node left cervical. According to this advanced disease, a palliative therapy with GnRH agonist was initiated. A second PSMA-11 PET/CT was performed 4 months later, which showed a very good response; thus, additional radiation of the pelvis and the draining lymphatic system was performed. PMID:26859213

  6. 18F-DOPA PET/CT but not 68Ga-DOTA-TOC PET/CT revealed the underlying cause of ectopic Cushing syndrome.

    PubMed

    Schalin-Jäntti, Camilla; Ahonen, Aapo; Seppänen, Marko

    2012-09-01

    F-DOPA PET/CT but not Ga-DOTA-TOC PET/CT revealed the cause of ectopic Cushing syndrome in a 61-year-old man. The patient presented with rapid weight gain, swollen legs, and sleep disturbances. Plasma potassium level was 2.7 mM (reference range, 3.3-4.9 mM), 24-hour urinary cortisol level was 13,124 nmol (reference range, 30-144 nmol), and plasma adrenocorticotropin level was 61 ng/L (reference range, <48 g/L). CT demonstrated prominent lymph nodes in the left lung hilus and hyperplastic adrenals but no primary tumor. Ga-DOTA-TOC PET/CT, which is recommended as the first-line PET imaging, was performed, but it was not diagnostic. Imaging with F-DOPA PET/CT revealed the underlying cause. PMID:22889786

  7. Lutetium-177 Labeled Peptides: The European Institute of Oncology Experience.

    PubMed

    Carollo, Angela; Papi, Stefano; Chinol, Marco

    2016-01-01

    Peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin analogues has shown encouraging results in various somatostatin receptor positive tumors. Partial remission rates up to 30% have been documented as well as significant improvements in quality of life and survival. This treatment takes advantage of the high specific binding of the radiolabeled peptide to somatostatin receptors overexpressed by the tumors thus being more effective on the tumor cells with less systemic side-effects. The development of macrocyclic chelators conjugated to peptides made possible the stable binding with various radionuclides. In particular 177Lu features favourable physical characteristics with a half-life of 6.7 days, emission of β- with energy of 0.5 MeV for treatment and γ-emissions suitable for imaging. The present contribution describes the learning process achieved at the European Institute of Oncology (IEO) since the first application of 90Y labeled peptides to the therapy of neuroendocrine tumors back in 1997. Continuous improvements led to the preparation of a safe 177Lu labeled peptide for human use. Our learning curve began with the identification of the optimal characteristics of the isotope paying attention to its chemical purity and specific activity along with the optimization of the parameters involved in the radiolabeling procedure. Also the radiation protection issues have been improved along the years and recently more and more attention has been devoted to the pharmaceutical aspects involved in the preparation. The overall issue of the quality has now been completed by drafting an extensive documentation with the goal to deliver a safe and reliable product to our patients. PMID:25771368

  8. The analysis of feasibility and effectiveness of vascular targeting radiotherapy based on a model of tumor growth and angiogenesis

    NASA Astrophysics Data System (ADS)

    Ding, Yihong

    site. Using an alternative radionuclide, 177Lu (0.498 MeV) to replace high-energy 90Y (2.282 MeV) in the model compound to treat small size tumors is also discussed. The low absorbed dose to tumor endothelium from 177Lu suggests that it is not an ideal choice for vascular targeting radiotherapy.

  9. Radioisotope research, production, and processing at the University of Missouri Research Reactor

    SciTech Connect

    Ehrhardt, G.J.; Ketring, A.R.; Ja, Wei; Ma, D.; Zinn, K.; Lanigan, J.

    1995-12-31

    The University of Missouri Research Reactor (MURR) is a 10 MW, light-water-cooled and moderated research reactor which first achieved criticality in 1996 and is currently the highest powered university-owned research reactor in the U.S. For many years a major supplier of reactor-produced isotopes for research and commercial purposes, in the last 15 years MURR has concentrated on development of reactor-produced beta-particle emitters for experimental use in nuclear medicine therapy of cancer and rheumatoid arthritis. MURR has played a major role in the development of bone cancer pain palliation with the agents {sup 153}Sm EDTMP and {sup 186}Re/{sup 188}Re HEDP, as well as in the use of {sup 186}Re, {sup 177}Lu, {sup 166}Ho, and {sup 105}Rh for radioimmunotherapy and receptor-agent-guided radiotherapy. MURR is also responsible for the development of therapeutic, {sup 90}Y-labeled glass microspheres for the treatment of liver tumors, a product ({sup 90}Y Therasphere{trademark}) which is currently an approved drug in Canada. MURR has also pioneered the development of {sup 188}W/{sup 188}Re and {sup 99}Mo/{sup 99m}Tc gel generators, which make the use of low specific activity {sup 188}W and {sup 99}Mo practical for such isotope generators.

  10. Peptide receptor radionuclide therapy (PRRT) for GEP-NETs.

    PubMed

    Bergsma, Hendrik; van Vliet, Esther I; Teunissen, Jaap J M; Kam, Boen L R; de Herder, Wouter W; Peeters, Robin P; Krenning, Eric P; Kwekkeboom, Dik J

    2012-12-01

    Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues plays an increasing role in the treatment of patients with inoperable or metastasised gatroenteropancreatic neuroendocrine tumours (GEP-NETs). (90)Y-DOTATOC and (177)Lu-DOTATATE are the most used radiopeptides for PRRT with comparable tumour response rates (about 15-35%). The side effects of this therapy are few and mild. However, amino acids should be used for kidney protection, especially during infusion of (90)Y-DOTATOC. Options to improve PRRT may include combinations of radioactive labelled somatostatin analogues and the use of radiosensitising drugs combined with PRRT. Other therapeutic applications of PRRT may include intra-arterial administration, neo-adjuvant treatment and additional PRRT cycles in patients with progressive disease, who have benefited from initial therapy. Considering the mild side-effects, PRRT may well become the first-line therapy in patients with metastasised or inoperable GEP-NETs if more widespread use of PRRT can be accomplished. PMID:23582925

  11. Radioembolization and the Dynamic Role of 90Y PET/CT

    PubMed Central

    Pasciak, Alexander S.; Bourgeois, Austin C.; McKinney, J. Mark; Chang, Ted T.; Osborne, Dustin R.; Acuff, Shelley N.; Bradley, Yong C.

    2014-01-01

    Before the advent of tomographic imaging, it was postulated that decay of 90 Y to the 0+ excited state of 90Zr may result in emission of a positron–electron pair. While the branching ratio for pair-production is small (~32 × 10−6), PET has been successfully used to image 90 Y in numerous recent patients and phantom studies. 90 Y PET imaging has been performed on a variety of PET/CT systems, with and without time-of-flight (TOF) and/or resolution recovery capabilities as well as on both bismuth-germanate and lutetium yttrium orthosilicate (LYSO)-based scanners. On all systems, resolution and contrast superior to bremsstrahlung SPECT has been reported. The intrinsic radioactivity present in LYSO-based PET scanners is a potential limitation associated with accurate quantification of 90 Y. However, intrinsic radioactivity has been shown to have a negligible effect at the high activity concentrations common in 90 Y radioembolization. Accurate quantification is possible on a variety of PET scanner models, with or without TOF, although TOF improves accuracy at lower activity concentrations. Quantitative 90 Y PET images can be transformed into 3-dimensional (3D) maps of absorbed dose based on the premise that the 90 Y activity distribution does not change after infusion. This transformation has been accomplished in several ways, although the most common is with the use of 3D dose-point-kernel convolution. From a clinical standpoint, 90 Y PET provides a superior post-infusion evaluation of treatment technical success owing to its improved resolution. Absorbed dose maps generated from quantitative PET data can be used to predict treatment efficacy and manage patient follow-up. For patients who receive multiple treatments, this information can also be used to provide patient-specific treatment-planning for successive therapies, potentially improving response. The broad utilization of 90 Y PET has the potential to provide a wealth of dose–response information, which may lead to development of improved radioembolization treatment-planning models in the future. PMID:24579065

  12. Radioembolization using 90Y-resin microspheres for patients with advanced hepatocellular carcinoma

    SciTech Connect

    Sangro, Bruno . E-mail: bsangro@unav.es; Bilbao, Jose I.; Boan, Jose; Martinez-Cuesta, Antonio; Benito, Alberto; Rodriguez, Javier; Panizo, Angel; Gil, Belen; Inarrairaegui, Mercedes; Herrero, Ignacio; Quiroga, Jorge; Prieto, Jesus

    2006-11-01

    Purpose: To investigate the antitumor effect of resin microspheres loaded with 90-yttrium against hepatocellular carcinoma and their safety in the setting of liver cirrhosis. Patients and Methods: Data from 24 consecutive patients with hepatocellular carcinoma (HCC) treated by radioembolization in the period from September 2003 to February 2005 were reviewed. Patients received no further antineoplastic therapy. A comprehensive evaluation was performed to prevent the risk of damage due to microsphere misplacing. Patients were discharged the day after microspheres injection. Results: Serious liver toxicity observed among cirrhotic patients in a first period was subsequently prevented by modifying the selection criteria and the method for calculating the activity to be administered. Among 21 patients evaluable for response using Response Evaluation Criteria in Solid Tumors (RECIST) criteria, a reduction in size of target lesions was observed in all but 1 patient. When considering only target lesions, disease control rate and response rate were 100% and 23.8%, respectively. However, 43% of patients progressed in the liver in the form of new lesions appearing a median time of 3 months after radioembolization. Conclusion: Our experience in these series of patients indicates that radioembolization using resin microspheres has a significant antitumor effect against HCC and that using stringent selection criteria and conservative models for calculating Radiation activity to be administered, radioembolization can be performed safely even in cirrhotic patients.

  13. Experiments in Radiochemistry: Paper Electrophorectic Separation of Superscript 90 Sr and Superscript 90 Y.

    ERIC Educational Resources Information Center

    Miekely, N.; Roldao, L. A.

