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Sample records for 177lu 51cr 153sm

  1. 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.

  2. 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.

  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. 177Lu-labeled Gold Nanoparticles for Radiation Therapy of Locally Advanced Breast Cancer

    NASA Astrophysics Data System (ADS)

    Yook, Simmyung

    Locally advanced breast cancer (LABC) occurs in about 10-15% of patients diagnosed with breast cancer (BC) and 30% of these patients have triple negative breast cancer (TNBC) that are often epidermal growth factor receptor (EGFR)-positive. The goal of the proposed research was design and evaluate preclinically a novel radiation nanomedicine for LABC composed of EGFR-targeted gold nanoparticles (AuNP) by covalently conjugating panitumumab and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) complexing 177Lu incorporated into a metal-chelating polymer (MCP) (177 Lu-T-AuNP) which could be used as a neoadjuvant treatment to improve the outcome of patients with LABC. 177Lu-T-AuNP were efficiently internalized by EGFR-positive BC cells and were significantly more effective than 177Lu-labeled and non-targeted (NT)-AuNP for killing these cells. For radiation treatment of EGFR-positive tumours, both 177Lu-T-AuNP and 177Lu-NT-AuNP were intratumourally (i.t.) injected into athymic mice with MDA-MB-468 BC xenografts for comparison. Biodistribution studies showed that 177Lu-T-AuNPs exhibited 2-fold higher tumour retention than 177Lu-NT-AuNPs following i.t. injection at 48 h p.i. Both forms of radiolabeled AuNP were highly effective for inhibiting tumour growth without normal organ toxicity due to local tumour retention of both form of AuNP. To minimize the displacement of 177Lu-labeled MCP from AuNP, polyethylene glycol (PEG) ligands presenting a disulfide [ 177Lu-DOTA-PEG-ortho-pyridyl disulfide (OPSS)], a lipoic acid (LA) [177Lu-DOTA-PEG-lipoic acid (LA)] or multi-LA [PEG- pGlu(177Lu-DOTA)8-LA4] for multivalent binding were synthesized and the stability of MCP-AuNP complexes determined. In vitro challenge study with thiol-containing molecules or human plasma, PEG-pGlu(DOTA)8-LA4-AuNP were most stable. In whole body elimination study, elimination of radioactivity due to displacement of 177Lu-MCP from AuNP in mice injected with 177Lu-DOTA-PEG-OPSS-AuNP was more

  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%).

  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. 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.

  8. 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).

  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. Potential therapeutic radiotracers: preparation, biodistribution and metabolic characteristics of 177Lu-labeled cyclic RGDfK dimer.

    PubMed

    Shi, Jiyun; Liu, Zhaofei; Jia, Bing; Yu, Zilin; Zhao, Huiyun; Wang, Fan

    2010-06-01

    In this study, we reported the preparation and evaluation of (177)Lu-DOTA-RGD2, (177)Lu-DOTA-Bz-RGD2 and (177)Lu-DTPA-Bz-RGD2 (RGD2 = E[c(RGDfK)](2)) as a potential therapeutic radiotracers for the treatment of integrin alpha(v)beta(3)-positive tumors. The BALB/c nude mice bearing the U87MG human glioma xenografts were used to evaluate the biodistribution characteristics and excretion kinetics of (177)Lu-DOTA-RGD2, (177)Lu-DOTA-Bz-RGD2 and (177)Lu-DTPA-Bz-RGD2. It was found that there were no major differences in their lipophilicity and biodistribution characteristics, particularly at latter time points. A major advantage of using DTPA-Bz as the bifunctional chelator (BFC) was its high radiolabeling efficiency (fast and high yield radiolabeling) at room temperature. Using DOTA and DOTA-Bz as BFCs, the radiolabeling kinetics was slow, and heating at 100 degrees C and higher DOTA-conjugate concentration were needed for successful (177)Lu-labeling. Therefore, DTPA-Bz is an optimal BFC for routine preparation of (177)Lu-labeled cyclic RGDfK peptides, and (177)Lu-DTPA-Bz-RGD2 is worthy of further investigation for targeted radiotherapy of integrin alpha(v)beta(3)-positive tumors.

  11. Standardization and measurement of gamma-ray probability per decay of 177Lu.

    PubMed

    Dias, Mauro S; Silva, Fabrício F V; Koskinas, Marina F

    2010-01-01

    The procedure followed by the Nuclear Metrology Laboratory (LMN), at the Nuclear and Energy Research Institute (IPEN), for the primary standardization of (177)Lu is described. This radionuclide is widely used in radiopharmacy due to its convenient half-life and emitted beta ray energies. The (177)Lu solution was supplied during an international comparison sponsored by BIPM in 2009 and the primary standardization has been accomplished by the 4pibeta-gamma coincidence method using a proportional counter in 4pi geometry coupled with two NaI(Tl) scintillation counters. The beta efficiency was varied by placing Collodion and aluminum absorbers over and under the radioactive source. The (177)Lu calibrated sources were also measured in a previously calibrated HPGe spectrometer, in order to obtain the emission probability per decay for the selected gamma-ray transitions. The experimental extrapolation curves were also compared with Monte Carlo simulations by means of code ESQUEMA developed at the LMN.

  12. 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.

  13. 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

  14. (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

  15. Camptothecin Enhances Cell Death Induced by (177)Lu-EDTMP in Osteosarcoma Cells.

    PubMed

    Kumar, Chandan; Vats, Kusum; Lohar, Sharad P; Korde, Aruna; Samuel, Grace

    2014-10-01

    Lutetium-177 is an assured therapeutic radionuclide with favorable half-life and suitable β(-) energy. Radiolabeled (177)Lu-EDTMP (Ethylenediamine tetramethylene phosphonic acid) is by and large used for bone pain palliation in cancer patients. In vitro cell studies are carried out in osteosarcoma cells MG-63 to evaluate the combined effect of anticancer drug camptothecin (CPT) and (177)Lu-EDTMP. Two concentrations of (177)Lu-EDTMP (3.7 and 37 MBq) were incubated with MG63 cell line for 48 hours with and without pretreatment of CPT (10 nM) for 1 hour. After completion of incubation, the cells were harvested and cellular toxicity was estimated by LDH, MTT, and trypan blue dye. Apoptotic DNA fragmentation was estimated by ELISA kit. The expression of proteins such as bcl2, PARP, and MAPK (mitogen-activated protein kinase) that were related to apoptotic signaling pathways was assessed by western blotting. The results indicated that cellular toxicity and apoptosis were relatively higher in MG63 cells that were treated with CPT prior to treating with (177)Lu-EDTMP in comparison with the corresponding individual controls.

  16. 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.

  17. Practical aspects of peptide receptor radionuclide therapy with [177Lu][DOTA0, Tyr3]octreotate.

    PubMed

    Bakker, W H; Breeman, W A P; Kwekkeboom, D J; De Jong, L C; Krenning, E P

    2006-12-01

    Lutetium-177 is increasingly used in patients for receptor-targeted radionuclide therapy with peptides such as [DOTA0,Tyr3]octreotate. In our therapy facility, we are performing yearly 400 treatments with each 7.4 GBq [177Lu][DOTA0,Tyr3]octreotate. Finger dosimetry data during radiolabeling reveal higher doses on the right hands of right-handed workers with the highest equivalent dose for the middle finger (53+/-12 microSv/GBq). Extrapolating dosimetry data, assuming 400 doses of 7.4 GBq per year performed by 4 workers, result in a mean equivalent dose of 23+/-11 mSv and 14+/-6 mSv for finger top and ring dose, respectively. Preparation of 400 doses will result in an effective dose of 0.5-1.5 mSv per year for these 4 workers. The extra radiation dose for workers during the radiolabeling of these doses thus remains below 10% of the legal annual limits, which is in accordance with the ALARA optimization principle. Based on measurements of the maximal radiation level at 1 m distance (7.5+/-3.6 microSv/h), patients treated with 7.4 GBq [177Lu][DOTA0,Tyr3]octreotate can already leave the therapy facility the next day. As radioactive waste streams are based on the half-lives of the used radionuclides, 177Lu-waste (t1/2=6.7 d) was initially collected along with the 131I-waste (t1/2=8 d). According to both manufacturers' specifications, 177Lu contains less than 0.4 kBq 177mLu/MBq 177Lu (at the end of neutron irradiation), when produced by the [176Lu n, gamma 177Lu] reaction via thermal neutron bombardment of enriched lutetium oxide. Unfortunately, because of the huge amounts of 177Lu used, contaminating 177mLu turned out to prevent the quick discharge of this waste, for some containers even after some years of storage. Therefore, a technique for calibrating 177mLu was developed, simultaneously confirming the manufacturer's specifications on the presence of 177mLu in 177Lu. Subsequently a reliable technique was developed to measure 177mLu in waste containers using a beta

  18. Radioactivity measurements of 177Lu, 111In and 123I by different absolute methods.

    PubMed

    Rezende, E A; Correia, A R; Iwahara, A; da Silva, C J; Tauhata, L; Poledna, R; da Silva, R L; de Oliveira, E M; de Oliveira, A E

    2012-09-01

    The activities of (177)Lu, (111)In and (123)I solutions have been absolutely determined using three different measurement methods. (177)Lu solution was standardized using the 4πβ(PC)-γ(NaI) coincidence and 4πβ(LS)-γ(NaI) live-timed anticoincidence methods. For the (111)In and (123)I solutions, besides these two mentioned methods, the coincidence sum-peak method was also applied. The measured activities results using these different methods are consistent within the evaluated experimental uncertainties demonstrating the equivalence of these methods. As an additional contribution to nuclear data, the half-lives have been determined using a well type IG12 ionization chamber.

  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. Radioactivity measurements of 177Lu, 111In and 123I by different absolute methods.

    PubMed

    Rezende, E A; Correia, A R; Iwahara, A; da Silva, C J; Tauhata, L; Poledna, R; da Silva, R L; de Oliveira, E M; de Oliveira, A E

    2012-09-01

    The activities of (177)Lu, (111)In and (123)I solutions have been absolutely determined using three different measurement methods. (177)Lu solution was standardized using the 4πβ(PC)-γ(NaI) coincidence and 4πβ(LS)-γ(NaI) live-timed anticoincidence methods. For the (111)In and (123)I solutions, besides these two mentioned methods, the coincidence sum-peak method was also applied. The measured activities results using these different methods are consistent within the evaluated experimental uncertainties demonstrating the equivalence of these methods. As an additional contribution to nuclear data, the half-lives have been determined using a well type IG12 ionization chamber. PMID:22401938

  1. [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

  2. 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

  3. (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.

  4. (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

  5. 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.

  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. 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

  9. 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

  10. (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

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

    DOE PAGES

    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

  12. 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

  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.

  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. 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

  16. 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

  17. 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.

  18. 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.

  19. 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.

  20. Realistic multi-cellular dosimetry for 177Lu-labelled antibodies: model and application

    NASA Astrophysics Data System (ADS)

    Marcatili, S.; Pichard, A.; Courteau, A.; Ladjohounlou, R.; Navarro-Teulon, I.; Repetto-Llamazares, A.; Heyerdahl, H.; Dahle, J.; Pouget, J. P.; Bardiès, M.

    2016-10-01

    Current preclinical dosimetric models often fail to take account of the complex nature of absorbed dose distribution typical of in vitro clonogenic experiments in targeted radionuclide therapy. For this reason, clonogenic survival is often expressed as a function of added activity rather than the absorbed dose delivered to cells/cell nuclei. We designed a multi-cellular dosimetry model that takes into account the realistic distributions of cells in the Petri dish, for the establishment of survival curves as a function of the absorbed dose. General-purpose software tools were used for the generation of realistic, randomised 3D cell culture geometries based on experimentally determined parameters (cell size, cell density, cluster density, average cluster size, cell cumulated activity). A mixture of Monte Carlo and analytical approaches was implemented in order to achieve as accurate as possible results while reducing calculation time. The model was here applied to clonogenic survival experiments carried out to compare the efficacy of Betalutin®, a novel 177Lu-labelled antibody radionuclide conjugate for the treatment of non-Hodgkin lymphoma, to that of 177Lu-labelled CD20-specific (rituximab) and non-specific antibodies (Erbitux) on lymphocyte B cells. The 3D cellular model developed allowed a better understanding of the radiative and non-radiative processes associated with cellular death. Our approach is generic and can also be applied to other radiopharmaceuticals and cell distributions.

  1. Synthesis and comparative biological evaluation of bifunctional ligands for radiotherapy applications of (90)Y and (177)Lu.

    PubMed

    Chong, Hyun-Soon; Sun, Xiang; Chen, Yunwei; Sin, Inseok; Kang, Chi Soo; Lewis, Michael R; Liu, Dijie; Ruthengael, Varyanna C; Zhong, Yongliang; Wu, Ningjie; Song, Hyun A

    2015-03-01

    Zevalin® is an antibody-drug conjugate radiolabeled with a cytotoxic radioisotope ((90)Y) that was approved for radioimmunotherapy (RIT) of B-cell non-Hodgkin's lymphoma. A bifunctional ligand that displays favorable complexation kinetics and in vivo stability is required for effective RIT. New bifunctional ligands 3p-C-DE4TA and 3p-C-NE3TA for potential use in RIT were efficiently prepared by the synthetic route based on regiospecific ring opening of aziridinium ions with prealkylated triaza- or tetraaza-backboned macrocycles. The new bifunctional ligands 3p-C-DE4TA and 3p-C-NE3TA along with the known bimodal ligands 3p-C-NETA and 3p-C-DEPA were comparatively evaluated for potential use in targeted radiotherapy using β-emitting radionuclides (90)Y and (177)Lu. The bifunctional ligands were evaluated for radiolabeling kinetics with (90)Y and (177)Lu, and the corresponding (90)Y or (177)Lu-radiolabeled complexes were studied for in vitro stability in human serum and in vivo biodistribution in mice. The results of the comparative complexation kinetic and stability studies indicate that size of macrocyclic cavity, ligand denticity, and bimodality of donor groups have a substantial impact on complexation of the bifunctional ligands with the radiolanthanides. The new promising bifunctional chelates in the DE4TA and NE3TA series were rapid in binding (90)Y and (177)Lu, and the corresponding (90)Y- and (177)Lu-radiolabeled complexes remained inert in human serum or in mice. The in vitro and in vivo data show that 3p-C-DE4TA and 3p-C-NE3TA are promising bifunctional ligands for targeted radiotherapy applications of (90)Y and (177)Lu.

  2. 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

  3. 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

  4. 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.

  5. 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

  6. 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

  7. 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.

  8. 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

  9. 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.

  10. 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.

  11. Targeted radionuclide therapy with A 177Lu-labeled anti-HER2 nanobody.

    PubMed

    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 therapy

  12. Estimation of specific activity of 177Lu by 'saturation assay' principle using DOTA as ligand.

    PubMed

    Pillai, Ambikalmajan M R; Chakraborty, Sudipta; Das, Tapas

    2015-01-01

    Lutetium-177 is a widely used therapeutic radionuclide in targeted therapy and it is important to know its specific activity at the time of radiopharmaceutical preparation, especially for radiolabeling peptides. However, there are no direct methods for the experimental determination of the specific activity which can be readily applied in a hospital radiopharmacy. A new technique based on the 'saturation assay' principle using DOTA as the binding agent for the estimation of specific activity of (177)Lu is reported. The studies demonstrate the proof of principle of this new assay technique. The method is general and can be modified and applied for the estimation of specific activity of other metallic radionuclides by using DOTA or other suitable chelating agents.

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  1. 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.

  2. [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

  3. 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.

  4. uPAR targeted radionuclide therapy with (177)Lu-DOTA-AE105 inhibits dissemination of metastatic prostate cancer.

    PubMed

    Persson, Morten; Juhl, Karina; Rasmussen, Palle; Brandt-Larsen, Malene; Madsen, Jacob; Ploug, Michael; Kjaer, Andreas

    2014-08-01

    The urokinase-type plasminogen activator receptor (uPAR) is implicated in cancer invasion and metastatic development in prostate cancer and provides therefore an attractive molecular target for both imaging and therapy. In this study, we provide the first in vivo data on an antimetastatic effect of uPAR radionuclide targeted therapy in such lesions and show the potential of uPAR positron emission tomography (PET) imaging for identifying small foci of metastatic cells in a mouse model of disseminating human prostate cancer. Two radiolabeled ligands were generated in high purity and specific activity: a uPAR-targeting probe ((177)Lu-DOTA-AE105) and a nonbinding control ((177)Lu-DOTA-AE105mut). Both uPAR flow cytometry and ELISA confirmed high expression levels of the target uPAR in PC-3M-LUC2.luc cells, and cell binding studies using (177)Lu-DOTA-AE105 resulted in a specific binding with an IC50 value of 100 nM in a competitive binding experiment. In vivo, uPAR targeted radionuclide therapy significantly reduced the number of metastatic lesions in the disseminated metastatic prostate cancer model, when compared to vehicle and nontargeted (177)Lu groups (p < 0.05) using bioluminescence imaging. Moreover, we found a significantly longer metastatic-free survival, with 65% of all mice without any disseminated metastatic lesions present at 65 days after first treatment dose (p = 0.047). In contrast, only 30% of all mice in the combined control groups treated with (177)Lu-DOTA-AE105mut or vehicle were without metastatic lesions. No treatment-induced toxicity was observed during the study as evaluated by observing animal weight and H&E staining of kidney tissue (dose-limiting organ). Finally, uPAR PET imaging using (64)Cu-DOTA-AE105 detected all small, disseminated metastatic foci when compared with bioluminescence imaging in a cohort of animals during the treatment study. In conclusion, uPAR targeted radiotherapy resulted in a significant reduction in the number of

  5. Precision electron-gamma spectroscopic data from the beta decay of 153Sm

    NASA Astrophysics Data System (ADS)

    Deepa, S.; Rani Rao, Dwaraka; Venkataramaniah, K.

    2016-02-01

    The decay of 153Sm was studied with a HPGe detector and a Si(Li) detector based electron transporter. Forty four gamma transitions belonging to sixteen excited levels in the daughter nucleus 153Eu were analyzed for their energies, emission intensities, conversion electron intensities and conversion coefficients. These values have resulted in the determination of precise beta emission intensities to the levels in 153Eu and in the construction of an internally consistent decay scheme. The present study will add to the decay data available on this radionuclide for reliable dose estimations for medical applications.

  6. 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

  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.

  8. 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

  9. 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

  10. Monte Carlo calculated TG-60 dosimetry parameters for the {beta}{sup -} emitter {sup 153}Sm brachytherapy source

    SciTech Connect

    Sadeghi, Mahdi; Taghdiri, Fatemeh; Hamed Hosseini, S.; Tenreiro, Claudio

    2010-10-15

    Purpose: The formalism recommended by Task Group 60 (TG-60) of the American Association of Physicists in Medicine (AAPM) is applicable for {beta} sources. Radioactive biocompatible and biodegradable {sup 153}Sm glass seed without encapsulation is a {beta}{sup -} emitter radionuclide with a short half-life and delivers a high dose rate to the tumor in the millimeter range. This study presents the results of Monte Carlo calculations of the dosimetric parameters for the {sup 153}Sm brachytherapy source. Methods: Version 5 of the (MCNP) Monte Carlo radiation transport code was used to calculate two-dimensional dose distributions around the source. The dosimetric parameters of AAPM TG-60 recommendations including the reference dose rate, the radial dose function, the anisotropy function, and the one-dimensional anisotropy function were obtained. Results: The dose rate value at the reference point was estimated to be 9.21{+-}0.6 cGy h{sup -1} {mu}Ci{sup -1}. Due to the low energy beta emitted from {sup 153}Sm sources, the dose fall-off profile is sharper than the other beta emitter sources. The calculated dosimetric parameters in this study are compared to several beta and photon emitting seeds. Conclusions: The results show the advantage of the {sup 153}Sm source in comparison with the other sources because of the rapid dose fall-off of beta ray and high dose rate at the short distances of the seed. The results would be helpful in the development of the radioactive implants using {sup 153}Sm seeds for the brachytherapy treatment.

  11. 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

  12. 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

  13. 142-Sm - a suitable positron emitter for uptake monitoring in 153-Sm EDTMP therapy

    SciTech Connect

    Beyer, G.J.; Donath, A.; Morel, C.

    1996-05-01

    The positron emitting isotopes {sup 86}Y and 83Sr are favoured candidates for monitoring the individual nuclide uptake in bone metastases with PET when {sup 90}Y or {sup 89}Sr are used in the therapy. It therefore seemed to be logical to propose the short-lived positron emitter {sup 142}Sm to perform the in vivo dosimetry in case cf {sup 153}Sm EDTMP therapy. {sup 142}Sm (72 min, 50 % positron branching) forms the 40 sec {sup 142}Pm with 95% positron decay rate. Three aspects will be discussed in the paper: the production of several GBq of the {sup 142}Sm in the required high quality, systematic studies of the biokinetic behaviour of radio-lanthanides with EDTMP as ligand and first dynamic PET studies using rabbits as animal model. Spallation reaction of 1 GeV protons interacting with a 100/g/cm{sup 2} Ta target in combination with an on line isotope separation process was used for the production of the radionuclides. The on line isotope separator facility ISOLDE at CERN provides excellent possibilities to produce {sup 142}Sm in multi GBq quantities, isotopically clean and carrier free. All other radio-lanthanides used in the study were produced at the ISOLDE facility as well. Using a number of long-lived radio-lanthanides we studied systematically the biokinetics of the lanthanides at different EDTMP concentrations and established clear relationships between biokinetics, EDTMP concentration and the ionic radius of the radioisotope used.

  14. Estimation of absorbed dose to the kidneys in patients after treatment with 177Lu-octreotate: comparison between methods based on planar scintigraphy

    PubMed Central

    2012-01-01

    Background Lu-[DOTA0, Tyr3]-octreotate (177Lu-octreotate) is used to treat neuroendocrine tumors with high somatostatin-receptor expression. 177Lu-octreotate is mainly excreted via the kidneys, but to some extent, accumulates in the kidney cortex due to, e.g., tubular reabsorption. Renal toxicity is one of the main limiting factors in 177Lu-octreotate treatment. Further knowledge of the biodistribution and dosimetry of 177Lu-octreotate in individual patients is needed. The aim of this study was to estimate the absorbed dose to the kidneys and compare the results obtained with planar imaging and different dosimetric methods: (1) conjugate-view (CV) method using patient-specific kidney sizes, (2) PA method, based on posterior images only, (3) CV method with reduced number of time points (CVreduced data), and (4) CV method using standard kidney sizes (CVstandard size). Methods Totally, 33 patients each received 3.4 to 8.2 GBq of 177Lu-octreotate up to five times, with infusion of lysine and arginine to block the renal uptake. Whole-body planar gamma camera images were acquired on days 0, 1, 2, and 7. The 177Lu concentration in the kidneys was determined by the CV method, and the absorbed dose was estimated with patient-specific organ sizes. Comparison to the CV method was made using posterior images only, together with the influence of the number of time points and with standard organ sizes. Results Large interindividual variations were found in the time-activity curve pattern and in the absorbed dose to the kidneys using the CV method: 0.33 to 2.4 Gy/GBq (mean =  0.80 Gy/GBq, SD = 0.30). In the individual patient, the mean deviation of all subsequent kidney doses compared to that of the first administration was 1% (SD = 19%) and 5% (SD = 23%) for the right and left kidneys, respectively. Excluding data for day 7 resulted in large variations in the absorbed dose. Conclusion Large interindividual variations in kidney dose were found, demonstrating the

  15. 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

  16. 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.

  17. 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

  18. 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.

  19. Using the 154 Sm(p,d) reaction to extend the level scheme of 153 Sm to the continuum region

    NASA Astrophysics Data System (ADS)

    Wilson, Emma; Beausang, Cornelius; Humby, Peter; Simon, Anna; Ross, Timothy; Hughes, Richard; Burke, James; Casperson, Robert; Koglin, Johnathon; Ota, Shuya; Allmond, James; McCleskey, Matthew; McCleskey, Ellen; Saastamoinen, Antti; Chyzh, Roman; Gell, Kristen; Tarlow, Tom; Vyas, Gargi; Starlite Collaboration

    2015-04-01

    Following an experiment performed at the Cyclotron Institute of Texas A&M University, the level scheme of 153 Sm is in the process of being extended. A beam of protons accelerated to 25 MeV impinged on an isotopically enriched 154 Sm target, inducing a (p,d) reaction, thereby producing energetically excited 153 Sm reaction products. The resulting γ-rays and deuterons were detected by the STARLiTe array, which consists of six Compton-suppressed HPGe gamma-ray detectors, and a ΔE-E Si telescope for charged particle identification. In the ongoing analysis of these data, the identification of new γ-rays has been possible. The deuteron spectrum will be used to identify high-lying continuum states, and angular momentum transfer values will be assigned using angular distributions and comparison with DWBA calculations. This work was partly supported by the US DofE under Grant Numbers DE-NA0001801, DE-FG02-05ER41379(UofR); DE-AC52-07NTJKTG(LLNL).

  20. 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

  1. 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

  2. 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

  3. 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.

  4. 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.

  5. Preclinical evaluation of a diabody-based (177)Lu-radioimmunoconjugate for CD22-directed radioimmunotherapy in a non-Hodgkin lymphoma mouse model.

    PubMed

    Weber, Tobias; Bötticher, Benedikt; Arndt, Michaela A E; Mier, Walter; Sauter, Max; Exner, Evelyn; Keller, Armin; Krämer, Susanne; Leotta, Karin; Wischnjow, Artjom; Grosse-Hovest, Ludger; Strumberg, Dirk; Jäger, Dirk; Gröne, Hermann-Josef; Haberkorn, Uwe; Brem, Gottfried; Krauss, Jürgen

    2016-10-28

    Radioimmunotherapy is considered as treatment option in recurrent and/or refractory B-cell non-Hodgkin lymphoma (B-NHL). To overcome the dose limiting bone marrow toxicity of IgG-based radioimmunoconjugates (RICs), we modified a humanized diabody with 5-, 10-, or 20-kDa polyethylene glycol (PEG) for CD22-targeted radioimmunotherapy using the low-energy β-emitter lutetium-177 ((177)Lu). A favorable pharmacokinetic profile was observed for the 10-kDa-PEG-diabody in nude mice being xenografted with subcutaneous human Burkitt lymphoma. Even at high doses of 16 MBq this diabody RIC was well tolerated by NOD Rag1(null) IL2rγ(null) (NRG) mice and did not reveal signs of organ long-term toxicity 80 days post injection. Combination therapy of the diabody RIC with unconjugated anti-CD20 Rituximab demonstrated therapeutic efficacy in established disseminated mantle cell lymphoma xenograft models. When compared with the combination of the IgG formatted (177)Lu anti-CD22 antibody and Rituximab, dual targeted therapy with the diabody RIC achieved an improved reduction of disease burden in the first nine days following treatment. The data indicate that the PEGylated anti-CD22 diabody may have potential for extending the repertoire of radiopharmaceuticals for the treatment of patients with B-NHL. PMID:27524505

  6. Multifunctional targeted therapy system based on (99m) Tc/(177) Lu-labeled gold nanoparticles-Tat(49-57)-Lys(3) -bombesin internalized in nuclei of prostate cancer cells.

    PubMed

    Jiménez-Mancilla, Nallely; Ferro-Flores, Guillermina; Santos-Cuevas, Clara; Ocampo-García, Blanca; Luna-Gutiérrez, Myrna; Azorín-Vega, Erika; Isaac-Olivé, Keila; Camacho-López, Miguel; Torres-García, Eugenio

    2013-11-01

    Radiolabeled gold nanoparticles may function simultaneously as radiotherapy and thermal ablation systems. The gastrin-releasing peptide receptor (GRP-r) is overexpressed in prostate cancer, and Lys(3) -bombesin is a peptide that binds with high affinity to the GRP-r. HIV Tat(49-57) is a cell-penetrating peptide that reaches the DNA. In cancer cells, (177) Lu shows efficient crossfire effect, whereas (99m) Tc that is internalized in the cancer cell nuclei acts as an effective system of targeted radiotherapy because of the biological Auger effect. The aim of this research was to evaluate the in vitro potential of (99m) Tc-labeled and (177) Lu-labeled gold nanoparticles conjugated to Tat(49-57)-Lys(3) -bombesin peptides ((99m) Tc/(177) Lu-AuNP-Tat-BN) as a plasmonic photothermal therapy and targeted radiotherapy system in PC3 prostate cancer cells. Peptides were conjugated to AuNPs (5 nm) by spontaneous reaction with the thiol group of cysteine (Cys). The effect on PC3 cell viability after laser heating of the AuNP-Tat-BN incubated with the cancer cells was conducted using an Nd:YAG laser pulsed for 5 ns at 532 nm (0.65 W/cm(2) ). For the (99m) Tc/(177) Lu-AuNP-Tat-BN to be obtained, the (177) Lu-DOTA-Gly-Gly-Cys and (99m) Tc-HYNIC-octreotide radiopeptides were first prepared and added simultaneously to a solution of AuNP-Tat-BN. (99m) Tc/(177) Lu-AuNP-Tat-BN (20 Bq/cell) was incubated with PC3 cells, and the effect on the cell proliferation was evaluated after 3 days. Fluorescence images of (99m) Tc/(177) Lu-AuNP-Tat-BN internalized in nuclei of PC3 were also obtained. After laser irradiation, the presence of AuNP-Tat-BN caused a significant increase in the temperature of the medium (46.4 vs 39.5 °C of that without AuNP) resulting in a significant decrease in PC3 cell viability down to 1.3%. After treatment with (99m) Tc/(177) Lu-AuNP-Tat-BN, the PC3 cell proliferation was inhibited. The nanosystem exhibited properties suitable for plasmonic

  7. Polyphosphoric acid capping radioactive/upconverting NaLuF4:Yb,Tm,153Sm nanoparticles for blood pool imaging in vivo.

    PubMed

    Peng, Juanjuan; Sun, Yun; Zhao, Lingzhi; Wu, Yongquan; Feng, Wei; Gao, Yanhong; Li, Fuyou

    2013-12-01

    Nanoparticles that circulate in the bloodstream for a prolonged period of time have important biomedicine applications. However, no example of lanthanide-based nanoparticles having a long-term circulation bloodstream has been reported to date. Herein, we report on difunctional radioactive and upconversion nanoparticles (UCNP) coated with polyphosphoric acid ligand, that is ethylenediamine tetramethylenephosphonic acid (EDTMP), for an application in single-photon emission computed tomography (SPECT) blood pool imaging. The structure, size and zeta-potential of the EDTMP-coated nanoparticles (EDTMP-UCNP) are verified using transmission electron microscopy and dynamic light scattering. Injection of radioisotope samarium-153-labeled EDTMP-UCNP (EDTMP-UCNP:(153)Sm) into mice reveal superior circulation time compared to control nanoparticles coated with citric acid (cit-UCNP:(153)Sm) and (153)Sm complex of EDTMP (EDTMP-(153)Sm). The mechanism for the extended circulation time may be attributed to the adhesion of EDTMP-UCNP on the membrane of red blood cells (RBCs). In vivo toxicity results show no toxicity of EDTMP-UCNP at the dose of 100 mg/kg, validating its safety as an agent for blood pool imaging. Our results provide a new strategy of nanoprobe for a long-term circulation bloodstream by introducing polyphosphoric acid as surface ligand.

  8. 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

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

    PubMed Central

    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

  10. 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

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

    PubMed

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

    2013-10-02

    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 (177)Lu-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.

  12. 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.

  13. 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

  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.

  15. Preparation, evaluation, and first clinical use of 177Lu-labeled hydroxyapatite (HA) particles in the treatment of rheumatoid arthritis: utility of cold kits for convenient dose formulation at hospital radiopharmacy.

    PubMed

    Chakraborty, Sudipta; Vimalnath, K V; Rajeswari, A; Shinto, Ajit; Sarma, H D; Kamaleshwaran, K; Thirumalaisamy, P; Dash, Ashutosh

    2014-06-15

    While radiation synovectomy (RSV) constitutes a successful paradigm for the treatment of arthritis, a major cornerstone of its success resides in the selection of appropriate radiolabeled agent. Among the radionuclide used for RSV, the scope of using (177)Lu [T1/2  = 6.65 d, Eβ(max)  = 497 keV, Eγ  = 113 KeV (6.4%), 208 KeV (11%)] seemed to be attractive owing to its suitable decay characteristics, easy availability, and cost-effective production route. The present article describes a formulation of (177)Lu-labeled hydroxyapatite (HA) using ready-to-use kits of HA particles of 1-10 µm size range. The developed kits enable convenient one-step preparation of (177)Lu-HA (400 ± 30 MBq doses) in high radiochemical purity (>99%) and stability at hospital radiopharmacy. The preparation showed promising results in pre-clinical studies carried out in Wistar rats bearing arthritis in knee joints. In preliminary clinical investigation, significant improvement in the disease conditions was reported in 10 patients with rheumatoid arthritis of knee joints treated with 333 ± 46 MBq doses of (177)Lu-HA. The studies reveal that while (177)Lu labeled HA particles holds considerable promise as a cost-effective agent for RSV, the adopted strategy of using HA kits could be a potential step toward wider clinical utilization of radiolanthanide-labeled HA particles.

  16. 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

  17. 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.

  18. 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

  19. 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

  20. [Radioprotection and environmental pollution by the use of the radionuclides 89Sr, 186Re, and 153Sm for pain palliation in metastatic bone diseases. Related calculations].

    PubMed

    Sbonias, Evangelos

    2005-01-01

    Due to the fact that the existing commercial analgesic drugs are not able to reduce effectively the pain caused by the metastatic bone disease, the use of radiopharmaceuticals with avidity to selectively localize in the metastatic skeletal sites, such as strondium-89 chloride (89Sr-Cl2), rhenium-186-hydroxy ethylene diphosphonate (186Re-HEDP), and samarium-153-ethylene diamine tetramethylene (153Sm-EDTMP), is widely accepted. However this medical application may be dangerous for the occupied personnel and more for general public, if radioactive waste is not properly disposed. In the following article we try to estimate the degree and the significance of that risk. For that reason we discuss the physical properties of these radionuclides and their distribution in the body of the patient. We conclude that 89Sr is not harmful for the physician, the attending personnel or those who live with the patient, because it radiates beta-radiation, while its gamma-radiation is negligeable. The radionuclides 186Re and 153Sm besides beta-radiation, also emit a perceptible amount of gamma-radiation. It has been shown that the exposure to gamma-radiation from these radionuclides of the physician, the attending personnel or those who live with the patient is very low as compared to the internationally accepted radioprotection limits. However the environmental contamination per treatment by either of these three radionuclides is not negligeable in comparison to the national and international accepted limits. Patients that are not in good clinical condition may pose an additional contamination danger to those attending them. For limiting radiocontamination, the annual number of treatments by the above three previous radionuclides, should be considered according to the ALARA principle in relation with the correct handling of these patients, and also considering the fundamentals of radioprotection. PMID:16142246

  1. 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

  2. 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

  3. Cross-sections for populating excited states in 150-153Sm via the (p,d) and (p,t) reactions

    NASA Astrophysics Data System (ADS)

    Humby, P.; Simon, A.; Beausang, C. W.; Gell, K.; Tarlow, T.; Vyas, G.; Ross, T. J.; Hughes, R. O.; Burke, J. T.; Casperson, R. J.; Koglin, J.; Ota, S.; Allmond, J. M.; McCleskey, M.; McCleskey, E.; Saastamoinen, A.; Chyzh, R.; Dag, M.

    2014-09-01

    Light ion transfer reactions were used to populate low/medium spin states in 150-154Sm via the (p,p' γ), (p,d γ) and (p,t γ) reactions. The 25 MeV proton beam, with an average current of 1 nA, was provided by the K-150 Cyclotron at the Cyclotron Institute of Texas A&M University. The outgoing charged particles and coincident gamma-rays were detected using the STARLiTeR arrays. STARs (Silicon Telescope Array for Reaction studies), a highly segmented ΔE-E silicon telescope, provides particle identification as well as the energies, times and angular distributions of the protons, deuterons and tritons in the exit channels. LiTeR (Livermore Texas Richmond array), an array of six BGO shielded HPGe clover detectors, records the energy, time and angular distribution of the coincident gamma rays, providing excellent selectivity of the states of interest. Preliminary results for the cross-sections for direct population of states in 150-153Sm will be presented. Light ion transfer reactions were used to populate low/medium spin states in 150-154Sm via the (p,p' γ), (p,d γ) and (p,t γ) reactions. The 25 MeV proton beam, with an average current of 1 nA, was provided by the K-150 Cyclotron at the Cyclotron Institute of Texas A&M University. The outgoing charged particles and coincident gamma-rays were detected using the STARLiTeR arrays. STARs (Silicon Telescope Array for Reaction studies), a highly segmented ΔE-E silicon telescope, provides particle identification as well as the energies, times and angular distributions of the protons, deuterons and tritons in the exit channels. LiTeR (Livermore Texas Richmond array), an array of six BGO shielded HPGe clover detectors, records the energy, time and angular distribution of the coincident gamma rays, providing excellent selectivity of the states of interest. Preliminary results for the cross-sections for direct population of states in 150-153Sm will be presented. This work was partly supported by the US Department of Energy

  4. Intestinal permeability to (/sup 51/Cr)EDTA in children with Crohn's disease and celiac disease

    SciTech Connect

    Turck, D.; Ythier, H.; Maquet, E.; Deveaux, M.; Marchandise, X.; Farriaux, J.P.; Fontaine, G.

    1987-07-01

    (/sup 51/Cr)EDTA was used as a probe molecule to assess intestinal permeability in 7 healthy control adults, 11 control children, 17 children with Crohn's disease, and 6 children with untreated celiac disease. After subjects fasted overnight, 75 kBq/kg (= 2 microCi/kg) /sup 51/Cr-labeled EDTA was given by mouth; 24-h urinary excretion of (/sup 51/Cr)EDTA was measured and expressed as a percentage of the total oral dose. Mean and SD were as follows: control adults 1.47 +/- 0.62, control children 1.59 +/- 0.55, and patients with Crohn's disease or celiac disease 5.35 +/- 1.94. The difference between control children and patients was statistically significant (p less than 0.001). These results show that intestinal permeability to (/sup 51/Cr)EDTA is increased among children with active or inactive Crohn's disease affecting small bowel only or small bowel and colon, and with untreated celiac disease. The (/sup 51/Cr)EDTA permeability test could facilitate the decision to perform more extensive investigations in children suspected of small bowel disease who have atypical or poor clinical and biological symptomatology.

  5. sup 51 Cr loss and lactate dehydrogenase (LDH) release in irradiated human tumor cells

    SciTech Connect

    Ts'ao, C.; Molteni, A.; Hinz, J. )

    1991-03-11

    Much of what is known about tumor cell radiosensitivity in vitro derives from the colony formation assay. Other endpoints of cytotoxicity in irradiated tumor cells are rarely examined. The purpose of this study was to determine whether loss of {sup 51}Cr from prelabeled cells and release of LDH could be used to quantify radiation injury in two cultured human tumor cell lines: a prostate carcinoma and a melanoma. Bovine aortic endothelial cells (EC) known to release {sup 51}Cr and LDH following irradiation, were cotested. Radioactivity and LDH activity in the culture medium were determined after 0-40 Gy of {sup 60}CO {gamma} rays. Proliferation of irradiated tumor cells was also studied. EC exhibited a time- and radiation dose-dependent increase in {sup 51}Cr and LDH release. Both tumor cell lines showed a time-dependent increase in {sup 51}Cr release, but this baseline release was not elevated after irradiation. LDH release from the prostate cancer cell line was observed within 8 hr after 40 Gy, and at 48 hr by 10 Gy. Irradiated melanoma cells, in contrast, never release excess LDH into the culture medium. Melanoma cells continued to proliferate after 10 Gy, while proliferation of prostate cancer cells was totally arrested by this dose of exposure. While {sup 51}Cr loss and LDH release appear to be sensitive indicators of radiation-induced damage in EC, they have limited value in the assessment of radiation-induced cytotoxicity in human prostate cancer and melanoma cells.

  6. (51Cr)EDTA intestinal permeability in children with cow's milk intolerance

    SciTech Connect

    Schrander, J.J.; Unsalan-Hooyen, R.W.; Forget, P.P.; Jansen, J. )

    1990-02-01

    Making use of ({sup 51}Cr)EDTA as a permeability marker, we measured intestinal permeability in a group of 20 children with proven cow's milk intolerance (CMI), a group of 17 children with similar complaints where CMI was excluded (sick controls), and a group of 12 control children. ({sup 51}Cr)EDTA test results (mean +/- SD) were 6.85 +/- 3.64%, 3.42 +/- 0.94%, and 2.61 +/- 0.67% in the group with CMI, the sick control, and the control group, respectively. When compared to both control groups, patients with cow's milk intolerance (CMI) showed a significantly increased small bowel permeability. We conclude that the ({sup 51}Cr)EDTA test can be helpful for the diagnosis of cow's milk intolerance.

  7. 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.

  8. 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

  9. Intestinal permeability to (/sup 51/Cr)EDTA in children with cystic fibrosis

    SciTech Connect

    Leclercq-Foucart, J.; Forget, P.; Sodoyez-Goffaux, F.; Zappitelli, A.

    1986-05-01

    Intestinal permeability was investigated in 14 children with cystic fibrosis making use of (/sup 51/Cr)EDTA as probe molecule. Ten normal young adults and 11 children served as controls. After oral administration of (/sup 51/Cr)EDTA, 24 h urine was collected. Urinary radioactivity was calculated and results expressed as percentage of oral dose excreted in 24 h urine. Mean and SEM were as follows: 2.51 +/- 0.21, 2.35 +/- 0.24, and 13.19 +/- 1.72 for control children, normal adults, and cystic fibrosis patients, respectively. The permeability differences between cystic fibrosis patients and either control children or control adults are significant (p less than 0.001).

  10. 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

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

    PubMed

    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 (131)I or (90)Y still remains ineffective for solid and radioresistant tumour treatment. Previous simulations have revealed that an increase in the number of (90)Y 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 (90)Y, (177)Lu, (131)I, (124)I, and (188)Re 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)). (90)Y and (188)Re 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

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

    PubMed

    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 (131)I or (90)Y still remains ineffective for solid and radioresistant tumour treatment. Previous simulations have revealed that an increase in the number of (90)Y 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 (90)Y, (177)Lu, (131)I, (124)I, and (188)Re 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)). (90)Y and (188)Re 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.

  13. Thermal neutron capture cross sections for the 152Sm(n,γ) 153Sm and 154Sm(n,γ) 155Sm reactions at 0.0536 eV energy

    NASA Astrophysics Data System (ADS)

    Uddin, M. S.; Chowdhury, M. H.; Hossain, S. M.; Latif, Sk. A.; Islam, M. A.; Hafiz, M. A.; Mubin, S. H.; Zakaria, A. K. M.; Yunus, S. M.; Azharul Islam, S. M.

    2008-11-01

    The neutron capture cross sections for the 152Sm(n,γ) 153Sm and 154Sm(n,γ) 155Sm reactions at 0.0536 eV neutron energy were measured using an activation technique based on the TRIGA Mark-II research reactor, relative to the reference reaction 197Au(n,γ) 198Au. The activity was measured nondestructively using gamma-ray spectroscopy. Our measured values at this neutron energy are the first ones and are compared with 1/ v based evaluated cross sections reported in the ENDF/B-VII and JENDL-3.3 libraries. The measured value for the 152Sm(n,γ) 153Sm reaction is 0.28% lower than JENDL-3.3 and 0.48% higher than ENDF/B-VII. Our value for the production of 155Sm is about 3% and 2.3% higher than the evaluated value with ENDF/B-VII and JENDL-3.3 at 0.0536 eV, respectively.

  14. Calorimetric method for determination of {sup 51}Cr neutrino source activity

    SciTech Connect

    Veretenkin, E. P. Gavrin, V. N.; Danshin, S. N.; Ibragimova, T. V.; Kozlova, Yu. P.; Mirmov, I. N.

    2015-12-15

    Experimental study of nonstandard neutrino properties using high-intensity artificial neutrino sources requires the activity of the sources to be determined with high accuracy. In the BEST project, a calorimetric system for measurement of the activity of high-intensity (a few MCi) neutrino sources based on {sup 51}Cr with an accuracy of 0.5–1% is created. In the paper, the main factors affecting the accuracy of determining the neutrino source activity are discussed. The calorimetric system design and the calibration results using a thermal simulator of the source are presented.

  15. 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

  16. 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.

  17. Assessment of glomerular filtration rate utilizing subcutaneously injected 51Cr-EDTA.

    PubMed

    Monteiro, M C; Alonso, G; Ajzen, H; Pereira, A B

    1994-11-01

    1. 51Cr-EDTA injected with lidocaine and epinephrine, as a subcutaneous button, is slowly absorbed, and a plasma level that is relatively stable can be maintained for a time sufficient to permit measurement of the renal clearance of EDTA, which is a measure of glomerular filtration rate (GFR). We studied this procedure in 32 normal volunteers and 24 patients with different glomerulopathies, comparing EDTA and creatinine clearances. In 20 patients these measurements were also compared with inulin clearance. 2. Creatinine clearance overestimates GFR due to tubular secretion of creatinine. This secretion is present even in patients with significantly reduced glomerular filtration rates. As a consequence, the lower the GFR the higher the overestimation will be. 3. A good correlation was obtained between the 51Cr-EDTA and inulin clearance: y(EDTA) = 4.21 + 0.88 x (inulin), r = 0.98. The procedure is simple to perform, and the radiotracer utilized is significantly less expensive than iothalamate. PMID:7549976

  18. Use of a /sup 51/Cr technique to detect gastrointestinal microbleeding associated with nonsteroidal antiinflammatory drugs

    SciTech Connect

    Lussier, A.; Arsenault, A.; Varady, J.; de Medicis, R.; Lussier, Y.; LeBel, E.

    1987-02-01

    Of techniques used to evaluate gastrointestinal (GI) bleeding, use of radiochromium (/sup 51/Cr)-tagged erythrocytes is the most quantitative and scientifically acceptable method. The value of this technique as well as systematic errors possible with its use are discussed. The medical literature concerning /sup 51/Cr evaluation of GI microbleeding with naproxen therapy is critically reviewed. We suggest that future studies using this technique be parallel, randomized, double-blind, and include a 1-week placebo baseline phase for all subjects. Treatment with nonsteroidal antiinflammatory drugs (NSAIDs) should last 3 to 4 weeks. A parallel group of subjects should receive placebo throughout the study. For valid statistical analyses, randomization must achieve baseline comparability of weight, height, age, and sex in the treatment groups. Data transformations may be necessary to satisfy the assumptions of the statistical model. Following these guidelines will enable investigators to better evaluate GI microbleeding during treatment with naproxen or other NSAIDs, and, hopefully, to establish the safety profiles of these drugs.37 references.

  19. Reversibility of increased intestinal permeability to 51Cr-EDTA in patients with gastrointestinal inflammatory diseases

    SciTech Connect

    Jenkins, R.T.; Jones, D.B.; Goodacre, R.L.; Collins, S.M.; Coates, G.; Hunt, R.H.; Bienenstock, J.

    1987-11-01

    Intestinal permeability in adults with inflammatory gastrointestinal diseases was investigated by measuring the 24-h urinary excretion of orally administered /sup 51/Cr-EDTA. Eighty controls along with 100 patients with Crohn's disease, 46 patients with ulcerative colitis, 20 patients with gluten-sensitive enteropathy, and 18 patients with other diseases were studied. In controls, the median 24-h excretion was 1.34%/24 h of the oral dose. Patients with Crohn's disease (median 2.96%/24 h), ulcerative colitis (median 2.12%/24 h), and untreated gluten-sensitive enteropathy (median 3.56%/24 h) had significantly elevated urinary excretion of the probe compared to controls (p less than 0.0001). Increased 24-h urinary excretion of /sup 51/Cr-EDTA had a high association with intestinal inflammation (p less than 0.0001). Test specificity and sensitivity were 96% and 57%, respectively. A positive test has a 96% probability of correctly diagnosing the presence of intestinal inflammation, whereas a negative test has a 50% probability of predicting the absence of disease.

  20. Application of the 51Cr-EDTA urinary recovery test for assessment of intestinal permeability in the horse.

    PubMed

    Escala, J; Gatherer, M E; Voûte, L; Love, S

    2006-04-01

    Altered intestinal permeability is implicated in the pathogenesis of diverse equine medical conditions including alimentary laminitis and protein-losing enteropathies associated with parasitic infection. The aims of this study were to assess the feasibility of applying the 51Cr-EDTA absorption test for the assessment of intestinal permeability in the horse, and to apply this test in horses with experimentally induced alterations in gastrointestinal function. Four healthy ponies were administered 36 MBq of 51Cr-EDTA via naso-gastric tube, and urine samples were collected into polythene bags strapped to the pony's abdomen. Total urine voided every 6 h was collected during each test, and 1 ml samples were taken for measurement of gamma-radiation. Urinary recovery of 51Cr-EDTA was measured following intravenous atropine sulphate or bethanecol, and following 22 and 46 days of administration of 250,000 third-stage cyathostome larvae. There was no significant difference in urinary 51Cr-EDTA recovery following the control treatment, and following atropine or bethanecol administration, but significant increases were detected in the animals with experimental cyathostome infection consistent with increased permeability of the intestinal membrane. Motility modifying agents (bethanecol and atropine) did not affect absorption of 51Cr-EDTA, suggesting that subtle changes in motility might not affect the ability of this test to detect altered intestinal permeability. The finding of increased urinary recovery of 51Cr-EDTA in ponies with cyathostome infection suggests that 51Cr-EDTA may be a useful marker for assessment of intestinal permeability in the horse.

  1. A prospective randomized trial: a comparison of the analgesic effect and toxicity of 153Sm radioisotope treatment in monotherapy and combined therapy including local external beam radiotherapy (EBRT) among metastatic castrate resistance prostate cancer (mCRPC) patients with painful bone metastases.

    PubMed

    Baczyk, M; Milecki, P; Pisarek, M; Gut, P; Antczak, A; Hrab, M

    2013-01-01

    Bone metastases in prostate cancer constitute the most frequent cause of systemic failure in treatment, which results in numerous complications and finally leads to patient's death. Pain is one of the first and most important clinical symptoms of bone metastases and can be found among more than 80% of patients. Therefore, the most analgetic effective and simultaneously the least toxic treatment is an important point of therapeutic management in this group of patients. The aim of this prospective clinical trial was a comparison of analgetic effectiveness and toxicity of monotherapy with 153Sm isotope to combined therapy (153Sm + EBRT) among patients diagnosed with multiple painful bone metastases due to CRPC (mCRPC). 177 patients with mCRPC were included into the prospective randomised clinical trial in which 89 patients were assigned to the 153Sm isotope monotherapy, while 88 patients were assigned to the combined therapy including 153Sm isotope therapy and EBRT. All patients were diagnosed (bone scan and X-ray or/and CT or/and MRI) with painful bone metastases (bone pain intensity >= 6 according to VAS classification). The following additional inclusion criteria were established: histologically confirmed adenocarcinoma of prostate, multifocal bone metastases, no prior chemotherapy or palliative radiotherapy to bone. All patients signed informed consent.The combination of the isotope therapy with EBRT was more effective analgetic treatment than isotope therapy alone. The highest pain decline was noticed in the first weeks after treatment termination. In the whole group, a total or partial analgesic effect was observed among 154 (87%) patients while among 23 (13%) patients there was a lack of analgesic effect or even pain intensification. The results of this clinical trial demonstrated that for patients with multiple mCRPC it is recommended to combine the 153Sm isotope therapy with local EBRT because of a greater analgetic effect. It is important to note that

  2. Measuring the activity of a {sup 51}Cr neutrino source based on the gamma-radiation spectrum

    SciTech Connect

    Gorbachev, V. V. Gavrin, V. N.; Ibragimova, T. V.; Kalikhov, A. V.; Malyshkin, Yu. M.; Shikhin, A. A.

    2015-12-15

    A technique for the measurement of activities of intense β sources by measuring the continuous gamma-radiation (internal bremsstrahlung) spectra is developed. A method for reconstructing the spectrum recorded by a germanium semiconductor detector is described. A method for the absolute measurement of the internal bremsstrahlung spectrum of {sup 51}Cr is presented.

  3. Permeability of the small intestine to (/sup 51/Cr)EDTA in children with acute gastroenteritis or eczema

    SciTech Connect

    Forget, P.; Sodoyez-Goffaux, F.; Zappitelli, A.

    1985-06-01

    Increased gut permeability to macromolecules is thought to be an important factor in the development of food hypersensitivity. The latter can develop in the course of acute gastroenteritis and could play a role in infantile eczema. The authors studied gut permeability in 10 normal adults, 11 control children, 7 children with acute gastroenteritis, and 8 patients with infantile eczema, making use of (/sup 51/Cr)EDTA as probe molecule. (/sup 51/Cr)EDTA was given orally (50-100 microCi); 24-h urinary excretion of (/sup 51/Cr)EDTA was measured and expressed as a percentage of the oral dose. Mean and standard error were 2.35 +/- 0.24, 2.51 +/- 0.21, 9.96 +/- 3.44, and 10.90 +/- 2.05 in normal adults, control children, and gastroenteritis and eczema patients, respectively. Differences between controls and either gastroenteritis (p less than 0.001) or eczema (p less than 0.001) patients are significant. The results support the hypothesis that increased gut permeability could play a role in food hypersensitivity.

  4. 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.

  5. Platelet turnover and kinetics in immune thrombocytopenic purpura: results with autologous 111In-labeled platelets and homologous 51Cr-labeled platelets differ

    SciTech Connect

    Heyns A du, P.; Badenhorst, P.N.; Loetter, M.G.P.; Pieters, H.; Wessels, P.; Kotze, H.F.

    1986-01-01

    Mean platelet survival and turnover were simultaneously determined with autologous 111In-labeled platelets (111In-AP) and homologous 51Cr-labeled platelets (51Cr-HP) in ten patients with chronic immune thrombocytopenic purpura (ITP). In vivo redistribution of the 111In-AP was quantitated with a scintillation camera and computer-assisted image analysis. The patients were divided into two groups: those with splenic platelet sequestration (spleen-liver 111In activity ratio greater than 1.4), and those with diffuse sequestration in the reticuloendothelial system. The latter patients had more severe ITP reflected by pronounced thrombocytopenia, decreased platelet turnover, and prominent early hepatic platelet sequestration. Mean platelet life span estimated with 51Cr-HP was consistently shorter than that of 111In-AP. Platelet turnover determined with 51Cr-HP was thus over-estimated. The difference in results with the two isotope labels was apparently due to greater in vivo elution of 51Cr. Although the limitations of the techniques should be taken into account, these findings indicate that platelet turnover is not always normal or increased in ITP, but is low in severe disease. We suggest that this may be ascribed to damage to megakaryocytes by antiplatelet antibody. The physical characteristics in 111In clearly make this radionuclide superior to 51Cr for the study of platelet kinetics in ITP.

  6. Use of 51Cr-labeled mononuclear cells for measuring the cellular immune response in mouse lungs

    SciTech Connect

    Zarkower, A.; Scheuchenzuber, W.J.; Ferguson, F.G.

    1981-02-01

    Spleen cells labeled with 51Cr were used in sensitized syngeneic mice to measure the degree of mononuclear cell infiltration into antigen-challenged tissues. With this method, increased cellular infiltration was found after footpad challenge of mice sensitized with sheep erythrocyte, Escherichia coli, and BCG antigens. Cellular response also was determined by using this technique in the lungs of mice sensitized with sheep erythrocytes and BCG. This procedure offers the opportunity to measure cellular infiltration, whether due to cellular or humoral influences, in tissues not easily accessible to conventional immunological manipulation.

  7. Use of /sup 51/Cr-labeled mononuclear cells for measuring the cellular immune response in mouse lungs

    SciTech Connect

    Zarkower, A.; Scheuchenzuber, W.J.; Ferguson, F.G.

    1981-02-01

    Spleen cells labeled with /sup 51/Cr were used in sensitized syngeneic mice to measure the degree of mononuclear cell infiltration into antigen-challenged tissues. With this method, increased cellular infiltration was found after footpad challenge of mice sensitized with sheep erythrocyte, Escherichia coli, and BCG antigens. Cellular response also was determined by using this technique in the lungs of mice sensitized with sheep erythrocytes and BCG. This procedure offers the opportunity to measure cellular infiltration, whether due to cellular or humoral influences, in tissues not easily accessible to conventional immunological manipulation.

  8. 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

  9. Comparative gastrointestinal blood loss associated with placebo, aspirin, and nabumetone as assessed by radiochromium (/sup 51/Cr)

    SciTech Connect

    Lussier, A.; Davis, A.; Lussier, Y.; Lebel, E.

    1989-03-01

    Nabumetone differs from most other nonsteroidal anti-inflammatory drugs. It is presented to the gut as a nonacidic prodrug, and is metabolized to its active form after absorption. Studies in animals and humans suggest it is less irritating to the gastrointestinal mucosa. This study compared the gastrointestinal microbleeding induced by nabumetone to aspirin (acetylsalicylic acid, ASA), and placebo in a double blind parallel study using chromium /sup 51/Cr labelled red cells to quantitate fecal blood loss (FBL) in healthy volunteers. Thirty subjects were randomized to treatment with nabumetone (2000 mg), ASA (3.6 g) or placebo for 21 days following a 7 day placebo period. Six subjects served as untreated controls. FBL in nabumetone treated subjects was not significantly different to placebo or untreated subjects. In contrast, ASA-treated subjects exhibited significantly increased FBL than the other 3 groups (P less than .0001).

  10. Comparison of whole body and tissue blood volumes in rainbow trout (Salmo gairdneri) with 125I bovine serum albumin and 51Cr-erythrocyte tracers

    USGS Publications Warehouse

    Gingerich, W.H.; Pityer, R.A.

    1989-01-01

    Total, packed cell and, plasma volume estimates were made for the whole body and selected tissues of rainbow trout by the simultaneous injection of radiolabelled trout erythrocyte (51Cr-RBC) and radioiodinated bovine serum albumin (125I-BSA) tracers. Blood volumes were estimated with both markers separately by the tracer-hematocrit method and as the combination of the 51Cr-RBC packed cell and 125I-BSA plasma volumes. Mean whole body blood volume was significantly less when calculated from the 51Cr-RBC tracer data (3.52±0.78 ml/100 g; ±SD) than when calculated with the 125I-BSA tracer (5.06±0.86 ml/100 g) or as the sum of the two volumes combined (4.49±0.60 ml/100 g). The whole body hematocrit (28±5%), estimated as the quotient of the 51Cr-RBC volume divided by the sum of the 125I-BSA and the 51Cr-RBC volumes, also was significantly less than the dorsal aortic microhematocrit (36±4%). Estimates of total blood volumes in most tissues were significantly smaller when calculated from the51Cr-RBC data than when calculated by the other two methods. Tissue blood volumes were greatest in highly vascularized and well perfused tissues and least in poorly vascularized tissues. The relative degree of vascularization among tissues generally remained the same regardless of whether the red cell or the plasma tracer was used to calculated blood volume. It is not clear whether the expanded plasma volume is the result of the distribution of erythrocyte-poor blood into the secondary circulation or the result of extravascular exchange of plasma proteins.

  11. Determination of optimal sampling times for a two blood sample clearance method using (51)Cr-EDTA in cats.

    PubMed

    Vandermeulen, Eva; De Sadeleer, Carlos; Piepsz, Amy; Ham, Hamphrey R; Dobbeleir, André A; Vermeire, Simon T; Van Hoek, Ingrid M; Daminet, Sylvie; Slegers, Guido; Peremans, Kathelijne Y

    2010-08-01

    Estimation of the glomerular filtration rate (GFR) is a useful tool in the evaluation of kidney function in feline medicine. GFR can be determined by measuring the rate of tracer disappearance from the blood, and although these measurements are generally performed by multi-sampling techniques, simplified methods are more convenient in clinical practice. The optimal times for a simplified sampling strategy with two blood samples (2BS) for GFR measurement in cats using plasma (51)chromium ethylene diamine tetra-acetic acid ((51)Cr-EDTA) clearance were investigated. After intravenous administration of (51)Cr-EDTA, seven blood samples were obtained in 46 cats (19 euthyroid and 27 hyperthyroid cats, none with previously diagnosed chronic kidney disease (CKD)). The plasma clearance was then calculated from the seven point blood kinetics (7BS) and used for comparison to define the optimal sampling strategy by correlating different pairs of time points to the reference method. Mean GFR estimation for the reference method was 3.7+/-2.5 ml/min/kg (mean+/-standard deviation (SD)). Several pairs of sampling times were highly correlated with this reference method (r(2) > or = 0.980), with the best results when the first sample was taken 30 min after tracer injection and the second sample between 198 and 222 min after injection; or with the first sample at 36 min and the second at 234 or 240 min (r(2) for both combinations=0.984). Because of the similarity of GFR values obtained with the 2BS method in comparison to the values obtained with the 7BS reference method, the simplified method may offer an alternative for GFR estimation. Although a wide range of GFR values was found in the included group of cats, the applicability should be confirmed in cats suspected of renal disease and with confirmed CKD. Furthermore, although no indications of age-related effect were found in this study, a possible influence of age should be included in future studies. PMID:20452793

  12. Simultaneous measurement of 59Fe and 51Cr in iron absorption studies using a whole-body scanner with mobile shielding.

    PubMed

    Marx, J J; van den Beld, B; van Dongen, R; Strackee, L H

    1980-07-01

    A whole-body scanner is described with a mobile shadow shield which affords a considerable reduction in space. The scanner has two NaI(T1) scintillation crystals of 4 x 6", placed at opposite sites of the subject. Background radiation, efficiency and geometric qualities made the scanner very useful for clinical whole-body counting. The equipment was used in iron absorption studies using a double isotope technique with 59Fe and 51Cr. After ingestion of an oral test dose total body kinetics of 59Fe and 51Cr was followed up to 60 days in 4 volunteers. Between days 3 and 10 the 51Cr, which was used as an non-absorbable indicator, had left the body completely. The 59Fe reached a constant value not before day 10, indicating that iron retention cannot be measured before that time. From repeated measurement of 59Fe and 51Cr directly after ingestion until the first defaecation it could be deduced that the coefficient of variation for 59Fe was less than 1.5% with a scanning time of 600 sec, and for 51Cr less than 5%. Extreme variations in geometry, such as measurement of the activity in a beaker and of the same amount after ingestion in the body, yielded practically the same value for 59Fe. The double isotope technique made it possible to measure not only iron retention but also mucosal uptake and mucosal transfer of iron. It is pointed out that measurement of the last two parameters of iron absorption is not possible in patients with serious obstipation or with very low mucosal uptake values. PMID:6780983

  13. Clinical evaluation of a /sup 51/Cr-labeled red blood cell survival test for in vivo blood compatibility testing

    SciTech Connect

    Pineda, A.A.; Dharkar, D.D.; Wahner, H.W.

    1984-01-01

    Modified red blood cell survival studies with use of 51Cr were performed in three groups of subjects. Group 1 consisted of normal subjects who were given labeled autologous blood, group 2 were subjects in need of blood transfusions and given labeled ABO and Rh crossmatch-compatible blood, and group 3 were patients in need of blood transfusion but in whom problems arose in finding compatible blood. The results of the studies suggest that for patients with blood compatibility problems, normal red blood cell survival values at 1 hour do not exclude the possibility of severe hemolysis 24 hours later. Thus, if a 1-hour test result is normal, the procedure should be extended routinely to 24 hours. Moreover, the test can be used to evaluate the clinical importance of antibodies. We showed that anti-Yka and anti-Lan were clinically significant, but high-titer, low-avidity antibodies, anti-Kna, anti-I, and anti-HI were clinically insignificant in the cases studied. This finding emphasizes the importance of an in vivo test for the final compatibility evaluation in complicated blood replacement problems.

  14. Decay Data Evaluation Project (DDEP): Updated decay data evaluations for (24)Na, (46)Sc, (51)Cr, (54)Mn, (57)Co, (59)Fe, (88)Y, (198)Au.

    PubMed

    Chechev, Valery P; Kuzmenko, Nikolay K

    2016-03-01

    Updated DDEP evaluations have been presented for the decay characteristics of the radionuclides (24)Na, (46)Sc, (51)Cr, (54)Mn, (57)Co, (59)Fe, (88)Y and (198)Au. Previous DDEP evaluations for these radionuclides were published in the BIPM-5 monographie in 2004. The experimental data published during the intervening period of 2004-2014 were taken into account in the current evaluations as well as other information: new compilations, analyses, and corrections. The updated evaluations are compared to previous results.

  15. Chemistry and bifunctional chelating agents for binding (177)Lu.

    PubMed

    Parus, Józef L; Pawlak, Dariusz; Mikolajczak, Renata; Duatti, Adriano

    2015-01-01

    A short overview of fundamental chemistry of lutetium and of structural characteristics of lutetium coordination complexes, as relevant for understanding the properties of lutetium-177 radiopharmaceuticals, is presented. This includes basic concepts on lutetium electronic structure, lanthanide contraction, coordination geometries, behavior in aqueous solution and thermodynamic stability. An illustration of the structure and binding properties of the most important chelating agents for the Lu(3+) ion in aqueous solution is also reported with specific focus on coordination complexes formed with linear and macrocyclic polydentate amino-carboxylate donor ligands.

  16. Lowering of tumoral interstitial fluid pressure by prostaglandin E(1) is paralleled by an increased uptake of (51)Cr-EDTA.

    PubMed

    Rubin, K; Sjöquist, M; Gustafsson, A M; Isaksson, B; Salvessen, G; Reed, R K

    2000-06-01

    High intra-tumoral fluid pressure (TP(IF)) may impair uptake of anticancer drugs into tumors, contributing to poor efficiency in treatment of carcinomas. Here, we demonstrate that lowering of TP(IF) parallels increased transport of (51)Cr-EDTA (m.w. 341) into tumor interstitium. Introduction of 15 microg prostaglandin E(1) (PGE(1)) -methyl ester into the s.c. tissue surrounding transplanted rat colonic (PROb) carcinomas or chemically-induced rat mammary carcinomas, lowered TP(IF) by 30%. Transcapillary transport into the interstitium of PROb tumors quantified by microdialysis increased by 39.6% after PGE(1) treatment 40 min prior to administration of (51)Cr-EDTA (n=6; p<0.05) compared to vehicle (n=10). In mammary tumors, PGE(1) increased transport into the tumors by 86.9% over controls (n=16; p<0.05). Both tumors had well developed stroma containing collagen and hyaluronan. Our data demonstrate that adjuvant treatment with PGE(1) lowers TP(IF), and enhances transport into the tumors. This principle may be of value as adjuvant therapy in treatment of solid malignancies with currently used anticancer drugs.

  17. Bioelimination of /sup 51/Cr and /sup 85/Sr by cockroaches, Gromphadorhina portentosa (Orthoptera: Blaberidae), as affected by mites, Gromphadorholaelaps schaeferi (parasitiformes: laelapidae)

    SciTech Connect

    Schowalter, T.D.; Crossley, D.A. Jr.

    1982-03-01

    This paper describes rates of Chromium-51 and Strontium-85 assimilation and bioelimination by the hissing cockroach, Gromphadorhina portentosa (Schaum), when the symbiotic mite, Gromphadorholaelaps schaeferi Till, was present or removed. Mite-infested cockroaches had significantly higher rates of /sup 51/Cr elimination relative to mite-free cockroaches, implying more rapid gut clearance times. We did not find a significant mite effect on /sup 85/Sr elimination by the host, but mite effects could have been masked by the apparently unique process of nutrient assimilation and elimination by G. portentosa. Conventional models of radioactive tracer bioelimination predict a rapid initial loss of tracer due to gut clearance, followed by a slower loss due to excretion of assimilated tracer. Our results indicated that assimilated /sup 85/Sr was eliminated earlier than unassimilated /sup 85/Sr was lost by defecation.

  18. Bioelimination of /sup 51/Cr and /sup 85/Sr by cockroaches, Gromphadorhina portentosa (orthoptera: blaberidae), as affected by mites, Gromphadorholaelaps schaeferi (parasitiformes: laelapidae)

    SciTech Connect

    Schowalter, T.D.; Crossley, D.A. Jr.

    1982-03-01

    The rates of Chromium-51 and Strontium-85 assimilation and bioelimination by the hissing cockroach, Gromphadorhina portentosa (Schaum) are described when the symbiotic mite, Gromphadorholaelaps schaeferi Till, was present or removed. Mite-infested cockroaches had significantly higher rates of /sup 51/Cr elimination relative to mite-free cockroaches, implying more rapid gut clearance times. The authors did not find a significant mite effect on /sup 85/Sr elimination by the host, but mite effects could have been masked by the apparently unique process of nutrient assimilation and elimination by G. portentosa. Conventional models of radioactive tracer bioelimination predict a rapid initial loss of tracer due to gut clearance, followed by a slower loss due to excretion of assimilated tracer. The results indicated that assimilated /sup 85/Sr was eliminated earlier than unassimilated /sup 85/Sr, which was lost by defecation.

  19. Experimental bacterial pneumonia in rabbits: polymorphonuclear leukocyte margination and sequestration in rabbit lungs and quantitation and kinetics of /sup 51/Cr-labeled polymorphonuclear leukocytes in E. coli-induced lung lesions

    SciTech Connect

    Cybulsky, M.I.; Movat, H.Z.

    1982-12-01

    A relationship between the circulating and marginal polymorphonuclear leukocyte (PMN) pools was documented using /sup 51/Cr-labeled leukocytes as a marker. /sup 51/Cr-leukocytes marginating in the lungs were found to decrease following a first-order exponential decline, while /sup 51/Cr radioactivity accumulated in the liver and the spleen. Intravenously administered endotoxin caused a rapid selective disappearance of PMNs from the circulation. The percentage of infused /sup 51/Cr cells disappearing was equal to the percentage of disappearance of host cells. The PMNs were found to sequester in the lungs, with peak sequestration of labeled cells occurring 5 min after an endotoxin challenge. Over the next 25 min the /sup 51/Cr radioactivity in the lungs declined. Large numbers of PMNs, probably newly derived from the bone marrow, were observed histologically to be sequestered in the lung vasculature 90 min after an endotoxin dose, while the early sequestration of circulating leukocytes could not be assessed histologically. Pulmonary inflammatory lesions were induced selectively with Escherichia coli in the left lower lobes of rabbits, leaving the right lower lobes as intrinsic controls. PMN-accumulation into the lesions was quantitated using /sup 51/Cr-labeled blood leukocytes. With the aid of /sup 125/I-labeled E. coli, a logarithmic dose-response relationship was found between the number of E. coli and of PMNs. Over a 6-hr period circulating PMNs were found to accumulate in a lesion in the left lower lobe, whereas in the control right lower lobe, leukocyte radioactivity declined. These findings were confirmed with the aid of lavages of the right and left lungs. Two peaks of PMN-accumulation were found by studying leukocyte kinetics: a larger peak between 0 and 6 hr and a smaller peak 18-24 hr after instillation of the microorganisms. Histologic studies confirmed the accumulation of leukocytes, and by 3 weeks showed a complete resolution of the lesions.

  20. Absolute 24 h quantification of 99Tcm-DMSA uptake in patients with severely reduced kidney function: a comparison with 51Cr-EDTA clearance.

    PubMed

    van de Wiele, C; van den Eeckhaut, A; Verweire, W; van Haelst, J P; Versijpt, J; Dierckx, R A

    1999-09-01

    The aim of this study was to determine whether absolute 24 h DMSA uptake measurements (%DMSA) correlate well with 51Cr-EDTA clearance measurements in patients with severely reduced kidney function (SRKF). Between 1990 and 1997, 55 of 482 patients who underwent EDTA clearance measurements also underwent %DMSA within 1 week. Of these, 31 were women and 24 were men (mean age 60 years; range 19-77 years). EDTA clearance was determined using the slope-intercept method. Absolute depth- and background-corrected %DMSA were determined 24 h following the injection of 185 MBq per 1.73 m2 freshly prepared 99Tcm-DMSA. All patients had EDTA clearance < or = 60 ml.min-1. Eighteen patients (group A: 9 men and 9 women, mean age 55.8 years, range 28-73 years) had EDTA clearance > 20 ml.min-1 (mean +/- S.D. = 30.9 +/- 13.8 ml.min-1), whereas 37 patients (group B: 22 women and 15 men, mean age 62.0 years, range 19-77 years) had EDTA clearance < 20 ml.min-1 (mean +/- S.D. = 10.2 +/- 6.6 ml.min-1). EDTA clearance correlated well with %DMSA for the patients as a whole and for group A (r = 0.87, P = 0.73; r = 0.79, P = 0.0001 respectively). The regression equation suggests that %DMSA is not a marker of early renal dysfunction. In group B, the r-value (r = 0.48, P = 0.004) suggests that %DMSA is reliable as a marker of severe renal dysfunction to the extent that it provides rough information. In conclusion, %DMSA may not be used as a marker of early renal impairment. Additionally, in patients with severely reduced kidney function (EDTA clearance < 20 ml.min-1), it only provides a rough estimate.

  1. Investigation of the neutron activation of endohedral rare earth metallofullerenes

    SciTech Connect

    Shilin, V. A. Lebedev, V. T.; Kolesnik, S. G.; Kozlov, V. S.; Grushko, Yu. S.; Sedov, V. P.; Kukorenko, V. V.

    2011-12-15

    Endohedral lanthanide metallofullerenes and their water-soluble biocompatible derivatives have been synthesized. The effect that fast-neutron irradiation has on the stability and nuclear physical properties of endohedral metallofullerenes that are used as magnetocontrast materials ({sup 46}Sc, {sup 140}La, {sup 141}Nd, {sup 153}Sm, {sup 152}Eu, {sup 154}Eu, {sup 153}Sm, {sup 160}Tb, {sup 169}Yb, {sup 170}Tm (isomers I and III), and {sup 177}Lu) is studied. Our hypothesis, according to which carbon-shell relaxation is based on the fast nonradiative processes of an electron shake-off type, is confirmed.

  2. Evaluation of the efficiency curve of a Cadmiun Telluride detector for low-energy photon spectrometry.

    PubMed

    Correia, Amanda Ribeiro; Iwahara, Akira; da Cruz, Paulo Alberto Lima; da Silva, Carlos José; Tauhata, Luiz; Poledna, Roberto; da Silva, Ronaldo Lins; de Queiroz Filho, Pedro Pacheco; Lopes, Ricardo Tadeu

    2016-10-01

    The performance of a Cadmiun Telluride (CdTe) detector for low energy photon spectrometry was evaluated. Collected data were analyzed using the basic software package available with the CdTe detector system and the COLEGRAM code developed for photopeak deconvolution at LNHB/France. Several calibrated point sources were used to determine the energy versus efficiency curve. The efficiency curve was used in the determination of main X-ray intensities of (153)Sm and (177)Lu.

  3. Evaluation of the efficiency curve of a Cadmiun Telluride detector for low-energy photon spectrometry.

    PubMed

    Correia, Amanda Ribeiro; Iwahara, Akira; da Cruz, Paulo Alberto Lima; da Silva, Carlos José; Tauhata, Luiz; Poledna, Roberto; da Silva, Ronaldo Lins; de Queiroz Filho, Pedro Pacheco; Lopes, Ricardo Tadeu

    2016-10-01

    The performance of a Cadmiun Telluride (CdTe) detector for low energy photon spectrometry was evaluated. Collected data were analyzed using the basic software package available with the CdTe detector system and the COLEGRAM code developed for photopeak deconvolution at LNHB/France. Several calibrated point sources were used to determine the energy versus efficiency curve. The efficiency curve was used in the determination of main X-ray intensities of (153)Sm and (177)Lu. PMID:27544313

  4. Excretion of radionuclides in human breast milk following administration of /sup 125/I-fibrinogen, /sup 99/Tc/sup m/-MAA and /sup 51/Cr-EDTA

    SciTech Connect

    Mattsson, S.; Johansson, L.; Nosslin, B.; Ahlgren, L.

    1981-06-01

    Very few biokinetic and dosimetric data for estimating the absorbed dose to a breast-feeding child are available in the literature. The few available are usually case reports. We have measured the activity concentration in breast milk from one patient after administration of /sup 125/I-fibrinogen, from two patients after administration of /sup 99/Tc/sup m/-macroaggregated albumin, and from one patient after administration of /sup 51/Cr-EDTA. We have compared our data with earlier published results and estimated the absorbed dose to the breast-feeding child using biokinetic data presented in this work and recently published S-values for new-born children.

  5. Effect of background region of interest and time-interval selection on glomerular filtration ratio estimation by percentage dose uptake of (99m)Tc-DTPA in comparison with (51)Cr-EDTA clearance in healthy cats.

    PubMed

    Debruyn, Katrien; Vandermeulen, Eva; Saunders, Jimmy H; Dobbeleir, André A; Ham, Hamphrey R; Peremans, Kathelijne

    2013-08-01

    Evaluation of glomerular function is a useful part of the diagnostic approach in animals suspected of having renal disease. Time-interval and background region of interest (bg ROI) selection are determining factors when calculating the glomerular filtration ratio (GFR) based on percentage uptake of (99m)technetium-labelled diethylene triamine penta-acetic acid ((99m)Tc-DTPA). Therefore, three different time intervals (60-120 s, 120-180 s, 60-180 s) and three different bg ROIs (C-shape, caudolateral, cranial + caudal) were investigated. In addition, global GFRs based on percentage dose uptake of (99m)Tc-DTPA for the different time-intervals and bg ROIs were compared with the global GFR based on (51)chromium-ethylene diaminic tetra-acetic acid ((51)Cr-EDTA) plasma clearance in nine healthy European domestic shorthair cats. Paired Student's t-tests and linear regression analysis were used to analyse the data. Different time intervals seemed to cause significant variation (P <0.01) in absolute GFR values, regardless of the choice of bg ROI. Significant differences (P <0.01) between bg ROIs were only observed in the 120-180s time interval between the C-shape and cranial + caudal bg ROI, and between the caudolateral and cranial + caudal bg ROI. The caudolateral bg ROI in the 60-180 s time interval showed the highest correlation coefficient (r = 0.882) between (99m)Tc-DTPA and (51)Cr-EDTA, although a significant difference (P <0.05) was present between both techniques. PMID:23349527

  6. 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.

  7. 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

  8. 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

  9. Marked Response to 177Lu Prostate-Specific Membrane Antigen Treatment in Patient With Metastatic Prostate Cancer.

    PubMed

    Soydal, Cigdem; Ozkan, Elgin; Akyurek, Serap; Kucuk, Nuriye Ozlem

    2016-02-01

    We present pretreatment Ga prostate-specific membrane antigen (PSMA) PET/CT and posttreatment Lu-PSMA whole-body scintigraphy images of a 60-year-old patient with metastatic prostate cancer who is dramatically responding to Lu-PSMA treatment. PMID:26505861

  10. The effect of chelator type on in vitro receptor binding and stability in 177Lu-labeled cetuximab and panitumumab.

    PubMed

    Novy, Zbynek; Laznickova, Alice; Mandikova, Jana; Barta, Pavel; Laznicek, Milan; Trejtnar, Frantisek

    2014-06-15

    Monoclonal antibodies are used in the therapy of various diseases. Thanks to their high specific uptake in target tissues, these antibodies can be utilized in targeted radioimmunotherapy as carriers of radioisotopes to tumors. However, important characteristics of antibodies such as target binding and stability in the organism may be affected by various structural parameters. This study has focused on the potential influence of selected chelators on radiochemical quality and in vitro receptor binding capacity in two modified monoclonal antibodies-cetuximab and panitumumab, both ligands of the epidermal growth factor receptor (EGFR). These two antibodies were each coupled with three macrocyclic chelators (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, 1,4,7-triazacyclononane-1,4,7-triacetic acid, and 3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-triene-4-(S)-(4-isothiocyanatobenzyl)-3,6,9-triacetic acid) and labeled with lutetium-177. The stability of the preparations was checked, and the cell binding to EGFR-expressing cell lines was examined. The used method led to very stable radiolabeled preparations. The results showed that binding to the target cells was not affected by the type of chelator. All three chelators may be useful for the labeling of cetuximab and panitumumab with lutetium-177 in future preclinical or clinical studies. Our study revealed previously unpublished fact that the type of chelator selected does not affect binding of EGFR-targeted antibodies labeled with lutetium-177.

  11. Marked Response to 177Lu Prostate-Specific Membrane Antigen Treatment in Patient With Metastatic Prostate Cancer.

    PubMed

    Soydal, Cigdem; Ozkan, Elgin; Akyurek, Serap; Kucuk, Nuriye Ozlem

    2016-02-01

    We present pretreatment Ga prostate-specific membrane antigen (PSMA) PET/CT and posttreatment Lu-PSMA whole-body scintigraphy images of a 60-year-old patient with metastatic prostate cancer who is dramatically responding to Lu-PSMA treatment.

  12. Detection of (154)Eu in patients post (153)Sm-EDTMP therapy using a clinical gamma camera.

    PubMed

    Hayes, Justin J; Pfund, John; Zouain, Nicolas

    2010-03-01

    Enhancements in radiation detection equipment at border crossings and airports resulted in a report to our institution from a Sm-EDTMP therapy patient who was questioned after triggering radiation alarms. Using a clinical SPECT camera in its service mode, gamma-ray spectroscopy was performed on three patients whose Sm-EDTMP injections were given between 4 mo and 2 y prior to this study. The spectra revealed the presence of high-energy photon peaks characteristic of those from Eu. While the presence of Eu in Sm injections is documented in the literature, the implications of its presence are not widely known. The results of this study show that Eu (t1/2 = 8.5 y) remains in the bones in detectable amounts for several years and may create concerning situations for post therapy patients at some security checkpoints. Institutions performing Sm-EDTMP therapy may want to inform their patients of this situation and provide a wallet card.

  13. Source self-attenuation in ionization chamber measurements of (57)Co solutions.

    PubMed

    Cessna, Jeffrey T; Golas, Daniel B; Bergeron, Denis E

    2016-03-01

    Source self-attenuation for solutions of (57)Co of varying density and carrier concentration was measured in nine re-entrant ionization chambers maintained at NIST. The magnitude of the attenuation must be investigated to determine whether a correction is necessary in the determination of the activity of a source that differs in composition from the source used to calibrate the ionization chamber. At our institute, corrections are currently made in the measurement of (144)Ce, (109)Cd, (67)Ga, (195)Au, (166)Ho, (177)Lu, and (153)Sm. This work presents the methods used as recently applied to (57)Co. A range of corrections up to 1% were calculated for dilute to concentrated HCl at routinely used carrier concentrations.

  14. 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.

  15. (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.

  16. 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

  17. Targeted Cancer Therapy with a Novel Anti-CD37 Beta-Particle Emitting Radioimmunoconjugate for Treatment of Non-Hodgkin Lymphoma

    PubMed Central

    Repetto-Llamazares, Ada H. V.; Larsen, Roy H.; Patzke, Sebastian; Fleten, Karianne G.; Didierlaurent, David; Pichard, Alexandre; Pouget, Jean Pierre; Dahle, Jostein

    2015-01-01

    177Lu-DOTA-HH1 (177Lu-HH1) is a novel anti-CD37 radioimmunoconjugate developed to treat non-Hodgkin lymphoma. Mice with subcutaneous Ramos xenografts were treated with different activities of 177Lu-HH1, 177Lu-DOTA-rituximab (177Lu-rituximab) and non-specific 177Lu-DOTA-IgG1 (177Lu-IgG1) and therapeutic effect and toxicity of the treatment were monitored. Significant tumor growth delay and increased survival of mice were observed in mice treated with 530 MBq/kg 177Lu-HH1 as compared with mice treated with similar activities of 177Lu-rituximab or non-specific 177Lu-IgG1, 0.9% NaCl or unlabeled HH1. All mice injected with 530 MBq/kg of 177Lu-HH1 tolerated the treatment well. In contrast, 6 out of 10 mice treated with 530 MBq/kg 177Lu-rituximab experienced severe radiation toxicity. The retention of 177Lu-rituximab in organs of the mononuclear phagocyte system was longer than for 177Lu-HH1, which explains the higher toxicity observed in mice treated with 177Lu-rituximab. In vitro internalization studies showed that 177Lu-HH1 internalizes faster and to a higher extent than 177Lu-rituximab which might be the reason for the better therapeutic effect of 177Lu-HH1. PMID:26066655

  18. Pharmaceutical and clinical development of phosphonate-based radiopharmaceuticals for the targeted treatment of bone metastases.

    PubMed

    Lange, Rogier; Ter Heine, Rob; Knapp, Russ Ff; de Klerk, John M H; Bloemendal, Haiko J; Hendrikse, N Harry

    2016-10-01

    Therapeutic phosphonate-based radiopharmaceuticals radiolabeled with beta, alpha and conversion electron emitting radioisotopes have been investigated for the targeted treatment of painful bone metastases for >35years. We performed a systematic literature search and focused on the pharmaceutical development, preclinical research and early human studies of these radiopharmaceuticals. The characteristics of an ideal bone-targeting therapeutic radiopharmaceutical are presented and compliance with these criteria by the compounds discussed is verified. The importance of both composition and preparation conditions for the stability and biodistribution of several agents is discussed. Very few studies have described the characterization of these products, although knowledge on the molecular structure is important with respect to in vivo behavior. This review discusses a total of 91 phosphonate-based therapeutic radiopharmaceuticals, of which only six agents have progressed to clinical use. Extensive clinical studies have only been described for (186)Re-HEDP, (188)Re-HEDP and (153)Sm-EDTMP. Of these, (153)Sm-EDTMP represents the only compound with worldwide marketing authorization. (177)Lu-EDTMP has recently received approval for clinical use in India. This review illustrates that a thorough understanding of the radiochemistry of these agents is required to design simple and robust preparation and quality control methods, which are needed to fully exploit the potential benefits of these theranostic radiopharmaceuticals. Extensive biodistribution and dosimetry studies are indispensable to provide the portfolios that are required for assessment before human administration is possible. Use of the existing knowledge collected in this review should guide future research efforts and may lead to the approval of new promising agents. PMID:27496068

  19. Pharmaceutical and clinical development of phosphonate-based radiopharmaceuticals for the targeted treatment of bone metastases.

    PubMed

    Lange, Rogier; Ter Heine, Rob; Knapp, Russ Ff; de Klerk, John M H; Bloemendal, Haiko J; Hendrikse, N Harry

    2016-10-01

    Therapeutic phosphonate-based radiopharmaceuticals radiolabeled with beta, alpha and conversion electron emitting radioisotopes have been investigated for the targeted treatment of painful bone metastases for >35years. We performed a systematic literature search and focused on the pharmaceutical development, preclinical research and early human studies of these radiopharmaceuticals. The characteristics of an ideal bone-targeting therapeutic radiopharmaceutical are presented and compliance with these criteria by the compounds discussed is verified. The importance of both composition and preparation conditions for the stability and biodistribution of several agents is discussed. Very few studies have described the characterization of these products, although knowledge on the molecular structure is important with respect to in vivo behavior. This review discusses a total of 91 phosphonate-based therapeutic radiopharmaceuticals, of which only six agents have progressed to clinical use. Extensive clinical studies have only been described for (186)Re-HEDP, (188)Re-HEDP and (153)Sm-EDTMP. Of these, (153)Sm-EDTMP represents the only compound with worldwide marketing authorization. (177)Lu-EDTMP has recently received approval for clinical use in India. This review illustrates that a thorough understanding of the radiochemistry of these agents is required to design simple and robust preparation and quality control methods, which are needed to fully exploit the potential benefits of these theranostic radiopharmaceuticals. Extensive biodistribution and dosimetry studies are indispensable to provide the portfolios that are required for assessment before human administration is possible. Use of the existing knowledge collected in this review should guide future research efforts and may lead to the approval of new promising agents.

  20. 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.

  1. Pm-149 DOTA bombesin analogs for potential radiotherapy. in vivo comparison with Sm-153 and Lu-177 labeled DO3A-amide-betaAla-BBN(7-14)NH(2).

    PubMed

    Hu, Fang; Cutler, Cathy S; Hoffman, Timothy; Sieckman, Gary; Volkert, Wynn A; Jurisson, Silvia S

    2002-05-01

    Promethium-149 (149Pm) is one of only three radiolanthanides that can be prepared in no carrier added concentrations. This high specific activity radiolanthanide is thus suitable for targeting limited numbers of specific receptors found on many tumor cells. Promethium-149 is a moderate energy beta(-) emitter (1.07 MeV (95.9%)) with a half-life of 2.21 days. Pm-149 also emits a low abundance of an imageable gamma ray (286 keV (3%)) that may allow in vivo tracking of the therapeutic dose. The 149Pm and Sm complexes with the DO3A-amide chelator with zero and three carbon spacers to the bombesin peptide analog BBN(7-14)NH(2) were synthesized and characterized. The Sm complexes were synthesized for macroscopic characterization purposes (ESI-MS, in vitro cell binding) since no stable isotopes of Pm are known. The biological properties of the 149Pm, 153Sm and 177Lu-DO3A-amide-betaAla-BBN complexes were compared in normal mouse biodistribution studies.

  2. 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

  3. Phagocytosis-induced 51Cr release from activated macrophages and blood mononuclears. Effect of colchicine and antioxidants

    SciTech Connect

    McGee, M.P.; Hale, A.H.

    1981-09-01

    The chromium-release test was adapted to the measurement of the cellular injury induced when activated macrophages phagocytose particulates. Macrophages obtained from rabbit lungs undergoing BCG-induced chronic inflammation released more chromium when incubated in the presence of phagocytosable particles than when incubated under resting conditions. Blood mononuclear cells, 40-60% monocytes, procured from the same BCG-injected animals, were less susceptible to phagocytosis-induced injury than the macrophages obtained from the lungs. The amount of chromium released by the activated macrophages was proportional to the number of particles present during incubation. In the presence of catalase, the amounts of chromium released by phagocytosing and resting macrophages were similar; in the presence of superoxide dismutase and cytochrome c, the amount of chromium released by phagocytosing macrophages was 13-35% less than the amount of chromium released by macrophages incubated without the antioxidants. In addition, colchicine, an inhibitor of degranulation also exerted partial inhibition of the chromium release. These results suggest that oxygen radicals and lysosomal contents contribute to the cellular injury that results from phagocytosis.

  4. 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.

  5. A free database of radionuclide voxel S values for the dosimetry of nonuniform activity distributions.

    PubMed

    Lanconelli, N; Pacilio, M; Lo Meo, S; Botta, F; Di Dia, A; Aroche, A Torres; Pérez, M A Coca; Cremonesi, M

    2012-01-21

    The increasing availability of SPECT/CT devices with advanced technology offers the opportunity for the accurate assessment of the radiation dose to the biological target volume during radionuclide therapy. Voxel dosimetry can be performed employing direct Monte Carlo radiation transport simulations, based on both morphological and functional images of the patient. On the other hand, for voxel dosimetry calculations the voxel S value method can be considered an easier approach than patient-specific Monte Carlo simulations, ensuring a good dosimetric accuracy at least for anatomic regions which are characterized by uniform density tissue. However, this approach has been limited because of the lack of tabulated S values for different voxel dimensions and radionuclides. The aim of this work is to provide a free dataset of values which can be used for voxel dosimetry in targeted radionuclide studies. Seven different radionuclides (89Sr, 90Y, 131I, 153Sm, 177Lu, 186Re, 188Re), and 13 different voxel sizes (2.21, 2.33, 2.4, 3, 3.59, 3.9, 4, 4.42, 4.8, 5, 6, 6.8 and 9.28 mm) are considered. Voxel S values are calculated performing simulations of monochromatic photon and electron sources in two different homogeneous tissues (soft tissue and bone) with DOSXYZnrc code, and weighting the contributions on the basis of the radionuclide emission spectra. The outcomes are validated by comparison with Monte Carlo simulations obtained with other codes (PENELOPE and MCNP4c) performing direct simulation of the radionuclide emission spectra. The differences among the different Monte Carlo codes are of the order of a few per cent when considering the source voxel and the bremsstrahlung tail, whereas the highest differences are observed at a distance close to the maximum continuous slowing down approximation range of electrons. These discrepancies would negligibly affect dosimetric assessments. The dataset of voxel S values can be freely downloaded from the website www.medphys.it.