    1982-01-01

    Using different supporting electrolytes, the influence of complex-forming equilibria on migration velocities of strontium-90 and yttrium-90 can be demonstrated in this experiment. Includes procedures and materials needed. (SK)

  14. Comparison of internal dose estimates obtained using organ-level, voxel S value, and Monte Carlo techniques

    SciTech Connect

    Grimes, Joshua; Celler, Anna

    2014-09-15

    Purpose: The authors’ objective was to compare internal dose estimates obtained using the Organ Level Dose Assessment with Exponential Modeling (OLINDA/EXM) software, the voxel S value technique, and Monte Carlo simulation. Monte Carlo dose estimates were used as the reference standard to assess the impact of patient-specific anatomy on the final dose estimate. Methods: Six patients injected with{sup 99m}Tc-hydrazinonicotinamide-Tyr{sup 3}-octreotide were included in this study. A hybrid planar/SPECT imaging protocol was used to estimate {sup 99m}Tc time-integrated activity coefficients (TIACs) for kidneys, liver, spleen, and tumors. Additionally, TIACs were predicted for {sup 131}I, {sup 177}Lu, and {sup 90}Y assuming the same biological half-lives as the {sup 99m}Tc labeled tracer. The TIACs were used as input for OLINDA/EXM for organ-level dose calculation and voxel level dosimetry was performed using the voxel S value method and Monte Carlo simulation. Dose estimates for {sup 99m}Tc, {sup 131}I, {sup 177}Lu, and {sup 90}Y distributions were evaluated by comparing (i) organ-level S values corresponding to each method, (ii) total tumor and organ doses, (iii) differences in right and left kidney doses, and (iv) voxelized dose distributions calculated by Monte Carlo and the voxel S value technique. Results: The S values for all investigated radionuclides used by OLINDA/EXM and the corresponding patient-specific S values calculated by Monte Carlo agreed within 2.3% on average for self-irradiation, and differed by as much as 105% for cross-organ irradiation. Total organ doses calculated by OLINDA/EXM and the voxel S value technique agreed with Monte Carlo results within approximately ±7%. Differences between right and left kidney doses determined by Monte Carlo were as high as 73%. Comparison of the Monte Carlo and voxel S value dose distributions showed that each method produced similar dose volume histograms with a minimum dose covering 90% of the volume (D90

  15. Three-dimensional radiobiological dosimetry of kidneys for treatment planning in peptide receptor radionuclide therapy

    SciTech Connect

    Baechler, Sebastien; Hobbs, Robert F.; Boubaker, Ariane; Buchegger, Franz; He Bin; Frey, Eric C.; Sgouros, George

    2012-10-15

    Purpose: Peptide receptor radionuclide therapy (PRRT) delivers high absorbed doses to kidneys and may lead to permanent nephropathy. Reliable dosimetry of kidneys is thus critical for safe and effective PRRT. The aim of this work was to assess the feasibility of planning PRRT based on 3D radiobiological dosimetry (3D-RD) in order to optimize both the amount of activity to administer and the fractionation scheme, while limiting the absorbed dose and the biological effective dose (BED) to the renal cortex. Methods: Planar and SPECT data were available for a patient examined with {sup 111}In-DTPA-octreotide at 0.5 (planar only), 4, 24, and 48 h post-injection. Absorbed dose and BED distributions were calculated for common therapeutic radionuclides, i.e., {sup 111}In, {sup 90}Y and {sup 177}Lu, using the 3D-RD methodology. Dose-volume histograms were computed and mean absorbed doses to kidneys, renal cortices, and medullae were compared with results obtained using the MIRD schema (S-values) with the multiregion kidney dosimetry model. Two different treatment planning approaches based on (1) the fixed absorbed dose to the cortex and (2) the fixed BED to the cortex were then considered to optimize the activity to administer by varying the number of fractions. Results: Mean absorbed doses calculated with 3D-RD were in good agreement with those obtained with S-value-based SPECT dosimetry for {sup 90}Y and {sup 177}Lu. Nevertheless, for {sup 111}In, differences of 14% and 22% were found for the whole kidneys and the cortex, respectively. Moreover, the authors found that planar-based dosimetry systematically underestimates the absorbed dose in comparison with SPECT-based methods, up to 32%. Regarding the 3D-RD-based treatment planning using a fixed BED constraint to the renal cortex, the optimal number of fractions was found to be 3 or 4, depending on the radionuclide administered and the value of the fixed BED. Cumulative activities obtained using the proposed simulated

  16. Differences in 3D dose distributions due to calculation method of voxel S-values and the influence of image blurring in SPECT

    NASA Astrophysics Data System (ADS)

    Pacilio, Massimiliano; Amato, Ernesto; Lanconelli, Nico; Basile, Chiara; Torres, Leonel Alberto; Botta, Francesca; Ferrari, Mahila; Cornejo Diaz, Nestor; Coca Perez, Marco; Fernández, María; Lassmann, Michael; Vergara Gil, Alex; Cremonesi, Marta

    2015-03-01

    This study compares 3D dose distributions obtained with voxel S values (VSVs) for soft tissue, calculated by several methods at their current state-of-the-art, varying the degree of image blurring. The methods were: 1) convolution of Dose Point Kernel (DPK) for water, using a scaling factor method; 2) an analytical model (AM), fitting the deposited energy as a function of the source-target distance; 3) a rescaling method (RSM) based on a set of high-resolution VSVs for each isotope; 4) local energy deposition (LED). VSVs calculated by direct Monte Carlo simulations were assumed as reference. Dose distributions were calculated considering spheroidal clusters with various sizes (251, 1237 and 4139 voxels of 3 mm size), uniformly filled with 131I, 177Lu, 188Re or 90Y. The activity distributions were blurred with Gaussian filters of various widths (6, 8 and 12 mm). Moreover, 3D-dosimetry was performed for 10 treatments with 90Y derivatives. Cumulative Dose Volume Histograms (cDVHs) were compared, studying the differences in D95%, D50% or Dmax (ΔD95%, ΔD50% and ΔDmax) and dose profiles. For unblurred spheroidal clusters, ΔD95%, ΔD50% and ΔDmax were mostly within some percents, slightly higher for 177Lu with DPK (8%) and RSM (12%) and considerably higher for LED (ΔD95% up to 59%). Increasing the blurring, differences decreased and also LED yielded very similar results, but D95% and D50% underestimations between 30-60% and 15-50%, respectively (with respect to 3D-dosimetry with unblurred distributions), were evidenced. Also for clinical images (affected by blurring as well), cDVHs differences for most methods were within few percents, except for slightly higher differences with LED, and almost systematic for dose profiles with DPK (-1.2%), AM (-3.0%) and RSM (4.5%), whereas showed an oscillating trend with LED. The major concern for 3D-dosimetry on clinical SPECT images is more strongly represented by image blurring than by differences among the VSVs

  17. Nuclear oncology, a fast growing field of nuclear medicine

    NASA Astrophysics Data System (ADS)

    Olivier, Pierre

    2004-07-01

    Nuclear Medicine in oncology has been for a long time synonymous with bone scintigraphy, the first ever whole body imaging modality, and with treatment of thyroid cancer with iodine-131. More recently, somatostatin receptor scintigraphy (SRS) using peptides such as 111In-labelled octreotide became a reference imaging method in the detection and staging of neuroendocrine tumors while 131I- and 123I-MIBG remain the tracers of reference for pheochromocytomas and neuroblastomas. Lymphoscintigraphic imaging based on peritumoral injection of 99mTc-labelled colloids supports, in combination with per operative detection, the procedure of sentinel node identification in breast cancers and melanomas. Positron Emission Tomography (PET) is currently experiencing a considerable growth in oncology based on the use of 18F-FDG (fluorodeoxyglucose), a very sensitive, although non-specific, tumor tracer. Development of instrumentation is crucial in this expansion of PET imaging with new crystals being more sensitive and hybrid imagers that permit to reduce the acquisition time and offer fused PET-CT images. Current developments in therapy can be classified into three categories. Radioimmunotherapy (RIT) based on monoclonal antibodies (or fragments) labelled with beta-emitters. This technique has recently made its entrance in clinical practice with a 90Y-labelled anti-CD20 antibody ( 90Y-ibritumomab tiuxetan (Zevalin ®)) approved in US for the treatment of some subtypes of non-Hodgkin's lymphoma. Radionuclide-bone pain palliation has experienced developments with 153Sm-EDTMP, 186Re-HEDP or 89Sr, efficient in patients with widespread disease. Last, the same peptides, as those used in SRS, are being developed for therapy, labelled with 90Y, 111In or 177Lu in patients who failed to respond to other treatments. Overall, nuclear oncology is currently a fast growing field thanks to the combined developments of radiopharmaceuticals and instrumentation.

  18. A radio-theranostic nanoparticle with high specific drug loading for cancer therapy and imaging.

    PubMed

    Satterlee, Andrew B; Yuan, Hong; Huang, Leaf

    2015-11-10

    We have developed a theranostic nanoparticle delivering the model radionuclide (177)Lu based on the versatile lipid-calcium-phosphate (LCP) nanoparticle delivery platform. Characterization of (177)Lu-LCP has shown that radionuclide loading can be increased by several orders of magnitude without affecting the encapsulation efficiency or the morphology of (177)Lu-LCP, allowing consistency during fabrication and overcoming scale-up barriers typical of nanotherapeutics. The choice of (177)Lu as a model radionuclide has allowed in vivo anticancer therapy in addition to radiographic imaging via the dual decay modes of (177)Lu. Tumor accumulation of (177)Lu-LCP was measured using both SPECT and Cerenkov imaging modalities in live mice, and treatment with just one dose of (177)Lu-LCP showed significant in vivo tumor inhibition in two subcutaneous xenograft tumor models. Microenvironment and cytotoxicity studies suggest that (177)Lu-LCP inhibits tumor growth by causing apoptotic cell death via double-stranded DNA breaks while causing a remodeling of the tumor microenvironment to a more disordered and less malignant phenotype. PMID:26341695

  19. ¹⁷⁷Lu-Labeled Agents for Neuroendocrine Tumor Therapy and Bone Pain Palliation in Uruguay.