  6. A free database of radionuclide voxel S values for the dosimetry of nonuniform activity distributions

    NASA Astrophysics Data System (ADS)

    Lanconelli, N.; Pacilio, M.; Lo Meo, S.; Botta, F.; Di Dia, A.; Torres Aroche, L. A.; Coca Pérez, M. A.; Cremonesi, M.

    2012-01-01

    The increasing availability of SPECT/CT devices with advanced technology offers the opportunity for the accurate assessment of the radiation dose to the biological target volume during radionuclide therapy. Voxel dosimetry can be performed employing direct Monte Carlo radiation transport simulations, based on both morphological and functional images of the patient. On the other hand, for voxel dosimetry calculations the voxel S value method can be considered an easier approach than patient-specific Monte Carlo simulations, ensuring a good dosimetric accuracy at least for anatomic regions which are characterized by uniform density tissue. However, this approach has been limited because of the lack of tabulated S values for different voxel dimensions and radionuclides. The aim of this work is to provide a free dataset of values which can be used for voxel dosimetry in targeted radionuclide studies. Seven different radionuclides (89Sr, 90Y, 131I, 153Sm, 177Lu, 186Re, 188Re), and 13 different voxel sizes (2.21, 2.33, 2.4, 3, 3.59, 3.9, 4, 4.42, 4.8, 5, 6, 6.8 and 9.28 mm) are considered. Voxel S values are calculated performing simulations of monochromatic photon and electron sources in two different homogeneous tissues (soft tissue and bone) with DOSXYZnrc code, and weighting the contributions on the basis of the radionuclide emission spectra. The outcomes are validated by comparison with Monte Carlo simulations obtained with other codes (PENELOPE and MCNP4c) performing direct simulation of the radionuclide emission spectra. The differences among the different Monte Carlo codes are of the order of a few per cent when considering the source voxel and the bremsstrahlung tail, whereas the highest differences are observed at a distance close to the maximum continuous slowing down approximation range of electrons. These discrepancies would negligibly affect dosimetric assessments. The dataset of voxel S values can be freely downloaded from the website www.medphys.it.

  7. 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.

  8. Evolving Important Role of Lutetium-177 for Therapeutic Nuclear Medicine.

    PubMed

    Pillai, Ambikalmajan M R; Knapp, Furn F Russ

    2015-01-01

    Lutetium-177 ((177)Lu) is a late entrant into the nuclear medicine therapy arena but is expected to become one of the most widely used therapeutic radionuclides. This paper analyses the reason for the increasing preference of (177)Lu as a therapeutic radionuclide. While the radionuclidic properties favor its use for several therapeutic applications, the potential for large scale production of (177)Lu is also an important aspect for its acceptability as a therapeutic radionuclide. This introductory discussion also summarizes some developing clinical uses and suggested future directions for applications of (177)Lu.

  9. Gastrointestinal absorption of metals (51Cr, 65Zn, 95mTc, 109Cd, 113Sn, 147Pm, and 238Pu) by rats and swine.

    PubMed

    Sullivan, M F; Miller, B M; Goebel, J C

    1984-12-01

    Adult and neonatal rats and neonatal pigs were gavaged with solutions of metal radionuclides to determine gastrointestinal absorption. Zinc-65 and technetium-95m were well-absorbed by both age groups; chromium-51, cadmium-109, tin-113, promethium-147, and plutonium-238 were not. The quantities of the poorly absorbed metals that were absorbed by neonates were between 4 and 100 times higher than those absorbed by adult rats. Autoradiograms prepared from the entire small intestine of the neonatal rat showed that 109Cd was retained in the duodenum. In contrast, measurements in the piglets showed much higher 109Cd retention in the ileum than in the duodenum. Autoradiograms and radiochemical measurements of 147Pm and 238Pu in both neonatal rats and swine showed the highest level of retention in the ileum. The results indicate that, for most of the metals studied, absorption from the gastrointestinal tract is substantially higher for neonatal than for adult rats.

  10. Accuracy of blood volume estimations in critically ill children using 125I-labelled albumin and 51Cr-labelled red cells.

    PubMed

    Linderkamp, O; Holthausen, H; Seifert, J; Butenandt, I; Riegel, K P

    1977-06-01

    Blood volume was estimated using 51chromium labelled red cells and 125iodinated human serum albumin in 5 children with sepsis, in 6 burned children and 7 children with acute lymphoblastic leukaemia. Studies of the equilibration pattern demonstrated that the mixing time of labelled red cells was prolonged to 40 minutes or more in 5 children, indicating the existence of slowly circulating red cells. Mixing of labelled albumin was complete within 10 minutes in 15 patients and within 20 minutes in all the children studied. In a burned patient with severe sepsis, exchange transfusion improved the clinical state and normalized the equilibration pattern of labelled red cells. The mean body/venous haematocrit ratio was 0.893+/-0.018 (SD) in the children with sepsis, 0.859+/-0.052 in the burned patients, and 0.916+/-0.078 in the children with acute lymphoblastic leukaemia, increasing with spleen size in the latter group. PMID:267010

  11. 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

  12. 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.

  13. Experimental radioimmunotherapy.

    PubMed

    Buchsbaum, D J; Langmuir, V K; Wessels, B W

    1993-01-01

    Radiolabeled monoclonal antibodies have been used for radioimmunotherapy studies with human tumor spheroids and murine and human tumor xenografts in experimental animals. This paper reviews the work that has been performed in these models with different types of cancer, and highlights those papers that have presented dosimetry estimates and attempts to correlate the findings. Radioimmunotherapy studies in multicell spheroids, as a model for micrometastases, have been performed in human neuroblastoma, colon cancer, and melanoma cell lines using 131I-, 125I-, 186Re-, and 212Bi-labeled antibodies. The uniform geometry of the spheroid has allowed radiation dose estimates to be made. Up to three logs of cell kill have been achieved with 131I- and 186Re-specific antibody with minimal toxicity from labeled nonspecific antibody, but 212Bi-antibody had little effect because of its short half-life as shown by Langmuir. It appears that the two most important factors for therapeutic efficacy in this model are good penetration of the radiolabeled antibody and an adequate radionuclide half-life to allow penetration of the immunoconjugate prior to significant radionuclide decay. Radioimmunotherapy studies in animals bearing transplants of colon cancer, leukemia, lymphoma, hepatoma, renal cell carcinoma, neuroblastoma, glioma, mammary carcinoma, small cell lung carcinoma, cervical carcinoma, ovarian carcinoma, and bladder cancer have been performed with 131I, 90Y, 186Re, 153Sm, and 177Lu beta emitting, and 212Bi alpha emitting radionuclides conjugated to monoclonal antibodies. A few studies compared different radionuclides in the same model system. The approaches that have been used in these studies to estimate tumor dosimetry include the MIRD approach, thermoluminescent dosimetry, autoradiography, and comparison to external irradiation. The majority of investigators have estimated the dose to tumor and normal organs using MIRD-based calculations (time-activity curve and

  14. Considerations of anthropometric, tissue volume, and tissue mass scaling for improved patient specificity of skeletal S values.

    PubMed

    Bolch, W E; Patton, R W; Shah, A R; Rajon, D A; Jokisch, D W

    2002-06-01

    It is generally acknowledged that reference man (70 kg in mass and 170 cm in height) does not adequately represent the stature and physical dimensions of many patients undergoing radionuclide therapy, and thus scaling of radionuclide S values is required for patient specificity. For electron and beta sources uniformly distributed within internal organs, the mean dose from self-irradiation is noted to scale inversely with organ mass, provided no escape of electron energy occurs at the organ boundaries. In the skeleton, this same scaling approach is further assumed to be correct for marrow dosimetry; nevertheless, difficulties in quantitative assessments of marrow mass in specific skeletal regions of the patient make this approach difficult to implement clinically. Instead, scaling of marrow dose is achieved using various anthropometric parameters that presumably scale in the same proportion. In this study, recently developed three-dimensional macrostructural transport models of the femoral head and humeral epiphysis in three individuals (51-year male, 82-year female, and 86-year female) are used to test the abilities of different anthropometric parameters (total body mass, body surface area, etc.) to properly scale radionuclide S values from reference man models. The radionuclides considered are 33P, 177Lu, 153Sm, 186Re, 89Sr, 166Ho, 32P, 188Re, and 90Y localized in either the active marrow or endosteal tissues of the bone trabeculae. S value scaling is additionally conducted in which the 51-year male subject is assigned as the reference individual; scaling parameters are then expanded to include tissue volumes and masses for both active marrow and skeletal spongiosa. The study concludes that, while no single anthropometric parameter emerges as a consistent scaler of reference man S values, lean body mass is indicated as an optimal scaler when the reference S values are based on 3D transport techniques. Furthermore, very exact patient-specific scaling of

  15. Accounting for beta-particle energy loss to cortical bone via paired-image radiation transport (PIRT).

    PubMed

    Shah, Amish P; Rajon, Didier A; Patton, Phillip W; Jokisch, Derek W; Bolch, Wesley E

    2005-05-01

    Current methods of skeletal dose assessment in both medical physics (radionuclide therapy) and health physics (dose reconstruction and risk assessment) rely heavily on a single set of bone and marrow cavity chord-length distributions in which particle energy deposition is tracked within an infinite extent of trabecular spongiosa, with no allowance for particle escape to cortical bone. In the present study, we introduce a paired-image radiation transport (PIRT) model which provides a more realistic three-dimensional (3D) geometry for particle transport in the skeletal site at both microscopic and macroscopic levels of its histology. Ex vivo CT scans were acquired of the pelvis, cranial cap, and individual ribs excised from a 66-year male cadaver (BMI of 22.7 kg m(-2)). For the three skeletal sites, regions of trabecular spongiosa and cortical bone were identified and segmented. Physical sections of interior spongiosa were taken and subjected to microCT imaging. Voxels within the resulting microCT images were then segmented and labeled as regions of bone trabeculae, endosteum, active marrow, and inactive marrow through application of image processing algorithms. The PIRT methodology was then implemented within the EGSNRC radiation transport code whereby electrons of various initial energies are simultaneously tracked within both the ex vivo CT macroimage and the CT microimage of the skeletal site. At initial electron energies greater than 50-200 keV, a divergence in absorbed fractions to active marrow are noted between PIRT model simulations and those estimated under existing techniques of infinite spongiosa transport. Calculations of radionuclide S values under both methodologies imply that current chord-based models may overestimate the absorbed dose to active bone marrow in these skeletal sites by 0% to 27% for low-energy beta emitters (33P, 169Er, and 177Lu), by approximately 4% to 49% for intermediate-energy beta emitters (153Sm, 186Re, and 89Sr), and by

  16. 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

  17. 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

  18. 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.

  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. 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.

  1. 10 CFR Appendix L to Part 110 - Illustrative List of Byproduct Materials Under NRC Export/Import Licensing Authority a

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ...) Krypton 87 (Kr 87) Lanthanum 140 (La 140) Lead 210 (Pb 210) Lutetium 177 (Lu 177) Manganese 52 (Mn 52) Manganese 54 (Mn 54) Manganese 56 (Mn 56) Mendelevium 258 (Md 258) Mercury 197m (Hg 197m) Mercury 197...

  2. 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

  3. 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

  4. 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.

  5. Overview of Development and Formulation of ¹⁷⁷Lu-DOTA-TATE for PRRT.

    PubMed

    Breeman, Wouter A P; Chan, Ho Sze; de Zanger, Rory M S; Konijnenberg, Mark K; de Blois, Erik

    2016-01-01

    Peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin analogs has become an established procedure for the treatment of patients suffering from inoperable neuroendocrine cancers over-expressing somatostatin receptors. Success of PRRT depends on the availability of the radiolabeled peptide with adequately high specific activity, so that required therapeutic efficacy can be achieved without saturating the limited number of receptors available on the target lesions. Specific activity of the radionuclide and the radiolabeled somatostatin analog are therefore an important parameters. Although these analogs have been investigated and improved, and successfully applied for PRRT for more than 15 years, there are still many possibilities for further improvements that fully exploit PRRT with 177Lu-DOTA-TATE. The here summarized data presented herein on increased knowledge of the components of 177Lu-DOTA-TATE (especially the purity of 177Lu and specific activity of 177Lu) and the reaction kinetics during labeling 177Lu-DOTA-TATE clearly show that the peptide dose and dose in GBq can be varied. Here we present an overview of the development, formulation and optimisation of 177Lu-DOTA-TATE, mainly addressing radiochemical parameters.

  6. T cell-mediated hepatitis in mice infected with lymphocytic choriomeningitis virus. Liver cell destruction by H-2 class I-restricted virus-specific cytotoxic T cells as a physiological correlate of the /sup 51/Cr-release assay

    SciTech Connect

    Zinkernagel, R.M.; Haenseler, E.; Leist, T.; Cerny, A.; Hengartner, H.; Althage, A.

    1986-10-01

    A model for immunologically T cell-mediated hepatitis was established in mice infected with lymphocytic choriomeningitis virus (LCMV). The severity of hepatitis was monitored histologically and by determination of changes in serum levels of the enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamate dehydrogenase (GLDH), and alkaline phosphatase (AP). Kinetics of histological disease manifestations, increases of liver enzyme levels in the serum, and cytotoxic T cell activities in livers and spleens all correlated and were dependent upon several parameters: LCMV-isolate; LCMV-WE caused extensive hepatitis, LCMV-Armstrong virtually none. Virus dose. Route of infection; i.v. or i.p. infection caused hepatitis, whereas infection into the footpad did not. The general genetic background of the murine host; of the strains tested, Swiss mice and A-strain mice were more susceptible than C57BL or CBA mice; BALB/c and DBA/2 mice were least susceptible. The degree of immunocompetence of the murine host; T cell deficient nu/nu mice never developed hepatitis, whereas nu/+ or +/+ mice always did. B cell-depleted anti-IgM-treated mice developed immune-mediated hepatitis comparably or even more extensively than control mice. Local cytotoxic T cell activity; mononuclear cells isolated from livers during the period of overt hepatitis were two to five times more active than equal numbers of spleen cells. Adoptive transfer of nylon wool-nonadherent anti-Thy-1.2 and anti-Lyt-2 plus C-sensitive, anti-L3T4 plus C-resistant lymphocytes into irradiated mice preinfected with LCMV-WE caused a rapid time- and dose-dependent linear increase of serum enzyme levels. This increase was caused by adoptive transfer of lymphocytes if immune cell donors and recipient mice shared class I, but not when they shared class II histocompatibility antigens.

  7. 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

  8. Production and Clinical Applications of Radiopharmaceuticals and Medical Radioisotopes in Iran.

    PubMed

    Jalilian, Amir Reza; Beiki, Davood; Hassanzadeh-Rad, Arman; Eftekhari, Arash; Geramifar, Parham; Eftekhari, Mohammad

    2016-07-01

    -meta-iodobenzylguanidine for treatment of neuroblastoma, pheochromocytoma, and other neuroendocrine tumors has been steadily increasing in major academic university hospitals. Also (153)Sm-EDTMP, (177)Lu-EDTMP, (90)Y-citrate, (90)Y-hydroxyapatite colloid, (188/186)Re-sulfur colloid, and (188/186)Re-HEDP have been locally developed and now routinely available for bone pain palliation and radiosynovectomy. Cu-64 has been available to the nuclear medicine community for some time. With recent reports in diagnostic and therapeutic applications of this agent especially in the field of oncology, we anticipate an expansion in production and availability. The initiation of the production line for gallium-68 generator is one of the latest exciting developments. We are proud that Iran would be joining the club of few nations with production lines for this type of generator. There are also quite a number of SPECT and PET tracers at research and preclinical stage of development preliminarily introduced for possible future clinical applications. Availability of fluorine-18 tracers and gallium-68 generators would no doubt allow rapid dissemination of PET/CT practices in various parts of our large country even far from a cyclotron facility. Also, local production and availability of therapeutic radiopharmaceuticals are going to open exciting horizons in the field of nuclear medicine therapy. Given the available manpower, local infrastructure of SPECT imaging, and rapidly growing population, the production of Tc-99m generators and cold kit would continue to flourish in Iran. PMID:27237443

  9. 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.

  10. 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

  11. Development and biological studies of ¹⁷⁷Lu-DOTA-rituximab for the treatment of Non-Hodgkin's lymphoma.

    PubMed

    Massicano, Adriana V F; Pujatti, Priscilla B; Alcarde, Lais F; Suzuki, Miriam F; Spencer, Patrick J; Araújo, Elaine B

    2016-01-01

    The optimization of DOTA-NHS-ester conjugation to Rituximab using different Ab:DOTA molar ratios (1:10, 1:20, 1:50 and 1:100) was studied. High radiochemical yield, in vitro stability and immunoreactive fraction were obtained for the Rituximab conjugated at 1:50 molar ratio, resulting in the incorporation of an average number of 4.9 ± 1.1 DOTA per Rituximab molecule. Labeling with 177Lu was performed in high specific activity with great in vitro stability. Biodistribution in healthy and xenographed mice showed tumor uptake and high in vivo stability as evidenced by low uptake in bone. The properties of 177Lu-DOTA-Rituximab prepared from DOTA-NHS-ester suggest the potential for the application of the 177Lu-labeled antibody in preliminary clinical studies.

  12. Standardization of Sm-153 solution by absolute methods.

    PubMed

    Dziel, T; Broda, R; Ziemek, T; Muklanowicz, A; Listkowska, A

    2014-05-01

    Standardization of (153)Sm by 4π(LS)-γ coincidence and anticoincidence counting and the CIEMAT/NIST method in three LS-counters is presented. This short half-life radionuclide is applied in tumor therapy and bone pain palliation. A simplified disintegration scheme of (153)Sm was applied in the calculation of the counting efficiency. Standard uncertainties of 0.4% for the (153)Sm measurements by the 4π(LS)-γ coincidence and anticoincidence techniques and 0.7% by the C/N method were evaluated, respectively. An agreement of the standardization results by both methods within the respective uncertainties was obtained. The half-life of (153)Sm of (1.92895±0.00024) days was determined during one month of measurements and correction for europium isotope impurities by the C/N method in the TriCarb 2910 LS-counter.

  13. Comparison of ⁹⁰Y and ¹⁷⁷Lu measurement capability in UK and European hospitals.

    PubMed

    Fenwick, Andrew; Baker, Michaela; Ferreira, Kelley; Keightley, John

    2014-05-01

    Comparison exercises involving (90)Y and (177)Lu were performed during 2009 and 2012, respectively, to assess the measurement capability of hospitals in the UK and Europe. The results from the measurement of a typical liquid solution of (90)Y show that only 40% of participants could measure the solution to within 5% of the certificated value and that a significant -6% bias was present due to the use of non-standard geometries for the calibration of equipment. The results from the measurement of a standard liquid solution of (177)Lu show that 81% of participants could measure to within 5% of the certificated value and in fact 65% of these results were within 2% of the certificated value, showing administered activities can be far more accurately measured for (177)Lu than for (90)Y and that (177)Lu has a far smaller geometry dependence. These studies were performed to identify specific measurement issues in the user community and to identify areas where future research should be focused. In addition to this the work allows the participants to adjust measurement practice and identify key measurement issues.

  14. 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).

  15. Biokinetics and dosimetry of several radiolabelled peptides in cancer cells

    NASA Astrophysics Data System (ADS)

    Rodríguez-Cortés, J.; Ferro-Flores, G.; de Murphy, C. Arteaga; Pedraza-López, M.; Ramírez-Iglesias, M. A. T.

    Radiolabelled peptides have been used as target-specific radiopharmaceuticals. The goal of this research was the in vitro assessment of the uptake, internalization, externalization, and efflux of five radiolabelled peptides in cancer cells to estimate radiation-absorbed doses from experimental biokinetic data. 177Lu-DOTA-octreotate, 188Re-lanreotide, and 99mTc-HYNIC-octreotide were studied in the AR42J cell line. The PC3 and NCIH69 cells were used for 99mTc-HYNIC-bombesin and 177Lu-DOTA-minigastrin, respectively. The cumulated activities in the membrane and cytoplasm were calculated by integration of the experimental time-activity curves and used for dosimetry calculations according to the Medical Internal Radiation Dose (MIRD) cellular methodology. The mean absorbed dose to the cell nucleus were 0.69±0.09, 0.11±0.08, 0.55±0.09, 3.45±0.48, and 3.30±0.65 Gy/Bq for 99mTc-HYNIC-bombesin, 99mTc-HYNIC-octreotide, 177Lu-DOTA-minigastrin, 177Lu-DOTA-octreotate, and 188Re-lanreotide, respectively. If radiopharmaceutical cell kinetics were not used and only uptake data were considered, the calculated doses would be overestimated up to 25 times.

  16. Optimizing lutetium 177-anti-carbonic anhydrase IX radioimmunotherapy in an intraperitoneal clear cell renal cell carcinoma xenograft model.

    PubMed

    Muselaers, Constantijn H J; Oosterwijk, Egbert; Bos, Desirée L; Oyen, Wim J G; Mulders, Peter F A; Boerman, Otto C

    2014-01-01

    A new approach in the treatment of clear cell renal carcinoma (ccRCC) is radioimmunotherapy (RIT) using anti-carbonic anhydrase IX (CAIX) antibody G250. To investigate the potential of RIT with lutetium 177 (177Lu)-labeled G250, we conducted a protein dose escalation study and subsequently an RIT study in mice with intraperitoneally growing ccRCC lesions. Mice with intraperitoneal xenografts were injected with 1, 3, 10, 30, or 100 μg of G250 labeled with 10 MBq indium 111 (111In) to determine the optimal protein dose. The optimal protein dose determined with imaging and biodistribution studies was used in a subsequent RIT experiment in three groups of 10 mice with intraperitoneal SK-RC-52 tumors. One group received 13 MBq 177Lu-DOTA-G250, a control group received 13 MBq nonspecific 177Lu-MOPC21, and the second control group was not treated and received 20 MBq 111In-DOTA-G250. The optimal G250 protein dose to target ccRCC in this model was 10 μg G250. Treatment with 13 MBq 177Lu-DOTA-G250 was well tolerated and resulted in significantly prolonged median survival (139 days) compared to controls (49-53 days, p  =  .015), indicating that RIT has potential in this metastatic ccRCC model.

  17. In Vivo Stabilization of a Gastrin-Releasing Peptide Receptor Antagonist Enhances PET Imaging and Radionuclide Therapy of Prostate Cancer in Preclinical Studies.

    PubMed

    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 (68)Ga-/(177)Lu-JMV4168 GRPR-antagonist. Co-injection of PA (300 µg) led to stabilization of (177)Lu-JMV4168 in murine peripheral blood. In PC-3 tumor-bearing mice, PA co-injection led to a two-fold increase in tumor uptake of (68)Ga-/(177)Lu-JMV4168, 1 h after injection. In positron emission tomography (PET) imaging with (68)Ga-JMV4168, PA co-injection substantially enhanced PC-3 tumor signal intensity. Radionuclide therapy with (177)Lu-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 (177)Lu-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.

  18. 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

  19. Radioisotope post-labeling upconversion nanophosphors for in vivo quantitative tracking.

    PubMed

    Sun, Yun; Liu, Qian; Peng, Juanjuan; Feng, Wei; Zhang, Yingjian; Yang, Pengyuan; Li, Fuyou

    2013-03-01

    Lanthanide based upconversion nanophosphors (UCNPs) attracted increasing attention for potential applications in bioimaging, while its in vivo behaviors are not clear until now due to no available quantification imaging tools. Herein, we developed a unique rare-earth cation-exchange-based postlabelling method to introduce (153)Sm into the lattice of UCNPs, providing this (153)Sm-postlabeling UCNP having bifunction of radioactive property and upconversion luminescence under excitation at 980 nm laser. This (153)Sm-postlabelling method shows rapid treatment time of <1 min, high labeling yield of >99%, and without usage of organic solvents. More importantly, this (153)Sm-postlabelling method is also suitable for most of rare earth nanoparticles to track their in vivo behaviors. The dynamic quantification studies of the in vivo fate of the rare-earth nanoparticles were further investigated by radioactive detection method such as single-photon emission computed tomography (SPECT) and gamma counter. The imaging results revealed that UCNPs were mainly captured by the mononuclear phagocyte system (liver and spleen). The amount of nanoparticles in liver arrived at its peak quicker and was about 15 fold of that in spleen. And the nanoparticles will be slowly excreted with the bile. Therefore, the concept of postlabeling (153)Sm onto lanthanide-based UCNPs may serve as a facile strategy of fabricating multifunctional nanoprobes for upconversion luminescence (UCL) and SPECT dual-modality imaging.

  20. 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

  1. Lutetium-177 Labeled Bombesin Peptides for Radionuclide Therapy.

    PubMed

    Reynolds, Tamila Stott; Bandari, Rajendra P; Jiang, Zongrun; Smith, Charles J

    2016-01-01

    The rare-earth radionuclides that decay by beta particle (β-) emission are considered to be ideal in the context of targeted radiotherapy. The rare-earth isotopes exist primarily in the 3+ oxidation state and are considered to be hard metal centers, requiring multidentate, hard donor ligands such as the poly(aminocarboxylates) for in vivo kinetic inertness. 177Lu is a rare-earth radionuclide that is produced in moderate specific activity (740 GBq/mg) by direct neutron capture of enriched 176Lu via the 176Lu(n,γ)177Lu nuclear reaction. 177Lu has a half-life of 6.71 d, decays by beta emission (Ebmax = 0.497 MeV), and emits two imagable photons (113keV, 3% and 208kev, 11%). High specific activity, no-carrier-added 177Lu can also be prepared by an indirect neutron capture nuclear reaction on a 176Yb target. Herein, we report upon bombesin (BBN) peptides radiolabeled with 177Lu. The impetus driving many of the research studies that we have described in this review is that the high-affinity gastrin releasing peptide receptor (GRPR, BBN receptor subtype 2, BB2) has been identified in tissue biopsy samples and immortalized cell lines of many human cancers and is an ideal biomarker for targeting early-stage disease. Early on, the ability of GRPR agonists to be rapidly internalized coupled with a high incidence of GRPR expression on various neoplasias was a driving force for the design and development of new diagnostic and therapeutic agents targeting GRP receptor-positive tumors. Recent reports, however, show compelling evidence that radiopharmaceutical design and development based upon antagonist-type ligand frameworks clearly bears reexamination. Last of all, the ability to target multiple biomarkers simultaneously via a heterodimeric targeting ligand has also provided a new avenue to investigate the dual targeting capacity of bivalent radioligands for improved in vivo molecular imaging and treatment of specific human cancers. In this report, we describe recent advances

  2. Neutron Activated Samarium-153 Microparticles for Transarterial Radioembolization of Liver Tumour with Post-Procedure Imaging Capabilities

    PubMed Central

    Hashikin, Nurul Ab. Aziz; Yeong, Chai-Hong; Abdullah, Basri Johan Jeet; Ng, Kwan-Hoong; Chung, Lip-Yong; Dahalan, Rehir; Perkins, Alan Christopher

    2015-01-01

    Introduction Samarium-153 (153Sm) styrene divinylbenzene microparticles were developed as a surrogate for Yttrium-90 (90Y) microspheres in liver radioembolization therapy. Unlike the pure beta emitter 90Y, 153Sm possess both therapeutic beta and diagnostic gamma radiations, making it possible for post-procedure imaging following therapy. Methods The microparticles were prepared using commercially available cation exchange resin, Amberlite IR-120 H+ (620–830 μm), which were reduced to 20–40 μm via ball mill grinding and sieve separation. The microparticles were labelled with 152Sm via ion exchange process with 152SmCl3, prior to neutron activation to produce radioactive 153Sm through 152Sm(n,γ)153Sm reaction. Therapeutic activity of 3 GBq was referred based on the recommended activity used in 90Y-microspheres therapy. The samples were irradiated in 1.494 x 1012 n.cm-2.s-1 neutron flux for 6 h to achieve the nominal activity of 3.1 GBq.g-1. Physicochemical characterisation of the microparticles, gamma spectrometry, and in vitro radiolabelling studies were carried out to study the performance and stability of the microparticles. Results Fourier Transform Infrared (FTIR) spectroscopy of the Amberlite IR-120 resins showed unaffected functional groups, following size reduction of the beads. However, as shown by the electron microscope, the microparticles were irregular in shape. The radioactivity achieved after 6 h neutron activation was 3.104 ± 0.029 GBq. The specific activity per microparticle was 53.855 ± 0.503 Bq. Gamma spectrometry and elemental analysis showed no radioactive impurities in the samples. Radiolabelling efficiencies of 153Sm-Amberlite in distilled water and blood plasma over 48 h were excellent and higher than 95%. Conclusion The laboratory work revealed that the 153Sm-Amberlite microparticles demonstrated superior characteristics for potential use in hepatic radioembolization. PMID:26382059

  3. Preclinical evaluation of multistep targeting of diasialoganglioside GD2 using an IgG-scFv bispecific antibody with high affinity for GD2 and DOTA metal complex.

    PubMed

    Cheal, Sarah M; Xu, Hong; Guo, Hong-fen; Zanzonico, Pat B; Larson, Steven M; Cheung, Nai-Kong

    2014-07-01

    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, an IgG-scFv BsAb was engineered using the sequences for the anti-GD2 humanized monoclonal antibody hu3F8 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 β-particle-emitting radiometals such as (177)Lu and (90)Y. A three-step regimen, including hu3F8-C825, a dextran-based clearing agent, and p-aminobenzyl-DOTA radiolabeled with (177)Lu (as (177)Lu-DOTA-Bn; t1/2 = 6.71 days), was optimized in immunocompromised mice carrying subcutaneous human GD2(+) neuroblastoma (NB) xenografts. Absorbed doses for tumor and normal tissues were approximately 85 cGy/MBq and ≤3.7 cGy/MBq, respectively, with therapeutic indices (TI) of 142 for blood and 23 for kidney. A therapy study (n = 5/group; tumor volume, 240 ± 160 mm(3)) with three successive PRIT cycles (total (177)Lu: ∼33 MBq; tumor dose ∼3,400 cGy), revealed complete tumor response in 5 of 5 animals, with no recurrence up to 28 days after treatment. Tumor ablation was confirmed histologically in 4 of 5 mice, and normal organs showed minimal overall toxicities. All nontreated mice required sacrifice within 12 days (>1.0-cm(3) tumor volume). We conclude that this novel anti-GD2 PRIT approach has sufficient TI to successfully ablate subcutaneous GD2(+)-NB in mice while sparing kidney and bone marrow.

  4. Nuclear medicine program progress report for quarter ending September 30, 1995

    SciTech Connect

    Knapp, F.F. Jr.; Ambrose, K.R.; Beets, A.L.; Luo, H.; McPherson, D.W.; Mirzadeh, S.

    1995-12-31

    In this report, we describe the results for study of the production of lutetium-177 ({sup 177}Lu) in the High Flux Isotope Reactor (HFIR). Two pathways for production of {sup 177}Lu were studied which involved both direct neutron capture on enriched {sup 176}Lu, {sup 176}Lu (n,{gamma}){sup 177}Lu, reaction and by decay of ytterbium-177 ({sup 177}Yb) produced by the {sup 176}Yb(n,{gamma}){sup 177}Yb ({beta}{sup {minus}} {sup {yields}}) reaction. Although the direct route is more straight forward and does not involve any separation steps, the indirect method via {beta}{sup {minus}}-decay of {sup 177}Yb has the advantage of providing carrier-free {sup 177}Lu, which would be required for antibody radiolabeling and other applications where very high specific activity is required.Substrates required for preparation of tissue-specific agents and several radioisotopes were also provided during this period through several Medical Cooperative Programs. These include the substrate for preparation of the ``BMIPP`` cardiac imaging which was developed in the ORNL Nuclear Medicine Program, which was provided to Dr. A. Giodamo, M.D. and colleagues at the Catholic University Hospital in Rome, Italy. Tungsten-188 produced in the ORNL HFIR was also provided to the Catholic University Hospital for fabrication of a tungsten-188/rhenium-188 generator to provide carrier-free rhenium-188 which will be used for preparation of rhenium-188 labeled methylenediphosphonate (MDP) for initial clinical evaluation for palliative treatment of bone pain (L. Troncone, M.D.). Samples of substrates for preparation of the new ORNL ``IQNP`` agent for imaging of muscarinic-cholinergic receptors were provided to the Karolinska Institute in Stockholm, Sweden, for preparation of radioiodinated IQNP for initial imaging studies with this new agent in monkeys and for tissue binding studies with human brain samples obtained from autopsy (C. Halldin, Ph.D.).

  5. Radioimmunotherapy of Metastatic Prostate Cancer with ¹⁷⁷Lu-DOTAhuJ591 Anti Prostate Specific Membrane Antigen Specific Monoclonal Antibody.

    PubMed

    Vallabhajosula, Shankar; Nikolopoulou, Anastasia; Jhanwar, Yuliya S; Kaur, Gurveen; Tagawa, Scott T; Nanus, David M; Bander, Neil H; Goldsmith, Stanley J

    2016-01-01

    Prostate specific membrane antigen (PSMA) is the single most well-validated prostate cancer (PCa)-specific cell membrane antigen known. It is present in high levels in 95% of PCa, and is an ideal target to develop radiopharmaceuticals for imaging studies and radionuclide therapy. Humanized J591 monoclonal antibody (mAb) binds specifically with nanomolar affinity to the extracellular domain of PSMA. After binding, the PSMA-antibody complex is rapidly internalized, increasing the potential utility of PSMA as a target for the delivery of mAb-conjugated radionuclides or cytotoxins. J591 mAb was labeled with 177Lu at a high specific activity (10-30 mCi/mg) using DOTA as the bifunctional chelate. The preclinical data in PSMA positive xenografts, strongly suggested that 177;Lu-J591 mAb is an ideal radiopharmaceutical for RIT of metastatic PCa. Since October 2000, five clinical studies (phase I and II) were performed in subjects with metastatic castration-resistant prostate cancer (CRPC) using 177Lu-J591. The methodology and the results of these clinical studies are briefly reviewed in this article. The maximum tolerated dose (MTD) as a single dose was 70 mCi2. Based on dose fractionation (DF), MTD was 90 mCi/m2(2 doses of 45 mCi/m2, 2 wks apart). Phase II study in patients with progressive metastatic CRPC, at a dose of 65- 70 mCi/m2 resulted in significant PSA declines in 60% of the patients. While myelosuppression was the dose limiting toxicity, DF alone or in combination with docetaxel also resulted in significant PSA declines with much less toxicity. 177Lu imaging studies demonstrated accurate targeting of known metastatic sites in >90% of patients and those with stronger PSMA expression by semi-quantitative imaging had more PSA declines. These clinical studies clearly documented the potential therapeutic value of radioimmunotherapy (RIT) in metastatic PCa.

  6. Phase II study of lutetium-177 labeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 for metastatic castration-resistant prostate cancer

    PubMed Central

    Tagawa, Scott T.; Milowsky, Matthew I.; Morris, Michael; Vallabhajosula, Shankar; Christos, Paul; Akhtar, Naveed H.; Osborne, Joseph; Goldsmith, Stanley J.; Larson, Steve; Taskar, Neeta Pandit; Scher, Howard I.; Bander, Neil H.; Nanus, David M.

    2013-01-01

    Purpose To assess the efficacy of a single infusion of radiolabeled anti-prostate specific membrane antigen monoclonal antibody J591 (177Lu-J591) by PSA decline, measurable disease response, and survival. Experimental Design In this dual-center phase II study, 2 cohorts with progressive metastatic castration-resistant prostate cancer received one dose of 177Lu-J591 (15 patients at 65 mCi/m2, 17 at 70 mCi/m2) with radionuclide imaging. Expansion cohort (n=15) received 70 mCi/m2 to verify response rate and examine biomarkers. Results 47 patients who progressed after hormonal therapies (55.3% also received prior chemotherapy) received 177Lu-J591. 10.6% experienced ≥ 50% decline in PSA, 36.2% experienced ≥ 30% decline, and 59.6% experienced any PSA decline following their single treatment. One of 12 with measurable disease experienced a partial radiographic response (8 with stable disease). Sites of prostate cancer metastases were targeted in 44 of 47 (93.6%) as determined by planar imaging. All experienced reversible hematologic toxicity with grade 4 thrombocytopenia occurring in 46.8% (29.8% received platelet transfusions) without significant hemorrhage. 25.5% experienced grade 4 neutropenia with 1 episode of febrile neutropenia. The phase I maximum tolerated dose (70 mCi/m2) resulted in more 30% PSA declines (46.9% vs 13.3%, p=0.048) and longer survival (21.8 vs 11.9 months, p=0.03), but also more grade 4 hematologic toxicity and platelet transfusions. No serious non-hematologic toxicity occurred. Those with poor PSMA imaging were less likely to respond. Conclusion A single dose of 177Lu-J591 was well-tolerated with reversible myelosuppression. Accurate tumor targeting and PSA responses were seen with evidence of dose-response. Imaging biomarkers appear promising. PMID:23714732

  7. 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.

  8. A Patient With Metastatic Sarcoma was Successfully Treated With Radiolabeled Somatostatin Analogs

    PubMed Central

    Crespo-Jara, Aurora; González Manzano, Ramón; Lopera Sierra, Maribel; Redal Peña, María Carmen; Brugarolas Masllorens, Antonio

    2016-01-01

    Abstract We present a sarcoma patient with a tumor reduction of more than 50% in lung metastasis after 2 single courses of the investigational medical product Lutathera (177Lu-DOTA0-Tyr3-octreotate). She was resistant to more than 6 lines of therapy including all the available active drugs in soft tissue sarcomas. The high expression of somatostatin receptors was shown by microarrays and Octreoscan. The overall duration of response exceeded 1 year. PMID:27355848

  9. 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

  10. The use of 185 MBq and 740 MBq of 153-samarium hydroxyapatite for knee synovectomy in haemophilia

    PubMed Central

    Calegaro, J U M; Machado, J; Furtado, R G; de Almeida, J S C; de Vasconcelos, A V P; de Barboza, M F; de Paula, A P

    2014-01-01

    The penetration of beta energy of 153-samarium (153Sm) (0.8 MeV) is not only appropriate for synovectomy of median articulations but is possible to improve the radiobiological effect using increased activities. The aim of this study was to assess the effectiveness of 185 MBq and 740 MBq of 153-samarium hydroxyapatite (153Sm-HA) in knees of haemophilic patients. Thirty-one patients – 36 knees, 30 males, were divided into two groups without coinjection of corticosteroid: A – 14 patients (17 knees) treated with intra-articular dose of 185 MBq of 153Sm-HA, average age 23 years; B – 17 patients (19 knees) with 740 MBq of 153Sm-HA, average age 21.3 years. The evaluation before and after 1 year of synovectomy used the following criteria: reduction in the number of haemarthroses and use of the coagulation factor and improvement in articular motility. Adverse-effects occurrence was considered too. Early and late scintigraphic studies were performed after synoviorthesis and no joint immobilization was recommended. The reduction in haemarthrosis and use of coagulation factor were: group 1 – 31.3% and 25%; group 2 – 81.5% and 79% with P < 0.001 respectively; no significant improvement in knees motility was noted for both groups. Four cases of mild reactional synovitis were observed in each group. The scintigraphic control showed homogenous distribution of the radiopharmaceuticals with no articular escape; the material was considered safe by its permanence in the articulation. We have significant improvement in the synovectomy of haemophilic knees with 740 MBq of 153Sm-HA; the less penetration of its beta radiation was compensated by the increased biological effect with the higher used activity. PMID:24330418

  11. Lu-177-Labeled Zirconia Particles for Radiation Synovectomy.

    PubMed

    Polyak, Andras; Nagy, Lívia Naszályi; Drotár, Eszter; Dabasi, Gabriella; Jóba, Róbert P; Pöstényi, Zita; Mikolajczak, Renata; Bóta, Attila; Balogh, Lajos

    2015-12-01

    The present article describes the preparation of β-emitter lutetium-177-labeled zirconia colloid and its preliminary physicochemical and biological evaluation of suitability for local radionuclide therapy. The new (177)Lu-labeled therapeutic radiopharmaceutical candidate was based on the synthesis mode of a previously described zirconia nanoparticle system. The size and shape of the developed radiopharmaceutical compound were observed through a scanning electron microscope and dynamic light scattering methods. The radiocolloid had a 1.7 μm mean diameter and showed high in vitro radiochemical and colloid size stability at room temperature and during the blood sera stability test. After the in vitro characterizations, the product was investigated in the course of the treatment of a spontaneously diseased dog veterinary patient's hock joint completed with single-photon emission computed tomography (SPECT) imaging follow-up measurements and a dual-isotope SPECT imaging tests with conventional (99m)Tc-methanediphosphonic acid bone scintigraphy. In the treated dog, no clinical side-effects or signs of histopathological changes of the joints were recorded during the treatment. SPECT follow-up studies clearly and conspicuously showed the localization of the (177)Lu-labeled colloid in the hock joint as well as detectable but negligible leakages of the radiocolloid in the nearest lymph node. On the basis of biological follow-up tests, the orthopedic team assumed that the (177)Lu-labeled zirconia colloid-based local radionuclide therapy resulted in a significant and long-term improvement in clinical signs of the patient without any remarkable side-effects.

  12. Towards Personalized Treatment of Prostate Cancer: PSMA I&T, a Promising Prostate-Specific Membrane Antigen-Targeted Theranostic Agent

    PubMed Central

    Chatalic, Kristell L.S.; Heskamp, Sandra; Konijnenberg, Mark; Molkenboer-Kuenen, Janneke D.M.; Franssen, Gerben M.; Clahsen-van Groningen, Marian C.; Schottelius, Margret; Wester, Hans-Jürgen; van Weerden, Wytske M.; Boerman, Otto C.; de Jong, Marion

    2016-01-01

    Prostate-specific membrane antigen (PSMA) is a well-established target for nuclear imaging and therapy of prostate cancer (PCa). Radiolabeled small-molecule PSMA inhibitors are excellent candidates for PCa theranostics—they rapidly and efficiently localize in tumor lesions. However, high tracer uptake in kidneys and salivary glands are major concerns for therapeutic applications. Here, we present the preclinical application of PSMA I&T, a DOTAGA-chelated urea-based PSMA inhibitor, for SPECT/CT imaging and radionuclide therapy of PCa. 111In-PSMA I&T showed dose-dependent uptake in PSMA-expressing tumors, kidneys, spleen, adrenals, lungs and salivary glands. Coadministration of 2-(phosphonomethyl)pentane-1,5-dioic acid (2-PMPA) efficiently reduced PSMA-mediated renal uptake of 111In-PSMA I&T, with the highest tumor/kidney radioactivity ratios being obtained using a dose of 50 nmol 2-PMPA. SPECT/CT clearly visualized subcutaneous tumors and sub-millimeter intraperitoneal metastases; however, high renal and spleen uptake in control mice (no 2-PMPA) interfered with visualization of metastases in the vicinity of those organs. Coadministration of 2-PMPA increased the tumor-to-kidney absorbed dose ratio during 177Lu-PSMA I&T radionuclide therapy. Hence, at equivalent absorbed dose to the tumor (36 Gy), coinjection of 2-PMPA decreased absorbed dose to the kidneys from 30 Gy to 12 Gy. Mice injected with 177Lu-PSMA I&T only, showed signs of nephrotoxicity at 3 months after therapy, whereas mice injected with 177Lu-PSMA I&T + 2-PMPA did not. These data indicate that PSMA I&T is a promising theranostic tool for PCa. PSMA-specific uptake in kidneys can be successfully tackled using blocking agents such as 2-PMPA. PMID:27162555

  13. Lu-177-Labeled Zirconia Particles for Radiation Synovectomy.

    PubMed

    Polyak, Andras; Nagy, Lívia Naszályi; Drotár, Eszter; Dabasi, Gabriella; Jóba, Róbert P; Pöstényi, Zita; Mikolajczak, Renata; Bóta, Attila; Balogh, Lajos

    2015-12-01

    The present article describes the preparation of β-emitter lutetium-177-labeled zirconia colloid and its preliminary physicochemical and biological evaluation of suitability for local radionuclide therapy. The new (177)Lu-labeled therapeutic radiopharmaceutical candidate was based on the synthesis mode of a previously described zirconia nanoparticle system. The size and shape of the developed radiopharmaceutical compound were observed through a scanning electron microscope and dynamic light scattering methods. The radiocolloid had a 1.7 μm mean diameter and showed high in vitro radiochemical and colloid size stability at room temperature and during the blood sera stability test. After the in vitro characterizations, the product was investigated in the course of the treatment of a spontaneously diseased dog veterinary patient's hock joint completed with single-photon emission computed tomography (SPECT) imaging follow-up measurements and a dual-isotope SPECT imaging tests with conventional (99m)Tc-methanediphosphonic acid bone scintigraphy. In the treated dog, no clinical side-effects or signs of histopathological changes of the joints were recorded during the treatment. SPECT follow-up studies clearly and conspicuously showed the localization of the (177)Lu-labeled colloid in the hock joint as well as detectable but negligible leakages of the radiocolloid in the nearest lymph node. On the basis of biological follow-up tests, the orthopedic team assumed that the (177)Lu-labeled zirconia colloid-based local radionuclide therapy resulted in a significant and long-term improvement in clinical signs of the patient without any remarkable side-effects. PMID:26683134

  14. 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.