    PubMed

    Balter, Henia; Victoria, Trindade; Mariella, Terán; Javier, Gaudiano; Rodolfo, Ferrando; Andrea, Paolino; Graciela, Rodriguez; Juan, Hermida; Eugenia, De Marco; Patricia, Oliver

    2016-01-01

    Lutetium-177 is an emerging radionuclide due its convenient chemical and nuclear properties. In this paper we describe the development and evaluation in Uruguay of the targeted 177Lu labelled radiopharmaceuticals EDTMP (for bone pain palliation) and DOTA-TATE (neuroendocrine tumors). We optimized the preparation of these 177Lu radiopharmaceuticals including radiolabelling, quality control methods, in vitro and in vivo stability and their therapeutic application in patients. Radiation dosimetry aspects of 177Lu are also included. Nine male patients with prostate cancer and four female patients with breast carcinoma with multiple bone metastatic lesions were treated with 177Lu-EDTMP. Four patients with gastroentheropancreatic neuroendocrine tumors (GEP-NET) and one patient with bronchial NET were treated with 1- 3 cycles with a cumulative dose of 4.44-22.2 GBq of 177Lu-DOTA-TATE. Scintigraphic images of the patients treated with 177Lu-EDTMP evidenced high and rapid uptake in bone metastasis, remaining after 7 days post administration. Images allow skeletal visualization with high definition and demonstrate increased uptake in bone metastases. For 177Lu-DOTA-TATE, partial remissions were obtained in 4 patients and the remaining patient did not show significant progression 3 months after the second cycle. No serious adverse effects were registered, even in two patients with confirmed renal disease and high risk for renal disease Dosimetry assessments confirm the predictive value of the personalized therapy with radiolabelled peptides. We found it is possible to accumulate high therapeutic doses in tumours in sequential administrations of 177Lu-DOTA-TATE, increasing the probability of biological response without significant impairment of the renal function in patients with risk factors. These results demonstrate the attractive therapeutic properties of these two 177Lu labelled agents and the feasibility of this metabolic therapy in regions far away from 177Lu producing

  20. Fine-Resolution Voxel S Values for Constructing Absorbed Dose Distributions at Variable Voxel Size

    PubMed Central

    Dieudonné, Arnaud; Hobbs, Robert F.; Bolch, Wesley E.; Sgouros, George; Gardin, Isabelle

    2010-01-01

    This article presents a revised voxel S values (VSVs) approach for dosimetry in targeted radiotherapy, allowing dose calculation for any voxel size and shape of a given SPECT or PET dataset. This approach represents an update to the methodology presented in MIRD pamphlet no. 17. Methods VSVs were generated in soft tissue with a fine spatial sampling using the Monte Carlo (MC) code MCNPX for particle emissions of 9 radionuclides: 18F, 90Y, 99mTc, 111In, 123I, 131I, 177Lu, 186Re, and 201Tl. A specific resampling algorithm was developed to compute VSVs for desired voxel dimensions. The dose calculation was performed by convolution via a fast Hartley transform. The fine VSVs were calculated for cubic voxels of 0.5 mm for electrons and 1.0 mm for photons. Validation studies were done for 90Y and 131I VSV sets by comparing the revised VSV approach to direct MC simulations. The first comparison included 20 spheres with different voxel sizes (3.8–7.7 mm) and radii (4–64 voxels) and the second comparison a hepatic tumor with cubic voxels of 3.8 mm. MC simulations were done with MCNPX for both. The third comparison was performed on 2 clinical patients with the 3D-RD (3-Dimensional Radiobiologic Dosimetry) software using the EGSnrc (Electron Gamma Shower National Research Council Canada)-based MC implementation, assuming a homogeneous tissue-density distribution. Results For the sphere model study, the mean relative difference in the average absorbed dose was 0.20% ± 0.41% for 90Y and −0.36% ± 0.51% for 131I (n = 20). For the hepatic tumor, the difference in the average absorbed dose to tumor was 0.33% for 90Y and −0.61% for 131I and the difference in average absorbed dose to the liver was 0.25% for 90Y and −1.35% for 131I. The comparison with the 3D-RD software showed an average voxel-to-voxel dose ratio between 0.991 and 0.996. The calculation time was below 10 s with the VSV approach and 50 and 15 h with 3D-RD for the 2 clinical patients. Conclusion This new

  1. ¹¹¹In-DTPA⁰-octreotide (Octreoscan), ¹³¹I-MIBG and other agents for radionuclide therapy of NETs.

    PubMed

    Bomanji, Jamshed B; Papathanasiou, Nikolaos D

    2012-02-01

    This paper is a critical review of the literature on NET radionuclide therapy with (111)In-DTPA(0)-octreotide (Octreoscan) and (131)I-MIBG, focusing on efficacy and toxicity. Some potential future applications and new candidate therapeutic agents are also mentioned. Octreoscan has been a pioneering agent for somatostatin receptor radionuclide therapy. It has achieved symptomatic responses and disease stabilization, but it is now outperformed by the corresponding β-emitter agents (177)Lu-DOTATATE and (90)Y-DOTATOC. (131)I-MIBG is the radionuclide therapy of choice for inoperable or metastatic phaeochromocytomas/paragangliomas, which avidly concentrate this tracer via the noradrenaline transporter. Symptomatic, biochemical and tumour morphological response rates of 50-89%, 45-74% and 27-47%, respectively, have been reported. (131)I-MIBG is a second-line radiopharmaceutical for treatment of enterochromaffin carcinoids, mainly offering the benefit of amelioration of hormone-induced symptoms. High specific activity, non-carrier-added (131)I-MIBG and meta-astato((211)At)-benzylguanidine (MABG) are tracers with potential for enhanced therapeutic efficacy, yet their integration into clinical practice awaits further exploration. Amongst other promising agents, radiolabelled exendin analogues show potential for imaging and possibly therapy of insulinomas, while preclinical studies are currently evaluating DOTA peptides targeting the CCK-2/gastrin receptors that are overexpressed by medullary thyroid carcinoma cells. PMID:22388626

  2. Cross-fire doses from beta-emitting radionuclides in targeted radiotherapy. A theoretical study based on experimentally measured tumor characteristics.

    PubMed

    Enger, S A; Hartman, T; Carlsson, J; Lundqvist, H

    2008-04-01

    A mathematical model based upon histological findings of cell cluster distributions in primary breast cancers and lymph node metastases was developed. The model is unique because it accounts for tumor cell cluster formations within both primary tumors and metastases. The importance of inter-cell cluster cross-fire radiation dose for beta-emitting radionuclides of different energies was studied. The cell clusters were simulated as spheres with 15, 25 and 50 microm radii having a homogeneous radioactivity distribution. The self-dose as well as the dose distribution around the spheres was calculated for seven radionuclides, (90)Y, (188)Re, (32)P, (186)Re, (159)Gd, (131)I and (177)Lu using the GEANT4 Monte Carlo code. Generally, the self-dose was decreasing with increasing energy of the emitted beta particles. An exception was (188)Re which, compared to (32)P, had higher beta energy as well as higher self-dose. This was due to the higher emission of conversion and Auger electrons in the (188)Re-decay. When the cell clusters had a mean distance that was shorter than the maximum range of beta-particles, then the inter-cluster cross-fire radiation contributed significantly to the absorbed dose. Thus, high-energy beta-particles may, in spite of a low self-dose to single clusters, still be favorable to use due to the contribution of inter-cluster cross-fire radiation. PMID:18364546

  3. A small-scale anatomical dosimetry model of the liver

    NASA Astrophysics Data System (ADS)

    Stenvall, Anna; Larsson, Erik; Strand, Sven-Erik; Jönsson, Bo-Anders

    2014-07-01

    Radionuclide therapy is a growing and promising approach for treating and prolonging the lives of patients with cancer. For therapies where high activities are administered, the liver can become a dose-limiting organ; often with a complex, non-uniform activity distribution and resulting non-uniform absorbed-dose distribution. This paper therefore presents a small-scale dosimetry model for various source-target combinations within the human liver microarchitecture. Using Monte Carlo simulations, Medical Internal Radiation Dose formalism-compatible specific absorbed fractions were calculated for monoenergetic electrons; photons; alpha particles; and 125I, 90Y, 211At, 99mTc, 111In, 177Lu, 131I and 18F. S values and the ratio of local absorbed dose to the whole-organ average absorbed dose was calculated, enabling a transformation of dosimetry calculations from macro- to microstructure level. For heterogeneous activity distributions, for example uptake in Kupffer cells of radionuclides emitting low-energy electrons (125I) or high-LET alpha particles (211At) the target absorbed dose for the part of the space of Disse, closest to the source, was more than eight- and five-fold the average absorbed dose to the liver, respectively. With the increasing interest in radionuclide therapy of the liver, the presented model is an applicable tool for small-scale liver dosimetry in order to study detailed dose-effect relationships in the liver.

  4. Myeloid neoplasms after chemotherapy and PRRT: myth and reality.

    PubMed

    Bodei, Lisa; Modlin, Irvin M; Luster, Markus; Forrer, Flavio; Cremonesi, Marta; Hicks, Rodney J; Ezziddin, Samer; Kidd, Mark; Chiti, Arturo

    2016-08-01

    Peptide receptor radionuclide therapy (PRRT) with (90)Y-octreotide or (177)Lu-octreotate is an effective treatment for inoperable or metastatic neuroendocrine tumors (NETs), particularly well-differentiated gastroenteropancreatic or bronchopulmonary NETs. PRRT is generally extremely well tolerated, with modest toxicity to target organs, kidney and bone marrow. Nevertheless, a priori concerns regarding long-term effects lead clinicians such as Brieau and coworkers, in this ERC issue, to ascribe to the combination of alkylating agents and PRRT the apparently high occurrence (n=4) of myeloproliferative events (therapy-related myeloid neoplasms (t-MNs)) in a small cohort of 20 progressive, advanced digestive NETs treated with PRRT after chemotherapy. Anecdotal reports of myelotoxic events should be placed in the correct perspective of larger series, where the reported incidence of these events is ~2%, with the aim of promoting a balanced awareness of the issue and unbiased and reasonable overall conclusions. For a comprehensive definition of the issue, we provide an evaluation of the occurrence of t-MN in patients treated with various myelotoxic treatments. PMID:27353035

  5. [Neuroendocrine tumors: Peptide receptors radionuclide therapy (PRRT)].

    PubMed

    Papamichail, Dimitris G; Exadaktylou, Paraskevi E; Chatzipavlidou, Vasiliki D

    2016-01-01

    Neuroendocrine tumors (neuroendocrine tumors-NET) are a heterogeneous group of neoplasms with a common embryological origin and diverse biological behavior, derived from cells of the neuroendocrine system, the system APUD (amine precursor uptake and decarboxylation). They are characterized by overexpression of all five somatostatin receptors (SSTR1-SSTR5), particularly type 2 (SST2). Surgical resection of the tumor is the treatment option, with a possibility of complete remission in patients with limited disease. Somatostatin analogs (octreotide and lanreotide) are the treatment of choice in patients with residual disease, particularly when it comes to NET non-pancreatic origin. Systemic chemotherapy is administered primarily to patients with poorly differentiated carcinomas. PRRT treatment is recommended in case of non-responsiveness of the disease. The ideal candidates for PRRT are patients with unresectable disease of high and intermediate differentiation. Somatostatine analogs radiolabelled with Indium-111 ((111)In), Yttrium-90 ((90)Y), Lutetium-177 ((177)Lu) and Bismuth-213 ((213)Bi), are selectively concentrated in the tumor cells, causing maximum tissue damage to tumors and with fewer effects on healthy tissue and the immune system. In the current review, it was demonstrated that patients with unresectable grade 1 or 2 disease showed increased PFS (progression free survival) and OS (overall survival), while quality of life was improved after PRRT treatment as compared to somatostatin analogs, chemotherapy and other targeted therapies. PMID:27035909

  6. VIDA: A Voxel-Based Dosimetry Method for Targeted Radionuclide Therapy Using Geant4

    PubMed Central

    Dewaraja, Yuni K.; Abramson, Richard G.; Stabin, Michael G.