  15. Development of an imaging-guided CEA-pretargeted radionuclide treatment of advanced colorectal cancer: first clinical results

    PubMed Central

    Schoffelen, R; Boerman, O C; Goldenberg, D M; Sharkey, R M; van Herpen, C M L; Franssen, G M; McBride, W J; Chang, C-H; Rossi, E A; van der Graaf, W T A; Oyen, W J G

    2013-01-01

    Background: Radiolabelled antibody targeting of cancer is limited by slow blood clearance. Pretargeting with a non-radiolabelled bispecific monoclonal antibody (bsMAb) followed by a rapidly clearing radiolabelled hapten peptide improves tumour localisation. The primary goals of this first pretargeting study in patients with the anti-CEACAM5 × anti-hapten (HSG) bsMAb, TF2, and the radiolabelled hapten-peptide, IMP288, were to assess optimal pretargeting conditions and safety in patients with metastatic colorectal cancer (CRC). Methods: Different dose schedules were studied in four cohorts of five patients: (1) shortening the interval between the bsMAb and peptide administration (5 days vs 1 day), (2) escalating the TF2 dose (from 75 to 150 mg), and (3) reducing the peptide dose (from 100 to 25 μg). After confirmation of tumour targeting by 111In-IMP288, patients were treated with a bsMAb/177Lu-IMP288 cycle. Results: Rapid and selective tumour targeting of the radiolabelled peptide was visualised within 1 h, with high tumour-to-tissue ratios (>20 at 24 h). Improved tumour targeting was achieved with a 1-day interval between the administration of the bsMAb and the peptide and with the 25-μg peptide dose. High 177Lu-IMP288 doses (2.5–7.4 GBq) were well tolerated, with some manageable TF2 infusion reactions, and transient grades 3–4 thrombocytopaenia in 10% of the patients who received 177Lu-IMP288. Conclusion: This phase I study demonstrates for the first time that pretargeting with bsMAb TF2 and radiolabelled IMP288 in patients with CEA-expressing CRC is feasible and safe. With this pretargeting method, tumours are specifically and rapidly targeted. PMID:23860529

  16. Cross sections of deuteron induced reactions on (nat)Sm for production of the therapeutic radionuclide ¹⁴⁵Sm and ¹⁵³Sm.

    PubMed

    Tárkányi, F; Hermanne, A; Takács, S; Ditrói, F; Csikai, J; Ignatyuk, A V

    2014-09-01

    At present, targeted radiotherapy (TR) is acknowledged to have great potential in oncology. A large list of interesting radionuclides is identified, including several radioisotopes of lanthanides, amongst them (145)Sm and (153)Sm. In this work the possibility of their production at a cyclotron was investigated using a deuteron beam and a samarium target. The excitation functions of the (nat)Sm(d,x)(145,153)Sm reactions were determined for deuteron energies up to 50 MeV using the stacked-foil technique and high-resolution γ-ray spectrometry. The measured cross sections and the contributing reactions were analyzed by comparison with results of the ALICE, EMPIRE and TALYS nuclear reaction codes. A short overview and comparison of possible production routes is given.

  17. Synthesis, characterization, and evaluation of radiometal-containing peptide nucleic acids.

    PubMed

    Stephan, Holger; Foerster, Christian; Gasser, Gilles

    2014-01-01

    Peptide nucleic acids (PNAs) have very attractive properties for applications in nuclear medicine. Because PNAs have high selectivity for DNA/RNA recognition, resistance to nuclease/protease degradation, and high thermal and radiolytic stabilities, PNA bioconjugates could transform the areas of diagnostic and therapeutic nuclear medicine. In this book chapter, we report on the current developments towards the preparation of radiometal-containing PNA constructs and summarize the protocols for labeling these probes with (99m)Tc, (111)In, (64)Cu, (90)Y, and (177)Lu.

  18. 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

  19. 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

  20. Metallofullerene-based Nanoplatform for Brain Tumor Brachytherapy and Longitudinal Imaging in a Murine Orthotopic Xenograft Model

    PubMed Central

    Shultz, Michael D.; Wilson, John D.; Fuller, Christine E.; Zhang, Jianyuan; Dorn, Harry C.

    2011-01-01

    Purpose: To demonstrate in an orthotopic xenograft brain tumor model that a functionalized metallofullerene (f-Gd3N@C80) can enable longitudinal tumor imaging and, when radiolabeled with lutetium 177 (177Lu) and tetraazacyclododecane tetraacetic acid (DOTA) (177Lu-DOTA-f-Gd3N@C80), provide an anchor to deliver effective brachytherapy. Materials and Methods: All experiments involving the use of mice were carried out in accordance with protocols approved by the institutional animal care and use committee. Human glioblastoma U87MG cells were implanted by using stereotactic procedures into the brains of 37 female athymic nude-Foxn1nu mice and allowed to develop into a tumor for 8 days. T1- and T2-weighted magnetic resonance (MR) imaging was performed in five mice. Biodistribution studies were performed in 12 mice at four time points over 7 days to evaluate gadolinium content. Survival studies involved 20 mice that received infusion of a nanoplatform by means of convection-enhanced delivery (CED) 8 days after tumor implantation. Mice in survival studies were divided into two groups: one comprised untreated mice that received f-Gd3N@C80 alone and the other comprised mice treated with brachytherapy that received 1.11 MBq of 177Lu-DOTA-f-Gd3N@C80. Survival data were evaluated by using Kaplan-Meier statistical methods. Results: MR imaging showed extended tumor retention (25.6% ± 1.2 of the infused dose at 52 days, confirmed with biodistribution studies) of the f-Gd3N@C80 nanoplatform, which enabled longitudinal imaging. Successful coupling of 177Lu to the f-Gd3N@C80 surface was achieved by using a bifunctional macrocyclic chelator. The extended tumor retention allowed for effective brachytherapy, as indicated by extended survival time (>2.5 times that of the untreated group) and histologic signs of radiation-induced tumor damage. Conclusion: The authors have developed a multimodal nanoplatform and have demonstrated longitudinal tumor imaging, prolonged intratumoral probe

  1. 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

  2. Peptide receptor radionuclide therapy for advanced neuroendocrine tumors.

    PubMed

    Bodei, Lisa; Cremonesi, Marta; Kidd, Mark; Grana, Chiara M; Severi, Stefano; Modlin, Irvin M; Paganelli, Giovanni

    2014-08-01

    Peptide receptor radionuclide therapy (PRRT) consists of the systemic administration of a synthetic peptide, labeled with a suitable β-emitting radionuclide, able to irradiate tumors and their metastases via internalization through a specific receptor (usually somatostatin S2), over-expressed on the cell membrane. After almost 2 decades of experience, PRRT, with either (90)Y-octreotide or (177)Lu-octreotate, has established itself to be an efficient and effective therapeutic modality. As a treatment, it is relatively safe up to the known thresholds of absorbed and bio-effective isotope dosages and the renal and hematological toxicity profiles are acceptable if adequate protective measures are undertaken.

  3. Chemoradiation therapy using cyclopamine-loaded liquid-lipid nanoparticles and lutetium-177-labeled core-crosslinked polymeric micelles.

    PubMed

    You, Jian; Zhao, Jun; Wen, Xiaoxia; Wu, Chunhui; Huang, Qian; Guan, Fada; Wu, Richard; Liang, Dong; Li, Chun

    2015-03-28

    Cyclopamine (CPA), a potent inhibitor of the Hedgehog pathway, has produced promising anticancer results in a number of preclinical studies. CPA has also been found to enhance tumor response to radiation therapy. However, CPA is water insoluble. A drug delivery system suitable for systemic administration of CPA is needed before CPA can be considered for clinical translation. We hypothesized that CPA solubilized in a liquid-lipid nanoparticle system (CPA-LLP) for intravenous injection would have desirable pharmacokinetic properties and increased anticancer efficacy. We further hypothesized that CPA-LLP would enhance the response of tumor cells to targeted radiotherapy delivered selectively through intratumoral injection of lutetium-177 bound to core-crosslinked polymeric micelles (CCPM-(177)Lu). We tested the combination therapy in 4T1 murine breast cancer and Miapaca-2 human pancreatic adenocarcinoma models. The results showed that CPA-LLP had higher antitumor cytotoxicity than free CPA (IC50 values [mean±SEM]: 2.7±0.2μM vs. 11.3±1.2μM against 4T1 cells; 1.8±0.2 vs. 17.1±1.26μM against Miapaca-2 cells; p<0.0001). In both cell lines, CPA-LLP resulted in significantly lower clonogenicity than free CPA (p<0.05). Moreover, in both cell lines, CPA-LLP significantly enhanced the cell response to CCPM-(177)Lu radiotherapy as measured by clonogenic assay (p<0.05). In 4T1 and Miapaca-2 mouse xenograft models, the combination of CPA-LLP and CCPM-(177)Lu delayed tumor growth more than either monotherapy did alone. In the 4T1 tumor model, tumor size at 16days after treatment was significantly smaller with the combination therapy than with all the other treatments. In the Miapaca-2 model, the combination therapy resulted in the highest rate of mouse survival and prevented tumor relapse. In conclusion, the combination of CPA-LLP and CCPM-(177)Lu was an effective strategy for treating breast and pancreatic cancer and deserves further investigation.

  4. Automated module radiolabeling of peptides and antibodies with gallium-68, lutetium-177 and iodine-131.

    PubMed

    De Decker, Mario; Turner, J Harvey

    2012-02-01

    Our objectives were to automate radiolabeling of therapeutic activities for safe, reliable, cost-effective, practical routine preparation of (177)Lu-radiopeptides, (131)I radioimmunotherapeutic agents, and (68)Ga-peptide PET diagnostics and, in particular, minimize radiation exposure to the radiopharmaceutical chemist. Reprogramming and adaptation of a commercially available synthetic module (IBA molecular; Synthera®) allowed high yield, fully automated, in-house radiolabeling of novel therapeutic and diagnostic radiopharmaceuticals under remote shielded sterile conditions. Radiochemical yield and purity was measured by instant thin-layer chromatography and high-performance liquid chromatography. (68)Ga-octreotate and (177)Lu-octreotate were synthesized, resulting in both radiochemical yield and radiochemical purity greater than 99%. Synthesis of (131)I-rituximab resulted in a yield of 60%, with a radiochemical purity greater than 99%. Using 400 MBq (68)GaCl(3) per synthesis, the estimated absorbed body and hand dose for a manual synthesis was 2 and 27 μ Sv, contrasting with automated synthesis exposure of 1.3 and 7.9 μ Sv. Using 8000 MBq (177)LuCl(3) per synthesis, the estimated absorbed body and hand dose for a manual synthesis was 44.7 and 75 μ Sv, contrasting with automated synthesis exposure of 2.5 and 20 μ Sv. Using 6000 MBq (131)I per synthesis, the estimated absorbed body and hand dose for a manual synthesis was 83.7 and 335 μ Sv, contrasting with automated synthesis exposure of 10.9 and 54.7 μ Sv. The reduction in radiation exposure by automated synthesis of radiopharmaceuticals in the Synthera® module was at least five fold. Automated synthesis of therapeutic (177)Lu and (131)I radiopharmaceuticals and (68)Ga PET agents in the shielded sterile Synthera® module is simple, practical, and efficient and virtually eliminates radiation exposure to the radiopharmaceutical chemist.

  5. Phase I Trial of Vertebral Intracavitary Cement and Samarium (VICS): Novel Technique for Treatment of Painful Vertebral Metastasis

    SciTech Connect

    Ashamalla, Hani; Cardoso, Erico; Macedon, Mark; Guirguis, Adel; Weng Lijun; Ali, Shamsah; Mokhtar, Bahaa; Ashamalla, Michael; Panigrahi, Nokul

    2009-11-01

    Purpose: Kyphoplasty is an effective procedure to alleviate pain in vertebral metastases. However, it has no proven anticancer activity. Samarium-153-ethylene diamine tetramethylene phosphonate ({sup 153}Sm-EDTMP) is used for palliative treatment of bone metastases. A standard dose of 1 mCi/kg is administrated intravenously. The present study was conducted to determine the feasibility of intravertebral administration of {sup 153}Sm with kyphoplasty. Methods and Materials: A total of 33 procedures were performed in 26 patients. Of these 26 patients, 7 underwent procedures performed at two vertebral levels. The mean age of the cohort was 64 years (range, 33-86). The kyphoplasty procedure was performed using a known protocol; 1-4 mCi of {sup 153}Sm was admixed with the bone cement and administered under tight radiation safety measures. Serial nuclear body scans were obtained. Pain assessment was evaluated using a visual analog pain score. Results: All patients tolerated the procedure well. No procedure-related morbidities were noted. No significant change had occurred in the blood counts at 1 month after the procedure. One case was not technically satisfactory. Nuclear scans revealed clear radiotracer uptake in the other 32 vertebrae injected. Except for the first patient, no radiation leakage was encountered. The mean pain score using the visual analog scale improved from 8.6 before to 2.8 after the procedure (p < .0001). Follow-up bone scans demonstrated a 43% decrease in the tracer uptake. Conclusion: The results of our study have shown that the combination of intravertebral administration of {sup 153}Sm and kyphoplasty is well tolerated with adequate pain control. No hematologic adverse effects were found. A reduction of the bone scan tracer uptake was observed in the injected vertebrae. Longer follow-up is needed to study the antineoplastic effect of the procedure.

  6. 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.

  7. 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.

  8. Effects of thrombin on the integrity of monolayers of cultured human endothelial cells

    SciTech Connect

    Galdal, K.S.; Evensen, S.A.; Brosstad, F.

    1982-09-01

    /sup 51/Cr-prelabelled endothelial cells (EC) in confluent monolayers were incubated in RPMI 1640 + foetal calf serum 20% (v/v) to which purified thrombin was added. Thrombin (greater than or equal to 0.1 NIH U/ml) significantly accelerated /sup 51/Cr-release and caused extensive but reversible cell contraction. Thrombin-exposed EC reacted to a new dose of thrombin with no appreciable shape change, but /sup 51/Cr-efflux was again accelerated. EC exposed to thrombin pretreated with N-bromosuccinimide (modifying the macromolecular site) or phenylmethylsulfonyl fluoride (blocking the serine site) retained normal morphology and did not leak excess amounts of /sup 51/Cr. Antithrombin III also inhibited the effect of thrombin. Pretreatment of EC with either indomethacin, aspirin, sulfinpyrazone, pronase or neuraminidase did not influence the effect of subsequent thrombin exposure.

  9. Improved methods for measuring radioactive tracer accumulation and excretion by microarthropods, with applications for the mite, Tyrophagus longior (Gervais) (Acarina: Acaridae)

    SciTech Connect

    Abbott, D.T.; Crossley, D.A. Jr.

    1980-07-01

    Radioisotope retention measurements of /sup 85/Sr and /sup 51/Cr in Tyrophagus longior (Gervais) were fit to 2- and 1-component models. Biological half-life for the rapid component of both radioisotopes was about 10 hours, with assimilation of /sup 85/Sr being 62%. The identification of /sup 51/Cr turnover as gut clearance must remain tentative. An inexpensive disposable culture chamber for measuring radioisotope retention in microarthropods is described.

  10. Improved methods for measuring radioactive tracer accumulation and excretion by microarthropods, with applications for a mite species, Tyrophagus longior (Acarina, Acaridae)

    SciTech Connect

    Abbott, D T; Crossley, Jr, D A

    1980-08-01

    Radioisotope retention measurements of /sup 85/Sr and /sup 51/Cr in Tyrophagus longior (Gervais) (Acari: Acaridae) were fit to 2 and 1 component models. Biological half-life for the rapid component of both radioisotopes was about 10 hours, with assimilation of /sup 85/Sr being 62%. The identification of /sup 51/Cr turnover as gut clearance must remain tentative. An inexpensive disposable culture chamber for measuring radioisotope retention in microarthropods is described along with details of methodology.

  11. Loss of /sup 51/chromium, lactate dehydrogenase, and /sup 111/indium as indicators of endothelial cell injury

    SciTech Connect

    Chopra, J.; Joist, J.H.; Webster, R.O.

    1987-11-01

    Injury to endothelial cells appears to be an important initial event in the pathogenesis of many diseases such as acute lung injury, venous and arterial thromboembolism, and atherosclerosis. Different methods for detecting damage to cultured endothelial cells have been described. However, their relative sensitivity as markers of endothelial cell damage has not been adequately determined. We compared the loss of /sup 51/Chromium (/sup 51/Cr), the cytoplasmic enzyme lactate dehydrogenase (LDH), and /sup 111/Indium (/sup 111/In) from endothelial cells upon exposure to several injurious agents. Cultured bovine pulmonary artery endothelial cells in confluent monolayers were labeled with /sup 51/Cr or /sup 111/Inoxine and exposed to increasing concentrations of the nonionic detergent, Triton X-100 (0.2 to 1%), hydrogen peroxide (1 to 500 microM), or neutrophils stimulated with phorbol myristate acetate. With all forms of injury, loss of /sup 51/Cr occurred earlier and to a greater extent than LDH loss which in turn was greater than loss of /sup 111/In. Substantial loss of /sup 51/Cr was observed in the absence of appreciable ultrastructural damage to endothelial cell external membranes. The findings may reflect the relative ease with which small molecules such as adenine nucleotides (/sup 51/Cr-labeled) escape whereas larger molecules such as LDH and proteins binding /sup 111/In are retained intracellularly. Thus, /sup 51/Cr loss appears to be a more sensitive indicator of sublytic endothelial cell injury than either /sup 111/In or LDH release.

  12. 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

  13. What a Difference a Carbon Makes: H4octapa vs H4C3octapa, Ligands for In-111 and Lu-177 Radiochemistry

    PubMed Central

    2015-01-01

    The acyclic ligands H4C3octapa and p-SCN-Bn-H4C3octapa were synthesized for the first time, using nosyl protection chemistry. These new ligands were compared to the previously studied ligands H4octapa and p-SCN-Bn-H4octapa to determine the extent to which the addition of a single carbon atom to the backbone of the ligand would affect metal coordination, complex stability, and, ultimately, utility for in vivo radiopharmaceutical applications. Although only a single carbon atom was added to H4C3octapa and the metal donor atoms and denticity were not changed, the solution chemistry and radiochemistry properties were drastically altered, highlighting the importance of careful ligand design and radiometal–ligand matching. It was found that [In(C3octapa)]− and [Lu(C3octapa)]− were substantially different from the analogous H4octapa complexes, exhibiting fluxional isomerization and a higher number of isomers, as observed by 1H NMR, VT-NMR, and 2D COSY/HSQC-NMR experiments. Past evaluation of the DFT structures of [In(octapa)]− and [Lu(octapa)]− revealed very symmetric complexes; in contrast, the [In(C3octapa)]− and [Lu(C3octapa)]− complexes were much less symmetric, suggesting lower symmetry and less rigidity than that of the analogous H4octapa complexes. Potentiometric titrations revealed the formation constants (log KML, pM) were ∼2 units lower for the In3+ and Lu3+ complexes of H4C3octapa when compared to that of the more favorable H4octapa ligand (∼2 orders of magnitude less thermodynamically stable). The bifunctional ligands p-SCN-Bn-H4C3octapa and p-SCN-Bn-H4octapa were conjugated to the antibody trastuzumab and radiolabeled with 111In and 177Lu. Over a 5 day stability challenge experiment in blood serum, 111In-octapa– and 111In-C3octapa–trastuzumab immunoconjugates were determined to be ∼91 and ∼24% stable, respectively, and 177Lu-octapa– and 177Lu-C3octapa–trastuzumab, ∼89% and ∼4% stable, respectively. This work suggests that 5

  14. SU-C-201-06: Utility of Quantitative 3D SPECT/CT Imaging in Patient Specific Internal Dosimetry of 153-Samarium with GATE Monte Carlo Package

    SciTech Connect

    Fallahpoor, M; Abbasi, M; Sen, A; Parach, A; Kalantari, F

    2015-06-15

    Purpose: Patient-specific 3-dimensional (3D) internal dosimetry in targeted radionuclide therapy is essential for efficient treatment. Two major steps to achieve reliable results are: 1) generating quantitative 3D images of radionuclide distribution and attenuation coefficients and 2) using a reliable method for dose calculation based on activity and attenuation map. In this research, internal dosimetry for 153-Samarium (153-Sm) was done by SPECT-CT images coupled GATE Monte Carlo package for internal dosimetry. Methods: A 50 years old woman with bone metastases from breast cancer was prescribed 153-Sm treatment (Gamma: 103keV and beta: 0.81MeV). A SPECT/CT scan was performed with the Siemens Simbia-T scanner. SPECT and CT images were registered using default registration software. SPECT quantification was achieved by compensating for all image degrading factors including body attenuation, Compton scattering and collimator-detector response (CDR). Triple energy window method was used to estimate and eliminate the scattered photons. Iterative ordered-subsets expectation maximization (OSEM) with correction for attenuation and distance-dependent CDR was used for image reconstruction. Bilinear energy mapping is used to convert Hounsfield units in CT image to attenuation map. Organ borders were defined by the itk-SNAP toolkit segmentation on CT image. GATE was then used for internal dose calculation. The Specific Absorbed Fractions (SAFs) and S-values were reported as MIRD schema. Results: The results showed that the largest SAFs and S-values are in osseous organs as expected. S-value for lung is the highest after spine that can be important in 153-Sm therapy. Conclusion: We presented the utility of SPECT-CT images and Monte Carlo for patient-specific dosimetry as a reliable and accurate method. It has several advantages over template-based methods or simplified dose estimation methods. With advent of high speed computers, Monte Carlo can be used for treatment planning

  15. Activation cross sections for reactions induced by 14 MeV neutrons on natural tantalum

    SciTech Connect

    Luo Junhua; Tuo Fei; Kong Xiangzhong

    2009-05-15

    Cross sections for (n,2n), (n,p), (n,n{sup '}{alpha}), (n,t), (n,d{sup '}), and (n,{alpha}) reactions have been measured on tantalum isotopes at the neutron energies of 13.5 to 14.7 MeV using the activation technique. Data are reported for the following reactions: {sup 181}Ta(n,2n){sup 180}Ta{sup g}, {sup 181}Ta(n,p){sup 181}Hf, {sup 181}Ta(n,n{sup '}{alpha}){sup 177}Lu{sup m}, {sup 181}Ta(n,t){sup 179}Hf{sup m2}, {sup 181}Ta(n,d{sup '}){sup 180}Hf{sup m}, and {sup 181}Ta(n,{alpha}){sup 178}Lu{sup m}. The neutron fluences were determined using the monitor reaction {sup 27}Al(n,{alpha}){sup 24}Na. Results were discussed and compared with the previous works.

  16. Standardization of (166m)Ho and 243Am/239Np by live-timed anti-coincidence counting with extending dead time.

    PubMed

    da Silva, C J; Loureiro, J S; Delgado, J U; Poledna, R; Moreira, D S; Iwahara, A; Tauhata, L; da Silva, R L; Lopes, R T

    2012-09-01

    The National Laboratory for Metrology of Ionizing Radiation (LNMRI)/Brazil acquired (166m)Ho and (243)Am/(239)Np solutions from commercial suppliers in order to realize primary standardization and therefore reducing the associated uncertainties. The method used in the standardization was the live-timed 4πβ(LS)-γ(ΝaI(Tl)) anticoincidence counting. The live-timed anticoincidence system is operated since 2006 in LNMRI and is composed of two MTR2 modules donated by Laboratoire National Henri Becquerel (LNE-LNHB)/France. The data acquisition system uses a homemade LabView program and an Excel file for calculus. These systems have been used for primary standardization at LNMRI for many radionuclides and recently took part in the (124)Sb and (177)Lu International Key Comparisons with good performance. PMID:22417696

  17. Metallofullerene-Nanoplatform-Delivered Interstitial Brachytherapy Improved Survival in a Murine Model of Glioblastoma Multiforme

    PubMed Central

    Wilson, John D.; Broaddus, William C.; Dorn, Harry C.; Fatouros, Panos P.; Chalfant, Charles E.; Shultz, Michael D.

    2012-01-01

    Fullerenes are used across scientific disciplines because of their diverse properties gained by altering encapsulated or surface bound components. In this study, the recently developed theranostic agent based on a radiolabeled functionalized metallofullerene (177Lu-DOTA-f-Gd3N@C80) was synthesized with high radiochemical yield and purity. The efficacy of this agent was demonstrated in two orthotopic xenograft brain tumor models of glioblastoma multiforme (GBM). A dose-dependent improvement in survival was also shown. The in vivo stability of the agent was verified through dual label measurements of biological elimination from the tumor. Overall, these results provide evidence that nanomaterial platforms can be used to deliver effective interstitial brachytherapy. PMID:22881865

  18. Application and Dosimetric Requirements for Gallium-68-labeled Somatostatin Analogues in Targeted Radionuclide Therapy for Gastroenteropancreatic Neuroendocrine Tumors.

    PubMed

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

    2015-10-01

    Neuroendocrine tumors (NETs) are associated with variable prognosis, with grade 1 and 2 NETs having more favorable outcomes than grade 3. Patients with gastroenteropancreatic (GEP)-NET need individualized interdisciplinary evaluations and treatment. New treatment options have become available with significant improvements in progression-free survival. Peptide receptor radionuclide therapy (PRRT) using (90)Y or (177)Lu-labeled somatostatin analogues (SSTa) has also shown promise in the treatment of advanced progressive NETs. (68)Ga-1,4,7,10-tetraazacyclodecane-1,4,7,10-tetraacetic acid (DOTA)-SSTa can be used as companion imaging agents to assist in radionuclide therapy selection. (68)Ga-DOTA-SSTa PET/computed tomography might also provide information for prognosis, tumor response assessment to PRRT, and internal dosimetry.

  19. Standardization of (166m)Ho and 243Am/239Np by live-timed anti-coincidence counting with extending dead time.

    PubMed

    da Silva, C J; Loureiro, J S; Delgado, J U; Poledna, R; Moreira, D S; Iwahara, A; Tauhata, L; da Silva, R L; Lopes, R T

    2012-09-01

    The National Laboratory for Metrology of Ionizing Radiation (LNMRI)/Brazil acquired (166m)Ho and (243)Am/(239)Np solutions from commercial suppliers in order to realize primary standardization and therefore reducing the associated uncertainties. The method used in the standardization was the live-timed 4πβ(LS)-γ(ΝaI(Tl)) anticoincidence counting. The live-timed anticoincidence system is operated since 2006 in LNMRI and is composed of two MTR2 modules donated by Laboratoire National Henri Becquerel (LNE-LNHB)/France. The data acquisition system uses a homemade LabView program and an Excel file for calculus. These systems have been used for primary standardization at LNMRI for many radionuclides and recently took part in the (124)Sb and (177)Lu International Key Comparisons with good performance.

  20. Synthesis of Lutetium Phosphate/Apoferritin Core-Shell Nanoparticles for Potential Applications in Radioimmunoimaging and Radioimmunotherapy of Cancers

    SciTech Connect

    Wu, Hong; Engelhard, Mark H.; Wang, Jun; Fisher, Darrell R.; Lin, Yuehe

    2008-04-01

    We report a novel approach for synthesizing LuPO4/apoferritin core-shell nanoparticles based on an apoferritin template, conjugated to the protein biotin. To prepare the nanoparticle conjugates, we used non-radioactive lutetium as a model target or surrogate for radiolutetium (177Lu). The central cavity, multi-channel structure, and chemical properties of apoferritin are well-suited for sequentially diffusing lutetium and phosphate ions into the cavity--resulting in a stable core-shell composite. We characterized the synthesized LuPO4/apoferritin nanoparticle using transmission electron microscopy (TEM) and x-ray photoelectron spectroscopy (XPS). We tested the pre-targeting capability of biotin-modified lutetium/apoferritin nanoparticle using streptavidin-modified magnetic beads and streptavidin-modified fluorescein isothiocyanate (FITC) tracer. This paper presents a simple, fast, and efficient method for synthesizing LuPO4/apoferritin nanoparticle conjugates with biotin for potential applications in radioimmunotherapy and radioimmunoimaging of cancer.

  1. Evaluation of CD146 as Target for Radioimmunotherapy against Osteosarcoma

    PubMed Central

    Bønsdorff, Tina B.; Abbas, Nasir; Bruland, Øyvind S.; Jonasdottir, Thora J.; Mælandsmo, Gunhild M.; Larsen, Roy H.

    2016-01-01

    Background Osteosarcoma is a rare form of cancer but with a substantial need for new active drugs. There is a particular need for targeted therapies to combat metastatic disease. One possible approach is to use an antibody drug conjugate or an antibody radionuclide conjugate to target the osteosarcoma metastases and circulating tumor cells. Herein we have evaluated a radiolabeled monoclonal antibody targeting CD146 both in vitro and in vivo. Methods and Results A murine monoclonal anti-CD146 IgG1 isotype antibody, named OI-3, was developed along with recombinant chimeric versions with human IgG1 or human IgG3 Fc sequences. Using flow cytometry, selective binding of OI-3 to human osteosarcoma cell lines OHS, KPDX and Saos-2 was confirmed. The results confirm a higher expression level of CD146 on human osteosarcoma cells than HER2 and EGFR; antigens targeted by commercially available therapeutic antibodies. The biodistribution of 125I-labeled OI-3 antibody variants was compared with 125I-labeled chimeric anti-EGFR antibody cetuximab in nude mice with subcutaneous OHS osteosarcoma xenografts. OI-3 was able to target CD146 expressing tumors in vivo and showed improved tumor to tissue targeting ratios compared with cetuximab. Subsequently, the three OI-3 variants were conjugated with p-SCN-Bn-DOTA and labeled with a more therapeutically relevant radionuclide, 177Lu, and their biodistributions were studied in the nude mouse model. The 177Lu-labeled OI-3 variants were stable and had therapeutically relevant biodistribution profiles. Dosimetry estimates showed higher absorbed radiation dose to tumor than all other tissues after administration of the chimeric IgG1 OI-3 variant. Conclusion Our results indicate that CD146 can be targeted in vivo by the radiolabeled OI-3 antibodies. PMID:27776176

  2. Quantification of β-Cell Mass in Intramuscular Islet Grafts Using Radiolabeled Exendin-4

    PubMed Central

    Espes, Daniel; Selvaraju, Ramkumar; Velikyan, Irina; Krajcovic, Martin; Carlsson, Per-Ola; Eriksson, Olof

    2016-01-01

    Background There is an increasing interest in alternative implantation sites to the liver for islet transplantation. Intramuscular implantation has even been tested clinically. Possibilities to monitor β-cell mass would be of huge importance not only for the understanding of islet engraftment but also for the decision of changing the immunosuppressive regime. We have therefore evaluated the feasibility of quantifying intramuscular β-cell mass using the radiolabeled glucagon like peptide-1 receptor agonist DO3A-VS-Cys40-Exendin-4. Methods One hundred to 400 islets were transplanted to the abdominal muscle of nondiabetic mice. After 3 to 4 weeks, 0.2 to 0.5 MBq [177Lu]DO3A-VS-Cys40-Exendin-4 was administered intravenously. Sixty minutes postinjection abdominal organs and graft bearing muscle were retrieved, and the radioactive uptake measured in a well counter within 10 minutes. The specific uptake in native and transplanted islets was assessed by autoradiography. The total insulin-positive area of the islet grafts was determined by immunohistochemistry. Results Intramuscular islet grafts could easily be visualized by this tracer, and the background uptake was very low. There was a linear correlation between the radioactivity uptake and the number of transplanted islets, both for standardized uptake values and the total radiotracer uptake in each graft (percentage of injected dose). The quantified total insulin area of surviving β cells showed an even stronger correlation to both standardized uptake values (R = 0.96, P = 0.0002) and percentage of injected dose (R = 0.88, P = 0.0095). There was no correlation to estimated α cell mass. Conclusions [177Lu]DO3A-VS-Cys40-Exendin-4 could be used to quantify β-cell mass after experimental intramuscular islet transplantation. This technique may well be transferred to the clinical setting by exchanging Lutetium-177 radionuclide to a positron emitting Gallium-68.

  3. In Vivo Monitoring of the Antiangiogenic Effect of Neurotensin Receptor-Mediated Radiotherapy by Small-Animal Positron Emission Tomography: A Pilot Study

    PubMed Central

    Maschauer, Simone; Ruckdeschel, Tina; Tripal, Philipp; Haubner, Roland; Einsiedel, Jürgen; Hübner, Harald; Gmeiner, Peter; Kuwert, Torsten; Prante, Olaf

    2014-01-01

    The neurotensin receptor (NTS1) has emerged as an interesting target for molecular imaging and radiotherapy of NTS-positive tumors due to the overexpression in a range of tumors. The aim of this study was to develop a 177Lu-labeled NTS1 radioligand, its application for radiotherapy in a preclinical model and the imaging of therapy success by small-animal positron emission tomography (µPET) using [68Ga]DOTA-RGD as a specific tracer for imaging angiogenesis. The 177Lu-labeled peptide was subjected to studies on HT29-tumor-bearing nude mice in vivo, defining four groups of animals (single dose, two fractionated doses, four fractionated doses and sham-treated animals). Body weight and tumor diameters were determined three times per week. Up to day 28 after treatment, µPET studies were performed with [68Ga]DOTA-RGD. At days 7–10 after treatment with four fractionated doses of 11–14 MBq (each at days 0, 3, 6 and 10), the tumor growth was slightly decreased in comparison with untreated animals. Using a single high dose of 51 MBq, a significantly decreased tumor diameter of about 50% was observed with the beginning of treatment. Our preliminary PET imaging data suggested decreased tumor uptake values of [68Ga]DOTA-RGD in treated animals compared to controls at day 7 after treatment. This pilot study suggests that early PET imaging with [68Ga]DOTA-RGD in radiotherapy studies to monitor integrin expression could be a promising tool to predict therapy success in vivo. Further successive PET experiments are needed to confirm the significance and predictive value of RGD-PET for NTS-mediated radiotherapy. PMID:24743103

  4. In vivo monitoring of the antiangiogenic effect of neurotensin receptor-mediated radiotherapy by small-animal positron emission tomography: a pilot study.

    PubMed

    Maschauer, Simone; Ruckdeschel, Tina; Tripal, Philipp; Haubner, Roland; Einsiedel, Jürgen; Hübner, Harald; Gmeiner, Peter; Kuwert, Torsten; Prante, Olaf

    2014-01-01

    The neurotensin receptor (NTS1) has emerged as an interesting target for molecular imaging and radiotherapy of NTS-positive tumors due to the overexpression in a range of tumors. The aim of this study was to develop a 177Lu-labeled NTS1 radioligand, its application for radiotherapy in a preclinical model and the imaging of therapy success by small-animal positron emission tomography (µPET) using [68Ga]DOTA-RGD as a specific tracer for imaging angiogenesis. The 177Lu-labeled peptide was subjected to studies on HT29-tumor-bearing nude mice in vivo, defining four groups of animals (single dose, two fractionated doses, four fractionated doses and sham-treated animals). Body weight and tumor diameters were determined three times per week. Up to day 28 after treatment, µPET studies were performed with [68Ga]DOTA-RGD. At days 7-10 after treatment with four fractionated doses of 11-14 MBq (each at days 0, 3, 6 and 10), the tumor growth was slightly decreased in comparison with untreated animals. Using a single high dose of 51 MBq, a significantly decreased tumor diameter of about 50% was observed with the beginning of treatment. Our preliminary PET imaging data suggested decreased tumor uptake values of [68Ga]DOTA-RGD in treated animals compared to controls at day 7 after treatment. This pilot study suggests that early PET imaging with [68Ga]DOTA-RGD in radiotherapy studies to monitor integrin expression could be a promising tool to predict therapy success in vivo. Further successive PET experiments are needed to confirm the significance and predictive value of RGD-PET for NTS-mediated radiotherapy. PMID:24743103

  5. 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.

  6. Effect of immunologic reactions on rat intestinal epithelium. Correlation of increased permeability to chromium 51-labeled ethylenediaminetetraacetic acid and ovalbumin during acute inflammation and anaphylaxis

    SciTech Connect

    Ramage, J.K.; Stanisz, A.; Scicchitano, R.; Hunt, R.H.; Perdue, M.H.

    1988-06-01

    In these studies we compared jejunal permeability to two probes--chromium 51-labeled ethylenediaminetetraacetic acid (51Cr-EDTA) (mol wt, 360) and ovalbumin (mol wt, 45,000)--under control conditions, during acute intestinal inflammation, and in response to systemic anaphylaxis. Acute inflammation was produced after infection with Nippostrongylus brasiliensis and rats were studied at day 0 (control), day 4 (early), day 10 (acute), and day 35 (postinfection). At the latter stage, immune rats were also studied during anaphylaxis induced by i.v. N. brasiliensis antigen. In each study, blood and urine were sampled over 5 h after the probes were simultaneously injected into ligated loops in anesthetized rats. In controls, small quantities (less than 0.04% and 0.002% of the administered dose for 51Cr-EDTA and ovalbumin, respectively) appeared in the circulation and plateaued at 1 h. During acute inflammation, the appearance of both probes continued to increase with time. Compared with controls, 5-h values for 51Cr-EDTA and ovalbumin were (a) significantly elevated at day 4 (p less than 0.005), (b) increased approximately 20-fold at day 10 (p less than 0.005 and less than 0.01, respectively), and (c) normal at day 35. Urinary recovery of 51Cr-EDTA followed the same pattern. During anaphylaxis, appearance of the probes in the circulation increased at 1 h to values approximately 10-fold those in controls (p less than 0.001 and less than 0.01, for 51Cr-EDTA and ovalbumin, respectively), and then declined. Urinary recovery of 51Cr-EDTA over 5 h was also significantly increased. We conclude that epithelial barrier function becomes impaired during both acute inflammation and anaphylaxis. In this rat model, gut permeability changes to 51Cr-EDTA reflect gut permeability changes to macromolecular antigens.

  7. Bone-seeking radiopharmaceuticals for treatment of osseous metastases, Part 1: α therapy with 223Ra-dichloride.

    PubMed

    Pandit-Taskar, Neeta; Larson, Steven M; Carrasquillo, Jorge A

    2014-02-01

    Metastatic disease to bone is commonly seen in the advanced stages of many cancers. The cardinal symptom, pain, is often the cause of significant morbidity and reduced quality of life. Treatment of bone pain includes nonsteroidal analgesics and opiates; however, long-term use of these drugs is commonly associated with significant side effects, and tolerance is common. External-beam radiation therapy is effective mainly in localized disease sites. Bone-targeting radiopharmaceuticals are beneficial in the management of patients with multiple metastatic lesions. This article focuses on the 3 most commonly used agents: the Food and Drug Administration-approved (89)Sr-chloride, (153)Sm-ethylenediaminetetramethylene phosphonic acid (EDTMP), and (223)Ra-dichloride. We will discuss the physical characteristics, clinical data, dosage, and administration of these agents, including optimal patient selection and toxicity associated with their use. These radioactive agents have proven efficacy in the treatment of painful osseous metastases from prostate cancer and breast cancer. Significant recent advances include use of these agents in combination with chemotherapy and the use of the α emitter (223)Ra-dichloride in prostate cancer, primarily to improve survival and skeletal related events. The review is presented in 2 parts. The first will discuss the characteristics and clinical use of (223)Ra-dichloride, and the second will discuss the β emitters (89)Sr and (153)Sm-EDTMP.

  8. Modeling the time dependent biodistribution of Samarium-153 ethylenediamine tetramethylene phosphonate using compartmental analysis

    PubMed Central

    Abbasian, Parandoush; Foroghy, Monika; Jalilian, Amir Reza; Hakimi, Amir; Shirvani-Arani, Simindokht

    2013-01-01

    Aim The main purpose of this work was to develop a pharmacokinetic model for the bone pain palliation agent Samarium-153 ethylenediamine tetramethylene phosphonate ([153Sm]-EDTMP) in normal rats to analyze the behavior of the complex. Background The use of compartmental analysis allows a mathematical separation of tissues and organs to determine the concentration of activity in each fraction of interest. Biodistribution studies are expensive and difficult to carry out in humans, but such data can be obtained easily in rodents. Materials and methods We have developed a physiologically based pharmacokinetic model for scaling up activity concentration in each organ versus time. The mathematical model uses physiological parameters including organ volumes, blood flow rates, and vascular permabilities; the compartments (organs) are connected anatomically. This allows the use of scale-up techniques to predict new complex distribution in humans in each organ. Results The concentration of the radiopharmaceutical in various organs was measured at different times. The temporal behavior of biodistribution of 153Sm-EDTMP was modeled and drawn as a function of time. Conclusions The variation of pharmaceutical concentration in all organs is described with summation of 6–10 exponential terms and it approximates our experimental data with precision better than 2%. PMID:24936338

  9. Radioactive chromium-ethylenediaminetetraacetic acid for determination of glomerular filtration rate in rabbits

    SciTech Connect

    Tvedegaard, E.; Kamstrup, O.

    1981-12-01

    Simultaneous determination of the glomerular filtration rate was made by the insulin clearance technique and by analysis of the plasma disappearance curve of radioactive chromium-ethylenediaminetetraacetic acid (/sup 51/Cr-EDTA) following an intravenous injection in 28 anaesthetized rabbits. In some rabbits, the renal function was reduced by previous surgery. The insulin clearances ranged from 2.7 to 17 ml/minute. By a double-exponential analysis of the plasma disappearance curve, the total plasma clearance of /sup 51/Cr-EDTA was found to exceed the inulin clearance by 12%. By the simpler slope-intercept analysis requiring only two blood samples, this value was 32%. The renal clearance of /sup 51/Cr-EDTA was 97% of inulin clearance. In nephrectomized rabbits, plasma clearance of /sup 51/Cr-EDTA was 0.7 ml/minute. At all levels of renal function, measurement of the plasma clearance rate of /sup 51/Cr-EDTA by the single injection technique allowed a fairly reliable estimate of the glomerular filtration rate.

  10. Cortical neurons exposed to glutamate rapidly leak preloaded chromium 51

    SciTech Connect

    Maulucci-Gedde, M.; Choi, D.W.

    1987-05-01

    The acute toxic effects of excess glutamate exposure on cortical neurons in culture was followed using a novel adaptation of the /sup 51/Cr efflux assay. Although the acute, sodium-dependent phase of glutamate neurotoxicity may contribute to several acute disease settings, including sustained seizures and stroke, functional aspects of the phenomenon have not been previously studied. We report here that the earliest morphologic sign of glutamate neurotoxicity, neuronal swelling, is accompanied by a large efflux of complexed /sup 51/Cr from preloaded neurons in the first hour after exposure, and that this efflux is detectable as early as 15 min after the onset of glutamate exposure. We suggest that this pathological burst of /sup 51/Cr may result from glutamate-induced leakiness of neuronal cell membranes.

  11. Determination of single and repeated red cell volumes by the indicator dilution method using carbon monoxide as the indicator

    SciTech Connect

    Fukui, M.; Shigemi, K. )

    1989-11-01

    The use of radioactive isotopes limits clinical applications of blood volume measurement in the ICU. We measured red cell volumes with carbon monoxide-labeled RBC in six dogs and five human volunteers. The measured values obtained on the dogs were compared with the simultaneous measurements with the {sup 51}Cr method; the ratio of the carbon monoxide to {sup 51}Cr values ranged from 0.86 to 1.17, and the mean ratio was 1.0 +/- 0.1 (SD), r = .93. We infer from these results that the carbon monoxide method has several advantages over the {sup 51}Cr method: (a) the short labeling time (about 1 min), (b) rapidly decreasing background levels of carbon monoxide with FIO2 1.0, and (c) repeatability at intervals of several hours.

  12. Accelerated removal of antibody-coated red blood cells from the circulation is accurately tracked by a biotin label

    PubMed Central

    Mock, Donald M.; Lankford, Gary L.; Matthews, Nell I.; Burmeister, Leon F.; Kahn, Daniel; Widness, John A.; Strauss, Ronald G.

    2013-01-01

    BACKGROUND Safe, accurate methods to reliably measure circulating red blood cell (RBC) kinetics are critical tools to investigate pathophysiology and therapy of anemia, including hemolytic anemias. This study documents the ability of a method using biotin-labeled RBCs (BioRBCs) to measure RBC survival (RCS) shortened by coating with a highly purified monomeric immunoglobulin G antibody to D antigen. STUDY DESIGN AND METHODS Autologous RBCs from 10 healthy D+ subjects were labeled with either biotin or 51Cr (reference method), coated (opsonized) either lightly (n = 4) or heavily (n = 6) with anti-D, and transfused. RCS was determined for BioRBCs and for 51Cr independently as assessed by three variables: 1) posttransfusion recovery at 24 hours (PTR24) for short-term RCS; 2) time to 50% decrease of the label (T50), and 3) mean potential life span (MPL) for long-term RCS. RESULTS BioRBCs tracked both normal and shortened RCS accurately relative to 51Cr. For lightly coated RBCs, mean PTR24, T50, and MPL results were not different between BioRBCs and 51Cr. For heavily coated RBCs, both short-term and long-term RCS were shortened by approximately 17 and 50%, respectively. Mean PTR24 by BioRBCs (84 ± 18%) was not different from 51Cr (81 ± 10%); mean T50 by BioRBCs (23 ± 17 days) was not different from 51Cr (22 ± 18 days). CONCLUSION RCS shortened by coating with anti-D can be accurately measured by BioRBCs. We speculate that BioRBCs will be useful for studying RCS in conditions involving accelerated removal of RBCs including allo- and autoimmune hemolytic anemias. PMID:22023312

  13. Effect of size and lipid composition on the pharmacokinetics of intravitreal liposomes

    SciTech Connect

    Barza, M.; Stuart, M.; Szoka, F. Jr.

    1987-05-01

    We investigated the influence of size and lipid composition on the pharmacokinetic behavior of liposomes and their contents in the rabbit eye. Small and large unilamellar vesicles (SUV and LUV), prepared with and without cholesterol in the membrane, were injected intravitreally in rabbits. The vesicles were labelled with /sup 125/I and contained /sup 51/Cr-EDTA in the aqueous compartment. The mode of elimination of the vesicles from the vitreous humor is uncertain but may be via the anterior route; /sup 51/Cr-EDTA, like gentamicin, probably is eliminated by the anterior route. The rate of clearance of the lipid label appeared to be related to the size but not to the cholesterol content of the liposomes. Liposome-encapsulation prolonged the half-life of /sup 51/Cr-EDTA by up to 11-fold in the vitreous humor of normal eyes. The prolongation was greatest with cholesterol-containing vesicles, presumably because these are most stable, and was somewhat greater with large than with small vesicles. For SUV and LUV, the rate of elimination of /sup 51/Cr-EDTA from the normal eye was determined mainly by the rate of leakage from the liposomes, whereas for SUV-cholesterol and LUV-cholesterol, it was determined mainly by the rate of clearance of the liposomes themselves. Both /sup 51/Cr-EDTA and liposomes (/sup 125/I label) had a shorter half-life in infected than in normal eyes. Encapsulation of /sup 51/Cr-EDTA prolonged its half-life by up to sevenfold in infected eyes; the effect was greatest with cholesterol-containing vesicles. These results suggest that both the structure of the liposome and the state of the eye may markedly affect the pharmacokinetic behavior of intravitreal liposomes.

  14. Ground state mass of 81Kr and the solar neutrino problem

    NASA Astrophysics Data System (ADS)

    Kouzes, R. T.; Lowry, M. M.; Bennett, C. L.

    1982-02-01

    The 81Br(3He,t)81Kr, reaction has been used to determine an improved value for the ground state mass of 81Kr. A comparison is made with 51V(3He,t)51Cr and the implications for calibration of the proposed bromine solar neutrino detector are presented. NUCLEAR REACTIONS 81Br(3He,t)81Kr, 51V(3He,t)51Cr, 87Rb(3He,t)87Sr, 85Rb(3He,t)85Sr, E(3He)=24.7 MeV; Q values measured, ground state 81Kr mass inferred.

  15. Standardization of (55)Fe by tracing method.

    PubMed

    Koskinas, M F; Pires, C A; Yamazaki, I M; Silva, E A; Dias, M S

    2008-01-01

    This work describes the procedure followed by the Laboratório de Metrologia Nuclear (LMN) for the standardization of (55)Fe by the tracing method. This technique was applied using two radionuclides, which decay by the electron capture process followed by a prompt gamma-ray, namely (51)Cr and (54)Mn, as tracers. The calibration was performed in a 4pibeta-gamma coincidence system. The efficiency was obtained by selecting a gamma-ray window set at the 320keV total absorption peak for (51)Cr and at 834keV for (54)Mn. PMID:18342526

  16. Monte Carlo simulation of age-dependent radiation dose from alpha- and beta-emitting radionuclides to critical trabecular bone and bone marrow targets

    NASA Astrophysics Data System (ADS)

    Dant, James T.; Richardson, Richard B.; Nie, Linda H.

    2013-05-01

    Alpha (α) particles and low-energy beta (β) particles present minimal risk for external exposure. While these particles can induce leukemia and bone cancer due to internal exposure, they can also be beneficial for targeted radiation therapies. In this paper, a trabecular bone model is presented to investigate the radiation dose from bone- and marrow-seeking α and β emitters to different critical compartments (targets) of trabecular bone for different age groups. Two main issues are addressed with Monte Carlo simulations. The first is the absorption fractions (AFs) from bone and marrow to critical targets within the bone for different age groups. The other issue is the application of 223Ra for the radiotherapy treatment of bone metastases. Both a static model and a simulated bone remodeling process are established for trabecular bone. The results show significantly lower AFs from radionuclide sources in the bone volume to the peripheral marrow and the haematopoietic marrow for adults than for newborns and children. The AFs from sources on the bone surface and in the bone marrow to peripheral marrow and haematopoietic marrow also varies for adults and children depending on the energy of the particles. Regarding the use of 223Ra as a radionuclide for the radiotherapy of bone metastases, the simulations show a significantly higher dose from 223Ra and its progeny in forming bone to the target compartment of bone metastases than that from two other more commonly used β-emitting radiopharmaceuticals, 153Sm and 89Sr. There is also a slightly lower dose from 223Ra in forming bone to haematopoietic marrow than that from 153Sm and 89Sr. These results indicate a higher therapy efficiency and lower marrow toxicity from 223Ra and its progeny. In conclusion, age-related changes in bone dimension and cellularity seem to significantly affect the internal dose from α and β emitters in the bone and marrow to critical targets, and 223Ra may be a more efficient

  17. Clinical and clinicopathologic effects of samarium-153-EDTMP administered intravenously to normal beagle dogs

    SciTech Connect

    Lattimer, J.C.; Corwin, L.A. Jr.; Stapleton, J.; Volkert, W.A.; Ehrhardt, G.J.; Ketring, A.R.; Hewett, J.E.; Simon, J.; Goeckeler, W.F. )

    1990-05-01

    A study was undertaken to determine the degree of acute bone marrow and vital organs injury sustained when dogs were administered doses of 153Sm-EDTMP calculated to irradiate an acute bone lesion arising from cancer metastasis to a dose considered palliative or even therapeutic (20-160 Gy). The study revealed significant (p less than 0.05) temporary depression of the bone marrow in all doses in the therapeutic (greater than 40 Gy) range. Palliative (20 Gy) doses caused significant leukocyte depression but insignificant (p greater than 0.05) depression of platelet and packed cell volumes when compared to control animals. A mild transient rise in the levels of serum alkaline phosphatase occurred immediately following radioisotope administration. All hematologic parameters had returned to normal by six weeks after the last injection of radioisotope. The study indicates potential for this compound as a safe, therapeutic radiopharmaceutical for treatment of cancer bone metastasis.

  18. First observation of low-energy γ-ray enhancement in the rare-earth region

    DOE PAGES

    Simon, Anna; Guttormsen, M.; Larsen, A. C.; Beausang, C. W.; Humby, P.; Burke, J. T.; Casperson, R. J.; Hughes, R. O.; Ross, T. J.; Allmond, James M.; et al

    2016-03-04

    Here, the γ-ray strength function and level density in the quasi-continuum of 151,153Sm have been measured using bismuth germanate shielded Ge clover detectors of the STARLiTeR system. The Compton shields allow an extraction of the γ strength down to unprecedentedly low γ energies of ≈ 500 keV. For the first time an enhanced low-energy γ-ray strength has been observed in the rare-earth region. In addition, for the first time both the upbend and the well-known scissors resonance have been observed simultaneously for the same nucleus. Hauser-Feshbach calculations show that this strength enhancement at low γ energies could have an impactmore » of 2 3 orders of magnitude on the (n, γ) reaction rates for r-process nucleosynthesis.« less

  19. Influence of voxel size on specific absorbed fractions and S-values in a mouse voxel phantom.

    PubMed

    Mohammadi, A; Kinase, S

    2011-02-01

    Photon and electron specific absorbed fractions (SAFs) and S-values have been evaluated using mouse voxel phantoms. In voxel phantoms, it is important to choose the voxel size carefully since it affects the accuracy of results. In this study, two mouse voxel phantoms were constructed, with cubic voxels, one with 0.1-mm sides and the other with 0.4-mm sides. The sources were considered to be distributed uniformly in the main organs and the radiation transport was simulated using the Monte Carlo code EGS4. It was found that the effect of voxel size on SAFs for self-irradiation was not high (<10 %) for electrons and photons. However, it was appreciable for cross-irradiation especially for electrons. The effect of voxel size was investigated on S-values for some beta emitters such as (131)I, (153)Sm, (188)Re and (90)Y.

  20. Studies on the biodistribution of dextrin nanoparticles

    NASA Astrophysics Data System (ADS)

    Gonçalves, C.; Ferreira, M. F. M.; Santos, A. C.; Prata, M. I. M.; Geraldes, C. F. G. C.; Martins, J. A.; Gama, F. M.

    2010-07-01

    The characterization of biodistribution is a central requirement in the development of biomedical applications based on the use of nanoparticles, in particular for controlled drug delivery. The blood circulation time, organ biodistribution and rate of excretion must be well characterized in the process of product development. In this work, the biodistribution of recently developed self-assembled dextrin nanoparticles is addressed. Functionalization of the dextrin nanoparticles with a DOTA-monoamide-type metal chelator, via click chemistry, is described. The metal chelator functionalized nanoparticles were labelled with a γ-emitting 153Sm3 + radioisotope and the blood clearance rate and organ biodistribution of the nanoparticles were obtained. The effect of PEG surface coating on the blood clearance rate and organ biodistribution of the nanoparticles was also studied.

  1. Dependence of Cr-EDTA absorption from the rumen on luminal osmotic pressure.

    PubMed

    Dobson, A; Sellers, A F; Gatewood, V H

    1976-11-01

    A method for the measurement of [51Cr]EDTA absorption from the ventral sac of the rumen with an error of the order of +/-10% is described. When a solution present in the rumen was hypotonic or isotonic, the absorption rate of [51Cr]EDTA expressed as a clearance was about 0.2 ml/min. This gave rise to negligible errors when [51Cr]EDTA was used as an unabsorbed marker to calculate net water movements. When the osmotic pressure in the rumen exceeded that of plasma by 30-40 mos-mol/kg, the absorption rate of [51Cr]EDTA appeared to be related to the degree of hypertonicity. Absorption rates as high as 8 ml/min were observed within a range of osmotic pressures normally encountered postprandially in the rumen. Under hypertonic conditions, a correction for the absorption of this large anion was necessary if passage of water into the lumen were not to be systematically overestimated.

  2. 10 CFR Appendix L to Part 110 - Illustrative List of Byproduct Materials Under NRC Export/Import Licensing Authority a

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ...) Cesium 129 (Cs 129) Cesium 131 (Cs 131) Cesium 134m (Cs 134m) Cesium 134 (Cs 134) Cesium 135 (Cs 135) Cesium 136 (Cs 136) Cesium 137 (Cs 137) Chlorine 36 (Cl 36) Chlorine 38 (Cl 38) Chromium 51 (Cr...

  3. 10 CFR Appendix L to Part 110 - Illustrative List of Byproduct Materials Under NRC Export/Import Licensing Authority a

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ...) Cesium 129 (Cs 129) Cesium 131 (Cs 131) Cesium 134m (Cs 134m) Cesium 134 (Cs 134) Cesium 135 (Cs 135) Cesium 136 (Cs 136) Cesium 137 (Cs 137) Chlorine 36 (Cl 36) Chlorine 38 (Cl 38) Chromium 51 (Cr...

  4. 10 CFR Appendix L to Part 110 - Illustrative List of Byproduct Materials Under NRC Export/Import Licensing Authority a

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ...) Cesium 129 (Cs 129) Cesium 131 (Cs 131) Cesium 134m (Cs 134m) Cesium 134 (Cs 134) Cesium 135 (Cs 135) Cesium 136 (Cs 136) Cesium 137 (Cs 137) Chlorine 36 (Cl 36) Chlorine 38 (Cl 38) Chromium 51 (Cr...

  5. Omega 3 fatty acids increase spontaneous release of cytosolic components from tumor cells

    SciTech Connect

    Jenski, L.J.; Sturdevant, L.K.; Ehringer, W.D.; Stillwell, W. )

    1991-05-01

    Mice fed menhaden (fish) oil or coconut oil-rich diets were inoculated intraperitoneally with a rapidly growing leukemia, T27A. After one week, the tumor cells were harvested, and 51Cr was used to label intracellular molecules. Spontaneous release of 51Cr was used as a measure of plasma membrane permeability. Compared to cells from mice fed coconut oil (rich in saturated fatty acids), tumor cells from mice fed menhaden oil (rich in long chain polyunsaturated omega 3 fatty acids) showed an increased level of spontaneous 51Cr release, which was exacerbated by increased temperature and reduced by extracellular protein. At physiological salt concentrations, the released 51Cr was detected in particles of approximately 2700 daltons. Enhanced permeability correlated with the incorporation of dietary (fish oil) omega 3 polyunsaturated fatty acids docosahexaenoic and eicosapentaenoic acid into the tumor cells. The results demonstrate that omega 3 fatty acids are incorporated into cellular constituents of tumor cells and change properties associated with the plasma membrane. This result suggests that dietary manipulation may be used to enhance tumor cell permeability and contribute to tumor eradication.

  6. Atrial natriuretic peptide increases microvascular blood flow and macromolecular escape during renin infusion in the hamster

    SciTech Connect

    Boric, M.P.; Albertini, R. )

    1990-02-01

    The effects of Atrial Natriuretic Peptide (ANP) on microvascular hemodynamics and macromolecular permselectivity were studied in the hamster cheek pouch under resting conditions and during intravenous renin infusion. Fluorescent intravital microscopy was used to observe arteriolar diameters and to detect escape of fluorescent dextran of 150 K-Daltons (FITC-Dx-150). Microvascular plasma flow was estimated by clearance of 51Cr-EDTA and net macromolecular transport by clearance of FITC-Dx-150. At rest, topical ANP (2-250 ng/ml) had no effect on arteriolar diameter, 51Cr-EDTA clearance, relative vascular conductance (RVC) or FITC-Dx-150 clearance. Infusion of renin (10 mU/Kg/Hr, iv) elevated systemic arterial pressure by 30% and reduced cheek pouch RVC by 26%. During renin infusion, topical ANP (50 ng/ml) produced transient arteriolar vasodilation, and increased 51Cr-EDTA clearance (+35%), RVC (+58%) and FITC-Dx-150 clearance (+54%), without affecting systemic pressure. ANP did not induce venular leakage sites under any condition, but changes in FITC-Dx-150 clearance were highly correlated with changes in 51Cr-EDTA clearance, suggesting that the larger macromolecular escape was due to increases in microvascular blood flow and capillary/post-capillary hydrostatic pressure.

  7. 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.

  8. 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

  9. 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

  10. 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

  11. Ulcerative colitis--a disease characterised by the abnormal colonic epithelial cell?

    PubMed

    Gibson, P R; van de Pol, E; Barratt, P J; Doe, W F

    1988-04-01

    The leakiness of the cell membranes of colonic epithelial cells isolated by the collagenase/Dispase technique from normal or diseased colons was assessed in a 4 h 51Cr release assay. Cells from normal, adenoma bearing or cancer bearing colons showed 51Cr release of 8% or less in almost all of 46 cell populations tested. In contrast, cells from mucosa affected by ulcerative colitis [11.9 (4.3%) n = 23] or Crohn's disease [8.4 (2.7%) n = 18] released significantly more 51Cr than the non-inflamed groups. Values are expressed as mean (SD). Overall, release values were greater in ulcerative colitis than Crohn's disease (p less than 0.01). In Crohn's disease, cells obtained from histologically inflamed mucosa released significantly more 51Cr [9.7 (2.5%) n = 11] than those from non-inflamed mucosa [6.4 (1.5%) n = 7, p less than 0.02] whereas, in ulcerative colitis, abnormal release values were found in 8 of 13 cell populations isolated from mucosa showing no histological evidence of active disease. In five patients with distal ulcerative colitis, cells from mucosa not apparently involved demonstrated normal 51Cr release in four of five studies despite abnormal release from cells from involved mucosa suggesting that a diffuse abnormality of the colonic epithelial cell is not usually present. These data indicate that chronic mucosal inflammation per se is associated with abnormalities of the colonic epithelial cell but that, in ulcerative colitis, the abnormality remains in many patients with quiescent disease. Identification of the local factors responsible for such an abnormality may contribute to an understanding of the pathogenesis of ulcerative colitis. PMID:3371720

  12. Effects of endotoxemia on systemic plasma loss and hematocrit in rats

    SciTech Connect

    van Lambalgen, A.A.; Rasker, M.T.; van den Bos, G.C.; Thijs, L.G.

    1988-11-01

    Endotoxemia in rats increases plasma extravasation but does not result in continuously rising hematocrit. These contradictory observations led us to design a study in anesthetized rats (C, control rats, n = 10; E, endotoxin rats, n = 10) in which we continuously measured in blood hematocrit (conductivity cell) and changes in concentration of 125I-HSA (human serum albumin) and 51Cr-labeled red cell (51Cr-RBC; multichannel analyzer) in an extracorporeal circuit. In two additional series of experiments we measured in blood samples changes in protein concentration (series II, C: n = 7, E: n = 7) and uptake of intraperitoneally injected 125I-HSA and 51Cr-RBC (reflecting lymph flow rate; series III, C: n = 6, E: n = 7). Endotoxemia was induced by infusion (iv, 0.2 ml/100 g.hr) of Escherichia coli endotoxin (20 mg/kg) from t = 0 to t = 60 min; controls received saline. Experiments ended at t = 120 (series I and II) or 150 min (series III). The endotoxemia resulted in a marked rise of serum lactate (by ca 500% at t = 120); heart rate increased and central venous pressure decreased (by ca 20 and -95% at t = 120, respectively). All rats showed characteristic changes in hematocrit during endotoxemia: an increase from t = 20 to t = 45 (by ca 9%) followed by a decrease to preshock values or less at t = 120. The 51Cr activity per microliter blood cells did not change, indicating that there was no red cell mobilization. Protein concentration and 125I-HSA activity also showed a temporary increase during endotoxemia, but 125I-HSA activity per gram protein was decreased. Peritoneal uptake of 125I-HSA and 51Cr-RBC was significantly increased during endotoxemia (by 200%).

  13. Cytopathic action of Naegleria fowleri amoebae on rat neuroblastoma target cells.

    PubMed

    Marciano-Cabral, F; Zoghby, K L; Bradley, S G

    1990-01-01

    The axenically cultured, weakly pathogenic Naegleria fowleri LEE and the highly pathogenic, mouse passaged N. fowleri LEEmp are cytopathic for B103 rat nerve cells in culture. Cytopathogenicity was measured by release of radiolabeled rubidium or radiolabeled chromium from B103 target cells. Cytopathogenicity was time-dependent for up to 18 h and dependent upon amoebae effector to nerve cell target ratios of less than 1:1. Release of 51Cr from B103 cells by either LEE or LEEmp amoebae was enhanced by addition of calcium or magnesium to medium free of these divalent cations but the ion-channel inhibitor, verapamil, or the ionophore A23187 and phorbol myristate acetate did not alter release of 51Cr from B103 cells cocultured with the amoebae. Cycloheximide or actinomycin D impaired release of 51Cr from B103 target cells injured by either LEE or LEEmp amoebae. Both strains of amoebae were fractionated by glass bead disruption and high speed centrifugation into membrane and soluble fractions. Each fraction was incubated with either 86Rb or 51Cr labeled nerve cells. The membrane fraction from LEEmp was more active than the soluble fraction in facilitating rubidium and chromium release. In contrast, the soluble fraction from LEE was more active than the membrane fraction in facilitating rubidium release from radiolabeled target cells. The sequential release of 86Rb and 51Cr from target cells rather than the simultaneous release of the two isotopes indicates that target cell death is due to the release of ions followed later by the release of large macromolecules. The results indicate that N. fowleri amoebae injure nerve cells by two alternate mechanisms, trogocytosis or contact-dependent lysis.

  14. An automated voxelized dosimetry tool for radionuclide therapy based on serial quantitative SPECT/CT imaging

    SciTech Connect

    Jackson, Price A.; Kron, Tomas; Beauregard, Jean-Mathieu; Hofman, Michael S.; Hogg, Annette; Hicks, Rodney J.

    2013-11-15

    Purpose: To create an accurate map of the distribution of radiation dose deposition in healthy and target tissues during radionuclide therapy.Methods: Serial quantitative SPECT/CT images were acquired at 4, 24, and 72 h for 28 {sup 177}Lu-octreotate peptide receptor radionuclide therapy (PRRT) administrations in 17 patients with advanced neuroendocrine tumors. Deformable image registration was combined with an in-house programming algorithm to interpolate pharmacokinetic uptake and clearance at a voxel level. The resultant cumulated activity image series are comprised of values representing the total number of decays within each voxel's volume. For PRRT, cumulated activity was translated to absorbed dose based on Monte Carlo-determined voxel S-values at a combination of long and short ranges. These dosimetric image sets were compared for mean radiation absorbed dose to at-risk organs using a conventional MIRD protocol (OLINDA 1.1).Results: Absorbed dose values to solid organs (liver, kidneys, and spleen) were within 10% using both techniques. Dose estimates to marrow were greater using the voxelized protocol, attributed to the software incorporating crossfire effect from nearby tumor volumes.Conclusions: The technique presented offers an efficient, automated tool for PRRT dosimetry based on serial post-therapy imaging. Following retrospective analysis, this method of high-resolution dosimetry may allow physicians to prescribe activity based on required dose to tumor volume or radiation limits to healthy tissue in individual patients.

  15. [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

  16. Determination of immunoreactive fraction of radiolabeled monoclonal antibodies: what is an appropriate method?

    PubMed

    Konishi, Shota; Hamacher, Klaus; Vallabhajosula, Shankar; Kothari, Paresh; Bastidas, Diago; Bander, Neil; Goldsmith, Stanley

    2004-12-01

    Determination of the immunoreactive fraction (IF) of radiolabeled monoclonal antibodies (MAb) is essential to the understanding of the effects of radiolabeling and subsequent target-specific tumor localization. There has been generally no accepted method of determining the IF of MAbs. The conventional method is based on a radioimmunoassay technique in which the fraction of radiolabeled MAb bound to antigen under conditions of "antigen excess" is determined. Lindmo et al. introduced a modified method in which the IF is determined by extrapolation to conditions representing "infinite antigen excess." Although the Lindmo method, in principle, is insensitive to experimental parameters, it does not always provide a reliable estimate of IF. We, therefore, evaluated an alternate method in which percent cell bound fraction is measured under conditions of fixed antigen concentration and various dilutions of radiolabeled MAb. We developed a mathematical equation to estimate immunoreactivity. J591 MAb specific for prostate-specific membrane antigen was radiolabeled with (111)In, (90)Y and (177)Lu to specific activities of 1-20 mCi/mg. We compared the effect of several experimental conditions on the determination of IF using all three different methods. The Lindmo method requires careful optimization of experimental conditions for each radiolabeled MAb. The alternate method, based on a fixed antigen concentration, appears to be practical and may provide a more reliable measure of immunoreactivity.

  17. 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

  18. 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

    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 (177)Lu- or (90)Y-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.

  19. 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

  20. 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

  1. 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

  2. Structure-Activity Relationship Studies of Amino Acid Substitutions in Radiolabeled Neurotensin Conjugates.

    PubMed

    Mascarin, Alba; Valverde, Ibai E; Mindt, Thomas L

    2016-01-01

    Radiolabeled derivatives of the peptide neurotensin (NT) and its binding sequence NT(8-13) have been studied as potential imaging probes and therapeutics for NT-1-receptor-positive cancer. However, a direct comparison of reported NT analogues, even if radiolabeled with the same radionuclide, is difficult because different techniques and models have been used for preclinical evaluations. In an effort to identify a suitable derivative of NT(8-13) for radiotracer development, we herein report a side-by-side in vitro comparison of radiometallated NT derivatives bearing some of the most commonly reported amino acid substitutions in their sequence. Performed investigations include cell internalization experiments, determinations of receptor affinity, measurements of the distribution coefficient, and blood serum stability studies. Of the [(177)Lu]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-labeled examples studied, analogues of NT(8-13) containing a short hydrophilic tetraethylene glycol (PEG4 ) spacer between the peptide and the radiometal complex, and a minimum number of substitutions of amino acid residues, exhibited the most promising properties in vitro. PMID:26593062

  3. 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.

  4. 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.

  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.

  6. Targeting uPAR with Antagonistic Recombinant Human Antibodies in Aggressive Breast Cancer

    PubMed Central

    LeBeau, Aaron M.; Duriseti, Sai; Murphy, Stephanie T.; Pepin, Francois; Hann, Byron; Gray, Joe W.; VanBrocklin, Henry F.; Craik, Charles S.

    2013-01-01

    Components of the plasminogen activation system (PAS) which are overexpressed in aggressive breast cancer subtypes offer appealing targets for development of new diagnostics and therapeutics. By comparing gene expression data in patient populations and cultured cell lines, we identified elevated levels of the urokinase plasminogen activation receptor (uPAR, PLAUR) in highly aggressive breast cancer subtypes and cell lines. Recombinant human anti-uPAR antagonistic antibodies exhibited potent binding in vitro to the surface of cancer cells expressing uPAR. In vivo these antibodies detected uPAR expression in triple negative breast cancer (TNBC) tumor xenografts using near infrared (NIR) imaging and 111In single-photon emission computed tomography (SPECT). Antibody-based uPAR imaging probes accurately detected small disseminated lesions in a tumor metastasis model, complementing the current clinical imaging standard 18F-fluorodeoxyglucose (FDG) at detecting non-glucose-avid metastatic lesions. A monotherapy study using the antagonistic antibodies resulted in a significant decrease in tumor growth in a TNBC xenograft model. Additionally, a radioimmunotherapy (RIT) study, using the anti-uPAR antibodies conjugated to the therapeutic radioisotope 177Lu, found that they were effective at reducing tumor burden in vivo. Taken together, our results offer a preclinical proof of concept for uPAR targeting as a strategy for breast cancer diagnosis and therapy using this novel human antibody technology. PMID:23400595

  7. Metastatic Insulinoma Managed with Radiolabeled Somatostatin Analog

    PubMed Central

    Costa, Ricardo; Bacchi, Carlos E.; Almeida Filho, Paulo

    2013-01-01

    Insulinoma is a rare pancreatic neuroendocrine tumor. Overproduction of insulin and associated hypoglycemia are hallmark features of this disease. Diagnosis can be made through demonstration of hypoglycemia and elevated plasma levels of insulin or C-Peptide. Metastatic disease can be detected through computerized tomography (CT) scans, magnetic resonance imaging (MRI), and positron emission tomography (PET)/CT. Somatostatin receptor scintigraphy can be used not only to document metastatic disease but also as a predictive marker of the benefit from therapy with radiolabeled somatostatin analog. Unresectable metastatic insulinomas may present as a major therapeutic challenge for the treating physician. When feasible, resection is the mainstay of treatment. Prevention of hypoglycemia is a crucial goal of therapy for unresectable/metastatic tumors. Diazoxide, hydrochlorothiazide, glucagon, and intravenous glucose infusions have been used for glycemic control yielding temporary and inconsistent results. Sandostatin and its long-acting depot forms have occasionally been used in the treatment of Octreoscan-positive insulinomas. Herein, we report a case of metastatic insulinoma with very difficult glycemic control successfully treated with the radiolabeled somatostatin analog lutetium (177LU). PMID:24455330

  8. Structure-Activity Relationship Studies of Amino Acid Substitutions in Radiolabeled Neurotensin Conjugates.

    PubMed

    Mascarin, Alba; Valverde, Ibai E; Mindt, Thomas L

    2016-01-01

    Radiolabeled derivatives of the peptide neurotensin (NT) and its binding sequence NT(8-13) have been studied as potential imaging probes and therapeutics for NT-1-receptor-positive cancer. However, a direct comparison of reported NT analogues, even if radiolabeled with the same radionuclide, is difficult because different techniques and models have been used for preclinical evaluations. In an effort to identify a suitable derivative of NT(8-13) for radiotracer development, we herein report a side-by-side in vitro comparison of radiometallated NT derivatives bearing some of the most commonly reported amino acid substitutions in their sequence. Performed investigations include cell internalization experiments, determinations of receptor affinity, measurements of the distribution coefficient, and blood serum stability studies. Of the [(177)Lu]-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-labeled examples studied, analogues of NT(8-13) containing a short hydrophilic tetraethylene glycol (PEG4 ) spacer between the peptide and the radiometal complex, and a minimum number of substitutions of amino acid residues, exhibited the most promising properties in vitro.

  9. Peptide receptor radionuclide therapy of Merkel cell carcinoma using (177)lutetium-labeled somatostatin analogs in combination with radiosensitizing chemotherapy: a potential novel treatment based on molecular pathology.

    PubMed

    Salavati, Ali; Prasad, Vikas; Schneider, Claus-Peter; Herbst, Rudolf; Baum, Richard Paul

    2012-05-01

    Few studies have been published on the safety and feasibility of synchronous use of peptide receptor radionuclide therapy (PRRNT), as source of internal radiation therapy, in combination with chemotherapy. In this study we reported a 53-year-old man with stage IV Merkel cell carcinoma (MCC), who underwent synchronous internal radiation therapy and chemotherapy. Based on presumable poor prognosis with chemotherapy only, functional similarities of MCC with other neuroendocrine tumors and available evidence of effectiveness and safety of synchronous use of external beam radiation therapy and chemotherapy in treatment of high-risk MCC patients, our interdisciplinary neuroendocrine tumor board recommended him to add PRRNT to his ongoing chemotherapy. He received 2 courses of (177)Lu-DOTATATE(1, 4, 7, 10-Tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid-1-D-Phe1-Tyr3-Thr8-octreotide) in combination with ongoing 8 cycles of liposomal doxorubicin based on standard protocols. Response to therapy was evaluated by (18)F-FDG and (68)gallium-somatostatin-receptor PET/CT. There was an impressive improvement of the clinical symptoms. However, follow-up PET/CT studies showed mixed pattern of response. Synchronous use of PRRNT and radiosensitizing chemotherapy seems safe and feasible in high risk MCC patients, however, further prospective studies and clinical trials are warranted to provide reliable evidence of possible pitfalls and effectiveness of PRRNT and (68)Ga-somatostatin-receptor PET/CT in the management of MCC.

  10. Cross section for inelastic neutron ''acceleration'' by {sup 178}Hf{sup m2}

    SciTech Connect

    Karamian, S. A.; Carroll, J. J.

    2011-02-15

    The scattering of thermal neutrons from isomeric nuclei may include events in which the outgoing neutrons have increased kinetic energy. This process has been called inelastic neutron acceleration, or INNA, and occurs when the final nucleus, after emission of the neutron, is left in a state with lower energy than that of the isomer. The result, therefore, is an induced depletion of the isomer to the ground state. A cascade of several {gamma}'s must accompany the neutron emission to release the high angular momentum of the initial isomeric state. INNA was previously observed in a few cases, and the measured cross sections were only in modest agreement with theoretical estimates. The most recent measurement of an INNA cross section was {sigma}{sub INNA}=258{+-}58 b for neutron scattering by {sup 177}Lu{sup m}. In the present work, an INNA cross section of {sigma}{sub INNA}=168 {+-} 33 b was deduced from measurements of the total burnup of the high-spin, four-quasiparticle isomer {sup 178}Hf{sup m2} during irradiation by thermal neutrons. Statistical estimates for the probability of different reaction channels past neutron absorption were used in the analysis, and the deduced {sigma}{sub INNA} was compared to the theoretically predicted cross section.

  11. Inhibition of MNK pathways enhances cancer cell response to chemotherapy with temozolomide and targeted radionuclide therapy.

    PubMed

    Grzmil, Michal; Seebacher, Jan; Hess, Daniel; Behe, Martin; Schibli, Roger; Moncayo, Gerald; Frank, Stephan; Hemmings, Brian A

    2016-09-01

    Current standard-of-care treatment for malignant cancers includes radiotherapy and adjuvant chemotherapy. Here, we report increased MAP kinase-interacting kinase (MNK)-regulated phosphorylation of translation initiation factor 4E (eIF4E) in glioma cells upon temozolomide (TMZ) treatment and in medullary thyroid carcinoma (MTC) cells in response to targeted radionuclide therapy. Depletion of MNK activity by using two MNK inhibitors, CGP57380 or cercosporamide, as well as by MNK1-specific knockdown sensitized glioblastoma (GBM) cells and GBM-derived spheres to TMZ. Furthermore, CGP57380 treatment enhanced response of MTC cells to (177)Lu-labeled gastrin analogue. In order to understand how MNK signaling pathways support glioma survival we analyzed putative MNK substrates by quantitative phosphoproteomics in normal condition and in the presence of TMZ. We identified MNK inhibitor-sensitive phosphorylation sites on eIF4G1, mutations of which either influenced eIF4E phosphorylation or glioma cell response to TMZ, pointing to altered regulation of translation initiation as a resistance mechanism. Pharmacological inhibition of overexpressed MNK1 by CGP57380 reduced eIF4E phosphorylation and induced association of inactive MNK1 with eIF4G1. Taken together, our data show an activation of MNK-mediated survival mechanisms in response to either glioma chemotherapy or MTC targeted radiation and suggest that inhibition of MNK activity represents an attractive sensitizing strategy for cancer treatments.

  12. A 25-Year Experience of Gastroenteropancreatic Neuroendocrine Tumors and Somatostatin (Congeners) Analogs: From Symptom Control to Antineoplastic Therapy.

    PubMed

    O'Dorisio, Thomas M; Anthony, Lowell B

    2015-01-01

    Radioimmunoassay technology was utilized in the discovery of somatostatin and was quickly brought into therapeutics; however, it took the development of somatostatin congeners to solve its limitations of a short half-life. Therapeutic medical control of hyperhormonal states such as acromegaly, carcinoid syndrome and VIPoma significantly advanced from a nonspecific approach to one that specifically and effectively targeted the underlying pathophysiology. Clinical care was transformed from nonspecific symptom control to one of a significant improvement in not only quality of life, but also quantity of life. These data submitted to US and European regulatory authorities for approval included many investigative sites with no uniform protocol and multiple investigational new drugs, and have not been previously published. This review includes the original data demonstrating the transformational impact this class of agents had on specific disease subsets resulting in regulatory approval 25 years ago. Autoradiography techniques using somatostatin resulted in identifying, localizing and characterizing its receptor subtypes. Translating in vitro data to in vivo resulted in scintigraphic whole body and SPECT scans with (111)In-pentetreotide and was incorporated into standard clinical care 20 years ago. (68)Ga-octreotide congeners using PET scanning offers a major imaging advance. Peptide receptor radiotherapy has evolved over the last 2 decades and utilizes several therapeutic isotopes, including (90)Y and (177)Lu. PMID:26303712

  13. 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

  14. Synthesis and radiolabeling of a somatostatin analog for multimodal imaging

    NASA Astrophysics Data System (ADS)

    Edwards, W. Barry; Liang, Kexian; Xu, Baogang; Anderson, Carolyn J.; Achilefu, Samuel

    2006-02-01

    A new multimodal imaging agent for imaging the somatostatin receptor has been synthesized and evaluated in vitro and in vivo. A somatostatin analog, conjugated to both 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaceticacid (DOTA) and cypate (BS-296), was synthesized entirely on the solid phase (Fmoc) and purified by RP-HPLC. DOTA was added as a ligand for radiometals such as 64Cu or 177Lu for either radio-imaging or radiotherapy respectively. Cytate, a cypatesomatostatin analog conjugate, has previously demonstrated the ability to visualize somatostatin receptor rich tumor xenografts and natural organs by optical imaging techniques. BS-296 exhibited low nanomolar inhibitory capacity toward the binding of radiolabeled somatostatin analogs in cell membranes enriched in the somatostatin receptor, demonstrating the high affinity of this multimodal imaging peptide and indicating its potential as a molecular imaging agent. 64Cu, an isotope for diagnostic imaging and radiotherapy, was selected as the isotope for radiolabeling BS-296. BS-296 was radiolabeled with 64Cu in high specific activity (200 μCi/μg) in 90% radiochemical yield. Addition of 2,5-dihydroxybenzoic acid (gentisic acid) prevented radiolysis of the sample, allowing for study of the 64Cu -BS-296 the day following radiolabeling. Furthermore, inclusion of DMSO at a level of 20% was found not to interfere with radiolabeling yields and prevented the adherence of 64Cu -BS-296 to the walls of the reaction vessel.

  15. Cytotoxic activity of lymphocytes from F 344 rats bearing intraocular tumor derived from human adenovirus 12-induced retinoblastoma-like cell line.

    PubMed

    Kobayashi, M; Mukai, N; Solish, S P; Pomeroy, M E

    1984-03-01

    Lymphocyte cytotoxicity using 51Cr releasing assay was investigated in 10 F344 rats bearing intraocular tumor derived from human adenovirus 12 (Ad 12)-induced retinoblastoma -like cell line (EXP-5). Lymphocytes obtained from tumor bored animal (1 X 10(6)/well) incubated with 51Cr-labelled EXP-5 cells (1 X 10(5)/well) for 24 hours, and counted by beta-scintillation counter. The cytotoxic activity of lymphocytes of transplanted animals was higher in 3 out of 10 subjected rats (24-30%) than in 10 rats of control (3-5%). The results support the view that the correspond animal model in its resemblance and suggested that the rats with retinal tumor have concomitant cell-mediated immunity in the early stage of tumor bearing.

  16. Chromium and vanadium effects on glucose and lipid metabolism of guinea pigs and obese and diabetic mice

    SciTech Connect

    Li, Y.C.

    1987-01-01

    Severe chromium deficiency in experimental animals may contribute to insulin resistance, impaired glucose tolerance and elevated serum cholesterol concentration. Vanadium also has been reported to be a nutritionally important element for both chicks and rats, but its function and even its essentiality are still in question. Chromium absorption even from supplemented diets is poor, thus efforts were made to study the site of absorption of /sup 51/Cr from CrCl/sub 3/. /sup 51/Cr was found to move very rapidly through the GI tract and appears to flow with dietary and secreted water. It was not absorbed from the stomach. In a study with guinea pigs, vanadate supplementation appeared to affect cholesterol fraction. Chromium supplementation lowered serum triacylglycerol concentrations at the end of an 18-week study. Since the previous study and others have indicated a role for chromium and vanadium in lipid carbohydrate metabolism, experiments were designed to compare effects of chromium and vanadium supplements on related parameters.

  17. Normal anti-Klebsiella lymphocytotoxicity in ankylosing spondylitis

    SciTech Connect

    Kinsella, T.D.; Fritzler, M.J.; Lewkonia, R.M.

    1986-03-01

    We compared in vitro lymphocytotoxicity (LCT) of peripheral blood lymphocytes (PBL), obtained from patients with ankylosing spondylitis (AS) and normal controls (NC). Assays were performed with antibacterial antisera prepared from AS- and NC-derived Klebsiella and coliforms Escherichia coli. LCT assessed by eosin staining was not significantly different in PBL of 12 AS patients and 28 controls when reacted with 3 Klebsiella and 1 E coli antisera. LCT assessed by /sup 51/Cr release was not significantly different for PBL of 20 age- and sex-matched pairs of AS patients and NC when reacted with 3 Klebsiella and 1 E coli antisera. Similarly, LCT-/sup 51/Cr of PBL of 15 matched AS and NC pairs was not significantly different for anti-K21, a serotype putatively implicated in Klebsiella-HLA-B27 antigenic cross-reactivity. Our results do not support the notion of molecular mimicry between Klebsiella and B27 in the pathogenesis of primary AS.

  18. Effects of in utero exposure to cyclophosphamide in mice. II. Assessment of immunocompetence of offspring from 5 to 10 weeks of age

    SciTech Connect

    Liakopoulou, A.; Buttar, H.S.; Nera, E.A.; Fernando, L. )

    1989-01-01

    Offspring of mice treated with cyclophosphamide (Cy; 1, 2.5 or 5 mg/kg) during pregnancy (6-18 days of gestation) and tested for immunocompetence from 5 to 10 weeks of age were found to have defective reticuloendothelial clearance. The main effects were: (a) increased elimination half time (T 1/2) of {sup 51}Cr-labeled SRBC from circulation, (b) decreased liver uptake of {sup 51}Cr and (c) impaired ability of the spleen, mostly affecting the female pups, to compensate for decreased liver uptake. The highest dose group suffered the most pronounced effects. This group was also found to have increased IgG immunoglobulin levels at 7 weeks of age. IgG antibody production in response to specific antigenic stimulation and delayed hypersensitivity reactions to oxazolone did not appear to be affected by Cy treatment.

  19. Acrylic microspheres in vivo. X. Elimination of circulating cells by active targeting using specific monoclonal antibodies bound to microparticles

    SciTech Connect

    Laakso, T.; Andersson, J.; Artursson, P.; Edman, P.; Sjoeholm, I.

    1986-01-13

    The elimination from the blood of /sup 51/Cr-labelled mouse erythrocytes modified with trinitrophenyl (TNP) groups was followed in mice. After 24 hours, when a stable concentration of the labelled erythrocytes has been attained, monoclonal anti-TNP-antibodies were given intravenously, either in free, soluble form, or bound to microparticles containing immobilized protein A. The anti-TNP-antibodies induced a rapid elimination of the TNP- and /sup 51/Cr-labelled erythrocytes. Over the 8-hours time period studied, the elimination rate was significantly faster when the antibodies were administered bound to the particles. After the elimination of the target cells, the radioactivity was found in the liver, spleen and bone marrow. These results and relevant control experiments indicate that a solid carrier (1) can be directed to a specific target cell with a specific antibody and (2) can induce a rapid elimination of the target cell from the circulation. 31 references, 1 figure, 2 tables.

  20. Assessment of clinical significance of anti-Ge in an untransfused man

    SciTech Connect

    Pearson, H.A.; Richards, V.L.; Wylie, B.R.; Bruce, D.; Watt, J.M.; Wilkie, D.; Kronenberg, H. )

    1991-03-01

    A 19-year-old, untransfused Melanesian man from Papua New Guinea was admitted to the hospital for repair of an atrial septal defect. His serum contained an alloantibody that reacted strongly on the indirect antiglobulin test and was identified as anti-Ge. Gerbich-negative blood was transfused following urgent surgery. A 51Cr red cell survival study performed 2 weeks after surgery yielded zero survival of Gerbich-positive cells after 24 hours. A monocyte-driven, antibody-dependent, cell-mediated cytotoxicity assay performed on both pretransfusion and posttransfusion serum samples and on concentrated serum showed less than 1 percent specific lysis of Gerbich-positive cells. This did not correlate with the indication of clinical significance predicted by the 51Cr study. Red cell adherence and phagocytosis, not evident in a monocyte monolayer assay using native serum, were demonstrable in 16 percent of monocytes by the use of concentrated serum.

  1. Posttransfusion survival of red cells frozen for 8 weeks after 42-day liquid storage in AS-3

    SciTech Connect

    Rathbun, E.J.; Nelson, E.J.; Davey, R.J.

    1989-03-01

    Current standards recommend that red cells (RBCs) should be frozen within 6 days of donation. There are situations, however, in which it is desirable to freeze RBCs that are older than 6 days, such as for the salvage of rare or autologous units. To determine the therapeutic efficacy of RBCs frozen after prolonged liquid storage, standard units were drawn from nine normal donors and stored at 4 degrees C for 42 days in a nutrient-additive solution, AS-3. 51CrRBC survival assays were performed (24-hour survival: 78.2 +/- 12.4%; n = 8) and the units were frozen at -80 degrees C in glycerol for 8 weeks. After deglycerolization, the mean RBC recovery was 81.0 +/- 4.1 percent and the mean 24-hour 51Cr survival was 78.0 +/- 9.1 percent. The index of therapeutic effectiveness (ITE) was determined by multiplying the postdeglycerolization 24-hour 51Cr survival by the mean RBC recovery (63.3 +/- 9.2). ITE values greater than 60 percent (75% 51Cr survival x 80% RBC recovery) were considered acceptable. Mean adenosine triphosphate levels declined from an initial 3.81 +/- 0.56 micromol per g of hemoglobin to 2.33 +/- 0.55 micromol per g after frozen storage. These findings show that an acceptable percentage of RBCs survives frozen storage after maximum liquid storage (mean ITE greater than 60%). If necessary, RBCs stored in AS-3 can be frozen at any time before 42 days.

  2. Chromium 51-ethylenediaminetetraacetate test: a useful test in the assessment of inflammatory bowel disease

    SciTech Connect

    O'Morain, C.A.; Abelow, A.C.; Chervu, L.R.; Fleischner, G.M.; Das, K.M.

    1986-11-01

    We evaluated the usefulness of urinary excretion values in assessing mucosal damage in inflammatory bowel disease after administration of chromium 51-labeled EDTA either orally or rectally. In the oral study, 19 controls, 18 patients with Crohn's disease, and 13 patients with ulcerative colitis were given 100 microCi /sup 51/Cr-EDTA by mouth. The amount of /sup 51/Cr-EDTA in a 24-hour urine collection was expressed as a percentage of the ingested dose. The patients with Crohn's disease of the small bowel excreted 6.3% +/- 4.3%, which was significantly (P less than 0.001) higher than the percentage in patients with ulcerative colitis (1.7% +/- 1.1%) and controls (1.4% +/- 0.6%). In the enema study, 19 patients with ulcerative colitis, two with Crohn's disease, two with radiation colitis, and four controls (spastic colitis, lactose intolerance) were given 100 microCi /sup 51/Cr-EDTA by retention enema. The patients with active colonic inflammation excreted 8.4% +/- 3.9% of the dose given by enema, which was significantly (P less than 0.01) higher than in other controls (1.9% +/- 0.91%) or patients with inactive colitis (2.2% +/- 1.9%). The /sup 51/Cr-EDTA excretion test is a safe, inexpensive test useful in evaluating patients with inflammatory bowel disease. It can be given orally to screen patients with abdominal complaints who are suspected of having Crohn's disease involving the small intestine, and when given by enema it provides additional objective assessment of idiopathic ulcerative colitis or proctitis.

  3. Determination of selected trace elements in foodstuffs and biological materials by destructive neutron activation analysis.