    2015-01-01

    Abstract We have developed the Voxel-Based Internal Dosimetry Application (VIDA) to provide patient-specific dosimetry in targeted radionuclide therapy performing Monte Carlo simulations of radiation transport with the Geant4 toolkit. The code generates voxel-level dose rate maps using anatomical and physiological data taken from individual patients. Voxel level dose rate curves are then fit and integrated to yield a spatial map of radiation absorbed dose. In this article, we present validation studies using established dosimetry results, including self-dose factors (DFs) from the OLINDA/EXM program for uniform activity in unit density spheres and organ self- and cross-organ DFs in the Radiation Dose Assessment Resource (RADAR) reference adult phantom. The comparison with reference data demonstrated agreement within 5% for self-DFs to spheres and reference phantom source organs for four common radionuclides used in targeted therapy (131I, 90Y, 111In, 177Lu). Agreement within 9% was achieved for cross-organ DFs. We also present dose estimates to normal tissues and tumors from studies of two non-Hodgkin Lymphoma patients treated by 131I radioimmunotherapy, with comparison to results generated independently with another dosimetry code. A relative difference of 12% or less was found between methods for mean absorbed tumor doses accounting for tumor regression. PMID:25594357

  7. Targeted radionuclide therapies for pancreatic cancer.

    PubMed

    Shah, M; Da Silva, R; Gravekamp, C; Libutti, S K; Abraham, T; Dadachova, E

    2015-08-01

    Pancreatic malignancies, the fourth leading cause of cancer deaths, have an aggressive behavior with poor prognosis, resulting in a 5-year survival rate of only 4%. It is typically a silent malignancy until patients develop metastatic disease. Targeted radionuclide therapies of cancer such as radiolabeled peptides, which bind to the receptors overexpressed by cancer cells and radiolabeled antibodies to tumor-specific antigens provide a viable alternative to chemotherapy and external beam radiation of metastatic cancers. Multiple clinical trials of targeted radionuclide therapy of pancreatic cancer have been performed in the last decade and demonstrated safety and potential efficacy of radionuclide therapy for treatment of this formidable disease. Although a lot of progress has been made in treatment of pancreatic neuroendocrine tumors with radiolabeled (90)Y and (177)Lu somatostatin peptide analogs, pancreatic adenocarcinomas remain a major challenge. Novel approaches such as peptides and antibodies radiolabeled with alpha emitters, pre-targeting, bispecific antibodies and biological therapy based on the radioactive tumorlytic bacteria might offer a potential breakthrough in treatment of pancreatic adenocarcinomas. PMID:26227823

  8. Targeted radionuclide therapies for pancreatic cancer

    PubMed Central

    Shah, M.; Da Silva, R.; Gravekamp, C.; Libutti, S. K.; Abraham, T.; Dadachova, E.

    2016-01-01

    Pancreatic malignancies, the 4th leading cause of cancer deaths, have an aggressive behavior with poor prognosis, resulting in a five-year survival rate of only 4%. It is typically a silent malignancy until patients develop metastatic disease. Targeted radionuclide therapies of cancer such as radiolabeled peptides which bind to the receptors overexpressed by cancer cells and radiolabeled antibodies to tumor-specific antigens provide a viable alternative to chemotherapy and external beam radiation of metastatic cancers. Multiple clinical trials of targeted radionuclide therapy of pancreatic cancer have been performed in the last decade and demonstrated safety and potential efficacy of radionuclide therapy for treatment of this formidable disease. While a lot progress has been made in treatment of pancreatic neuroendocrine tumors with radiolabeled with 90Y and 177Lu somatostatin peptide analogues, pancreatic adenocarcinomas remain a major challenge. Novel approaches such as peptides and antibodies radiolabeled with alpha emitters, pre-targeting, bispecific antibodies and biological therapy based on the radioactive tumorlytic bacteria might offer a potential breakthrough in treatment of pancreatic adenocarcinomas. PMID:26227823

  9. Bone Marrow Recovery and Subsequent Chemotherapy Following Radiolabeled Anti-Prostate-Specific Membrane Antigen Monoclonal Antibody J591 in Men with Metastatic Castration-Resistant Prostate Cancer

    PubMed Central

    Tagawa, Scott T.; Akhtar, Naveed H.; Nikolopoulou, Anastasia; Kaur, Gurveen; Robinson, Brian; Kahn, Renee; Vallabhajosula, Shankar; Goldsmith, Stanley J.; Nanus, David M.; Bander, Neil H.

    2013-01-01

    Radioimmunotherapy (RIT) has demonstrated efficacy with acceptable toxicity leading to approval in non-Hodgkin’s lymphoma, but has been slower to develop for the treatment of advanced solid tumors. Prostate cancer (PC) represents a good candidate for RIT based upon high exposure to circulating antibodies at common disease sites with a specific, highly expressed cell-surface antigen of prostate-specific membrane antigen. Four phase I and II trials utilizing 177Lu- or 90Y-J591 have been reported. Long-term toxicity and chemotherapy administration was analyzed. As expected, the only serious toxicity observed was myelosuppression. Grade 4 thrombocytopenia occurred in 33.3% without significant hemorrhage and grade 4 neutropenia occurred in 17.3% with 0.07% febrile neutropenia. Nearly all subjects (97.3%) recovered to grade 0 or 1 platelets and all had complete neutrophil recovery. The majority (81.3%) received chemotherapy at any time, with 61.3% receiving chemotherapy following RIT. Ten subjects underwent bone marrow biopsies at some point in their disease course following RIT for low counts; all had diffuse PC infiltration without evidence of myelodysplasia or leukemia. As expected, myelosuppression occurs following therapeutic doses of RIT for men with metastatic castration-resistant PC. However, toxicity is predictable and self-limited, with the majority of patients who do not refuse able to receive cytotoxic chemotherapy following RIT. PMID:23986881

  10. VIDA: a voxel-based dosimetry method for targeted radionuclide therapy using Geant4.

    PubMed

    Kost, Susan D; Dewaraja, Yuni K; Abramson, Richard G; Stabin, Michael G

    2015-02-01

    We have developed the Voxel-Based Internal Dosimetry Application (VIDA) to provide patient-specific dosimetry in targeted radionuclide therapy performing Monte Carlo simulations of radiation transport with the Geant4 toolkit. The code generates voxel-level dose rate maps using anatomical and physiological data taken from individual patients. Voxel level dose rate curves are then fit and integrated to yield a spatial map of radiation absorbed dose. In this article, we present validation studies using established dosimetry results, including self-dose factors (DFs) from the OLINDA/EXM program for uniform activity in unit density spheres and organ self- and cross-organ DFs in the Radiation Dose Assessment Resource (RADAR) reference adult phantom. The comparison with reference data demonstrated agreement within 5% for self-DFs to spheres and reference phantom source organs for four common radionuclides used in targeted therapy ((131)I, (90)Y, (111)In, (177)Lu). Agreement within 9% was achieved for cross-organ DFs. We also present dose estimates to normal tissues and tumors from studies of two non-Hodgkin Lymphoma patients treated by (131)I radioimmunotherapy, with comparison to results generated independently with another dosimetry code. A relative difference of 12% or less was found between methods for mean absorbed tumor doses accounting for tumor regression. PMID:25594357

  11. Current Status of Prostate-Specific Membrane Antigen Targeting in Nuclear Medicine: Clinical Translation of Chelator Containing Prostate-Specific Membrane Antigen Ligands Into Diagnostics and Therapy for Prostate Cancer.

    PubMed

    Kratochwil, Clemens; Afshar-Oromieh, Ali; Kopka, Klaus; Haberkorn, Uwe; Giesel, Frederik L

    2016-09-01

    The prostate-specific membrane antigen (PSMA) is expressed by approximately 90% of prostate carcinomas. The expression correlates with unfavorable prognostic factors, such as a high Gleason score, infiltrative growth, metastasis, and hormone-independence. The high specificity, especially in the undifferentiated stage, makes it an excellent target for diagnosis and therapy. Therefore, antibodies and small molecule inhibitors have been developed for imaging and therapy. In 2011 PSMA-11, a ligand that consists of the Glu-urea-motif and the chelator HBED-CC, which can be exclusively radiolabeled with (68)Ga for PET imaging, presented the clinical breakthrough for prostate cancer diagnostics. In two large diagnostic studies (n = 319 and n = 248) PET/CT with PSMA-11 successfully localized the recurrent tumor in approximately 90% of patients with biochemical relapse. Integrating PSMA-PET/CT into the planning phase of radiotherapy, the treatment concept is changed in 30%-50% of the patients. The combination of the Glu-urea-motif with DOTA, which can be labeled with several diagnostic and therapeutic radionuclides, opened new avenues for therapeutic usage of the small-molecule PSMA ligands. In the beginning of 2016, there are four confirmative reports (n = 19, n = 24, n = 30, and n = 56) from four different centers reporting a PSA response in approximately 70% of patients treated with (177)Lu-labeled PSMA ligands. In conclusion, the data available up to now indicate a widespread use of PSMA ligands for diagnostic applications with respect to staging, detection of recurrence, or metastases in patients with rising tumor markers and for therapy in case of failure of guideline-compliant treatment. PMID:27553466

  12. Molecular Imaging of Urogenital Diseases

    PubMed Central

    Cho, Steve Y.; Szabo, Zsolt; Morgan, Russell H.