    PubMed

    Bayat, I; Etehadiyan, M; Ansar, M

    1995-01-01

    Concentration of trace elements in Nescafé, Fariman sugar, and Sadaf turmeric and mercury content in cancerous blood were determined by radiochemical, neutron activation analysis. By this separation method levels of 110mAg, 198Au, 203Hg, 76Se, 51Cr, 24Na, 42K, 99Mo, 122Sb, 82Br, 59Fe, 60Co were measured without interference in the gamma spectroscopy. A nondestructive method has also been used for the analysis of sodium, potassium, and bromine. PMID:8748216

  4. Intestinal permeability in patients with coeliac disease and dermatitis herpetiformis.

    PubMed Central

    Bjarnason, I; Marsh, M N; Price, A; Levi, A J; Peters, T J

    1985-01-01

    Intestinal permeability was investigated in patients with coeliac disease and dermatitis herpetiformis by a 51Chromium-labelled ethylenediaminetetraacetate (51Cr-EDTA) absorption test and the results correlated with histomorphometric analysis and intraepithelial lymphocyte counts of jejunal biopsies. The mean (+/- SD) 24 hour urine excretion of 51Cr-EDTA in 34 healthy volunteers was 1.9 +/- 0.5% of the orally administered test dose. Patients with untreated coeliac disease (19) or untreated dermatitis herpetiformis (five) excreted significantly more 51Cr-EDTA than controls (5.9 +/- 2.7% and 4.6 +/- 2.1%, respectively, p less than 0.001) and all were outside the normal range of 1.0-2.6%. Patients with coeliac disease (42) treated for 6 months-23 years (mean 5 years) and patients with dermatitis herpetiformis (11) treated for 6 months-8 years (mean 3 years) excreted significantly more 51Cr-EDTA than controls, 4.2 +/- 2.4% p less than 0.0001 and 3.0 +/- 0.9% p less than 0.003 respectively. Eleven of 14 (79%) treated patients with coeliac disease with an entirely normal jejunal mucosae demonstrated abnormal intestinal permeability. Intestinal permeability did not correlate significantly with either the mucosal height/crypt depth ratio or intraepithelial lymphocyte counts in jejunal biopsies from patients with untreated or treated coeliac disease. The demonstration of a persistent increase in intestinal permeability in patients with both coeliac disease and dermatitis herpetiformis may suggest a common pathogenetic mechanism in both disorders. It is postulated that altered permeability may facilitate the entry of gluten or a fraction thereof into the lamina propria where it causes a cascade of immunological events. PMID:3934051

  5. Role of mucus in gastric mucosal injury induced by local ischemia/reperfusion.

    PubMed

    Seno, K; Joh, T; Yokoyama, Y; Itoh, M

    1995-09-01

    The role of gastric mucus was evaluated in a rat model of gastric epithelial damage induced by local ischemia/reperfusion (I/R) stress. In this model, blood-to-lumen chromium 51-labeled ethylenediaminetetraacetic acid (51Cr-EDTA) clearance served as an index of injury. Tetraprenyl acetone (TPA; 100 mg, 200 mg/kg IP) was used to stimulate mucus production. Administration of TPA increased both the hexosamine content in gastric tissue and the amount of alcian blue-periodic acid Schiff (AB-PAS) stained mucus in the mucosa in a dose-dependent manner. Increases in 51Cr-EDTA clearance induced by I/R were significantly attenuated by TPA in a dose-dependent manner. N-acetyl-L-cysteine (NAC; 0.6%, 0.8%) was perfused into the gastric lumen to assess the effect of reduction in mucus on the injury induced by I/R. Although mean values of hexosamine content were increased by perfusion with NAC, AB-PAS-stained mucus in the mucosa was significantly decreased in a dose-dependent manner. Perfusion of NAC did not change basal 51Cr-EDTA clearance but significantly exacerbated the increase in clearance induced by I/R in a dose-dependent manner. These results indicate that gastric mucus protects the gastric mucosa against I/R stress in vivo. PMID:7665977

  6. Enhancement of tumor necrosis factor-induced endothelial cell injury by cycloheximide

    SciTech Connect

    Nolop, K.B.; Ryan, U.S. )

    1990-08-01

    Tumor necrosis factor (TNF), a potent polypeptide mediator released by activated monocytes and macrophages, has a number of proinflammatory effects on endothelial cells. TNF is cytotoxic to tumor cells in vivo and in vitro, but TNF-induced toxicity to endothelial cells is less well established. We now report that cycloheximide (CHX), an inhibitor of protein synthesis, renders endothelial cells highly susceptible to TNF-induced lysis. TNF alone did not change the overall rate of protein synthesis by endothelial cells, whereas the addition of CHX completely abolished protein synthesis. Endothelial cells incubated in TNF alone in high concentrations (up to 1,000 U/ml) showed minimal rounding up and release of 51Cr. Likewise, CHX alone (5 micrograms/ml) had no significant effect on endothelial cell morphology and release of 51Cr. However, incubation of endothelial cells in both CHX and TNF caused injury in a dose-dependent manner. Morphological evidence of cell retraction, rounding, and detachment began within 2 h, but specific 51Cr release did not begin to rise until after 4 h. These changes were not observed when endothelial cells were incubated with TNF/CHX at 4 degrees C. The combination of TNF/CHX was lethal to all endothelial cells tested (bovine pulmonary artery, human umbilical vein, and human aorta), with human aortic cells showing the most pronounced changes. We conclude that healthy endothelial cells are resistant to TNF-induced lysis, but inhibition of their ability to make protein renders them highly susceptible.

  7. Normal survival of Rh0 (D) negative, LW (a+) red cells in a patient with allo-anti LWa.

    PubMed

    Cummings, E; Pisciotto, P; Roth, G

    1984-01-01

    The serum of an Rh0 (D)+ Caucasian female with a prior history of transfusions contained anti- LWa , reacting moderately with Rh0 (D)+ and weakly with Rh0 (D)- red cells at the antiglobulin phase. Since transfusions were required, Chromium (51Cr) survival studies and mononuclear phagocyte assays (MPA) were used to predict in vivo survival. The MPA value of 6% of the positive control predicted a low likelihood of clinically significant extravascular destruction and 51Cr survival studies indicated greater than 95% survival at 1 h and 78% survival at 20 h for rr erythrocytes. Transfusion of 4 units of Rh0 (D)-, serologically incompatible red cells increased the hemoglobin from 5.2 to 11.4 g/dl and the titer of anti- LWa against rr red cells from 4 to 1,024 7 days after the transfusion. A second 51Cr survival also indicated normal survival of rr erythrocytes. 3 additional Rh0 (D)- units were successfully transfused. PMID:6428046

  8. Method for the quantitation of gastric emptying time of gel test meals.

    PubMed

    Russell, J; Bass, P

    1984-09-01

    Isotopic markers were developed to allow measurement of the gastric emptying times of homogeneous and nonhomogeneous gel meals. Meals containing the dietary fibers psyllium and guar gum presented as homogeneous, viscous gels while meals containing the synthetic polymer polycarbophil presented as discrete gel particle-water mixtures. Fiber meals were labeled differently than polycarbophil meals. Fiber meals were labeled with 51Cr-CM-Sephadex. The marker was uniformly suspended in meals containing at least 1% guar or 2% psyllium. In contrast, polycarbophil particles were labeled by hydrating the dried granules with saline in which Na2(51)CrO4 had been dissolved. Use of the markers to measure gastric emptying was demonstrated in dogs fitted with duodenal cannulas. Half of the fiber meals emptied from the stomach in about 40 min without significant dilution by secretions. In contrast, only 8% of the polycarbophil particles emptied by 90 min. Particle-specific labeling of polycarbophil was important because the meal effluent was diluted extensively by secretions. We conclude that 51Cr-CM-Sephadex and soluble Cr-51 may be used as meal markers for estimation of the gastric emptying times of certain homogeneous and nonhomogeneous gel-type meals, respectively.

  9. Assimilation efficiency for sediment-sorbed benzo(a)pyrene by Diporeia spp.

    USGS Publications Warehouse

    Lydy, M.J.; Landrum, P.F.

    1993-01-01

    Two methods are currently available for determining contaminant assimilation efficiencies (AE) from ingested material in benthic invertebrates. These methods were compared using the Great Lakes amphipod Diporeia spp. and [14C]benzo(a)pyrene (BaP) sorbed to Florissant sediment (< 63 µm). The first approach, the direct measurement method, uses total organic carbon as a tracer and yielded AE values ranging from 45.9~50.4%. The second approach, the dual-labeled method, uses 51Cr as a non-assimilated tracer and did not yield AE values for our data. The inability of the dual-labeled approach to estimate AEs was due, in part, to the selective feeding by Diporeia resulting in a failure of the non-assimilated tracer (51Cr) to track with the assimilated tracer ([14C]BaP). The failure of the dual-labeled approach was not a result of an uneven distribution of the labels among particle size classes, but more likely resulted from differential sorption of the two isotopically labeled materials to particles of differing composition. The [14C]BaP apparently sorbs to organic particles that are selectively ingested, while the 51Cr apparently sorbs to particles which are selectively excluded by Diporeia. The dual-labeled approach would be a viable and easier experimental approach for determining AE values if the characteristics that govern selective feeding can be determined.

  10. Role of mucus in gastric mucosal injury induced by local ischemia/reperfusion.

    PubMed

    Seno, K; Joh, T; Yokoyama, Y; Itoh, M

    1995-09-01

    The role of gastric mucus was evaluated in a rat model of gastric epithelial damage induced by local ischemia/reperfusion (I/R) stress. In this model, blood-to-lumen chromium 51-labeled ethylenediaminetetraacetic acid (51Cr-EDTA) clearance served as an index of injury. Tetraprenyl acetone (TPA; 100 mg, 200 mg/kg IP) was used to stimulate mucus production. Administration of TPA increased both the hexosamine content in gastric tissue and the amount of alcian blue-periodic acid Schiff (AB-PAS) stained mucus in the mucosa in a dose-dependent manner. Increases in 51Cr-EDTA clearance induced by I/R were significantly attenuated by TPA in a dose-dependent manner. N-acetyl-L-cysteine (NAC; 0.6%, 0.8%) was perfused into the gastric lumen to assess the effect of reduction in mucus on the injury induced by I/R. Although mean values of hexosamine content were increased by perfusion with NAC, AB-PAS-stained mucus in the mucosa was significantly decreased in a dose-dependent manner. Perfusion of NAC did not change basal 51Cr-EDTA clearance but significantly exacerbated the increase in clearance induced by I/R in a dose-dependent manner. These results indicate that gastric mucus protects the gastric mucosa against I/R stress in vivo.

  11. Decreased chromate uptake in Pseudomonas fluorescens carrying a chromate resistance plasmid.

    PubMed Central

    Ohtake, H; Cervantes, C; Silver, S

    1987-01-01

    CrO4(2-) resistance in Pseudomonas fluorescens LB300(pLHB1) was related to reduced uptake of CrO4(2-) relative to the plasmidless strain LB303. 51CrO4(2-) was transported mainly via the SO4(2-) active transport system; thus, cells grown with 0.15 mM cysteine, a repressor of the SO4(2-) transport system, were much more resistant to CrO4(2-) than those grown with 0.15 mM djenkolic acid, which derepressed the 35SrO4(2-) uptake system. Kinetics of 51CrO4(2-) uptake by P. fluorescens with and without the plasmid showed that the Vmax for 51CrO4(2-) uptake with the resistant strain was 2.2 times less than the Vmax for the sensitive strain, whereas the Km remained constant. PMID:3112130

  12. [166Dy]Dy/166Ho hydroxide macroaggregates: an in vivo generator system for radiation synovectomy.

    PubMed

    Ferro-Flores, G; Hernández-Oviedo, O; Arteaga de Murphy, C; Tendilla, J I; Monroy-Guzmán, F; Pedraza-López, M; Aldama-Alvarado, K

    2004-12-01

    Radiation synovectomy is an effective treatment in patients suffering from inflammatory-rheumatoid and degenerative joint diseases. The aim of this work was to examine the feasibility of preparing dysprosium-166 (166Dy)/holmium-166(166Ho) hydroxide macroaggregates ([166Dy]Dy/166Ho-HM) as an in vivo generator for radiation synovectomy evaluating whether the stability of 166Dy-HM and 166Ho-HM complexes is maintained when the daughter 166Ho is formed. The Monte Carlo (MCNP4B) theoretical depth dose profile for the in vivo [166Dy]Dy/166Ho generator system in a joint model was calculated and compared with that produced by 90Y, 153Sm and 166Ho. 166Dy was obtained by neutron irradiation of enriched 164Dy2O3 in a Triga Mark III reactor. Macroaggregates were prepared by reaction of [166Dy]DyCl3 with 0.5 M NaOH in an ultrasonic bath. [166Dy]Dy/166Ho-HM was obtained with radiochemical purity >99.5% and with the majority of particles in the 2-5 microm range. In vitro studies demonstrated that the radio-macroaggregates are stable in saline solution and human serum without a significant change in the particle size over 14 d, suggesting that no translocation of the daughter nucleus occurs subsequent to beta- decay of 166Dy. Biological studies in normal rats demonstrated high retention in the knee joint even 7 d after [166Dy]Dy/166Ho-HM administration. The Monte Carlo (MCNP4B) theoretical depth dose profiles in a joint model, showed that the in vivo [166Dy]Dy/166Ho generator system would produce 25% and 50% less radiation dose to the articular cartilage and bone surface, respectively, than that produced by 90Y or pure 166Ho in a treatment with the same therapeutic dose to the synovium surface. Despite that 153Sm showed the best depth dose profile sparing doses to healthy tissues, the use of 166Dy could provide the advantage of being applied in patients that cannot be reached within a few hours from a nuclear reactor and to produce less radiation exposure to the medical personnel

  13. Urinary recovery of orally administered chromium 51-labeled EDTA, lactulose, rhamnose, d-xylose, 3-O-methyl-d-glucose, and sucrose in healthy adult male Beagles.

    PubMed

    Frias, Rafael; Steiner, Jörg M; Williams, David A; Sankari, Satu; Westermarck, Elias

    2012-05-01

    Objective-To provide values for gastrointestinal permeability and absorptive function tests (GIPFTs) with chromium 51 ((51)Cr)-labeled EDTA, lactulose, rhamnose, d-xylose, 3-O-methyl-d-glucose, and sucrose in Beagles and to evaluate potential correlations between markers. Animals-19 healthy adult male Beagles. Procedures-A test solution containing 3.7 MBq of (51)Cr-labeled EDTA, 2 g of lactulose, 2 g of rhamnose, 2 g of d-xylose, 1 g of 3-O-methyl-d-glucose, and 8 g of sucrose was administered intragastrically to each dog. Urinary recovery of each probe was determined 6 hours after administration. Results-Mean ± SD (range) percentage urinary recovery was 6.3 ± 1.6% (4.3% to 9.7%) for (51)Cr-labeled EDTA, 3.3 ± 1.1% (1.7% to 5.3%) for lactulose, 25.5 ± 5.0% (16.7% to 36.9%) for rhamnose, and 58.8% ± 11.0% (40.1% to 87.8%) for 3-O-methyl-d-glucose. Mean (range) recovery ratio was 0.25 ± 0.06 (0.17 to 0.37) for (51)Cr-labeled EDTA to rhamnose, 0.13 ± 0.04 (0.08 to 0.23) for lactulose to rhamnose, and 0.73 ± 0.09 (0.60 to 0.90) for d-xylose to 3-O-methyl-d-glucose. Median (range) percentage urinary recovery was 40.3% (31.6% to 62.7%) for d-xylose and 0% (0% to 0.8%) for sucrose. Conclusions and Clinical Relevance-Reference values in healthy adult male Beagles for 6 of the most commonly used GIPFT markers were determined. The correlation between results for (51)Cr-labeled EDTA and lactulose was not as prominent as that reported for humans and cats; thus, investigators should be cautious in the use and interpretation of GIPFTs performed with sugar probes in dogs with suspected intestinal dysbiosis.

  14. Macrocyclic complexes of scandium radionuclides as precursors for diagnostic and therapeutic radiopharmaceuticals.

    PubMed

    Majkowska-Pilip, A; Bilewicz, A

    2011-02-01

    The aim of this study was to evaluate new ligands which can be applied for labeling biomolecules with scandium radionuclides. Two radionuclides of scandium, (47)Sc and (44)Sc, are perspective radioisotopes for radiotherapy and diagnostic imaging. (47)Sc decays with a half-life of 3.35 days and a maximum β(-) energy of 600 keV and could be an alternative to carrier added (177)Lu radionuclide for targeted radionuclide therapy. Another scandium radionuclide (44)Sc (t(1/2) = 3.92 h) is an ideal β(+) emitter for PET diagnosis. It can be obtained as a daughter of the long-lived (44)Ti (t(1/2) = 60.4 y) from (44)Ti/(44)Sc generator. For complexation of scandium radionuclides macrocyclic ligands having a cavity size similar to Sc(3+) ionic radius were selected: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7 triacetic acid (NOTA), 1,4,7-triazacyclodecane-1,4,7 triacetic acid and 1,4,7-triazacycloundecane triacetic acid, and analogs of NOTA with 10, 11 and 12 atoms of the carbon in the ring. Our results have shown that from the studied macrocyclic ligands studied DOTA is most efficient for binding scandium radionuclides (44)Sc and (47)Sc to biomolecules. The determined stability constant of Sc-DOTA complex logK = 27.0 is comparable with stability constants for Y(3+) and heaviest lanthanides but is higher than those for In(3+) and Ga(3+). Also (46)Sc-DOTATATE conjugate exhibits high stability in-vitro studies. The (13)C NMR studies have shown that Sc-DOTA like Lu-DOTA forms in solution complexes with eight-coordination geometry. The lipophilicity of Sc-DOTATATE is nearly identical to that of Lu-DOTATATE, which suggests similar receptor affinity of both radioconjugates.

  15. Production of Endohedral Fullerenes by Ion Implantation

    SciTech Connect

    Diener, M.D.; Alford, J. M.; Mirzadeh, S.

    2007-05-31

    The empty interior cavity of fullerenes has long been touted for containment of radionuclides during in vivo transport, during radioimmunotherapy (RIT) and radioimaging for example. As the chemistry required to open a hole in fullerene is complex and exceedingly unlikely to occur in vivo, and conformational stability of the fullerene cage is absolute, atoms trapped within fullerenes can only be released during extremely energetic events. Encapsulating radionuclides in fullerenes could therefore potentially eliminate undesired toxicity resulting from leakage and catabolism of radionuclides administered with other techniques. At the start of this project however, methods for production of transition metal and p-electron metal endohedral fullerenes were completely unknown, and only one method for production of endohedral radiofullerenes was known. They therefore investigated three different methods for the production of therapeutically useful endohedral metallofullerenes: (1) implantation of ions using the high intensity ion beam at the Oak Ridge National Laboratory (ORNL) Surface Modification and Characterization Research Center (SMAC) and fullerenes as the target; (2) implantation of ions using the recoil energy following alpha decay; and (3) implantation of ions using the recoil energy following neutron capture, using ORNL's High Flux Isotope Reactor (HFIR) as a thermal neutron source. While they were unable to obtain evidence of successful implantation using the ion beam at SMAC, recoil following alpha decay and neutron capture were both found to be economically viable methods for the production of therapeutically useful radiofullerenes. In this report, the procedures for preparing fullerenes containing the isotopes {sup 212}Pb, {sup 212}Bi, {sup 213}Bi, and {sup 177}Lu are described. None of these endohedral fullerenes had ever previously been prepared, and all of these radioisotopes are actively under investigation for RIT. Additionally, the chemistry for

  16. Implementation and validation of collapsed cone superposition for radiopharmaceutical dosimetry of photon emitters

    NASA Astrophysics Data System (ADS)

    Sanchez-Garcia, Manuel; Gardin, Isabelle; Lebtahi, Rachida; Dieudonné, Arnaud

    2015-10-01

    Two collapsed cone (CC) superposition algorithms have been implemented for radiopharmaceutical dosimetry of photon emitters. The straight CC (SCC) superposition method uses a water energy deposition kernel (EDKw) for each electron, positron and photon components, while the primary and scatter CC (PSCC) superposition method uses different EDKw for primary and once-scattered photons. PSCC was implemented only for photons originating from the nucleus, precluding its application to positron emitters. EDKw are linearly scaled by radiological distance, taking into account tissue density heterogeneities. The implementation was tested on 100, 300 and 600 keV mono-energetic photons and 18F, 99mTc, 131I and 177Lu. The kernels were generated using the Monte Carlo codes MCNP and EGSnrc. The validation was performed on 6 phantoms representing interfaces between soft-tissues, lung and bone. The figures of merit were γ (3%, 3 mm) and γ (5%, 5 mm) criterions corresponding to the computation comparison on 80 absorbed doses (AD) points per phantom between Monte Carlo simulations and CC algorithms. PSCC gave better results than SCC for the lowest photon energy (100 keV). For the 3 isotopes computed with PSCC, the percentage of AD points satisfying the γ (5%, 5 mm) criterion was always over 99%. A still good but worse result was found with SCC, since at least 97% of AD-values verified the γ (5%, 5 mm) criterion, except a value of 57% for the 99mTc with the lung/bone interface. The CC superposition method for radiopharmaceutical dosimetry is a good alternative to Monte Carlo simulations while reducing computation complexity.

  17. Implementation and validation of collapsed cone superposition for radiopharmaceutical dosimetry of photon emitters.

    PubMed

    Sanchez-Garcia, Manuel; Gardin, Isabelle; Lebtahi, Rachida; Dieudonné, Arnaud

    2015-10-21

    Two collapsed cone (CC) superposition algorithms have been implemented for radiopharmaceutical dosimetry of photon emitters. The straight CC (SCC) superposition method uses a water energy deposition kernel (EDKw) for each electron, positron and photon components, while the primary and scatter CC (PSCC) superposition method uses different EDKw for primary and once-scattered photons. PSCC was implemented only for photons originating from the nucleus, precluding its application to positron emitters. EDKw are linearly scaled by radiological distance, taking into account tissue density heterogeneities. The implementation was tested on 100, 300 and 600 keV mono-energetic photons and (18)F, (99m)Tc, (131)I and (177)Lu. The kernels were generated using the Monte Carlo codes MCNP and EGSnrc. The validation was performed on 6 phantoms representing interfaces between soft-tissues, lung and bone. The figures of merit were γ (3%, 3 mm) and γ (5%, 5 mm) criterions corresponding to the computation comparison on 80 absorbed doses (AD) points per phantom between Monte Carlo simulations and CC algorithms. PSCC gave better results than SCC for the lowest photon energy (100 keV). For the 3 isotopes computed with PSCC, the percentage of AD points satisfying the γ (5%, 5 mm) criterion was always over 99%. A still good but worse result was found with SCC, since at least 97% of AD-values verified the γ (5%, 5 mm) criterion, except a value of 57% for the (99m)Tc with the lung/bone interface. The CC superposition method for radiopharmaceutical dosimetry is a good alternative to Monte Carlo simulations while reducing computation complexity. PMID:26406778

  18. 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

  19. 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.

  20. Modular syntheses of H₄octapa and H₂dedpa, and yttrium coordination chemistry relevant to ⁸⁶Y/⁹⁰Y radiopharmaceuticals.

    PubMed

    Price, Eric W; Cawthray, Jacqueline F; Adam, Michael J; Orvig, Chris

    2014-05-21

    The ligands H2dedpa, H4octapa, p-SCN-Bn-H2dedpa, and p-SCN-Bn-H4octapa were synthesized using a new protection chemistry approach, with labile tert-butyl esters replacing the previously used methyl esters as protecting groups for picolinic acid moieties. Additionally, the ligands H2dedpa and p-SCN-Bn-H2dedpa were synthesized using nosyl protection chemistry for the first time. The use of tert-butyl esters allows for deprotection at room temperature in trifluoroacetic acid (TFA), which compares favorably to the harsh conditions of refluxing HCl (6 M) or LiOH that were previously required for methyl ester cleavage. H4octapa has recently been shown to be a very promising (111)In and (177)Lu ligand for radiopharmaceutical applications; therefore, coordination chemistry studies with Y(3+) are described to assess its potential for use with (86)Y/(90)Y. The solution chemistry of H4octapa with Y(3+) is shown to be suitable via solution NMR studies of the [Y(octapa)](-) complex and density functional theory (DFT) calculations of the predicted structure, suggesting properties similar to those of the analogous In(3+) and Lu(3+) complexes. The molecular electrostatic potential (MEP) was mapped onto the molecular surface of the DFT-calculated coordination structures, suggesting very similar and even charge distributions between both the Lu(3+) and Y(3+) complexes of octapa(4-), and coordinate structures between 8 (ligand only) and 9 (ligand and one H2O). Potentiometric titrations determined H4octapa to have a formation constant (log K(ML)) with Y(3+) of 18.3 ± 0.1, revealing high thermodynamic stability. This preliminary work suggests that H4octapa may be a competent ligand for future (86)Y/(90)Y radiopharmaceutical applications.

  1. 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

  2. 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

  3. 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

  4. 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.

  5. Implementation and validation of collapsed cone superposition for radiopharmaceutical dosimetry of photon emitters.

    PubMed

    Sanchez-Garcia, Manuel; Gardin, Isabelle; Lebtahi, Rachida; Dieudonné, Arnaud

    2015-10-21

    Two collapsed cone (CC) superposition algorithms have been implemented for radiopharmaceutical dosimetry of photon emitters. The straight CC (SCC) superposition method uses a water energy deposition kernel (EDKw) for each electron, positron and photon components, while the primary and scatter CC (PSCC) superposition method uses different EDKw for primary and once-scattered photons. PSCC was implemented only for photons originating from the nucleus, precluding its application to positron emitters. EDKw are linearly scaled by radiological distance, taking into account tissue density heterogeneities. The implementation was tested on 100, 300 and 600 keV mono-energetic photons and (18)F, (99m)Tc, (131)I and (177)Lu. The kernels were generated using the Monte Carlo codes MCNP and EGSnrc. The validation was performed on 6 phantoms representing interfaces between soft-tissues, lung and bone. The figures of merit were γ (3%, 3 mm) and γ (5%, 5 mm) criterions corresponding to the computation comparison on 80 absorbed doses (AD) points per phantom between Monte Carlo simulations and CC algorithms. PSCC gave better results than SCC for the lowest photon energy (100 keV). For the 3 isotopes computed with PSCC, the percentage of AD points satisfying the γ (5%, 5 mm) criterion was always over 99%. A still good but worse result was found with SCC, since at least 97% of AD-values verified the γ (5%, 5 mm) criterion, except a value of 57% for the (99m)Tc with the lung/bone interface. The CC superposition method for radiopharmaceutical dosimetry is a good alternative to Monte Carlo simulations while reducing computation complexity.

  6. Gamma scintigraphic evaluation of floating gastroretentive tablets of metformin HCl using a combination of three natural polymers in rabbits

    PubMed Central

    Razavi, Mahboubeh; Karimian, Hamed; Yeong, Chai Hong; Chung, Lip Yong; Nyamathulla, Shaik; Noordin, Mohamed Ibrahim

    2015-01-01

    The present research was aimed at formulating a metformin HCl sustained-release formulation from a combination of polymers, using the wet granulation technique. A total of 16 formulations (F1–F16) were produced using different combinations of the gel-forming polymers: tamarind kernel powder, salep (palmate tubers of Orchis morio), and xanthan. Post-compression studies showed that there were no interactions between the active drug and the polymers. Results of in vitro drug-release studies indicated that the F10 formulation which contained 5 mg of tamarind kernel powder, 33.33 mg of xanthan, and 61.67 mg of salep could sustain a 95% release in 12 hours. The results also showed that F2 had a 55% similarity factor with the commercial formulation (C-ER), and the release kinetics were explained with zero order and Higuchi models. The in vivo study was performed in New Zealand White rabbits by gamma scintigraphy; the F10 formulation was radiolabeled using samarium (III) oxide (153Sm2O3) to trace transit of the tablets in the gastrointestinal tract. The in vivo data supported the retention of F10 formulation in the gastric region for 12 hours. In conclusion, the use of a combination of polymers in this study helped to develop an optimal gastroretentive drug-delivery system with improved bioavailability, swelling, and floating characteristics. PMID:26273196

  7. Harnessing the bone-seeking ability of Ca(II)-like metal ions in the treatment of metastatic cancer and resorption disorders.

    PubMed

    Weekes, D M; Orvig, C

    2016-04-21

    Metal ions are naturally retained by skeletal tissues in living systems because of their high affinity for the hydroxyapatite-like mineral matrix that makes up cortical bone. This is particularly true for metal ions that bear a close resemblance to calcium(ii) (such as the lanthanides or alkaline earth metals), and in a few key cases this targeting ability has been exploited in order to develop medicinal agents that are intended to treat bones which have become diseased. In this review, we focus on two areas where this has been particularly effective: first is in the diagnosis and therapy of metastatic bone cancer, in which radioactive metal ions including (99m)Tc, (153)Sm, and (223)Ra are used to image, alleviate, and ablate harmful cancerous legions with good specificity versus healthy tissues; second is the use of trivalent lanthanides to treat osteoporosis, an emerging concept which has gathered significance over the last 15 years, and is now entering preclinical trials with carefully designed systems.

  8. Investigation of low/medium spin excited states in 150-154Sm via the (p,d) and (p,t) reactions

    NASA Astrophysics Data System (ADS)

    Humby, P.; Simon, A.; Beausang, C.; Gell, K.; Tarlow, T.; Vyas, G.; Ross, T. J.; Hughes, R. O.; Burke, J. T.; Casperson, R. J.; Koglin, J.; Ota, S.; Allmond, J. M.; McCleskey, M.; McCleskey, E.; Saastamoinen, A.; Chyzh, R.; Dag, M.

    2014-03-01

    Low/medium spin excited states of 151,153Sm and 150,152Sm were studied via the (p,d) and (p,t) reactions, respectively, utilizing the STARLITER arrays at the Cyclotron Institute of Texas A&M University. In the experiment 152Sm and 154Sm targets were bombarded with 25 MeV protons and the outgoing light charged particles (p, d and t) in the exit channels were detected using the STARS ΔE - E silicon telescope, thus allowing particle identification and a measurement of the nuclear excitation energy. Six BGO shielded HPGe detectors were used to observe the emitted gamma rays in coincidence with the particles. A post-run measurement of gamma rays emitted from the activated target allowed an improved measurement of the half life of the 96 minute Jπ =8- isomer of 152Eu. Preliminary results are presented. This work was partly supported by the US Department of Energy under Grants No. DE-FG52-06NA26206 and No. DE-FG02-05ER41379.

  9. Palliative treatment of bone metastases with samarium-153 EDTMP at onset of pain.

    PubMed

    Gallicchio, Rosj; Giacomobono, Sabrina; Nardelli, Anna; Pellegrino, Teresa; Simeon, Vittorio; Gattozzi, Domenico; Maddalena, Francesca; Mainenti, Pierpaolo; Storto, Giovanni

    2014-07-01

    We evaluated the pain response and daily discomfort in patients suffering from a borderline degree of bone pain due to breast or lung cancer bone metastases, who had undergone early palliative radionuclide treatment. The results were compared with those from patients who had received standard analgesic therapy. Twenty-one patients (65.7 ± 3 years; 17 women) with metastatic bone cancer underwent samarium-153 (Sm-153) ethylene diamine tetramethylene phosphonate (EDTMP) administration (group A) and 18 patients (64.3 ± 8 years; 16 women)continued to receive standard analgesics (group B; control group). The patients kept a daily pain diary assessing both their discomfort and the pain at specific sites by means of a visual analog scale, rating from 0 (no discomfort–no pain)to 10 (worst discomfort–pain). These diaries were reviewed weekly for 2 months and three physicians rated the pain response on a scale from -2 (considerable deterioration) to +2 (considerable improvement). Baseline characteristics were similar in both groups. The reduction of total discomfort and of bone pain in group A was significantly greater compared to group B (p < 0.0001). A significant improvement of clinical conditions was observed in group A, where the physician rate changed from -1 to 1, compared to group B in which the rate changed from -1 to 0. Sm-153 EDTMP therapy can be considered for patients with bone pain from breast and lung cancer in advance, i.e.,before the establishment of severe pain syndrome.

  10. Gamma scintigraphic evaluation of floating gastroretentive tablets of metformin HCl using a combination of three natural polymers in rabbits.

    PubMed

    Razavi, Mahboubeh; Karimian, Hamed; Yeong, Chai Hong; Chung, Lip Yong; Nyamathulla, Shaik; Noordin, Mohamed Ibrahim

    2015-01-01

    The present research was aimed at formulating a metformin HCl sustained-release formulation from a combination of polymers, using the wet granulation technique. A total of 16 formulations (F1-F16) were produced using different combinations of the gel-forming polymers: tamarind kernel powder, salep (palmate tubers of Orchis morio), and xanthan. Post-compression studies showed that there were no interactions between the active drug and the polymers. Results of in vitro drug-release studies indicated that the F10 formulation which contained 5 mg of tamarind kernel powder, 33.33 mg of xanthan, and 61.67 mg of salep could sustain a 95% release in 12 hours. The results also showed that F2 had a 55% similarity factor with the commercial formulation (C-ER), and the release kinetics were explained with zero order and Higuchi models. The in vivo study was performed in New Zealand White rabbits by gamma scintigraphy; the F10 formulation was radiolabeled using samarium (III) oxide ((153)Sm2O3) to trace transit of the tablets in the gastrointestinal tract. The in vivo data supported the retention of F10 formulation in the gastric region for 12 hours. In conclusion, the use of a combination of polymers in this study helped to develop an optimal gastroretentive drug-delivery system with improved bioavailability, swelling, and floating characteristics. PMID:26273196

  11. Structural Characterization of Sm(III)(EDTMP).

    PubMed

    Yang, Y; Pushie, M J; Cooper, D M L; Doschak, M R

    2015-11-01

    Samarium-153 ethylenediamine-N,N,N',N'-tetrakis(methylenephosphonic acid) ((153)Sm-EDTMP, or samarium lexidronam), also known by its registered trademark name Quadramet, is an approved therapeutic radiopharmaceutical used in the palliative treatment of painful bone metastases. Typically, patients with prostate, breast, or lung cancer are most likely to go on to require bone pain palliation treatment due to bone metastases. Sm(EDTMP) is a bone-seeking drug which accumulates on rapidly growing bone, thereby delivering a highly region-specific dose of radiation, chiefly through β particle emission. Even with its widespread clinical use, the structure of Sm(EDTMP) has not yet been characterized at atomic resolution, despite attempts to crystallize the complex. Herein, we prepared a 1:1 complex of the cold (stable isotope) of Sm(EDTMP) under alkaline conditions and then isolated and characterized the complex using conventional spectroscopic techniques, as well as with extended X-ray absorption fine structure (EXAFS) spectroscopy and density functional structure calculations, using natural abundance Sm. We present the atomic resolution structure of [Sm(III)(EDTMP)-8H](5-) for the first time, supported by the EXAFS data and complementary spectroscopic techniques, which demonstrate that the samarium coordination environment in solution is in agreement with the structure that has long been conjectured.

  12. Studies with nonradioisotopic sodium chromate. I. Development of a technique for measuring red cell volume

    SciTech Connect

    Heaton, W.A.; Hanbury, C.M.; Keegan, T.E.; Pleban, P.; Holme, S. )

    1989-10-01

    A nonradioisotopic method for measuring red cell volume that involves the use of 52Cr-sodium chromate as the red cell label and of graphite furnace atomic absorption analysis of chromium is described. The technique allows the labelling of 20 mL of packed red cells with 40 to 50 micrograms of sodium chromate (Na2CrO4) in 30 minutes at 22 degrees C with 94 +/- 6 percent uptake. Approximately 40 micrograms of Na2CrO4 was injected for in vivo studies. This results in posttransfusion in vivo red cell chromium levels after sample processing in the range of 1 to 7 micrograms per L, which could be quantitated accurately (coefficient of variation = 4.7%) by Zeeman electrothermal atomic absorption spectrophotometry. The labeling concentration of chromium did not cause increased hemolysis, and the labeled cells exhibited an osmotic fragility curve similar to that of unlabeled, fresh ACD red cells. Red cell glutathione peroxidase was unaffected by labeling, although glutathione reductase was reduced by approximately 13 percent (p less than 0.05). The 52Cr red cell volume-measuring method was evaluated by concurrent in vivo studies with the standard 51Cr and 125I-albumin methods for that procedure. Simultaneous measurement of red cell volumes in seven volunteers by the 51Cr, 52Cr, and 125I-albumin techniques correlated highly with each other (r greater than 0.76), with mean values of 2294 +/- 199, 2191 +/- 180, and 2243 +/- 291 mL, respectively. The standard deviations of the differences were small: 134 mL for 52Cr versus 51Cr and 183 mL for 52Cr versus 125I.

  13. Folic acid absorption determined by a single stool sample test--a double-isotope technique. The folic acid absorption capacity in children

    SciTech Connect

    Hjelt, K. )

    1989-10-01

    The fractional folic acid absorption (FAFol) was determined in 66 patients with various gastrointestinal diseases by a double-isotope technique, employing a single stool sample test (SSST) as well as a complete stool collection. The age of the patients ranged from 2.5 months to 16.8 years (mean 6.3 years). The test dose was administered orally and consisted of 50 micrograms of (3H)folic acid (monoglutamate) (approximately 20 muCi), carmine powder, and 2 mg 51CrCl3 (approximately 1.25 muCi) as the unabsorbable tracer. The whole-body radiation given to a 1-year-old child averaged 4.8 mrad only. The stool and napkin contents were collected and homogenized by the addition of 300 ml chromium sulfuric acid. A 300-ml sample of the homogenized stool and napkin contents, as well as 300 ml chromium sulfuric acid (75% vol/vol) containing the standards, were counted for the content of 51Cr in a broad-based well counter. The quantity of (3H)folic acid was determined by liquid scintillation, after duplicate distillation. Estimated by SSST, the FAFol, which employs the stool with the highest content of 51Cr corresponding to the most carmine-colored stool, correlated closely with the FAFol based on complete stool collection (r = 0.96, n = 39, p less than 0.0001). The reproducibility of FAFol determined by SSST was assessed from repeated tests in 18 patients. For a mean of 81%, the SD was 4.6%, which corresponded to a coefficient of variation of 5.7%.

  14. Respiratory clearance of aerosolized radioactive solutes of varying molecular weight

    SciTech Connect

    Huchon, G.J.; Montgomery, A.B.; Lipavsky, A.; Hoeffel, J.M.; Murray, J.F.

    1987-05-01

    To determine the influence of varying molecular weight (mol wt) on respiratory clearance of aerosolized solutes, we studied eight radiopharmaceuticals, each administered to four dogs: sodium /sup 99m/Tc pertechnetate (TcO4), /sup 99m/Tc glucoheptonate ((/sup 99m/Tc)GH), 51Cr-ethylenedinitrotetraacetate ((51Cr)EDTA), /sup 99m/Tc diethylenetriaminepentaacetate ((99mTc) DTPA), /sup 111/In diethylenetriaminepentaacetate ((/sup 111/In)DTPA), /sup 67/Ga desferoxaminemesylate ((/sup 67/Ga)DFOM), /sup 99m/Tc dextran ((/sup 99m/Tc)DX) and /sup 111/In transferrin ((/sup 111/In)TF). After aerosolization (0.8 m MMD, 2.4 GSD), clearance was determined for 30 min and then corrected by intravenous injection for nonairspace radioactivity. In-TF clearance (0.11 +/- 0.10%/min) was lower than TcO4 (6.32 +/- 0.62%/min), (/sup 99m/Tc)GH (1.50 +/- 0.37%/min), (/sup 51/Cr)EDTA (2.38 +/- 1.02%/min), (/sup 99m/Tc)DTPA (3.51 +/- 0.40%/min), (/sup 111/In)DTPA (2.35 +/- 0.42%/min), (/sup 67/Ga) DFOM (1.99 +/- 0.49%/min) and (/sup 99m/Tc)DX (1.81 +/- 0.75%/min) clearances (p less than 0.001). TcO4 clearance was higher than others (p less than 0.001). Technetium binding to DX was unsatisfactory; aerosolization caused unbinding from DTPA. We conclude that respiratory clearance of large mol wt solutes within 30 min is negligible and, that clearance of molecules between 347-5099 daltons differs greatly, suggesting that binding and/or intrapulmonary retention affect transfer.

  15. Antioxidant defense mechanisms of endothelial cells and renal tubular epithelial cells in vitro: role of the glutathione redox cycle and catalase.

    PubMed

    Andreoli, S P; Mallett, C; McAteer, J A; Williams, L V

    1992-09-01

    We recently demonstrated that endothelial cells are more susceptible than renal tubular epithelial cells to oxidant injury and that renal tubular epithelial cells with proximal tubular characteristics including porcine proximal tubular epithelial cells, opossum kidney proximal tubular epithelial cells, and normal human kidney cortical epithelial cells are more susceptible to oxidant injury than the distal nephron-derived Madin Darby canine kidney cell line. To determine the basis of this differential response, we evaluated several antioxidant defenses in the five cell lines. Glutathione levels were not significantly different among the five cell lines, but catalase and glutathione reductase levels were significantly (p less than 0.01) lower in endothelial cells compared to all renal tubular epithelial cells. Among renal tubular epithelial cells, Madin Darby canine kidney cells had significantly (p less than 0.05) higher glutathione peroxidase activity. To further evaluate the role of antioxidant defenses in limiting oxidant injury, we determined two responses to oxidant injury (ATP depletion and 51Cr release) when glutathione was depleted with buthionine sulfoxamine and when catalase was inhibited with aminotriazole. Oxidant-induced ATP depletion was accentuated when catalase was inhibited as well as when glutathione was depleted with buthionine sulfoxamine. In contrast, inhibition of catalase had little or no effect on 51Cr release, whereas glutathione depletion resulted in accentuated 51Cr release. We conclude that the increased susceptibility of endothelial cells to oxidant injury as compared with epithelial cells is associated with lower antioxidant defenses. Disruption of the glutathione redox cycle results in accentuated ATP depletion and lytic injury, whereas inhibition of catalase results in accentuated ATP depletion with little effect on lytic injury.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. Mechanisms of the fetomaternal transfer of Na+ across the dually perfused placenta of the rat.

    PubMed

    Stulc, J; Stulcová, B; Sibley, C P

    1995-03-01

    In order to investigate mechanisms of fetal-maternal (F-M) transfer of Na+, clearance of 22Na+ and 51Cr-EDTA was measured simultaneously across the dually perfused placenta of the rat. In eight experiments clearance was measured successively in the F-M (Kfm) and in the maternal-fetal (M-F; Kmf) directions. Clearance of 22Na+ in the two directions was approximately equal (Kmf = 11.6 +/- 2.0 microliters/min; Kfm = 11.1 +/- 1.7 microliters/min: mean +/- s.d.) while Kfm of 51Cr-EDTA (4.4 +/- 0.7 microliters/min) was nearly double Kmf (2.4 +/- 0.8 microliters/min) for this tracer. Even greater asymmetry in the transfer of 51Cr-EDTA was found when measured across intact (non-perfused) placenta. It is suggested that this asymmetry is caused by volume flow in the F-M direction. In other experiments transfer was measured in the F-M direction only. Ouabain (0.1 mM) on the maternal side and reduced concentration of Na+ (25 mM) on the fetal side had no effect on the F-M transfer of the tracers. Reducing the temperature of the preparation by 5 degrees C significantly decreased transfer of 22Na+. The transfer of 22Na was inversely related to the concentration of K+ on the fetal side. These observations suggest that the F-M transfer of Na+ has three components: diffusion through paracellular routes; convective flow by filtration through wide placental pores, and transcellular transport by a mechanism which is uncertain at present.

  17. Faecalibacterium prausnitzii supernatant improves intestinal barrier function in mice DSS colitis.

    PubMed

    Carlsson, Anders H; Yakymenko, Olena; Olivier, Isabelle; Håkansson, Fathima; Postma, Emily; Keita, Asa V; Söderholm, Johan D

    2013-10-01

    OBJECTIVE. The intestinal microbiota plays a substantial role in the pathogenesis of inflammatory bowel disease (IBD). Faecalibacterium prausnitzii (FP) is underrepresented in IBD patients and have been suggested to have anti-inflammatory effects in mice. Increased intestinal permeability is common in IBD but the relationship between FP and intestinal barrier function has not been investigated. Our aim was to study treatment with FP supernatant on intestinal barrier function in a dextran sodium sulfate (DSS) colitis mice model. MATERIAL AND METHODS. C57BL/6 mice received 3% DSS in tap water ad libitum during five days to induce colitis. From day 3 the mice received a daily gavage with FP supernatant or broth during seven days. Ileum and colon were mounted in Ussing chambers for permeability studies with (51)Cr-EDTA and Escherichia coli K-12. Colon was saved for Western blot analyses of tight junction proteins. RESULTS. DSS-treated mice showed significant weight loss and colon shortening. Gavage with FP supernatant resulted in a quicker recovery after DSS treatment and less extensive colonic shortening. Ileal mucosa of DSS mice showed a significant increase in (51)Cr-EDTA-passage compared to controls. (51)Cr-EDTA passage was significantly decreased in mice receiving FP supernatant. No significant differences were observed in passage of E. coli K12. Western blots showed a trend to increased claudin-1 and claudin-2 expressions in DSS mice. CONCLUSIONS. Supernatant of FP enhances the intestinal barrier function by affecting paracellular permeability, and may thereby attenuate the severity of DSS-induced colitis in mice. These findings suggest a potential role of FP in the treatment of IBD.

  18. Hematological aspect of Rh deficiency syndrome: a case report and a review of the literature

    SciTech Connect

    Nash, R.; Shojania, A.M.