    2013-01-01

    There is an expanding and exciting repertoire of PET imaging radiotracers for urogenital diseases, particularly in prostate cancer, renal cell cancer, and renal function. Prostate cancer is the most commonly diagnosed cancer in men. With growing therapeutics options for the treatment of metastatic and advanced prostate cancer, improved functional imaging of prostate cancer beyond the limitations of conventional computed tomography (CT) and bone scan (BS) is becoming increasingly important for both clinical management and drug development. PET radiotracers beyond 18F-Fluorodeoxyglucose (FDG) for prostate cancer include 18F-Sodium Fluoride, 11C-Choline and 18F-Fluorocholine and 11C-Acetate. Other emerging and promising PET radiotracers include a synthetic L-leucine amino acid analog (anti-18F-FACBC), dihydrotestosterone analog (18F-FDHT) and prostate specific membrane antigen (PSMA) based PET radiotracers (ex. 18F-DCFBC, 89Zr-DFO-J591, 68Ga(HBED-CC)). Larger prospective and comparison trials of these PET radiotracers are needed to establish the role of PET/CT in prostate cancer. Renal cell cancer imaging with FDG PET/CT although available can be limited, especially for detection of the primary tumor. Improved renal cell cancer detection with carbonic anhydrase IX (CAIX) based antibody (124I-girentuximab) and radioimmunotherapy targeting with 177Lu-cG250 appear promising. Evaluation of renal injury by imaging renal perfusion and function with novel PET radiotracers include p-18F-fluorohippurate (18F-PFH) and hippurate m-cyano-p-18F-fluorohippurate (18F-CNPFH) and Rubidium-82 chloride (typically used for myocardial perfusion imaging). Renal receptor imaging of the renal renin angiotensin system with a variety of selective PET radioligands are also becoming available for clinical translation. PMID:24484747

  13. Use of the GEANT4 Monte Carlo to determine three-dimensional dose factors for radionuclide dosimetry

    NASA Astrophysics Data System (ADS)

    Amato, Ernesto; Italiano, Antonio; Minutoli, Fabio; Baldari, Sergio

    2013-04-01

    The voxel-level dosimetry is the most simple and common approach to internal dosimetry of nonuniform distributions of activity within the human body. Aim of this work was to obtain the dose "S" factors (mGy/MBqs) at the voxel level for eight beta and beta-gamma emitting radionuclides commonly used in nuclear medicine diagnostic and therapeutic procedures. We developed a Monte Carlo simulation in GEANT4 of a region of soft tissue as defined by the ICRP, divided into 11×11×11 cubic voxels, 3 mm in side. The simulation used the parameterizations of the electromagnetic interaction optimized for low energy (EEDL, EPDL). The decay of each radionuclide (32P, 90Y, 99mTc, 177Lu, 131I, 153Sm, 186Re, 188Re) were simulated homogeneously distributed within the central voxel (0,0,0), and the energy deposited in the surrounding voxels was mediated on the 8 octants of the three dimensional space, for reasons of symmetry. The results obtained were compared with those available in the literature. While the iodine deviations remain within 16%, for phosphorus, a pure beta emitter, the agreement is very good for self-dose (0,0,0) and good for the dose to first neighbors, while differences are observed ranging from -60% to +100% for voxels far distant from the source. The existence of significant differences in the percentage calculation of the voxel S factors, especially for pure beta emitters such as 32P or 90Y, has already been highlighted by other authors. These data can usefully extend the dosimetric approach based on the voxel to other radionuclides not covered in the available literature.

  14. Significant impact of transient deterioration of renal function on dosimetry in PRRT.

    PubMed

    Van Binnebeek, Sofie; Baete, Kristof; Terwinghe, Christelle; Vanbilloen, Bert; Haustermans, Karin; Mortelmans, Luc; Borbath, Ivan; Van Cutsem, Eric; Verslype, Chris; Mottaghy, Felix M; Verbruggen, Alfons; Deroose, Christophe M

    2013-01-01

    Peptide receptor radionuclide therapy (PRRT), with (90)Y-DOTATOC and (177)Lu-DOTATATE as most clinically used radiopeptides, is widely used in the management of metastatic neuroendocrine tumors. With respect to radiation dosimetry, the kidneys are the critical organ for (90)Y-DOTATOC. Renal irradiation is significant because of reabsorption of the radiopeptide from the proximal tubuli and the resulting retention in the interstitium, mainly in the inner cortical zone. The high energy and consequently wide range in tissue of the yttrium-90 beta particle result in high absorbed doses to the kidney cortex and medulla. Accurate renal dosimetry can help minimizing radiation nephropathy. We report a case of a 69-year-old candidate for PRRT with an acceptable kidney function at the time of screening. When performing (111)In-octreotide pretreatment dosimetry 3 weeks later, we observed a drastic deterioration in kidney function, caused by undisclosed non-steroidal anti-inflammatory drug intake. The calculated kidney biological effective dose (BED) was 153 Gy after four projected cycles. PRRT was canceled as our full-course BED limit is 37 Gy and the patient was switched to morphine analgesics. Renal function normalized after 3 months and repeated dosimetry yielded an acceptable kidney BED of 28 Gy after four projected cycles (7 Gy/cycle). This case emphasizes that acute kidney insufficiency can yield toxic kidney doses in a single therapy cycle, with an inherent risk of persistent renal insufficiency. All clinical factors which might influence kidney function should be verified at screening and before PRRT administration. PMID:22961123

  15. PET/CT and Bremsstrahlung Imaging After 90Y DOTANOC Therapy for Rectal Net With Liver Metastases.

    PubMed

    Abdülrezzak, Ümmühan; Kula, Mustafa; Tutuş, Ahmet; Buyukkaya, Fikret; Karaca, Halit

    2015-10-01

    Peptide receptor radionuclide therapy with Lu or Y is promising with successful results in somatostatin receptor-positive tumors. In all radiation therapies, knowledge of the radiation dose received by the target, and other organs in the body is essential to evaluate the risks and benefits of any procedure. We report a case of liver metastases from a rectal neuroendocrine tumor, which was treated with Y DOTANOC. Posttreatment whole-body planar images were acquired through Bremsstrahlung radiations of Y on a γ-camera, and thoracolumbar PET/CT images were acquired on PET. PMID:26204211

  16. Determination of Radiation Absorbed Dose to Primary Liver Tumors and Normal Liver Tissue Using Post-Radioembolization 90Y PET

    PubMed Central

    Srinivas, Shyam M.; Natarajan, Navin; Kuroiwa, Joshua; Gallagher, Sean; Nasr, Elie; Shah, Shetal N.; DiFilippo, Frank P.; Obuchowski, Nancy; Bazerbashi, Bana; Yu, Naichang; McLennan, Gordon

    2014-01-01

    Background: Radioembolization with Yttrium-90 (90 Y) microspheres is becoming a more widely used transcatheter treatment for unresectable hepatocellular carcinoma (HCC). Using post-treatment 90 Y positron emission tomography/computerized tomography (PET/CT) scans, the distribution of microspheres within the liver can be determined and quantitatively assessed. We studied the radiation dose of 90 Y delivered to liver and treated tumors. Methods: This retrospective study of 56 patients with HCC, including analysis of 98 liver tumors, measured and correlated the dose of radiation delivered to liver tumors and normal liver tissue using glass microspheres (TheraSpheres®) to the frequency of complications with modified response evaluation criteria in solid tumors (mRECIST). 90 Y PET/CT and triphasic liver CT scans were used to contour treated tumor and normal liver regions and determine their respective activity concentrations. An absorbed dose factor was used to convert the measured activity concentration (Bq/mL) to an absorbed dose (Gy). Results: The 98 studied tumors received a mean dose of 169 Gy (mode 90–120 Gy; range 0–570 Gy). Tumor response by mRECIST criteria was performed for 48 tumors that had follow-up scans. There were 21 responders (mean dose 215 Gy) and 27 non-responders (mean dose 167 Gy). The association between mean tumor absorbed dose and response suggests a trend but did not reach statistical significance (p = 0.099). Normal liver tissue received a mean dose of 67 Gy (mode 60–70 Gy; range 10–120 Gy). There was a statistically significant association between absorbed dose to normal liver and the presence of two or more severe complications (p = 0.036). Conclusion: Our cohort of patients showed a possible dose–response trend for the tumors. Collateral dose to normal liver is non-trivial and can have clinical implications. These methods help us understand whether patient adverse events, treatment success, or treatment failure can be attributed to the dose that the tumor or normal liver received. PMID:25353006

  17. Melanoma targeting property of a Lu-177-labeled lactam bridge-cyclized alpha-MSH peptide.

    PubMed

    Guo, Haixun; Miao, Yubin

    2013-04-15

    The purpose of this study was to determine the melanoma targeting property of (177)Lu-DOTA-GGNle-CycMSHhex in B16/F1 melanoma-bearing C57 mice. (177)Lu-DOTA-GGNle-CycMSHhex exhibited high receptor-mediated melanoma uptake and fast urinary clearance. The tumor uptake of (177)Lu-DOTA-GGNle-CycMSHhex was 20.25 ± 4.59 and 21.63 ± 6.27% ID/g at 0.5 and 2h post-injection, respectively. Approximately 83% of injected dose cleared out the body via urinary system at 2h post-injection. (177)Lu-DOTA-GGNle-CycMSHhex showed high tumor to normal organ uptake ratios except for the kidneys. The tumor/kidney uptake ratios of (177)Lu-DOTA-GGNle-CycMSHhex were 2.76 and 1.74 at 2 and 24h post-injection. The melanoma lesions were clearly visualized by SPECT/CT using (177)Lu-DOTA-GGNle-CycMSHhex as an imaging probe at 2h post-injection. Overall, high melanoma uptake coupled with fast urinary clearance of (177)Lu-DOTA-GGNle-CycMSHhex underscored its potential for melanoma treatment in the future. PMID:23473679

  18. Monoclonal antibody-based therapy of a human tumor xenograft with a 177lutetium-labeled immunoconjugate

    SciTech Connect

    Schlom, J.; Siler, K.; Milenic, D.E.; Eggensperger, D.; Colcher, D.; Miller, L.S.; Houchens, D.; Cheng, R.; Kaplan, D.; Goeckeler, W. )

    1991-06-01

    {sup 177}Lutetium ({sup 177}Lu) is a member of the family of elements known as lanthanides or rare earths. Monoclonal antibody (MAb) CC49, a murine IgG1, which is reactive with the tumor-associated antigen, TAG-72, has been shown previously to react with a wide range of human carcinomas; CC49 reacts to a different epitope on the TAG-72 molecule than MAb B72.3 and has a higher binding affinity. We report here the first use of a {sup 177}Lu-labeled immunoconjugate, {sup 177}Lu-CC49, in an experimental therapy model for human carcinoma. {sup 177}Lu-CC49 was shown to delay the growth of established LS-174T human colon carcinomas in athymic mice at a single dose of 50 microCi. Overt toxicity was observed with the administration of approximately 500 microCi of {sup 177}Lu-CC49 in which 5 of 9 mice died of apparent marrow toxicity. A single administration of 200 or 350 microCi of {sup 177}Lu-CC49, however, was shown to eliminate established tumors through the 77-day observation period after MAb administration. Dose fractionation experiments revealed that at least 750 microCi of {sup 177}Lu-CC49 (250 microCi/week for 3 consecutive weeks) was well tolerated in that 9 of 10 mice survived. Moreover, this dose schedule was able to eliminate the growth of relatively large (300 mm3) human colon tumor xenografts in 90% of the animals treated. Single-dose and dose fractionation studies were also carried out with an isotype-matched control MAb, {sup 177}Lu-MOPC-21. In all dose schedules, a large differential was seen between the therapeutic effects of the {sup 177}Lu-CC49 versus that of the {sup 177}Lu-control MAb. The merits and limitations of the use of {sup 177}Lu-labeled immunoconjugates (in particular, {sup 177}Lu-CC49) are discussed in terms of potential novel therapeutics for human carcinoma.

  19. Synthesis and evaluation of Lys¹(α,γ-Folate)Lys³(¹⁷⁷Lu-DOTA)-Bombesin(1-14) as a potential theranostic radiopharmaceutical for breast cancer.

    PubMed

    Aranda-Lara, Liliana; Ferro-Flores, Guillermina; Azorín-Vega, Erika; Ramírez, Flor de María; Jiménez-Mancilla, Nallely; Ocampo-García, Blanca; Santos-Cuevas, Clara; Isaac-Olivé, Keila

    2016-01-01

    The aim of this work was to synthesize Lys(1)(α,γ-Folate)-Lys(3)((177)Lu-DOTA)-Bombesin (1-14) ((177)Lu-Folate-BN), as well as to assess its potential for molecular imaging and targeted radiotherapy of breast tumors expressing folate receptors (FR) and gastrin-releasing peptide receptors (GRPR). Radiation absorbed doses of (177)Lu-Folate-BN (74 MBq, i.v.) estimated in athymic mice with T47D-induced breast tumors (positive to FR and GRPR), showed tumor doses of 23.9±2.1 Gy. T47D-tumors were clearly visible (Micro-SPECT/CT images). (177)Lu-Folate-BN demonstrated properties suitable as a theranostic radiopharmaceutical. PMID:26545016

  20. Beta emitters rhenium-188 and lutetium-177 are equally effective in radioimmunotherapy of HPV-positive experimental cervical cancer.

    PubMed

    Phaeton, Rebecca; Jiang, Zewei; Revskaya, Ekaterina; Fisher, Darrell R; Goldberg, Gary L; Dadachova, Ekaterina

    2016-01-01

    Cervical cancer caused by the infection with the human papillomavirus (HPV) remains the fourth leading killer of women worldwide. Therefore, more efficacious treatments are needed. We are developing radioimmunotherapy (RIT) of HPV-positive cervical cancers by targeting E6 and E7 viral oncoproteins expressed by the cancer cells with the radiolabeled monoclonal antibodies (mAbs). To investigate the influence of different radionuclides on the RIT efficacy-we performed RIT of experimental cervical cancer with Rhenium-188 ((188) Re) and Lutetium-177 ((177) Lu)-labeled mAb C1P5 to E6. The biodistribution of (188) Re- and (177) Lu-labeled C1P5 was performed in nude female mice bearing CasKi cervical cancer xenografts and the radiation dosimetry calculations for the tumors and organs were carried out. For RIT the mice were treated with 7.4 MBq of either (188) Re-C1P5 or (177) Lu-C1P5 or left untreated, and observed for their tumor size for 28 days. The levels of (188) Re- and (177) Lu-C1P5 mAbs-induced double-strand breaks in CasKi tumors were compared on days 5 and 10 post treatment by staining with anti-gamma H2AX antibody. The radiation doses to the heart and lungs were similar for both (177) Lu-C1P5 and (188) Re-C1P5. The dose to the liver was five times higher for (177) Lu-C1P5. The doses to the tumor were 259 and 181 cGy for (177) Lu-C1P5 and (188) Re-C1P5, respectively. RIT with either (177) Lu-C1P5 or (188) Re-C1P5 was equally effective in inhibiting tumor growth when each was compared to the untreated controls (P = 0.001). On day 5 there was a pronounced staining for gamma H2AX foci in (177) Lu-C1P5 group only and on day 10 it was observed in both (177) Lu-C1P5 and (188) Re-C1P5 groups. (188) Re- and (177) Lu-labeled mAbs were equally effective in arresting the growth of CasKi cervical tumors. Thus, both of these radionuclides are candidates for the clinical trials of this approach in patients with advanced, recurrent or metastatic cervical cancer. PMID:26625938

  1. Studies on the Labeling of Ethylenediaminetetramethylene Phosphonic Acid, Methylene Diphosphonate, Sodium Pyrophosphate and Hydroxyapatite with Lutetium-177 for use in Nuclear Medicine.

    PubMed

    Abbasi, Imtiaz Ahmed

    2015-01-01

    For the treatment of skeletal metastasis, a therapeutic radionuclide tagged with a bone seeking ligand is required, while for radiation synovectomy (RS), a therapeutic radionuclide irreversibly attached to pre-formed particles of appropriate size is required. Radio lanthanides are mostly therapeutic, and ligands containing phosphate groups are predominantly bone seekers. Exploiting these facts, number of new therapeutic radiopharmaceuticals could be developed. Labeling of four phosphate containing materials was pursued in the present study. It was hypothesized that various (177)Lu-labeled bone-seeking complexes such as (177)Lu-ethylenediaminetetramethylene phosphonic acid (EDTMP), (177)Lu-methylene diphosphonate (MDP) and (177)Lu-pyrophosphate (PYP) could be developed as agents for palliative radiotherapy of bone pain due to skeletal metastases, and (177)Lu-Hydroxyapatite (HA) could be developed as an agent for radiosynovectomy of small joints. Lyophilized kit vials of EDTMP, MDP and sodium pyrophosphate (Na-PYP) were formulated. HA particles were synthesized locally and purity was checked by high-performance liquid chromatography (HPLC). (177)Lu was labeled with EDTMP, MDP, PYP, and HA and the behavior of all was studied by radio-thin layer chromatography (TLC) radio-HPLC and radio-electrophoresis. Radio-TLC confirmed the labeling. HPLC analysis too verified the labeling. Radio-electrophoresis results depicted peaks for (177)Lu-MDP, (177)Lu-EDTMP and (177)Lu-PYP at 3.37 ± 0.06 cm, 5.53 ± 0.15 cm and 7.03 ± 0.06 cm respectively confirming negative charge on each specie as all migrated toward positive anode. All 3 methods verified the labeling. The study demonstrated that EDTMP, MDP and PYP form stable complexes with (177)Lu in injectable solution form. HA particulates could too be labeled with (177)Lu with high radiochemical yields (>98%) in suspension form. Former three could be utilized as bone-pain palliation agents for the treatment of bone metastases, and

  2. Studies on the Labeling of Ethylenediaminetetramethylene Phosphonic Acid, Methylene Diphosphonate, Sodium Pyrophosphate and Hydroxyapatite with Lutetium-177 for use in Nuclear Medicine

    PubMed Central

    Abbasi, Imtiaz Ahmed

    2015-01-01

    For the treatment of skeletal metastasis, a therapeutic radionuclide tagged with a bone seeking ligand is required, while for radiation synovectomy (RS), a therapeutic radionuclide irreversibly attached to pre-formed particles of appropriate size is required. Radio lanthanides are mostly therapeutic, and ligands containing phosphate groups are predominantly bone seekers. Exploiting these facts, number of new therapeutic radiopharmaceuticals could be developed. Labeling of four phosphate containing materials was pursued in the present study. It was hypothesized that various 177Lu-labeled bone-seeking complexes such as 177Lu-ethylenediaminetetramethylene phosphonic acid (EDTMP), 177Lu-methylene diphosphonate (MDP) and 177Lu-pyrophosphate (PYP) could be developed as agents for palliative radiotherapy of bone pain due to skeletal metastases, and 177Lu-Hydroxyapatite (HA) could be developed as an agent for radiosynovectomy of small joints. Lyophilized kit vials of EDTMP, MDP and sodium pyrophosphate (Na-PYP) were formulated. HA particles were synthesized locally and purity was checked by high-performance liquid chromatography (HPLC). 177Lu was labeled with EDTMP, MDP, PYP, and HA and the behavior of all was studied by radio-thin layer chromatography (TLC) radio-HPLC and radio-electrophoresis. Radio-TLC confirmed the labeling. HPLC analysis too verified the labeling. Radio-electrophoresis results depicted peaks for 177Lu-MDP, 177Lu-EDTMP and 177Lu-PYP at 3.37 ± 0.06 cm, 5.53 ± 0.15 cm and 7.03 ± 0.06 cm respectively confirming negative charge on each specie as all migrated toward positive anode. All 3 methods verified the labeling. The study demonstrated that EDTMP, MDP and PYP form stable complexes with 177Lu in injectable solution form. HA particulates could too be labeled with 177Lu with high radiochemical yields (>98%) in suspension form. Former three could be utilized as bone-pain palliation agents for the treatment of bone metastases, and the later could be

  3. SU-E-J-03: A Comprehensive Comparison Between Alpha and Beta Emitters for Cancer Radioimmunotherapy

    SciTech Connect

    Huang, C.Y.; Guatelli, S; Oborn, B; Allen, B

    2014-06-01

    Purpose: The purpose of this study is to perform a comprehensive comparison of the therapeutic efficacy and cytotoxicity of alpha and beta emitters for Radioimmunotherapy (RIT). For each stage of cancer development, specific models were built for the separate objectives of RIT to be addressed:a) kill isolated cancer cells in transit in the lymphatic and vascular circulation,b) regress avascular cell clusters,c) regress tumor vasculature and tumors. Methods: Because of the nature of short range, high LET alpha and long energy beta radiation and heterogeneous antigen expression among cancer cells, the microdosimetric approach is essential for the RIT assessment. Geant4 based microdosimetric models are developed for the three different stages of cancer progression: cancer cells, cell clusters and tumors. The energy deposition, specific energy resulted from different source distribution in the three models was calculated separately for 4 alpha emitting radioisotopes ({sup 211}At, {sup 213}Bi, {sup 223}Ra and {sup 225}Ac) and 6 beta emitters ({sup 32}P, {sup 33}P, {sup 67}Cu, {sup 90}Y, {sup 131}I and {sup 177}Lu). The cell survival, therapeutic efficacy and cytotoxicity are determined and compared between alpha and beta emitters. Results: We show that internal targeted alpha radiation has advantages over beta radiation for killing isolated cancer cells, regressing small cell clusters and also solid tumors. Alpha particles have much higher dose specificity and potency than beta particles. They can deposit 3 logs more dose than beta emitters to single cells and solid tumor. Tumor control probability relies on deep penetration of radioisotopes to cancer cell clusters and solid tumors. Conclusion: The results of this study provide a quantitative understanding of the efficacy and cytotoxicity of RIT for each stage of cancer development.