    1987-03-01

    The hematological aspects of the original case of Rhmod are reported. The subject, as in other reported cases, had a chronic hemolytic anemia characterized by stomatocytosis, reduced osmotic fragility, and abnormal autohemolysis correctable with the addition of glucose. The /sup 51/Cr red cell survival studies showed the spleen to be the preferential site of red cell destruction and splenectomy produced a dramatic improvement in red cell survival. The topic of Rh deficiency syndrome (Rhnull and Rhmod) is briefly reviewed with regard to the number of cases reported, to genetic aspects, to the hematological findings, and to the results of splenectomy.

  19. Effect of nitrogen pressure on the hardness and chemical states of TiAlCrN coatings

    SciTech Connect

    Sullivan, Jonathan F.; Huang Feng; Barnard, John A.; Weaver, Mark L.

    2005-01-01

    TiAlCrN coatings were reactively sputtered from a Ti{sub 0.37}Al{sub 0.51}Cr{sub 0.12} alloy target in this study with a nitrogen partial pressure ranging from 0% to 25% of the total pressure. The effects of the incorporation of nitrogen into the coatings on the hardness, elastic modulus, and chemical state of the metal atoms in the coatings were investigated. The hardness and reduced modulus of the coatings increased with increasing nitrogen partial pressures. The formation of ternary nitrides was inferred from the noticeable difference in the chemical states from those for the corresponding binary nitrides.

  20. Decreased NK killing in patients with multiple sclerosis: An analysis on the level of the single effector cell in peripheral blood and cerebrospinal fluid in relation to the activity of the disease

    PubMed Central

    Merrill, Jean; Jondal, M.; Seeley, Janet; Ullberg, M.; Sidén, Å.

    1982-01-01

    Natural killer cell activity has earlier been shown to be depressed in patients with multiple sclerosis (MS) (Benczur et al., 1980). In the present study, this defect was more clearly characterized in different stages of the disease. By using a single-cell cytotoxicity assay in agarose (Grimm & Bonavida, 1979), in combination with the conventional 51Cr-release, the number of target-binding cells (TBCs) and the fraction of active killer cells therein could be compared with the radioisotope release in the different patient groups. It was found that patients with active and chronic MS showed lower natural killer (NK) activity in the 51Cr-release assay as compared with age and sex-matched controls, in contrast to stable MS patients who were comparable with their control group. The single cell cytotoxicity assay demonstrated that acute MS patients had a decreased number of TBCs in peripheral blood and that they also had a decreased percentage of active NK cells in their TBC fractions. Patients with chronic MS were normal in the single-cell cytotoxicity assay. When cells present in CSF were analysed in acute and chronic MS, few cells were found with target binding capacity and only in two instances out of 13 could any cytotoxicity at all be detected. Patients with other neurological diseases (OND) were found to have detectable NK activity in CSF in six cases out of ten in the single-cell assay. OND patients as a group also had higher peripheral NK activity in the 51Cr-release assay as compared with the control group. When peripheral and CSF cells from MS patients and OND patients were treated with interferon, no increase in TBCs or fraction of killer cells in TBCs was found. In the 51Cr-release assay, comparable increases in cytotoxicity were found in all groups. One possible explanation for the stage-related NK suppression seen in the present investigation may be a decreased interferon production combined with immune-complex induced, macrophage-produced prostaglandins

  1. Clinical uses of radiolabeled platelets

    SciTech Connect

    Datz, F.L.; Christian, P.E.; Baker, W.J.

    1985-12-01

    Platelets were first successfully radiolabeled in 1953. At that time, investigators were primarily interested in developing a technique to accurately measure platelet life span in both normal and thrombocytopenic patients. Studies using platelets labeled with /sup 51/Cr have shown shortened platelet survival times in a number of diseases including idiopathic thrombocytopenic purpura, coronary artery disease, and diabetes mellitus. More recently, labels such as /sup 111/In have been developed that allow in vivo imaging of platelets. Indium-111 platelets are being used to better understand the pathophysiology of atherosclerosis, thrombophlebitis, pulmonary embolism and clotting disorders, and to improve the clinical diagnosis of these diseases.

  2. Procedure for granulokinetic studies in the horse with chromium-51

    SciTech Connect

    Carakostas, M.C.; Moore, W.E.; Smith, J.E.

    1981-04-01

    A procedure with chromium-51 (51Cr) as the cell label that maintains high-cell viability for studying granulocyte kinetics in horses is described. The procedure combines and modifies several methods for isolating leukocytes and granulocytes for use in the horse when a large volume of labeled cells is required. Also described is an improved technique for measuring granulocyte specific activity in large serial blood samples, using a Ficoll-sedimentation method. The procedure should be useful for determining granulocyte kinetics in the horse, the only major domestic species for which such data are not available.

  3. Isolation and identification of normal killer cells from Syrian hamsters

    SciTech Connect

    Matveeva, V.A.; Klyuchareva, T.E.

    1986-09-01

    This paper gives data on isolation of normal killer cells from the blood and various tissues of Syrian hamsters in a Percoll density gradient and their identification on the basis of morphologic criteria and cytotoxic activity (CTA). CTA of the isolated cells was studied in the cytotoxic test with target cells of a human MOLT-4 thymoma cell labeled with /sup 51/Cr. Isolation of large granular lymphocytes from blood, spleen, and bone marrow of Syrian hamsters in Percoll density gradient is shown in the results of five experiments used for cells of each type.

  4. Deficient natural killer cell function in preeclampsia

    SciTech Connect

    Alanen, A.; Lassila, O.

    1982-11-01

    Natural killer cell activity of peripheral blood lymphocytes was measured against K-562 target cells with a 4-hour /sup 51/Cr release assay in 15 primigravid women with preeclamptic symptoms. Nineteen primigravid women with an uncomplicated pregnancy and 18 nonpregnant women served as controls. The natural killer cell activity of preeclamptic women was observed to be significantly lower than that of both control groups. Natural killer cells in preeclamptic women responded normally to augmentation caused by interferon. These findings give further evidence for the participation of the maternal immune system in this pregnancy disorder.

  5. Determination of soil adhesion to plastic surfaces using a radioactive tracer.

    PubMed

    Pesonen-Leinonen, E; Redsven, I; Neuvonen, P; Hurme, K-R; Pääkkö, M; Koponen, H-K; Pakkanen, T T; Uusi-Rauva, A; Hautala, M; Sjöberg, A-M

    2006-02-01

    A quantitative radiochemical test procedure was developed for investigating soil adhesion on polyvinyl chloride (PVC) model materials containing different plasticizers (DOP and Hexamoll) and commercial flooring materials. A repeatable test procedure was developed, including soiling and cleaning with a Mini Cleanability Tester. Three soils all containing 51Cr emitting gamma radiation were used. The materials were subjected to successive soiling and cleaning cycles in order to generate soil accumulation. The type and amount of plasticizer appeared to affect soil adhesion on plastic model materials. PMID:16146694

  6. Immunoadjuvant activity of amphotericin B as displayed in mice infected with Candida albicans.

    PubMed Central

    Bistoni, F; Vecchiarelli, A; Mazzolla, R; Puccetti, P; Marconi, P; Garaci, E

    1985-01-01

    Mice receiving a single intraperitoneal injection of amphotericin B showed increased resistance to subsequent challenge with either Candida albicans or Staphylococcus aureus. This enhancement of resistance was obvious in terms of both survival criteria and clearance of the intravenously injected organism from different organs. The protective effect of amphotericin B was conditioned by dose, time of drug administration, and size of yeast or bacterial inoculum and was reversed by cyclophosphamide. Effector cells from mice treated with amphotericin B displayed enhanced fungicidal activity in vitro as measured in a short-term 51Cr release assay. Macrophages from intact animals exposed in vitro to amphotericin B also acquired strong candidacidal reactivity. PMID:3890731

  7. An experimental comparison of radioactive labels with potential application to lymphocyte migration studies in patients.

    PubMed Central

    Rannie, G H; Thakur, M L; Ford, W L

    1977-01-01

    The suitability of two radionuclides (99mTc, 111In) for labelling lymphocytes have been evaluated in rats by comparison with a standard method using 51Cr. For the study of lymphocyte migration in patients labelling with 111In-labelled oxine is clearly the most promising because both in vivo and in vitro it remains associated with lymphocytes and the labelled cells migrate normally into lymphoid tissues. The physical characteristics of 111In are also favourable. Not only does 99mTc rapidly dissociate from lymphocytes but also it compromises their ability to recirculate from blood to lymph. PMID:589868

  8. Nuclear Decay Data for the International Reactor Dosimetry Library for Fission and Fusion (IRDFF): Updated Evaluations of the Half-Lives and Gamma Ray Intensities

    NASA Astrophysics Data System (ADS)

    Chechev, Valery P.; Kuzmenko, Nikolay K.

    2016-02-01

    Updated evaluations of the half-lives and prominent gamma ray intensities have been presented for 20 radionuclides - dosimetry reaction residuals. The new values of these decay characteristics recommended for the IRDFF library were obtained using the approaches and methodology adopted by the working group of the Decay Data Evaluation Project (DDEP) cooperation. The experimental data published up to 2014 were taken into account in updated evaluations. The list of radionuclides includes 3H, 18F, 22Na, 24Na, 46Sc, 51Cr, 54Mn, 59Fe, 57Co, 60Co, 57Ni, 64Cu, 88Y, 132Te, 131I, 140Ba, 140La, 141Ce, 182Ta, 198Au.

  9. An example of anti-JMH with characteristics of a clinically significant antibody.

    PubMed

    Geisland, J; Corgan, M; Hillard, B

    1990-01-01

    The authors studied an example of red cell anti-JMH (John Milton Hagen) that exhibited several characteristics of a possible clinically significant antibody able to cause red cell destruction in vivo. Strong serological reactivity, a positive monocyte monolayer assay, and immunoglobulin subclass determination as IgG3 all indicate possible ability to destroy red cells. A51Cr-labeled red cell survival study was not done as the patient did not require red cell transfusions but may be recommended for this patient if transfusions become necessary.

  10. Endoplasmic reticulum chaperone glucose regulated protein 170-Pokemon complexes elicit a robust antitumor immune response in vivo.

    PubMed

    Yuan, Bangqing; Xian, Ronghua; Wu, Xianqu; Jing, Junjie; Chen, Kangning; Liu, Guojun; Zhou, Zhenhua

    2012-07-01

    Previous evidence suggested that the stress protein grp170 can function as a highly efficient molecular chaperone, binding to large protein substrates and acting as a potent vaccine against specific tumors when purified from the same tumor. In addition, Pokemon can be found in almost all malignant tumor cells and is regarded to be a promising candidate for the treatment of tumors. However, the potential of the grp170-Pokemon chaperone complex has not been well described. In the present study, the natural chaperone complex between grp170 and the Pokemon was formed by heat shock, and its immunogenicity was detected by ELISPOT and (51)Cr-release assays in vitro and by tumor bearing models in vivo. Our results demonstrated that the grp170-Pokemon chaperone complex could elicit T cell responses as determined by ELISPOT and (51)Cr-release assays. In addition, immunized C57BL/6 mice were challenged with subcutaneous (s.c.) injection of Lewis cancer cells to induce primary tumors. Treatment of mice with the grp170-Pokemon chaperone complex also significantly inhibited tumor growth and prolonged the life span of tumor-bearing mice. Our results indicated that the grp170-Pokemon chaperone complex might represent a powerful approach to tumor immunotherapy and have significant potential for clinical application. PMID:22317751

  11. Clinical significance of anti-Yt(b). Report of a case using a 51-chromium red cell survival study

    SciTech Connect

    Levy, G.J.; Selset, G.; McQuiston, D.; Nance, S.J.; Garratty, G.; Smith, L.E.; Goldfinger, D.

    1988-05-01

    Several published reports have documented the variable survival of Yt(a+) red cells (RBC) in patients with anti-Yt(a) as measured by 51-Chromium (Cr)-labeled RBC survival studies. Similar studies with anti-Yt(b) have not been reported. A /sup 51/Cr-labeled RBC survival study was performed using Yt(b+) RBCs and a monocyte monolayer assay in a young hemodialysis patient who required chronic transfusion therapy and who had developed anti-Yt(b). The survival of the transfused RBCs was 100 and 93 percent at 1 and 24 hours, respectively, with a half life of 21 days at termination of the study (normal, 28 to 32 days). These results showed no evidence of rapid destruction of the Yt(b+) RBCs, indicating that this patient could be transfused safely with blood from Yt(b+) donors. Long-term survival of the /sup 51/Cr-labeled Yt(b+) RBCs was shortened moderately, however, a finding that correlated with a slightly abnormal monocyte monolayer assay test.

  12. Activation of human NKCC by moderate exercise: increased frequency of NK cells with enhanced capability of effector--target lytic interactions.

    PubMed Central

    Targan, S; Britvan, L; Dorey, F

    1981-01-01

    In the present study we examined the mechanism of human natural killer cellular cytotoxicity (NKCC) augmentation by 5 min of moderate exercise and its interrelationship to in vitro interferon (IFN) activation. Cytotoxicity was measured by employing both a single-cell cytotoxic assay and a standard 3-hr chromium-51 (51Cr) release assay. The former was used to assess changes at the single NK cell--target cell level and the latter to assess changes in overall lytic capacity of a given population of NK cells. Several findings were obtained: (1) moderate exercise augmented NKCC in vivo by recruiting a 'new' population of active cytotoxic NK cells. (2) This 'new' population of active cells probably was derived from cells which can bind targets but are non-cytotoxic. (3) In a standard 51Cr-release assay, additional augmentation of these exercise-activated cells occurred in vitro following exposure to interferon. (4) This additional increase in cytotoxicity produced no alteration in the frequency of killer cells as viewed at the single cell level. (5) Thus interferon's capacity to increase further the overall lytic ability of exercise-activated NK cells was not due to its activation of an additional subset of pre-NK cells, but due to its increasing the capacity of effector--target lytic interactions (recycling) of the same set of NK and pre-NK cells. PMID:6172225

  13. Effects of melanin-induced free radicals on the isolated rat peritoneal mast cells

    SciTech Connect

    Ranadive, N.S.; Shirwadkar, S.; Persad, S.; Menon, I.A.

    1986-03-01

    Pheomelanin from human red hair (RHM) produces considerably more cellular damage in Ehrlich ascites carcinoma cells when subjected to radiations of wavelength 320-700 nm than eumelanin from black hair (BHM). Irradiation of RHM generated large amounts of superoxide while BHM did not produce detectable amounts of superoxide. The present investigations describe the effects of irradiation of mast cells in the presence of various natural and synthetic melanins. Irradiation of mast cells in the presence of RHM and red hair melanoprotein released large amounts of histamine while BHM and synthetic melanins prepared from dopa, cysteinyldopa, or a mixture of dopa and cysteinyldopa did not release histamine. The release of histamine at lower concentrations of RHM was not accompanied by the release of /sup 51/Cr from chromium-loaded cells, suggesting that this release was of noncytotoxic nature. On the other hand, the release of histamine at higher concentrations of RHM was due to cell lysis since both histamine and cytoplasmic marker /sup 51/Cr were released to the same extent. The release evoked by large concentration RHM was not inhibited by superoxide dismutase or catalase. This suggests that the cell lysis under these conditions was not due to H/sub 2/O/sub 2/ or O-2. The finding that mast cells release histamine when irradiated in the presence of RHM suggests that the immediate and late-phase reactions seen in sunburn may in part be due to the release of mediators from these cells.

  14. Blood volume of nonsplenectomized and splenectomized cats before and after acute hemorrhage

    SciTech Connect

    Breznock, E.M.; Strack, D.

    1982-10-01

    Blood volume (BV) was determined in awake, nonsplenectomized (NSPX) and splenectomized (SPX) cats before and after hemorrhage (6 ml/kg). Each NSPX cat had a determined BV at least 10 ml/kg greater than the same cat after splenectomy. The mean BV of SPX cats was 43.4 +/- 8.94. ml kg (4.3% of body weight). The calculated RBC masses of NSPX and SPX cats were 17.0 +/- 4.07 and 12.2 +/- 1.12 ml/kg, respectively. Each NSPX cat had apparent RBC masses of 5 ml/kg greater than that of the same cat after splenectomy was done. At 1 hour after a hemorrhage, the BV and RBC masses determined in SPX cats were 46.7 +/- 12.1 and 9.7 +/- 1.90 ml/kg, respectively. Extravascular-to-intravascular fluid flux (calculated from RBC masses and plasma protein dilution) was approximately 0.80% of body weight. The indirect method with /sup 51/Cr-labeled RBC for BV determination was accurate and precise in awake, SPX cats; in awake, NSPX cats, the /sup 51/Cr-labeled RBC dilution method was precise, but not accurate. The spleen in the cat resulted in marked overestimations of BV and RBC masses.

  15. Flow cytometric and radioisotopic determinations of platelet survival time in normal cats and feline leukemia virus-infected cats

    SciTech Connect

    Jacobs, R.M.; Boyce, J.T.; Kociba, G.J.

    1986-01-01

    This study demonstrates the potential usefulness of a flow cytometric technique to measure platelet survival time in cats utilizing autologous platelets labeled in vitro with fluorescein isothiocyanate (FITC). When compared with a 51Cr method, no significant differences in estimated survival times were found. Both the 51Cr and FITC-labeling procedures induced similar changes in platelet shape and collagen-induced aggregation. Platelets labeled with FITC had significantly greater volumes compared with those of glutaraldehyde-fixed platelets. These changes were primarily related to the platelet centrifugation and washing procedures rather than the labels themselves. This novel technique potentially has wide applicability to cell circulation time studies as flow cytometry equipment becomes more readily available. Problems with the technique are discussed. In a preliminary study of the platelet survival time in feline leukemia virus (FeLV)-infected cats, two of three cats had significantly reduced survival times using both flow cytometric and radioisotopic methods. These data suggest increased platelet turnover in FeLV-infected cats.

  16. Studies on Erythropoiesis in Uremic and Post-Transplant (Renal) Patients Utilizing Radioactive Iron and Chromium

    PubMed Central

    Farooki, M. S.; Kimber, R. W.

    1971-01-01

    The association of anemia with chronic renal disease is well known. The striking hematologic improvement following a successful renal allotransplantation led to the present study. Using radioactive 59Fe, ferrokinetic measurements were carried out in nine uremic patients (seven with and two without anemia), four post-allotransplant cases, three patients with iron deficiency anemia and a group of five normal subjects. Erythrocyte life-span was calculated by 51Cr-labelled, autotransfused red cells in all patients who had had transplants and in three patients with renal anemia. The results showed that in patients with renal anemia the plasma radioiron clearance was slightly delayed but the 59Fe incorporation into the circulating erythrocytes was significantly decreased. Red cell life-span was moderately shortened in two out of three uremic patients investigated. The findings constitute evidence of ineffective erythropoiesis in patients with renal anemia. By comparison, the four transplant patients showed normal 59Fe plasma clearance and red cell incorporation; the 51Cr erythrocyte survival was normal in all four patients. PMID:4931770

  17. The role of neutrophilic mediators in acute inflammation of the gut

    SciTech Connect

    von Ritter, C.

    1988-01-01

    Activation of granulocytes within the lamina propria by luminally derived bacterial products may represent an important mechanism in the pathogenesis of inflammatory bowel disease. One objective of this thesis was to determine the effects of luminal perfusion with N-formyl-methionyl-leucyl-phenylalanine (FMLP), a bacterial product that attracts and activates granulocytes, on mucosal permeability in different regions of the rat small intestine and colon. Mucosal permeability was measured using the blood-to-lumen clearance of {sup 51}Cr-EDTA during luminal perfusion with FMLP dissolved in Tyrode's solution. Of the bowel segments studied, mucosal permeability was significantly increased only in the distal 10 cm of the ileum. In order to define the role of neutrophilic oxidants in FMLP-induced ileitis, we evaluated the protective effect of several free radical scavengers and antioxidant enzymes. Pretreatment with the either superoxide dismutase or catalase had no effect on the FMLP-induced increase in mucosal permeability. However, treatment with either Mn-desferrioxamine, PZ51, desferrioxamine, or dimethylsulfoxide significantly attenuated FMLP-induced mucosal damage. Non-oxidative toxins released from activated neutrophil may be another mechanism by which FMLP increases mucosal permeability. In order to investigate the role of neutrophilic proteases in FMLP-induced ileitis, the effects of the nonspecific protease inhibitor soybean trypsin inhibitor, and the elastase inhibitors MeOSuc-Ala-Ala-Pro-Val-CH{sub 2}Cl(MAAPV) and Eglin C on the FMLP-induced increases in {sup 51}Cr-EDTA clearance were determined.

  18. Protein digestion and absorption in the blind loop syndrome.

    PubMed

    Curtis, K J; Prizont, R; Kim, Y S

    1979-12-01

    Protein digestion and absorption was studied in rats with 6-week-old surgically constructed self-filling intestinal blind loops and steatorrhea, ie, blind-loop animals and controls were fed a 14C-labeled protein meal containing a nonabsorbable marker, 51CrCl3, and sacrificed 1 or 2 hr later. Intestinal contents were analyzed for 14C, 51Cr, protein, trypsin, and the products of digestion. At 1 hr, 14C absorption was greater in controls, but at 2 hr there was no difference in absorption between the two groups. Marker studies showed that blind-loop filling resulted in a delay of the progression of intestinal contents distally. Intraluminal trypsin and porteolysis were similar in the two groups. Endogenous protein was greater in the blind-loop animals. The early stages of the blind-loop syndrome may be characterized by delayed protein absorption secondary to blind-loop filling, which is compensated for by the distal gut resulting in an absence of overall protein malabsorption.

  19. Antibody-dependent cellular cytotoxicity-mediated serotherapy against murine neuroblastoma. I. In vitro and in vivo treatment using normal, gamma-irradiated and immune-stimulated rat effector cells.

    PubMed

    Byfield, J E; Zerubavel, R; Fonkalsrud, E W

    1982-01-01

    The in vitro and in vivo activity has been investigated of antisera prepared against a murine (C-1300) neuroblastoma line (MNB) capable of differentiation. An antibody-dependent cellular cytotoxicity (ADCC) reaction was employed using rat spleen cells (RSC). ADCC activity in vitro (using 51Cr-release) was shown, but a maximum of only 50% of the immunologically releasable 51Cr was achieved. Nevertheless, in vivo (syngeneic mouse-tumor flank assay) significant delays were obtained in tumor onset and lethality. Under ideal circumstances, i.e., coating of tumor cells prior to inoculation and high RSC effector cell ratios, a significant number of animals could be cured of substantial tumor burdens (10(6) cells). While close proximity of the site of injection of effector cells was required (ectopic injections of RSC were ineffective), the anti-MNB ADCC was shown to be quite active in vivo without external precoating of the cells with antisera. RCS obtained from BCG-treated rats were more numerous and slightly more effective. RSC obtained from gamma-radiated animals retained normal activity. With appropriate antisera this approach could be useful under selected clinical circumstances.

  20. Oxidant-mediated ciliary dysfunction. Possible role in airway disease

    SciTech Connect

    Burman, W.J.; Martin, W.J. 2d.

    1986-03-01

    The effects of reactive species of oxygen on the airway are not well known. This study examined the effects of hydrogen peroxide (H2O2) on the structure and function of the airway epithelium. Tracheal rings were prepared from 200 g male rats. Damage to the airway epithelium was assayed by monitoring the ciliary beat frequency, the release of 51Cr, and histology. H2O2 at concentrations of 1.0 mM and above caused a very rapid decrease in ciliary beat frequency. After ten minutes' exposure to 1.0 mM, the ciliary beat frequency was 72 +/- 20 percent of control. Release of 51Cr was a less sensitive measure with significant release occurring after four hours of exposure to ciliotoxic concentrations of H2O2. Histologic changes were not evident within the experimental time period. All toxic effects of H2O2 were completely blocked by catalase. This study shows that H2O2 causes a rapid decline in ciliary activity and suggests that oxidant-mediated ciliary dysfunction could play a role in the pathogenesis of airway disease. The ciliary beat frequency provides a sensitive, physiologically relevant parameter for the in vitro study of these diseases.

  1. In vitro induction of tumor-specific immunity. VI: analysis of specificity of immune response by cellular competitive inhibition: limitations and advantages of the technique.

    PubMed

    Chism, S E; Burton, R C; Grail, D L; Bell, P M; Warner, N L

    1977-01-01

    The cellular competitive inhibition 51Cr-release assay makes two distinct contributions to the in vitro study of cell-mediated immunity. It allows target cells which are not amenable to isotopic labelling to be investigated for their antigenic specificity, and it provides a means, complementary to the direct cytotoxicity assay, of estimating qualitative and quantitative differences in antigen expression on intact normal and neoplastic cells. Various parameters of a micro-51Cr-release inhibition assay have been studied, and it was found that the assay conditions markedly influenced both the sensitivity and specificity. It is concluded that optimal assay conditions for specificity include: 1) moderate levels of lysis on the linear part of the CL/T titration curve, 2) avoidance of prolonged assay times, and 3) low ratios of blocker to target cells. When tumor cells with large cell volumes are used as competitive inhibitor (blocker) cells, non-specific blocking will occur; limits have been defined for this particular micro-inhibition assay which, in general, exclude these effects.

  2. Radioactivity of neutron-irradiated cat's-eye chrysoberyls

    NASA Astrophysics Data System (ADS)

    Tang, S. M.; Tay, T. S.

    1999-04-01

    The recent report of marketing of radioactive chrysoberyl cat's-eyes in South-East Asian markets has led us to use an indirect method to estimate the threat to health these color-enhanced gemstones may pose if worn close to skin. We determined the impurity content of several cat's-eye chrysoberyls from Indian States of Orissa and Kerala using PIXE, and calculated the radioactivity that would be generated from these impurities and the constitutional elements if a chrysoberyl was irradiated by neutrons in a nuclear reactor for color enhancement. Of all the radioactive nuclides that could be created by neutron irradiation, only four ( 46Sc, 51Cr, 54Mn and 59Fe) would not have cooled down within a month after irradiation to the internationally accepted level of specific residual radioactivity of 2 nCi/g. The radioactivity of 46Sc, 51Cr and 59Fe would only fall to this safe limit after 15 months and that of 54Mn could remain above this limit for several years.

  3. Time-courses in the retention of food material in the bivalves Potamocorbula amurensis and Macoma balthica significance to the absorption of carbon and chromium

    USGS Publications Warehouse

    Decho, Alan W.; Luoma, Samuel N.

    1991-01-01

    Time courses for ingestion, retention and release via feces of microbial food was investigated using 2 bivalves with different feeding strategies, Potamocorbula amurensis and Macoma balthica. The results showed 2 pathways for the uptake of food material in these clams. The first is represented by an initial label pulse in the feces. The second pathway operates over longer time periods. Inert 51Cr-labeled beads were used to determine time frames for these pathways. The first pathway, involving extracellular digestion and intestinal uptake, is relatively inefficient in the digestion of bacterial cells by P. amurensis but more efficient in M. balthica. The second pathway, involving intracellular digestion within the digestive gland of both clams, was highly efficient in absorbing  bacterial carbon, and was responsible for most chromium uptake. Differences in the overall retention of microbial 51Cr and 14C relate not to gut-passage times but to the processing and release strategies of the food material by these 2 clams..

  4. Endoplasmic reticulum chaperone glucose regulated protein 170-Pokemon complexes elicit a robust antitumor immune response in vivo.

    PubMed

    Yuan, Bangqing; Xian, Ronghua; Wu, Xianqu; Jing, Junjie; Chen, Kangning; Liu, Guojun; Zhou, Zhenhua

    2012-07-01

    Previous evidence suggested that the stress protein grp170 can function as a highly efficient molecular chaperone, binding to large protein substrates and acting as a potent vaccine against specific tumors when purified from the same tumor. In addition, Pokemon can be found in almost all malignant tumor cells and is regarded to be a promising candidate for the treatment of tumors. However, the potential of the grp170-Pokemon chaperone complex has not been well described. In the present study, the natural chaperone complex between grp170 and the Pokemon was formed by heat shock, and its immunogenicity was detected by ELISPOT and (51)Cr-release assays in vitro and by tumor bearing models in vivo. Our results demonstrated that the grp170-Pokemon chaperone complex could elicit T cell responses as determined by ELISPOT and (51)Cr-release assays. In addition, immunized C57BL/6 mice were challenged with subcutaneous (s.c.) injection of Lewis cancer cells to induce primary tumors. Treatment of mice with the grp170-Pokemon chaperone complex also significantly inhibited tumor growth and prolonged the life span of tumor-bearing mice. Our results indicated that the grp170-Pokemon chaperone complex might represent a powerful approach to tumor immunotherapy and have significant potential for clinical application.

  5. Age-dependent alterations of Fc gamma receptor-mediated effector functions of human polymorphonuclear leucocytes.

    PubMed Central

    Fülöp, T; Fóris, G; Wórum, I; Leövey, A

    1985-01-01

    Changes in the effector functions in polymorphonuclear leucocytes (PMNL), harvested from blood of young and aged healthy subjects of both sexes, were studied. FC gamma-receptor (Fc gamma R)-mediated incorporation of IgG coated 51Cr-HRBC significantly increased in the aged male group, while the phagocytosis of pre-opsonized fungi (Saccharomyces cerevisiae and Candida albicans) was independent of both the age and sex. However, the intracellular killing capacity of neutrophils obtained from aged male subjects significantly decreased toward 51Cr-labelled c. albicans. The antibody-dependent cellular cytotoxicity (ADCC) was also impaired with ageing in both sexes. The age-dependent decrease in the effector functions of PMNL may be explained, among others, by the fact that during yeast cell incorporation the increased cAMP level does not return to the basic level in the old group. On the other hand, the cGMP level which increased in PMNL of aged subjects does not show any progressive increase as in the young subjects, but remains unchanged. The oxidative metabolism producing free radicals being necessary for the effective intracellular killing and ADCC diminished in PMNL of aged subjects of both sexes. The above findings indicate that the adaptation of cyclic nucleotide system and the oxidative burst to the cell activation becomes impaired with ageing. PMID:2994926

  6. Luciferase mRNA Transfection of Antigen Presenting Cells Permits Sensitive Nonradioactive Measurement of Cellular and Humoral Cytotoxicity.

    PubMed

    Omokoko, Tana A; Luxemburger, Uli; Bardissi, Shaheer; Simon, Petra; Utsch, Magdalena; Breitkreuz, Andrea; Türeci, Özlem; Sahin, Ugur

    2016-01-01

    Immunotherapy is rapidly evolving as an effective treatment option for many cancers. With the emerging fields of cancer vaccines and adoptive cell transfer therapies, there is an increasing demand for high-throughput in vitro cytotoxicity assays that efficiently analyze immune effector functions. The gold standard (51)Cr-release assay is very accurate but has the major disadvantage of being radioactive. We reveal the development of a versatile and nonradioactive firefly luciferase in vitro transcribed (IVT) RNA-based assay. Demonstrating high efficiency, consistency, and excellent target cell viability, our optimized luciferase IVT RNA is used to transfect dividing and nondividing primary antigen presenting cells. Together with the long-lasting expression and minimal background, the direct measurement of intracellular luciferase activity of living cells allows for the monitoring of killing kinetics and displays paramount sensitivity. The ability to cotransfect the IVT RNA of the luciferase reporter and the antigen of interest into the antigen presenting cells and its simple read-out procedure render the assay high-throughput in nature. Results generated were comparable to the (51)Cr release and further confirmed the assay's ability to measure antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. The assay's combined simplicity, practicality, and efficiency tailor it for the analysis of antigen-specific cellular and humoral effector functions during the development of novel immunotherapies. PMID:27057556

  7. Demonstration of NK cell-mediated lysis of varicella-zoster virus (VZV)-infected cells: characterization of the effector cells

    SciTech Connect

    Tilden, A.B.; Cauda, R.; Grossi, C.E.; Balch, C.M.; Lakeman, A.D.; Whitley, R.J.

    1986-06-01

    Infection with varicella-zoster virus (VZV) rendered RAJI cells more susceptible to lysis by non-adherent blood lymphocytes. At an effector to target ratio of 80:1 the mean percentage of /sup 51/Cr release of VZV-infected RAJI cells was 41 +/- 12%, whereas that of uninfected RAJI cells was 15 +/- 6%. The increased susceptibility to lysis was associated with increased effector to target conjugate formation in immunofluorescence binding assays. The effector cells cytotoxic for VZV-infected RAJI cells were predominantly Leu-11a/sup +/ Leu-4/sup -/ granular lymphocytes as demonstrated by fluorescence-activated cell sorting. The effector cell active against VZV-infected RAJI cells appeared similar to those active against herpes simplex virus (HSV)-infected cells, because in cold target competition experiments the lysis of /sup 51/Cr-labeled VZV-infected RAJI cells was efficiently inhibited by either unlabeled VZV-infected RAJI cells (mean 71% inhibition, 2:1 ratio unlabeled to labeled target) or HSV-infected RAJI cells (mean 69% inhibition) but not by uninfected RAJI cells (mean 10% inhibition). In contrast, competition experiments revealed donor heterogeneity in the overlap between effector cells for VZV- or HSV-infected RAJI vs K-562 cells.

  8. Neutrophil-mediated protection of cultured human vascular endothelial cells from damage by growing Candida albicans hyphae

    SciTech Connect

    Edwards, J.E. Jr.; Rotrosen, D.; Fontaine, J.W.; Haudenschild, C.C.; Diamond, R.D.

    1987-05-01

    Interactions were studied between human neutrophils and cultured human umbilical vein endothelial cells invaded by Candida albicans. In the absence of neutrophils, progressive Candida germination and hyphal growth extensively damaged endothelial cell monolayers over a period of 4 to 6 hours, as determined both by morphological changes and release of /sup 51/Cr from radiolabeled endothelial cells. Monolayers were completely destroyed and replaced by hyphae after 18 hours of incubation. In contrast, when added 2 hours after the monolayers had been infected with Candida, neutrophils selectively migrated toward and attached to hyphae at points of hyphal penetration into individual endothelial cells (observed by time-lapse video-microscopy). Attached neutrophils spread over hyphal surfaces both within and beneath the endothelial cells; neutrophil recruitment to initial sites of leukocyte-Candida-endothelial cell interactions continued throughout the first 60 minutes of observation. Neutrophil spreading and stasis were observed only along Candida hyphae and at sites of Candida-endothelial cell interactions. These events resulted in 58.0% killing of Candida at 2 hours and subsequent clearance of Candida from endothelial cell monolayers, as determined by microcolony counts and morphological observation. On introduction of additional neutrophils to yield higher ratios of neutrophils to endothelial cells (10 neutrophils:1 endothelial cell), neutrophil migration toward hyphal elements continued. Despite retraction or displacement of occasional endothelial cells by invading Candida and neutrophils, most endothelial cells remained intact, viable, and motile as verified both by morphological observations and measurement of /sup 51/Cr release from radiolabeled monolayers.

  9. Distinct signal transduction pathways for activation of rabbit alveolar macrophages in vitro by cotton bract tannin.

    PubMed

    Prévost, M C; Soulat, J M; Comminges, C; Maury, E; Aslane, R; Cohen-Jonathan, E; Cariven, C; Lauque, D; Chap, H

    1996-05-01

    These experiments were designed to study signal transduction pathways in alveolar macrophages stimulated by condensed tannin or zymosan. Condensed tannins, present in cotton mill dust, alter the host-defense function of alveolar macrophages and may contribute to the pathogenesis of byssinosis. We tried to determine the early steps in signal transduction mechanisms of cell activation by tannin. With the quantification of 51Cr release, we determined that tannin was cytotoxic for the cells after 30 min activation with 130 micrograms for 2 x 10(6) cells. 51Cr release was similar for control cells and zymosan- or 30 micrograms tannin-activated cells. Using the luciferine luciferase reaction, we showed that tannin markedly depleted ATP cell content. In inositol-labeled cells, tannin increased inositolphosphate release in a dose-dependent manner. In lysoPAF-labeled cells, tannin induced synthesis of phosphatidic acid and diglycerides. In the presence of ethanol, the level of tannin-induced phosphatidic acid was slightly reduced, and phosphatidylethanol was synthesized. No phosphatidylethanol was found in alveolar macrophages stimulated by zymosan in the presence of ethanol. GF 109203X, a specific inhibitor of protein kinase C decreased only tannin-induced phosphatidylethanol synthesis. In conclusion, tannin (at 30 or 130 micrograms/ml) activated an inositol phospholipase C in alveolar membranes. Phosphatidylcholine phospholipases C and D were found only at the higher concentration of tannin.

  10. Imaging Lung Clearance of Radiolabeled Tumor Cells to Study Mice with Normal, Activated or Depleted Natural Killer (NK) Cells

    SciTech Connect

    Kulkarni, P.V.; Bennett, M.; Constantinescu, A.; Arora, V.; Viguet, M.; Antich, P.; Parkey, R.W.; Mathews, D.; Mason, R.P.; Oz, O.K.

    2003-08-26

    Lung clearance of 51CR and 125I iododeoxyuridine (IUDR) labeled cancer cells assess NK cell activity. It is desirable to develop noninvasive imaging technique to assess NK activity in mice. We labeled target YAC-1 tumor cells with 125I, 111In, 99mTc, or 67Ga and injected I.V. into three groups of BALB/c mice. Animals were treated with medium (group I), 300mg/kg cyclophosmamide (CY) to kill NK cell (group II), or anti-LY49C/1) (ab')2 mAb to augment NK function (group III). Lungs were removed 15 min or 2 h later for tissue counting. Control and treated mice were imaged every 5 min with a scintillating camera for 1 h after 15 min of infusion of the 111In labeled cells. Lung clearance increased after 15 min (lodging: 60-80%) and (2 h retention: 3-7%). Similar results were obtained with all the isotopes studied. Images distinguished the control and treated mice for lung activity. Cells labeled with 111In, 99mTc or 67Ga are cleared similar to those labeled with 51Cr or 125I. NK cell destruction of tumor cells may be assessed by noninvasive imaging method either by SPECT (99mTc, 111In, 67Ga) or by PET (68Ga)

  11. Luciferase mRNA Transfection of Antigen Presenting Cells Permits Sensitive Nonradioactive Measurement of Cellular and Humoral Cytotoxicity

    PubMed Central

    Omokoko, Tana A.; Luxemburger, Uli; Bardissi, Shaheer; Simon, Petra; Utsch, Magdalena; Breitkreuz, Andrea; Türeci, Özlem; Sahin, Ugur

    2016-01-01

    Immunotherapy is rapidly evolving as an effective treatment option for many cancers. With the emerging fields of cancer vaccines and adoptive cell transfer therapies, there is an increasing demand for high-throughput in vitro cytotoxicity assays that efficiently analyze immune effector functions. The gold standard 51Cr-release assay is very accurate but has the major disadvantage of being radioactive. We reveal the development of a versatile and nonradioactive firefly luciferase in vitro transcribed (IVT) RNA-based assay. Demonstrating high efficiency, consistency, and excellent target cell viability, our optimized luciferase IVT RNA is used to transfect dividing and nondividing primary antigen presenting cells. Together with the long-lasting expression and minimal background, the direct measurement of intracellular luciferase activity of living cells allows for the monitoring of killing kinetics and displays paramount sensitivity. The ability to cotransfect the IVT RNA of the luciferase reporter and the antigen of interest into the antigen presenting cells and its simple read-out procedure render the assay high-throughput in nature. Results generated were comparable to the 51Cr release and further confirmed the assay's ability to measure antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. The assay's combined simplicity, practicality, and efficiency tailor it for the analysis of antigen-specific cellular and humoral effector functions during the development of novel immunotherapies. PMID:27057556

  12. Cronic effects of vasopressin on fluid volume distribution in conscious dogs

    SciTech Connect

    Merrill, D.C.; Cowley, A.W. Jr.

    1987-01-01

    Previous studies have suggested that acute elevations of arginine vasopressin (AVP) may result in an extravascular to intravascular shift of fluid independent of any change in total body H/sub 2/O (TBW). The present studies examined the chronic influence of elevated AVP on fluid volume distribution in five splenectomized, sodium-deprived conscious dogs. During 4 days of continuous intravenous AVP infusion the computerized average 24-h total body weight was maintained within 110 g of the control value by means of a sensitive servo-controlled scale device. Urine flow and urine osmolality averaged 335 +/- 52 ml/day and 637 +/- 36 mosmol/kg during the preinfusion period and changed to levels averaging 151 +/- 14 and 1377 +/- 121 with elevated AVP. Chromium-51-labeled red cell volume (/sup 51/Cr RBC), plasma volume (Evans blue), TBW (/sup 3/H/sub 2/O), calculated total blood volume (using /sup 51/Cr RBC and Hct), and mean arterial pressure remained unchanged during the AVP infusion period. Plasma protein, sodium, and osmolality also remained unchanged with elevated AVP. The authors conclude from the present studies that AVP has minimal or chronic influence on internal volume redistribution.

  13. Migration of human lymphocytes. I. A model using the mouse as host.

    PubMed Central

    Morgan, K; Holt, P J

    1978-01-01

    The distribution of radioactivity after the intravenous injection of 51Cr-labelled human lymphocytes has been examined in normal mice, irradiated mice, mice treated with anti-platelet antiserum and in mice treated with colloidal carbon. Pre-treatment with carbon and anti-platelet antiserum appears to protect the human lymphocytes from uptake by the host's reticuloendothelial system (RES). Comparison of tissue radioactivity in carbon-treated mice after the injection of viable human lymphocytes with that found after the injection of dead cells and soluble or insoluble cell debris showed that radioactivity recovered in the spleen and lymph nodes is primarily due to the migration of viable lymphocytes into these tissues. Thus the measurement of radioactivity in lymph nodes of carbon-treated mice after the injection of 51Cr-labelled human lymphocytes can be used as a model of these lymphocytes' ability to migrate into the lymph nodes during recirculation and to study factors influencing this migration. PMID:721139

  14. A new sensitive assay for measurement of cell-mediated cytotoxicity to intact layers of cultured human keratinocytes.

    PubMed

    De Bueger, M M; Van Els, C A; Kempenaar, J; Ponec, M; Goulmy, E

    1990-02-20

    A cytotoxicity assay for sensitive measurement of cell-mediated lympholysis (CML) of human cultured keratinocytes (cK) is described. The usage of 51Cr-labeled keratinocytes in intact layers as target cells in this assay allows objective and accurate determination of lysis of keratinocytes which have not undergone trypsin- and suspension-induced membrane changes. Furthermore, the problem of high spontaneous 51Cr release values encountered with suspended keratinocytes is overcome. The assay was applied to study antigen-specific CML of cK by cloned cytotoxic T cells (CTL) and to determine the effect of IFN-gamma on the susceptibility of cK to lysis. The results showed that HLA-A2 specific CTLs could reproducibly lyse cK of HLA-A2 positive healthy skin donors both with and without incubation of cK with IFN-gamma. Applications of this keratinocyte cytotoxicity assay lie in determining the antigenic expression of human cK, in analysis of effector cell/keratinocyte interactions in CML and of the modulatory effects of cytokines on these mechanisms. The assay thus may provide a helpful tool in gaining insight into the role of CML of keratinocytes in the destruction of inflamed skin. PMID:2108219

  15. The effects of Pasteurella haemolytica lipopolysaccharide on bovine pulmonary artery endothelial cells in cell culture

    SciTech Connect

    Paulsen, D.B.

    1989-01-01

    This study examined the potential role of Pasteurella haemolytica Al lipopolysaccharide (LPS) in the pathogenesis of the vascular lesions of pneumonic pasteurellosis. Bovine pulmonary artery endothelia cells (BPAEC) were the test model. The direct toxic potential of P. Haemolytica LPS on BPAEC was examined by cell detachment assays, morphologic alterations, and membrane damage as reflected in the leakage of large internal molecules such as LDH and {sup 51}Cr-labeled molecules. LPS-induced effects having potential for causing indirect vascular damage were studied and included neutrophil-adherence to and arachidonic acid-release from BPAEC. Several substances were examined for their ability to inhibit the LPS-induced cytotoxicity. Pasteurella haemolytica LPS caused direct toxic effects in BPAEC. Cell-detachment, LDH-leakage, {sup 51}Cr-leakage, and {sup 3}H-arachidonic acid-release proceeded with similar time- and dose-dependency after exposure of BPAEC to LPS. Morphologic alterations were observed as early as one-half hour after LPS-exposure and became collectively more severe with time. Neutrophil adherence to BPAEC was increased by LPS through independent effects on both cells types. The adherence required protein synthesis in both cell types.

  16. Platelet size does not correlate with platelet age

    SciTech Connect

    Thompson, C.B.; Love, D.G.; Quinn, P.G.; Valeri, C.R.

    1983-08-01

    The relationship between platelet size and in vivo aging was investigated in the baboon using size-dependent platelet subpopulations separated by counterflow centrifugation. The separation characteristics, size, lactate dehydrogenase (LDH) activity, and dense-body content of the baboon platelet subpopulations were similar to those previously observed in studies of human platelets. Three independent labeling techniques were used: (1) in vivo labeling with /sup 75/Se-methionine, (2) in vitro labeling with /sup 51/Cr, and (3) in vivo labeling with 14C-serotonin. Maximal incorporation of all three labels showed a close correlation between the mean platelet volume (MPV) of each fraction and the platelet radioactivity. The onset of incorporation and rate of accumulation of /sup 75/Se-methionine were comparable in all fractions when corrected for differences in volume, suggesting that platelet size heterogeneity was present from the time of release of the platelets from the bone marrow. Survival studies using /sup 51/Cr and /sup 14/C-serotonin showed no translocation of the label from one fraction to another in the circulation over time. In vivo survival values for the three radionuclides showed a slight but significant correlation between the lifespan and the MPV of the fractions. The data suggest that large platelets were not younger platelets, but rather platelets with a longer life-span. Platelet size heterogeneity is the result of production factors in the bone marrow and not maturation in the circulation.