  4. Peptide receptor radionuclide therapy with somatostatin analogues in neuroendocrine tumors.

    PubMed

    Giovacchini, Giampiero; Nicolas, Guillaume; Forrer, Flavio

    2012-06-01

    Neuroendocrine tumors (NETs) are rare tumors with variable malignant behavior. The majority of NETs express increased levels of somatostatin (SST) receptors, particularly SST2 receptors. Radiolabeled peptides specific for the SST2 receptors may be used for diagnosis of NETs and for peptide receptor radionuclide therapy (PRRT). [(111)In-DTPA(0)]-octreotide has been the first peptide used for PRRT. This radiolabeled peptide, emitting Auger electrons, often induced symptomatic relief, but objective morphological responses were rarely documented. After the introduction of the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) other peptides, primarily [DOTA(0),Tyr(3)]octreotate (DOTATATE) and [DOTA(0),Tyr(3)]octreotide (DOTATOC) were labeled with (90)Y or (177)Lu and used for therapy applications. The rate of objective response obtained with these radiolabeled peptides ranges between 6% and 46%, owing to differences in inclusion criteria adopted in different studies, length and type of therapy, and criteria of evaluation of the response. The present data in the literature do not allow defining the most suitable peptide and radionuclide for the treatment of NETs. Instead emerging evidence indicates that a combination of nuclides with different physical characteristics might be more effective than the use of a single nuclide. Kidney and bone marrow toxicity are the limiting factors for PRRT. Mild toxicity is often encountered while severe toxicity is rarer. Toxicity could be reduced and therapeutic efficacy enhanced by patient-specific dosimetry. Future directions include different issues of PRRT, such as defining the most suitable treatment scheme, evaluation of new peptides with different affinity profiles to other SST receptor subtypes, and reduction of toxicity. PMID:22292758

  5. Targeted radiotherapy of bone malignancies.

    PubMed

    Jansen, David R; Krijger, Gerard C; Kolar, Zvonimir I; Zonnenberg, Bernard A; Zeevaart, Jan Rijn

    2010-12-01

    The severe pain associated with many disorders affecting bone account for a large proportion of cases of patient morbidity, due to the encumbrance of mobility and therefore, compromised quality of life. Skeletal metastasis is one such condition, which generally complicates the treatment of the primary cancers such as that of the breast, prostate and lung - causing intense pain and eventually even mortality. This paper presents examples of various approaches explored and proposed in the ongoing search to identify better radiopharmaceuticals for the treatment of bone disorders such as metastases. The primary objective of these developments is to alleviate the debilitating pain commonly associated with bone lesions. The efficacy of a radiotherapeutic agent intended for the treatment of diseased bone is particularly dependent on the radiation dose to the tumor cells and on the extent to which suppression of bone marrow or other critical organs can be avoided. Therefore, the design rationale requires careful consideration of the choice radionuclide and especially ensuring that the drug selectively targets the lesion or tumor site. The options pursued include the use of radioisotopes with an intrinsic affinity for bone, such as (89)Sr or (223)Ra, or the design of bone-seeking ligands, such as phosphonates, to selectively deliver the radionuclide to the target, e.g. [(153)Sm]Sm-EDTMP. A combination of the above may too be possible, where the bone seeking ligand facilitates the selective accumulation of a radionuclide, which by itself is also bone homing. In terms of therapeutic application radionuclides with various decay modes are proposed, including beta (-) emitters: (153)Sm, (89)Sr, (186)Re, (188)Re, (32)P, (177)Lu and (170)Tm; alpha (α) emitters: (223)Ra and (225)Ra; and Auger or conversion electron emitter: (117)mSn. From a purely diagnostic perspective, the radioisotopes used for imaging include the well known photon emitting (99)mTc, and positron emitters (18)F

  6. Use of molecular targeted agents for the diagnosis, staging and therapy of neuroendocrine malignancy

    PubMed Central

    2010-01-01

    Abstract Imaging of neuroendocrine tumours (NET) poses significant challenges because of the heterogeneous biology of the tumours that are represented by this class of neoplasia. NET can range from benign lesions to highly aggressive cancers. Structural imaging techniques have suboptimal sensitivity in most published series and diagnosis is often delayed until metastatic disease is present. Current guidelines emphasise the importance of functional imaging for evaluating the extent of NET. The mainstay of this type of imaging has been somatostatin receptor scintigraphy (SRS) with [111In]diethylenetriaminepentaacetic acid-octreotide (Octreoscan™). Routine use of single-photon emission computed tomography (SPECT) and particularly of hybrid SPECT/computed tomography (CT) has significantly improved localisation of tumour sites and evaluation of somatostatin receptor (SSTR) expression, which is important for predicting the likelihood of response to somatostatin analogues (SSA). Positron emission tomography (PET) can also now be used for evaluating SSTR expression. There are a number of peptides that have been evaluated but [68Ga]tetraazocyclodecanetetraacetic acid (DOTA)-octreotate (GaTate) PET/CT, which has been shown to be significantly more sensitive for detecting small lesions than Octreoscan™, is now probably the preferred agent because high uptake in known sites of disease provides a diagnostic pair for assessing suitability of patients for [177Lu]DOTA-octreotate (LuTate) peptide receptor radionuclide therapy (PRRT). A range of other radiolabelled SSA has also been used for PRRT. Lesions without SSTR expression require alternative imaging and therapeutic strategies. Although fluorodeoxyglucose (FDG) uptake in low-grade NET is not generally increased relative to normal tissues, the loss of differentiation that often accompanies loss of SSTR expression may be associated with a significant increase in glycolytic metabolism and an accompanying improvement in the

  7. SU-E-CAMPUS-I-05: Internal Dosimetric Calculations for Several Imaging Radiopharmaceuticals in Preclinical Studies and Quantitative Assessment of the Mouse Size Impact On Them. Realistic Monte Carlo Simulations Based On the 4D-MOBY Model

    SciTech Connect

    Kostou, T; Papadimitroulas, P; Kagadis, GC; Loudos, G

    2014-06-15

    Purpose: Commonly used radiopharmaceuticals were tested to define the most important dosimetric factors in preclinical studies. Dosimetric calculations were applied in two different whole-body mouse models, with varying organ size, so as to determine their impact on absorbed doses and S-values. Organ mass influence was evaluated with computational models and Monte Carlo(MC) simulations. Methods: MC simulations were executed on GATE to determine dose distribution in the 4D digital MOBY mouse phantom. Two mouse models, 28 and 34 g respectively, were constructed based on realistic preclinical exams to calculate the absorbed doses and S-values of five commonly used radionuclides in SPECT/PET studies (18F, 68Ga, 177Lu, 111In and 99mTc).Radionuclide biodistributions were obtained from literature. Realistic statistics (uncertainty lower than 4.5%) were acquired using the standard physical model in Geant4. Comparisons of the dosimetric calculations on the two different phantoms for each radiopharmaceutical are presented. Results: Dose per organ in mGy was calculated for all radiopharmaceuticals. The two models introduced a difference of 0.69% in their brain masses, while the largest differences were observed in the marrow 18.98% and in the thyroid 18.65% masses.Furthermore, S-values of the most important target-organs were calculated for each isotope. Source-organ was selected to be the whole mouse body.Differences on the S-factors were observed in the 6.0–30.0% range. Tables with all the calculations as reference dosimetric data were developed. Conclusion: Accurate dose per organ and the most appropriate S-values are derived for specific preclinical studies. The impact of the mouse model size is rather high (up to 30% for a 17.65% difference in the total mass), and thus accurate definition of the organ mass is a crucial parameter for self-absorbed S values calculation.Our goal is to extent the study for accurate estimations in small animal imaging, whereas it is known

  8. Society of Nuclear Medicine--57th annual meeting.

    PubMed

    Searle, Ben

    2010-08-01

    The 57th Annual Meeting of the Society of Nuclear Medicine, held in Salt Lake City, UT, USA, included topics covering new developments in imaging agents and radiopharmaceutical therapies in the field of nuclear medicine. This conference report highlights selected presentations related to imaging of the brain, the prediction of heart disease, and the detection and treatment of various cancers. Investigational drugs discussed include TF-2 plus [68Ga]IMP-288 and TF-2 plus [111In]IMP-288 (both Immunomedics Inc), [11C]PBR-170 (Royal Prince Alfred Hospital/Australian Nuclear Science & Technology Organization), [11C]LY-2795050 (Eli Lilly & Co), yttrium (90Y) clivatuzumab tetraxetan (Garden State Cancer Center/Immunomedics Inc), [18F]LMI-1195 (Lantheus Medical Imaging Inc), fluciclovine (18F) (GE Healthcare/Nihon Medi-Physics Co Ltd), [99mTc]MIP-1340 and [99mTc]MIP-1407 (both Molecular Insight Pharmaceuticals Inc). PMID:20721816

  9. Phase I study of radioimmunotherapy with an anti-CD20 murine radioimmunoconjugate ((90)Y-ibritumomab tiuxetan) in relapsed or refractory indolent B-cell lymphoma.

    PubMed

    Watanabe, Takashi; Terui, Shoji; Itoh, Kuniaki; Terauchi, Takashi; Igarashi, Tadahiko; Usubuchi, Noriko; Nakata, Masanobu; Nawano, Shigeru; Sekiguchi, Naohiro; Kusumoto, Shigeru; Tanimoto, Kazuki; Kobayashi, Yukio; Endo, Keigo; Seriu, Taku; Hayashi, Masaki; Tobinai, Kensei

    2005-12-01

    We conducted a phase I study to evaluate the safety and efficacy of radioimmunotherapy with yttrium-90-ibritumomab tiuxetan (Y2B8) in Japanese patients with relapsed or refractory indolent B-cell lymphoma. Indium-111-labeled ibritumomab tiuxetan (In2B8; 3.5 or 5 mCi [129.5 or 185 MBq]) was administered on day 1, followed by serial gamma-camera imaging to investigate the distribution of In2B8 in the whole body of patients and to judge the feasibility of Y2B8 administration. Y2B8 with a dose of 0.3 mCi/kg (11.1 MBq/kg) or 0.4 mCi/kg (14.8 MBq/kg) was administered on day 8. Grade 4 neutropenia and grade 3 thrombocytopenia were observed in three of nine of the patients evaluated for safety. Critical toxicities (prolonged thrombocytopenia or severe non-hematological toxicities) were observed in two of six patients in the 0.4 mCi/kg (14.8 MBq/kg) dose group but were not seen in any of the three patients in the 0.3 mCi/kg (11.1 MBq/kg) dose group. The non-hematological toxicities of the nine patients were of grade 2 or less, except in two patients who had been heavily treated previously. They experienced critical toxicities such as infection, diarrhea, hyponatremia and prolonged thrombocytopenia, as well as other frequent grade 2 non-hematological toxicities. Although the pharmacokinetic profiles were similar to those in the US study, one of the two patients was clarified retrospectively as showing abnormal biodistribution of In2B8 in the bone marrow, as judged by an independent third party panel of radiologists. Five of the 10 participants achieved complete responses or unconfirmed complete responses and two partial responses. In conclusion, the recommended dose of Y2B8 for the subsequent phase II study for Japanese patients is 0.4 mCi/kg (14.8 MBq/kg). This dose of radioimmunotherapy was feasible when patients with altered biodistribution of In2B8 were excluded, and it was highly effective. (Cancer Sci 2005; 96: 903-910). PMID:16367911

  10. Long-lived impurities of 90Y-labeled microspheres, TheraSphere and SIR-spheres, and the impact on patient dose and waste management.

    PubMed

    Metyko, John; Williford, John M; Erwin, William; Poston, John; Jimenez, Sandra

    2012-11-01

    Yittrium-90 microsphere brachytherapy procedures have increased in number due to their efficacy in treating some unresectable metastatic liver tumors. The discovery of long-lived impurities in two microsphere products, first reported between 2006 and 2007, has resulted in some radiation safety concerns. Since then, microsphere production processes have been refined, which reportedly lead to a reduction in detectable by-products. In this study unused vials of TheraSphere and SIR-Spheres, manufactured in early January 2011, were analyzed to identify and quantify the low-level radioactive impurities. Absorbed dose calculations were performed to assess the potential increased dose to the patient due to long-lived impurities. Results showed that while the SIR-Spheres vials contained no detectable impurities (contrary to other published results in the literature), the TheraSphere vials contained 17 radionuclides in one sample and 15 in the other. The dominant impurities were Y and Y, with specific activities ranging from 0.99 ± 3.40 × 10 kBq mg to 6.30 ± 0.40 kBq mg at vendor assay date. Other impurities were on the order of Bq mg. Based on Medical Internal Radiation Dose (MIRD) liver and lung dose estimates, the long-lived impurities would be expected to increase an administered dose by less than 0.1% from the prescribed dose. PMID:23026974

  11. Electron-Ion Mixed Conduction of BaCe0.90Y0.10O3-δ Thin Film Generated by Ru Substitution

    NASA Astrophysics Data System (ADS)

    Ochi, Masanori; Tsuchiya, Takashi; Yamaguchi, Shohei; Suetsugu, Takaaki; Suzuki, Naoya; Kobayashi, Masaki; Minohara, Makoto; Horiba, Koji; Kumigashira, Hiroshi; Higuchi, Tohru

    2016-03-01

    The structural and electrical properties of a c-axis-oriented BaCe0.85Ru0.05Y0.10O3-δ (BCRY) thin film on an Al2O3(0001) substrate depending on film thickness have been studied. The lattice constant of the c-axis decreases with increasing film thickness. The electrical conductivity is higher in the thin film with a small lattice constant. The activation energy (EA) of the dry BCRY thin film with a high conductivity is 0.26 eV, which corresponds to half of that of the bulk ceramic. The BCRY thin film exhibits electron-ion mixed conduction with a small EA of 0.18 eV below 400 °C in H2O atmosphere. The Ce3+ state created by oxygen vacancies, which locates at the top of the valence band, plays an important role in the electron-ion mixed conduction or proton conduction of the BCRY thin film.

  12. Recommendations of the American Association of Physicists in Medicine on dosimetry, imaging, and quality assurance procedures for {sup 90}Y microsphere brachytherapy in the treatment of hepatic malignancies

    SciTech Connect

    Dezarn, William A.; Cessna, Jeffery T.; DeWerd, Larry A.; and others

    2011-08-15

    Yttrium-90 microsphere brachytherapy of the liver exploits the distinctive features of the liver anatomy to treat liver malignancies with beta radiation and is gaining more wide spread clinical use. This report provides a general overview of microsphere liver brachytherapy and assists the treatment team in creating local treatment practices to provide safe and efficient patient treatment. Suggestions for future improvements are incorporated with the basic rationale for the therapy and currently used procedures. Imaging modalities utilized and their respective quality assurance are discussed. General as well as vendor specific delivery procedures are reviewed. The current dosimetry models are reviewed and suggestions for dosimetry advancement are made. Beta activity standards are reviewed and vendor implementation strategies are discussed. Radioactive material licensing and radiation safety are discussed given the unique requirements of microsphere brachytherapy. A general, team-based quality assurance program is reviewed to provide guidance for the creation of the local procedures. Finally, recommendations are given on how to deliver the current state of the art treatments and directions for future improvements in the therapy.

  13. Changes in Normal Liver and Spleen Volume after Radioembolization with {sup 90}Y-Resin Microspheres in Metastatic Breast Cancer Patients: Findings and Clinical Significance

    SciTech Connect

    Paprottka, Philipp M. Schmidt, G. P.; Trumm, C. G.; Hoffmann, R. T.; Reiser, M. F.; Jakobs, T. F.

    2011-10-15

    Purpose: In clinical trials with yttrium-90-resin-microspheres for the management of colorectal cancer liver metastases, it was observed that radioembolization might result in splenomegaly and an increase in portal vein size. Subclinical hepatitis in normal liver tissue as well as the effects of radioembolization and prior chemotherapy are suspected to be responsible for this phenomenon. The purpose of this study was to quantify the changes in liver and spleen volume and portal vein diameter after radioembolization. Methods: Twenty-seven patients with liver-dominant metastatic disease from breast cancer who had not responded to chemotherapy or had to abandon chemotherapy because of its toxic effects were evaluated. Changes in liver and spleen volume and portal vein diameter as well as liver tumor volume and diameter were quantified using computed tomography scans. Results: Radioembolization was associated with a significant mean decrease in the whole liver volume of 10.2% (median 16.7%; P = 0.0024), mainly caused by a reduction in the right lobe volume (mean 16.0%; P < 0.0001). These changes were accompanied by a significant increase in the diameter of the main portal vein (mean 6.8%; P < 0.0001) as well as splenic volume (mean 50.4%; P < 0.0001). Liver-tumor volume and diameter decreased by a median of 24 and 39.7%. Conclusions: Radioembolization is an effective treatment for tumor size reduction in patients with breast cancer liver metastases. Treatment is associated with changes of hepatic parenchymal volume, splenic volume, and portal vein size that appear not to represent clinically important sequelae in this patient cohort.

  14. Pharmacokinetic, Dosimetry and Toxicity Study of ¹⁷⁷Lu-EDTMP in Patients: Phase 0/I study.

    PubMed

    Bal, Chandrasekhar; Arora, Geetanjali; Kumar, Praveen; Damle, Nishikant; Das, Tapas; Chakraborty, Sudipta; Banerjee, Sharmila; Venkatesh, Meera; Zaknun, John J; Pillai, M R A

    2016-01-01

    177Lu-EDTMP has been proposed as a potent bone pain palliation agent owing to theoretical advantage of reduced bone marrow suppression resulting from the low β(-) energy and a suitably long half-life facilitating its wider distribution with less loss from radioactive decay. Herein, we report the pharmacokinetics, dosimetry and toxicity analysis of 177Lu-EDTMP in patients (phase-0/I study). In a phase-0 study, the biokinetics of skeletal and non-skeletal uptake of 177Lu-EDTMP was assessed in 6 patients with metastatic prostate cancer using tracer doses (172.7-206.9MBq). Data of whole skeletal uptake, blood and fractionated urine samples were obtained and dosimetric calculations were performed using the OLINDA/EXM 1.0 software. Prolonged bone retention was observed in all patients. Excretion was mainly via the renal route and blood clearance was rapid and biphasic. Mean estimated red marrow dose was 0.80±0.15mGy/MBq while mean total-body dose was 0.16±0.04mGy/MBq. A maximum tolerated dose (MTD) of 2000-3250MBqfor 177Lu-EDTMP was calculated. For the phase-I study, 21 patients with metastatic prostate cancer were given a therapeutic dose of 177Lu- EDTMP (692-5550MBq). Toxiciy (WHO), evaluated by assessment of hemoglobin levels, platelet and leukocyte counts over 12 weeks, was mainly limited to anemia or thrombocytopenia. Only transient toxicity was observed in 14/21 patients, of which 6 had baseline toxicity. Beyond the MTD, a significantly higher number of patients displayed grade 3-4 toxicity. Pain relief, assessed by VAS pain score, was observed in 86% patients with median relief duration of 7 weeks. The results demonstrate that 177Lu-EDTMP has excellent pharmacokinetic and dosimetric properties, besides being safe and effective. Along with estimating radiation dose values to certain critical organs, we have also proposed an MTD for 177Lu-EDTMP that correlated well with toxicity data. The encouraging dosimetry and toxicity data of 177Lu-EDTMP reported provide the

  15. Lu-177 preparation for radiotherapy application.

    PubMed

    Park, Ul Jae; Lee, Jun-Sig; Choi, Kang Hyuk; Nam, Sung Soo; Yu, Kook Hyun

    2016-09-01

    A separation study using a (176)Yb target for the preparation of nca (177)Lu, which is a beta-emitting nuclide used not only in radioimmunotherapy applications but also in the treatment of various lesions, has been performed. A material having a better selectivity and separation efficiency for Lu than Yb was developed, and the separation conditions of (177)Lu were derived using this from a neutron irradiated (176)Yb target. The separation material was an organo-ceramic hybrid material containing a phosphate group. Adsorption behavior was determined through batch experiments, and (177)Lu separation from the Yb target was evaluated through column experiments. The Yb target, with a 99.72% in (176)Yb, was irradiated in the irradiation hole of HANARO, which has a thermal neutron flux of 1.6E+14ncm(-2)s(-1). The batch experiments revealed that the organo-ceramic hybrid material (Sol-POS) had a separation factor of 1.6 at 0.5M HCl. Separation was performed through extraction chromatography using a 5mg enriched Yb target, and the separation yield of the NCA (177)Lu was about 78%. If the amount of Yb target is increased to produce curies level (177)Lu, additional purification will be needed. PMID:27295512

  16. Beta camera for static and dynamic imaging of charged-particle emitting radionuclides in biologic samples

    SciTech Connect

    Ljunggren, K.; Strand, S.E. )

    1990-12-01

    A detection system based on microchannel plates has been constructed to image charged particles emitted by radionuclides in biomedical samples. This technique has significant advantages over conventional film autoradiography