  17. Matrix fibronectin disruption and altered endothelial cell adhesion induced by activated leukocytes

    SciTech Connect

    Vincent, P.; Richards, P.; Saba, T.; DelVecchio, P.

    1986-03-01

    Sequestration of activated leukocytes (PMN) within the lung may contribute to pulmonary vascular injury following trauma, sepsis, or intravascular coagulation. Monolayers of cultured rat endothelial cells were utilized to evaluate the effect of activated PMNs on endothelial cell attachment and the extracellular fibronectin matrix over a 4 hr incubation interval. Rat endothelial cells were identified by immunofluorescent staining of Factor VIII R:Ag. Endothelial cells were labeled with /sup 51/Cr in order to establish a cell injury assay in which the release of pelletable (cell associated) or non-pelletable activity was measured in the media. PMN activation was verified by chemiluminescence activity. Following phorbol myristate acetate (PMA) the leukocytes aggregated, chemiluminesced, and caused detachment of /sup 51/Cr endothelial cells. Endothelial detachment increased as a function of time with a plateau by 3 hrs. Immunofluorescent analysis of extracellular fibronectin in endothelial cell cultures revealed disruption of the fibrillar matrix fibronectin in association with endothelial cell disadhesion. Matrix fibronectin disruption was not seen with PMNs or PMA alone. Thus, disruption of the fibronectin matrix by released proteases may contribute to endothelial cell detachment.

  18. Dating High Temperature Mineral Fabrics in Lower Crustal Granulite Facies Rocks

    NASA Astrophysics Data System (ADS)

    Stowell, H. H.; Schwartz, J. J.; Tulloch, A. J.; Klepeis, K. A.; Odom Parker, K.; Palin, M.; Ramezani, J.

    2015-12-01

    Granulite facies rocks may record strain that provides a record of compressional and/or extensional crustal events in hot orogenic cores and the roots of magmatic arcs. Although the precise timing of these events is important for constructing tectonic histories, it is often difficult to determine due to uncertain relationships between isotopic signatures, mineral growth, and textural features that record strain. In addition, there may be large uncertainties in isotope data due to intracrystalline diffusion and multiple crystallization events. L-S tectonites in lower crustal rocks from Fiordland, NZ record the early stages of extensional collapse of thickened magmatic arc crust. The precise age of these fabrics is important for constraining the timing of extension that led to opening of the Tasman Sea. High temperature granulite facies L-S fabrics in garnet reaction zones (GRZ) border syn- to post-deformational leucosomes. U-Pb zircon, Lu-Hf garnet, and Sm-Nd garnet ages, and trace elements in these phases indicate the complexity of assigning precise and useful ages. Zircon have soccer ball morphology with patchy and sector zoned CL. Zircon dates for igneous host and adjacent GRZ range over ca. 17 Ma. 236U-208Pb LA-ICP-MS are 108-125 Ma, N=124 (host & GRZ); however, chemical abrasion (CA) shifts GRZ dates ca. 2 Ma older. 236U-208Pb SHRIMP-RG dates cluster in 2 groups: 118.5±0.8 Ma, N=23 and 111.0±0.8 Ma, N=6. CA single crystal TIMS dates also fall into 2 groups: 117.6±0.1 Ma, N=4 and 116.6±0.2 Ma N=4. Garnet isochron ages determined from coarse garnet selvages adjacent to leucosomes range from 112.8±2.2 (147Sm-143Nd, 10 pts.) to 114.8±3.5 (177Lu-176Hf, 6 pts.) Ma. Zircon dates from all methods show ranges (>10 Ma) and 2 distinct populations. Host and GRZ zircon cannot be readily distinguished by age, lack younger rims, but have distinct Th/U trends and Eu/Eu* vs. Hf ratios. Difference in zircon trace element composition indicates either early leucosome

  19. Melanoma Therapy with Rhenium-Cyclized Alpha Melanocyte Stimulating Hormone Peptide Analogs

    SciTech Connect

    Thomas P Quinn

    2005-11-22

    Malignant melanoma is the 6th most commonly diagnosed cancer with increasing incidence in the United States. It is estimated that 54,200 cases of malignant melanoma will be newly diagnosed and 7,600 cases of death will occur in the United States in the year 2003 (1). At the present time, more than 1.3% of Americans will develop malignant melanoma during their lifetime (2). The average survival for patients with metastatic melanoma is about 6-9 months (3). Moreover, metastatic melanoma deposits are resistant to conventional chemotherapy and external beam radiation therapy (3). Systematic chemotherapy is the primary therapeutic approach to treat patients with metastatic melanoma. Dacarbazine is the only single chemotherapy agent approved by FDA for metastatic melanoma treatment (5). However, the response rate to Dacarbazine is only approximately 20% (6). Therefore, there is a great need to develop novel treatment approaches for metastatic melanoma. The global goal of this research program is the rational design, characterization and validation of melanoma imaging and therapeutic radiopharmaceuticals. Significant progress has been made in the design and characterization of metal-cyclized radiolabeled alpha-melanocyte stimulating hormone peptides. Therapy studies with {sup 188}Re-CCMSH demonstrated the therapeutic efficacy of the receptor-targeted treatment in murine and human melanoma bearing mice (previous progress report). Dosimetry calculations, based on biodistribution data, indicated that a significant dose was delivered to the tumor. However, {sup 188}Re is a very energetic beta-particle emitter. The longer-range beta-particles theoretically would be better for larger tumors. In the treatment of melanoma, the larger primary tumor is usually surgically removed leaving metastatic disease as the focus of targeted radiotherapy. Isotopes with lower beta-energies and/or shorter particle lengths should be better suited for targeting metastases. The {sup 177}Lu

  20. The NUKDOS software for treatment planning in molecular radiotherapy.

    PubMed

    Kletting, Peter; Schimmel, Sebastian; Hänscheid, Heribert; Luster, Markus; Fernández, Maria; Nosske, Dietmar; Lassmann, Michael; Glatting, Gerhard

    2015-09-01

    The aim of this work was the development of a software tool for treatment planning prior to molecular radiotherapy, which comprises all functionality to objectively determine the activity to administer and the pertaining absorbed doses (including the corresponding error) based on a series of gamma camera images and one SPECT/CT or probe data. NUKDOS was developed in MATLAB. The workflow is based on the MIRD formalism For determination of the tissue or organ pharmacokinetics, gamma camera images as well as probe, urine, serum and blood activity data can be processed. To estimate the time-integrated activity coefficients (TIAC), sums of exponentials are fitted to the time activity data and integrated analytically. To obtain the TIAC on the voxel level, the voxel activity distribution from the quantitative 3D SPECT/CT (or PET/CT) is used for scaling and weighting the TIAC derived from the 2D organ data. The voxel S-values are automatically calculated based on the voxel-size of the image and the therapeutic nuclide ((90)Y, (131)I or (177)Lu). The absorbed dose coefficients are computed by convolution of the voxel TIAC and the voxel S-values. The activity to administer and the pertaining absorbed doses are determined by entering the absorbed dose for the organ at risk. The overall error of the calculated absorbed doses is determined by Gaussian error propagation. NUKDOS was tested for the operation systems Windows(®) 7 (64 Bit) and 8 (64 Bit). The results of each working step were compared to commercially available (SAAMII, OLINDA/EXM) and in-house (UlmDOS) software. The application of the software is demonstrated using examples form peptide receptor radionuclide therapy (PRRT) and from radioiodine therapy of benign thyroid diseases. For the example from PRRT, the calculated activity to administer differed by 4% comparing NUKDOS and the final result using UlmDos, SAAMII and OLINDA/EXM sequentially. The absorbed dose for the spleen and tumour differed by 7% and 8

  1. 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

  2. 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

  3. Cathepsin S-cleavable, multi-block HPMA copolymers for improved SPECT/CT imaging of pancreatic cancer.

    PubMed

    Fan, Wei; Shi, Wen; Zhang, Wenting; Jia, Yinnong; Zhou, Zhengyuan; Brusnahan, Susan K; Garrison, Jered C

    2016-10-01

    This work continues our efforts to improve the diagnostic and radiotherapeutic effectiveness of nanomedicine platforms by developing approaches to reduce the non-target accumulation of these agents. Herein, we developed multi-block HPMA copolymers with backbones that are susceptible to cleavage by cathepsin S, a protease that is abundantly expressed in tissues of the mononuclear phagocyte system (MPS). Specifically, a bis-thiol terminated HPMA telechelic copolymer containing 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. Three maleimide modified linkers with different sequences, including cathepsin S degradable oligopeptide, scramble oligopeptide and oligo ethylene glycol, were subsequently synthesized and used for the extension of the HPMA copolymers by thiol-maleimide click chemistry. All multi-block HPMA copolymers could be labeled by (177)Lu with high labeling efficiency and exhibited high serum stability. In vitro cleavage studies demonstrated highly selective and efficient cathepsin S mediated cleavage of the cathepsin S-susceptible multi-block HPMA copolymer. A modified multi-block HPMA copolymer series capable of Förster Resonance Energy Transfer (FRET) was utilized to investigate the rate of cleavage of the multi-block HPMA copolymers in monocyte-derived macrophages. Confocal imaging and flow cytometry studies revealed substantially higher rates of cleavage for the multi-block HPMA copolymers containing the cathepsin S-susceptible linker. The efficacy of the cathepsin S-cleavable multi-block HPMA copolymer was further examined using an in vivo model of pancreatic ductal adenocarcinoma. Based on the biodistribution and SPECT/CT studies, the copolymer extended with the cathepsin S susceptible linker exhibited significantly faster clearance and lower non-target retention without compromising tumor targeting. Overall, these results indicate that

  4. Cathepsin S-cleavable, multi-block HPMA copolymers for improved SPECT/CT imaging of pancreatic cancer.

    PubMed

    Fan, Wei; Shi, Wen; Zhang, Wenting; Jia, Yinnong; Zhou, Zhengyuan; Brusnahan, Susan K; Garrison, Jered C

    2016-10-01

    This work continues our efforts to improve the diagnostic and radiotherapeutic effectiveness of nanomedicine platforms by developing approaches to reduce the non-target accumulation of these agents. Herein, we developed multi-block HPMA copolymers with backbones that are susceptible to cleavage by cathepsin S, a protease that is abundantly expressed in tissues of the mononuclear phagocyte system (MPS). Specifically, a bis-thiol terminated HPMA telechelic copolymer containing 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. Three maleimide modified linkers with different sequences, including cathepsin S degradable oligopeptide, scramble oligopeptide and oligo ethylene glycol, were subsequently synthesized and used for the extension of the HPMA copolymers by thiol-maleimide click chemistry. All multi-block HPMA copolymers could be labeled by (177)Lu with high labeling efficiency and exhibited high serum stability. In vitro cleavage studies demonstrated highly selective and efficient cathepsin S mediated cleavage of the cathepsin S-susceptible multi-block HPMA copolymer. A modified multi-block HPMA copolymer series capable of Förster Resonance Energy Transfer (FRET) was utilized to investigate the rate of cleavage of the multi-block HPMA copolymers in monocyte-derived macrophages. Confocal imaging and flow cytometry studies revealed substantially higher rates of cleavage for the multi-block HPMA copolymers containing the cathepsin S-susceptible linker. The efficacy of the cathepsin S-cleavable multi-block HPMA copolymer was further examined using an in vivo model of pancreatic ductal adenocarcinoma. Based on the biodistribution and SPECT/CT studies, the copolymer extended with the cathepsin S susceptible linker exhibited significantly faster clearance and lower non-target retention without compromising tumor targeting. Overall, these results indicate that

  5. Gamma scintigraphic study of the hydrodynamically balanced matrix tablets of Metformin HCl in rabbits

    PubMed Central

    Razavi, Mahboubeh; Karimian, Hamed; Yeong, Chai Hong; Sarji, Sazilah Ahmad; Chung, Lip Yong; Nyamathulla, Shaik; Noordin, Mohamed Ibrahim

    2015-01-01

    The purpose of this study is to evaluate the in vitro and in vivo performance of gastro-retentive matrix tablets having Metformin HCl as model drug and combination of natural polymers. A total of 16 formulations were prepared by a wet granulation method using xanthan, tamarind seed powder, tamarind kernel powder and salep as the gel-forming agents and sodium bicarbonate as a gas-forming agent. All the formulations were evaluated for compendial and non-compendial tests and in vitro study was carried out on a USP-II dissolution apparatus at a paddle speed of 50 rpm. MOX2 formulation, composed of salep and xanthan in the ratio of 4:1 with 96.9% release, was considered as the optimum formulation with more than 90% release in 12 hours and short floating lag time. In vivo study was carried out using gamma scintigraphy in New Zealand White rabbits, optimized formulation was incorporated with 10 mg of 153Sm for labeling MOX2 formulation. The radioactive samarium oxide was used as the marker to trace transit of the tablets in the gastrointestinal tract. The in vivo data also supported retention of MOX2 formulation in the gastric region for 12 hours and were different from the control formulation without a gas and gel forming agent. It was concluded that the prepared floating gastro-retentive matrix tablets had a sustained-release effect in vitro and in vivo, gamma scintigraphy played an important role in locating the oral transit and the drug-release pattern. PMID:26124637

  6. Rapid separation of fresh fission products (draft)

    SciTech Connect

    Dry, D. E.; Bauer, E.; Petersen, L. A.

    2003-01-01

    The fission of highly eruiched uranium by thermal neutrons creates dozens of isotopic products. The Isotope and Nuclear Chemistry Group participates in programs that involve analysis of 'fiesh' fission products by beta counting following radiochemical separations. This is a laborious and time-consuming process that can take several days to generate results. Gamma spectroscopy can provide a more immediate path to isolopic activities, however short-lived, high-yield isotopes can swamp a gamma spectrum, making difficult the identification and quantification of isotopes on the wings and valley of the fission yield curve. The gamma spectrum of a sample of newly produced fission products is dominated by the many emissions of a very few high-yield isotopes. Specilkally, {sup 132}Te (3.2 d), its daughter, {sup 132}I(2 .28 h), {sup 140}Ba (12.75 d), and its daughter {sup 140}La (1.68 d) emit at least 18 gamma rays above 100 keV that are greater than 5% abundance. Additionally, the 1596 keV emission fiom I4'La imposes a Compton background that hinders the detection of isotopes that are neither subject to matrix dependent fractionation nor gaseous or volatile recursors. Some of these isotopes of interest are {sup 111}Ag, {sup 115}Cd, and the rare earths, {sup 153}Sm, {sup 154}Eu, {sup 156}Eu, and {sup 160}Tb. C-INC has performed an HEU irradiation and also 'cold' carrier analyses by ICP-AES to determine methods for rapid and reliable separations that may be used to detect and quantify low-yield fission products by gamma spectroscopy. Results and progress will be presented.

  7. Calculating dosimetry parameters in brachytherapy using the continuous beta spectrum of Sm-153 in the Monte Carlo simulation approach

    NASA Astrophysics Data System (ADS)

    Shahrabi, Mohammad; Tavakoli-Anbaran, Hossien

    2015-02-01

    Calculation of dosimetry parameters by TG-60 approach for beta sources and TG-43 approach for gamma sources can help to design brachytherapy sources. In this work, TG-60 dosimetry parameters are calculated for the Sm-153 brachytherapy seed using the Monte Carlo simulation approach. The continuous beta spectrum of Sm-153 and probability density are applied to simulate the Sm-153 source. Sm-153 is produced by neutron capture during the 152Sm( n,)153Sm reaction in reactors. The Sm-153 radionuclide decays by beta rays followed by gamma-ray emissions with half-life of 1.928 days. Sm-153 source is simulated in a spherical water phantom to calculate the deposited energy and geometry function in the intended points. The Sm-153 seed consists of 20% samarium, 30% calcium and 50% silicon, in cylindrical shape with density 1.76gr/cm^3. The anisotropy function and radial dose function were calculated at 0-4mm radial distances relative to the seed center and polar angles of 0-90 degrees. The results of this research are compared with the results of Taghdiri et al. (Iran. J. Radiat. Res. 9, 103 (2011)). The final beta spectrum of Sm-153 is not considered in their work. Results show significant relative differences even up to 5 times for anisotropy functions at 0.6, 1 and 2mm distances and some angles. MCNP4C Monte Carlo code is applied in both in the present paper and in the above-mentioned one.

  8. Gamma scintigraphic study of the hydrodynamically balanced matrix tablets of Metformin HCl in rabbits.

    PubMed

    Razavi, Mahboubeh; Karimian, Hamed; Yeong, Chai Hong; Sarji, Sazilah Ahmad; Chung, Lip Yong; Nyamathulla, Shaik; Noordin, Mohamed Ibrahim

    2015-01-01

    The purpose of this study is to evaluate the in vitro and in vivo performance of gastro-retentive matrix tablets having Metformin HCl as model drug and combination of natural polymers. A total of 16 formulations were prepared by a wet granulation method using xanthan, tamarind seed powder, tamarind kernel powder and salep as the gel-forming agents and sodium bicarbonate as a gas-forming agent. All the formulations were evaluated for compendial and non-compendial tests and in vitro study was carried out on a USP-II dissolution apparatus at a paddle speed of 50 rpm. MOX2 formulation, composed of salep and xanthan in the ratio of 4:1 with 96.9% release, was considered as the optimum formulation with more than 90% release in 12 hours and short floating lag time. In vivo study was carried out using gamma scintigraphy in New Zealand White rabbits, optimized formulation was incorporated with 10 mg of (153)Sm for labeling MOX2 formulation. The radioactive samarium oxide was used as the marker to trace transit of the tablets in the gastrointestinal tract. The in vivo data also supported retention of MOX2 formulation in the gastric region for 12 hours and were different from the control formulation without a gas and gel forming agent. It was concluded that the prepared floating gastro-retentive matrix tablets had a sustained-release effect in vitro and in vivo, gamma scintigraphy played an important role in locating the oral transit and the drug-release pattern. PMID:26124637

  9. The distribution and degradation of radiolabeled superparamagnetic iron oxide nanoparticles and quantum dots in mice

    PubMed Central

    Freund, Barbara; Heine, Markus; Waurisch, Christian; Stachowski, Gordon M; Hickey, Stephen G; Eychmüller, Alexander; Heeren, Jörg

    2015-01-01

    Summary 51Cr-labeled, superparamagnetic, iron oxide nanoparticles (51Cr-SPIOs) and 65Zn-labeled CdSe/CdS/ZnS-quantum dots (65Zn-Qdots) were prepared using an easy, on demand, exchange-labeling technique and their particokinetic parameters were studied in mice after intravenous injection. The results indicate that the application of these heterologous isotopes can be used to successfully mark the nanoparticles during initial distribution and organ uptake, although the 65Zn-label appeared not to be fully stable. As the degradation of the nanoparticles takes place, the individual transport mechanisms for the different isotopes must be carefully taken into account. Although this variation in transport paths can bring new insights with regard to the respective trace element homeostasis, it can also limit the relevance of such trace material-based approaches in nanobioscience. By monitoring 51Cr-SPIOs after oral gavage, the gastrointestinal non-absorption of intact SPIOs in a hydrophilic or lipophilic surrounding was measured in mice with such high sensitivity for the first time. After intravenous injection, polymer-coated, 65Zn-Qdots were mainly taken up by the liver and spleen, which was different from that of ionic 65ZnCl2. Following the label for 4 weeks, an indication of substantial degradation of the nanoparticles and the release of the label into the Zn pool was observed. Confocal microscopy of rat liver cryosections (prepared 2 h after intravenous injection of polymer-coated Qdots) revealed a colocalization with markers for Kupffer cells and liver sinusoidal endothelial cells (LSEC), but not with hepatocytes. In J774 macrophages, fluorescent Qdots were found colocalized with lysosomal markers. After 24 h, no signs of degradation could be detected. However, after 12 weeks, no fluorescent nanoparticles could be detected in the liver cryosections, which would confirm our 65Zn data showing a substantial degradation of the polymer-coated CdSe/CdS/ZnS-Qdots in the

  10. Transcapillary exchange in the cat salivary gland during secretion, bradykinin infusion and after chronic duct ligation.

    PubMed Central

    Mann, G E; Smaje, L H; Yudilevich, D L

    1979-01-01

    1. Capillary permeability-surface area products for 86Rb, [51Cr]EDTA (mol. wt. 357), [57Co]cyanocobalamin (mol. wt. 1353) and [125I]insulin (approximate mol. wt. 6000) have been measured using the single-circulation, multiple-tracer dilution technique in the in situ perfused submandibular salivary gland during parasympathetic nerve stimulation, close-arterial bradykinin infusion and following chronic duct ligation. 2. In glands with a natural blood supply, permeability-surface area for 86Rb and [51Cr]EDTA increased during parasympathetic stimulation, but this was shown to be related to the concomitant increase in blood flow rather than to a change in capillary permeability or in surface area. 3. In glands perfused at constant flow, parasympathetic stimulation led to a decrease in permeability-surface area for EDTA (-19.1 +/- 5.2%, mean +/- S.E., n = 5, P less than 0.05) cyanocobalamin (-12.3 +/- 6.0, n = 12, P less than 0.05), and insulin (-15.3 +/- 4.8, n = 11, P less than 0.02). It is suggested that this may be the result of a redistribution of flow from the acinar microcirculation to a less permeable ductal vasculature. 4. Bradykinin infusion had no significant effect on permeability-surface area for EDTA and cyanocobalamin in perfused glands. 5. In perfused glands, ligation of the submandibular duct for 3--12 days reduced permeability-surface area (ml.min-1.g-1) for [51Cr]EDTA from 5.26 +/- 0.60 (mean +/- S.E., n = 9) to 4.20 +/- 0.12 (n = 4, P less than 0.30), [57Co]cyanocobalamin from 3.22 +/- 0.12 (n = 48) to 2.02 +/- 0.08 (n = 15, P less than 0.001) and [125I]insulin from 1.52 +/- 0.07 (n = 39) to 0.72 +/- 0.23 (n = 11, P less than 0.001). PMID:119844

  11. Evidence for active maternal-fetal transport of Na+ across the placenta of the anaesthetized rat.

    PubMed

    Stulc, J; Stulcová, B; Sibley, C P

    1993-10-01

    1. In order to investigate mechanisms of Na+ transfer, the unidirectional maternal-fetal clearance (Kmf) of 22Na+ and of 51Cr-EDTA (a marker of paracellular diffusion) was measured across the intact or umbilically or dually perfused placenta of the anaesthetized rat. 2. The Kmf of 22Na+ in the intact preparation (18.5 +/- 2.7 microliters min-1, mean +/- S.D., n = 105 placentas) exceeded that of 51Cr-EDTA in the same experiments (1.4 +/- 0.3 microliters min-1) by more than ten times, whereas the difference in their diffusion coefficients in water was only 2-fold. In the perfused preparations the difference in the Kmf values was 6-fold. 3. Assuming that a simple model of paracellular diffusion through wide pores was one component of transfer, the Kmf of 51Cr-EDTA and the diffusion coefficients were used to calculate a component of 22Na+ clearance (Kmf,residual) and of Na+ flux (Jmf,residual) across the perfused placentas which could not be accounted for by transfer through the paracellular route. 4. Kmf,residual of 22Na+ across the dually perfused placenta was significantly lower when temperature was reduced, the temperature quotient (Q10) of the transfer being about 2. Kmf,residual was also significantly lower when 0.1 mM ouabain was perfused on the fetal side. Jmf,residual exhibited saturation kinetics characterized by an apparent Michaelis constant (Km) of 90 mM. Kmf,residual was not influenced by 0.5 mM frusemide, 0.5 mM amiloride or by 0.5 mM hydrochlorothiazide administered to the maternal side. It was significantly increased by 1 mM alanine on the maternal side suggesting that the coupled transfer of Na+ and amino acids may contribute significantly to the maternal-fetal flux of Na+. 5. These observations suggest that most (80%) of the maternal-fetal flux of Na+ across the rat placenta is effected by active transcellular transport. This transport involves passive entry of Na+ into the trophoblast from the maternal side by a largely unknown saturable mechanism

  12. Techniques for measuring red cell, platelet, and WBC survival

    SciTech Connect

    Mayer, K.; Freeman, J.E.

    1986-01-01

    Blood cell survival studies yield valuable information concerning production and destruction of cells circulating in the bloodstream. Methodologies for the measurement of red cell survival include nonisotopic methods such as differential agglutination and hemolysis. The isotopic label may be radioactive or, if not, will require availability of a mass spectrograph. These methods fall into two categories, one where red cells of all ages are labeled (/sup 51/Cr, DFP32, etc.) and those employing a cohort label of newly formed cells (/sup 14/C glycine, /sup 75/Se methionine, etc.). Interpretation of results for methodology employed and mechanism of destruction, random or by senescence, are discussed. A similar approach is presented for platelet and leukocyte survival studies. The inherent difficulties and complications of sequestration, storage, and margination of these cells are emphasized and discussed. 38 references.

  13. In vitro sensitization of human lymphocytes to a myeloma cell-related antigen

    SciTech Connect

    Whitson, M.E.; Griffin, G.D.; Novelli, G.D.; Solomon, A.

    1981-01-01

    Peripheral blood lymphocytes from normal human donors were cocultivated with cells from two established human multiple myeloma cell lines, RPMI 8226 and K-737, and with lymphoblastoid cells from a third B cell line, RAMM. After a comparison of three methods of lymphocyte sensitization, a 6-day incubation protocol with equal numbers of normal lymphocytes and mitomycin C-treated tumor cells was selected. Cells fom the RPMI 8226 myeloma line stimulated the differentiation of lymphocytes into cytotoxic effector cells as measured by /sup 51/Cr release from labeled target cells. The RPMI 8226-sensitized lymphocytes were cytotoxic for myeloma cells (RPMI 8226 and K-737) and for lymphoblastoid cells (RAMM) but not for cells from human lung tumor lines (A549, A427, MB9812), a breast carcinoma line (ALAB), a normal diploid fibroblast line (HSBP), or normal lymphocytes.

  14. Mediation of macrophage cytolytic and phagocytic activities by antibodies of different classes and class-specific Fc-receptors.

    PubMed

    Walker, W S

    1977-08-01

    The classes of antibodies that mediate the phagocytosis and cytolysis of 51Cr-labeled chicken erythrocytes by IC-21 macrophages, an established line of mouse peritoneal macrophages, were identified. The phagocytic activity of IC-21 macrophages, as determined by a functional inhibition assay with mouse myeloma proteins, depended mainly on IgM and IgG2a antibodies and to a lesser extent on IgG2b antibodies. Extracellular cytolysis of target cells was mediated solely by IgG2b antibodies. These results correlate with the previously documented specificities of discrete Fc-receptors for IgG2a and IgG2b immunoglobulins on IC-21 cells. Thus, phagocytosis and cytolysis appear to be mediated by antibodies of different classes operating through separate and distinct sites on the surface of IC-21 macrophages. PMID:886183

  15. Technical considerations in the study of /sup 111/In-oxine labelled platelet survival patterns in dogs

    SciTech Connect

    Sharefkin, J.; Rich, N.M.

    1982-04-01

    A detailed technique for labelling canine platelets with /sup 111/In-oxine for the study of platelet survival patterns in four to six dogs at a time was developed. Useful modifications of earlier methods included splitting of the platelet rich plasma into multiple aliquots to improve pelleting efficiency at low gravity forces, use of saved platelet poor plasma to flush out injection syringes, and prompt use of commercial /sup 111/In-oxine sources 3 to 5 minutes after mixing with Ringer's Citrate Dextrose. Avoidable pitfalls of the method included excessive lengths of incubation time in plasma free medium and loss of labelling efficacy by exposure of the chelate to iron or other metal contaminants in glassware. The method was used to study changes in platelet survival time in dogs with large synthetic arterial prostheses, and gave results in good agreement with earlier studies using /sup 51/Cr labelled platelets.

  16. Loss of tubular creatinine secretion as the only sign of tubular proximal cell dysfunction in light chain proximal tubulopathy

    PubMed Central

    Stehlé, Thomas; Vignon, Marguerite; Flamant, Martin; Figueres, Marie-Lucile; Rabant, Marion; Rodenas, Anita; Noël, Laure-Hélène; Arnulf, Bertrand; Vidal-Petiot, Emmanuelle

    2016-01-01

    Abstract Light chain proximal tubulopathy (LCPT) is a rare disease, characterized by cytoplasmic inclusions of light chain (usually kappa) immunoglobulins. Clinical presentation is usually a Fanconi syndrome. The proximal tubular dysfunction can be incomplete, and exceptional cases of LCPT without any tubular dysfunction have even been described. Here, we report a case of LCPT in which the only sign of proximal tubulopathy is the absence of secretion of creatinine, as assessed by the simultaneous measurement of renal clearance of creatinine and 51CrEDTA. The loss of tubular creatinine secretion as a sign of tubular proximal cell dysfunction ought to be identified in patients with light chain proximal tubulopathy as it leads to a clinically relevant underestimation of GFR by the creatinine-derived equations. The prevalence and prognostic significance of this particular proximal tubular damage in LCPT remain to be determined. PMID:27367983

  17. Excitation functions of alpha particle induced reactions on natTi up to 40 MeV

    NASA Astrophysics Data System (ADS)

    Uddin, M. S.; Scholten, B.

    2016-08-01

    Excitation functions of the reactions natTi(α,x)48Cr, natTi(α,x)48V and natTi(α,x)46,48Sc were determined by the stacked-foil activation technique up to 40 MeV. The radioactivities produced in the natTi target were measured by γ-ray spectrometry using HPGe detector. The reaction natTi(α,x)51Cr was used to determine the beam parameters. New experimental values for the above reactions have been obtained. An intercomparison of our data with the available literature values has been done. The cross section results obtained in this work could be useful in defining new monitor reactions, radiation safety and isotope production.

  18. In vitro phagocytosis and intracellular survival of Campylobacter jejuni with phagocytes

    SciTech Connect

    Kiehlbauch, J.A.

    1986-01-01

    In vitro phagocytosis and intracellular survival of Campylobacter jejuni was studied using three types of mononuclear phagocytes: a J774G8 peritoneal macrophage line, resident BABL/c peritoneal macrophages and human peripheral blood monocytes. In phagocytosis assays using CFU determinations, phagocytosis increased steadily over an 8 hr time period. Results obtained using a /sup 51/Cr assay indicated no consistent significant difference between phagocytosis of C. jejuni between the three mononuclear phagocytes or PMN's and that maximum infection occurred prior to 0.5 hr and maintained throughout the 4 hr assay. Further investigation of the mechanism of attachment and entry of C. jejuni revealed this process required the expenditure of energy by the phagocyte, but was not inhibited by inhibitors of microfilament functions. In addition, phagocytosis was enhanced by the presence of 20% FCS,

  19. Subcutaneous administration of carrier erythrocytes: slow release of entrapped agent

    SciTech Connect

    DeLoach, J.R.; Corrier, D.E.

    1988-08-01

    Carrier erythrocytes administered subcutaneously in mice release encapsulated molecules at the injection site and through cells that escape the injection site. One day postinjection, the efflux of encapsulated (/sup 14/C)sucrose, (/sup 3/H)inulin, and /sup 51/Cr-hemoglobin from the injection site was 45, 55, and 65%, respectively. Intact carrier erythrocytes escaped the injection site and entered the blood circulation carrying with them the encapsulated molecules. Most of the encapsulated (/sup 3/H)inulin that reached whole blood circulated within erythrocytes. Small but measurable numbers of encapsulated molecules were trapped within lymph nodes. Subcutaneous injection of carrier erythrocytes may allow for limited extravascular tissue targeting of drugs.

  20. Ferrokinetic and erythrocyte survival studies in healthy and anemic cats

    SciTech Connect

    Madewell, B.R.; Holmes, P.H.; Onions, D.E.

    1983-03-01

    Erythrocyte survival and ferrokinetic studies were adapted to the cat. For 5 clinically healthy 4- to 9-month-old cats, mean /sup 51/Cr-labeled erythrocyte survival was 144 hours, and mean plasma /sup 59/Fe-labeled transferrin disappearance halftime was 51 minutes. Erythrocyte use of radioiron was rapid and efficient, with 50% to 80% of labeled iron incorporated into the erythron by 100 hours after injection into the cat. Six cats with feline leukemia virus infection were studied. For 2 cats with erythroid aplasia associated with C subgroup of feline leukemia virus, erythrocyte survival times were similar to those determined for the healthy cats, but plasma radioiron disappearance half time and erythrocyte use of radioiron were markedly diminished.

  1. Changes in lymphoid populations of ageing CBA and NZB mice

    PubMed Central

    Zatz, Marion M.; Mellors, R. C.; Lance, E. M.

    1971-01-01

    Changes in subpopulations of lymphoid cells of normal (CBA) and autoimmune (NZB) mice were studied as a function of age, by observing migration patterns of 51Cr labelled lymph node, spleen and thymus cells from donors aged 8 days to 12 months. The method permits analysis of the proportions and numbers of recirculating and non-recirculating lymphocytes in lymphoid compartments. Changes in the lymphoid populations of CBA mice were found, which could be attributed to the normal processes of maturation and senescence. In NZB mice relative and absolute decreases in the recirculating cell content of lymph node and spleen were observed which coincided with the time of development of autoimmunity. The significance of these results, in relation to altered immunocompetence with age, is discussed. PMID:5576663

  2. Alteration of the electrophoretic mobility of human peripheral blood mononuclear cells following treatment with dimethyl sulfoxide

    SciTech Connect

    Skrabut, E.M.; Catsimpoolas, N.; Kurtz, S.R.; Griffith, A.L.; Valeri, C.R.

    1983-12-01

    Studies have been conducted to determine the effects of DMSO and freezing on the electrophoretic distribution of peripheral blood mononuclear cells. Sodium (/sup 51/Cr)chromate was used to label the cells, and the distributions of cell number and cell-associated radioactivity were determined. Cells treated with DMSO had a narrower distribution of electrophoretic mobilities when compared with those not treated. DMSO-treated cells also demonstrated a more homogeneous distribution of radioactivity relative to the cell distribution than did the nontreated cells. The freezing of DMSO-treated cells did not result in any additional alteration of electrophoretic pattern compared to DMSO treatment alone. Analysis by linear categorization techniques indicated that the DMSO-treated and nontreated cells were completely distinguished by their electrophoretic behavior.

  3. Mycoplasma pneumoniae induces cytotoxic activity in guinea pig bronchoalveolar cells

    SciTech Connect

    Kist, M.; Koester, H.; Bredt, W.

    1985-06-01

    Precultured guinea pig alveolar macrophages (AM) and freshly harvested alveolar cells (FHAC) activated by interaction with Mycoplasma pneumoniae were cytotoxic for xenogeneic /sup 75/selenomethionine-labeled tumor target cells. Phagocytosis of whole opsonized or nonopsonized M. pneumoniae cells was more effective in eliciting cytotoxicity than uptake of sonicated microorganisms. The addition of living mycoplasma cells to the assay system enhanced the cytotoxic effect considerably. Target cells were significantly more susceptible to the cytotoxic action of phagocytes if they were coated with mycoplasma antigen or cocultured together with M. pneumoniae. The activation of the phagocytes could be inhibited by 2-deoxy-D-glucose but not by antimicrobial substances suppressing mycoplasma protein synthesis. It was accompanied by /sup 51/Cr release without detectable signs of cell damage. The supernatants of activated cells were cytotoxic for approximately 24 h. Inhibition, release, and cytotoxic activity indicate the necessity of an intact metabolism of the effector cells and suggest a secretion of cytotoxic substances.

  4. The volume of vascular compartment in rat hind limb muscles

    PubMed Central

    Law, R. O.; Phelps, C. F.

    1966-01-01

    1. A non-recirculatory perfusion system has been developed suitable for the perfusion of the hind limbs of small experimental animals. 2. By means of it a solution of T. 1824-labelled serum albumin has been introduced into the vascular compartment of the hind limbs of female rats under isogravimetric conditions. Excision and analysis of certain muscles has been used to provide information concerning the percentage distribution of the labelled albumin within these muscles. 3. Experiments have been carried out in vivo employing [131I]labelled serum albumin and [51Cr]labelled erythrocytes in order to compare the vascular volumes determined under in vivo conditions and in perfusions, and to estimate the capillary haematocrit in vivo. 4. The physiological validity of the methods used and the results obtained has been discussed. PMID:5972152

  5. Absorption of methylmercury by the fetal guinea pig during mid to late gestation

    SciTech Connect

    Kelman, B.J.; Steinmetz, S.E.; Walter, B.K.; Sasser, L.B.

    1980-01-01

    Pregnant guinea pigs were injected with CH/sub 3/ /sup 203/HgCl at 22, 40, 47, 59, and 66 days of gestation, and fetal tissues were obtained 24 hours later. Autologous fetal erythrocytes were labeled with /sup 51/Cr and used to label the fetal blood pool at each gestational age except 22 days so that tissue-bound Hg could be calculated. In general, Hg absorbed by the whole fetus increased during gestation, in parallel with increasing tissue mass, while Hg found in whole placentas remained the same. Liver, kidney, blood, and brain contained the highest Hg concentration early in gestation. While it is difficult to interpret the potential effects of the increased Hg concentrations, particular attention should be paid to the brain, since it is considered a target tissue in MeHg toxicity.

  6. Ouabain sensitivity is linked to ras -transformation in human HOS cells.

    PubMed

    Benade, L E; Talbot, N; Tagliaferri, P; Hardy, C; Card, J; Noda, M; Najam, N; Bassin, R H

    1986-04-29

    Mouse cells transformed by the retroviral oncogene v-Ki- ras are significantly more sensitive to the toxic effects of 1mM ouabain than are their nontransformed counterparts. We have extended these findings to a human cell line (HOS). HOS cells (ATCC CRL 1543) are relatively resistant to treatment with 1 microM ouabain while KHOS cells (transformed by Kirsten murine sarcoma virus) are extremely sensitive. Two flat revertant cell lines isolated from the KHOS line and lacking the v- ras gene sequences are resistant to ouabain. This effect may be observed morphologically and can also be demonstrated by dye exclusion and plating efficiency tests. In addition, the toxic effects of ouabain may be rapidly and efficiently quantitated in a 51Cr-release assay. This differential lethality may be used to enrich the proportion of non-transformed revertants in populations of mutagen-treated transformed cells.

  7. Ouabain sensitivity is linked to ras -transformation in human HOS cells

    SciTech Connect

    Benade, L.E.; Talbot, N.; Tagliaferri, P.; Hardy, C.; Card, J.; Noda, M.; Najam, N.; Bassin, R.H.

    1986-04-29

    Mouse cells transformed by the retroviral oncogene v-Ki- ras are significantly more sensitive to the toxic effects of 1mM ouabain than are their nontransformed counterparts. We have extended these findings to a human cell line (HOS). HOS cells (ATCC CRL 1543) are relatively resistant to treatment with 1 microM ouabain while KHOS cells (transformed by Kirsten murine sarcoma virus) are extremely sensitive. Two flat revertant cell lines isolated from the KHOS line and lacking the v- ras gene sequences are resistant to ouabain. This effect may be observed morphologically and can also be demonstrated by dye exclusion and plating efficiency tests. In addition, the toxic effects of ouabain may be rapidly and efficiently quantitated in a /sup 51/Cr-release assay. This differential lethality may be used to enrich the proportion of non-transformed revertants in populations of mutagen-treated transformed cells.

  8. Band gap states of Ti, V, and Cr in 4H-silicon carbide

    NASA Astrophysics Data System (ADS)

    Achtziger, Norbert; Witthuhn, Wolfgang

    1997-07-01

    Band gap states of Ti, V, and Cr in n-type 4H-SiC were investigated by radiotracer deep level transient spectroscopy (DLTS). Doping with the radioactive isotopes 48V and 51Cr was done by recoil implantation followed by annealing (1600 K). Repeated DLTS measurements during the elemental transmutation of these isotopes to 48Ti and 51V, respectively, reveal the corresponding concentration changes of band gap states. Thus, six levels are identified in the band gap: Cr levels at 0.15, 0.18, and 0.74 eV, one V level at 0.97 eV, and two Ti levels at 0.13 and 0.17 eV below the conduction band edge.

  9. Band gap states of V and Cr in 6H-silicon carbide

    NASA Astrophysics Data System (ADS)

    Achtziger, N.; Grillenberger, J.; Witthuhn, W.

    Band gap states of Ti, V and Cr in n-type 6H-SiC were investigated by radiotracer deep level transient spectroscopy (DLTS). Doping with the radioactive isotopes 48V and 51Cr was done by recoil implantation followed by annealing (1600 K). Repeated DLTS measurements during the elemental transmutation of these isotopes to 48Ti and 51V respectively revealed the corresponding concentration changes of band gap states. Thus, three levels were identified in the band gap: a Cr level at 0.54 eV and two V levels at 0.71 and 0.75 eV below the conduction band edge. There are no deep levels of Ti in the upper part of the band gap.

  10. Adsorption of inorganic and organic ions to polycarbophil as a means of sustained-release dosage formulation.

    PubMed

    See, N A; Russell, J; Connors, K A; Bass, P

    1987-06-01

    The adsorption and desorption of drugs and inorganic ions to and from polycarbophil (PC), a polymer, were investigated to determine if PC would be a suitable carrier for sustained-release dosage formulations. Both in vitro and in vivo experiments with a polycarbophil-atropine sulfate complex demonstrated the gradual-release properties of this system. Adsorbed Cr3+ ions, like atropine, are released slowly. In contrast, 51CrO4(2-) ions are predominantly bound in an irreversible manner. A third group of drugs minimally adsorbed to PC under the conditions studied. We conclude that PC under both in vitro and in vivo conditions is able to bind certain ions and drugs and then release them over a period of time in a predictable and repeatable manner.

  11. Hypersplenism in Wilson's disease.

    PubMed

    Strickland, G T; Chang, N K; Beckner, W M

    1972-03-01

    Thirteen patients with Wilson's disease were compared with seven cirrhotic and 13 normal controls to define better the haematological abnormalities in this condition. Hypersplenism (anaemia, leukopenia, thrombocytopenia, and reduced red cell survival) commonly occurred in patients with both Wilson's disease and cirrhosis. These abnormalities correlated with splenic enlargement. Despite reduced haematocrits, red cell mass was greater in these two groups than in normal controls. Plasma volume and the body haematocrit/peripheral haematocrit ratios were also greater in patients with Wilson's disease and cirrhosis. Increased splenic sequestration of (51)Cr-tagged red blood cells was not demonstrated in any subjects. The hypersplenism in patients with Wilson's disease is similar to that found in patients with cirrhosis from other causes.

  12. Estimates of plasma, packed cell and total blood volume in tissues of the rainbow trout (Salmo gairdneri )

    USGS Publications Warehouse

    Gingerich, W.H.; Pityer, R.A.; Rach, J.J.

    1987-01-01

    Total blood volume and relative blood volumes in selected tissues were determined in non-anesthetized, confined rainbow trout by using super(51)Cr-labelled trout erythrocytes as a vascular space marker. Mean total blood volume was estimated to be 4.09 plus or minus 0.55 ml/100 g, or about 75% of that estimated with the commonly used plasma space marker Evans blue dye. Relative tissue blood volumes were greatest in highly perfused tissues such as kidney, gills, brain and liver and least in mosaic muscle. Estimates of tissue vascular spaces, made using radiolabelled erythrocytes, were only 25-50% of those based on plasma space markers. The consistently smaller vascular volumes obtained with labelled erythrocytes could be explained by assuming that commonly used plasma space markers diffuse from the vascular compartment.

  13. The SOX experiment in the neutrino physics

    NASA Astrophysics Data System (ADS)

    Di Noto, L.; Agostini, M.; Althenmüller, K.; Bellini, G.; Benziger, J.; Berton, N.; Bick, D.; Bonfini, G.; Bravo-Berguño, D.; Caccianiga, B.; Cadonati, L.; Calaprice, F.; Caminata, A.; Cavalcante, P.; Chavarria, A.; Chepurnov, A.; Cribier, M.; DAngelo, D.; Davini, S.; Derbin, A.; Durero, M.; Empl, A.; Etenko, A.; Farinon, S.; Fischer, V.; Fomenko, K.; Franco, D.; Gabriele, F.; Gaffiot, J.; Galbiati, C.; Gazzana, S.; Ghiano, C.; Giammarchi, M.; Göger-Neff, M.; Goretti, A.; Grandi, L.; Gromov, M.; Hagner, C.; Houdy, Th.; Hungerford, E.; Ianni, Al.; Ianni, An.; Jonquères, N.; Kobychev, V.; Korablev, D.; Korga, G.; Kryn, D.; Lasserre, T.; Laubenstein, M.; Lehnert, T.; Lewke, T.; Litvinovich, E.; Lombardi, F.; Lombardi, P.; Ludhova, L.; Lukyanchenko, G.; Machulin, I.; Manecki, S.; Maneschg, W.; Marcocci, S.; Maricic, J.; Meindl, Q.; Mention, G.; Meroni, E.; Meyer, M.; Miramonti, L.; Misiaszek, M.; Montuschi, M.; Mosteiro, P.; Musenich, R.; Muratova, V.; Oberauer, L.; Obolensky, M.; Ortica, F.; Otis, K.; Pallavicini, M.; Papp, L.; Perasso, L.; Perasso, S.; Pocar, A.; Ranucci, G.; Razeto, A.; Re, A.; Romani, A.; Rossi, N.; Saldanha, R.; Salvo, C.; Schönert, S.; Scola, L.; Simgen, H.; Skorokhvatov, M.; Smirnov, O.; Sotnikov, A.; Sukhotin, S.; Suvorov, Y.; Tartaglia, R.; Testera, G.; Veyssière, C.; Vivier, M.; Vogelaar, R. B.; von Feilitzsch, F.; Wang, H.; Winter, J.; Wojcik, M.; Wright, A.; Wurm, M.; Zaimidoroga, O.; Zavatarelli, S.; Zuber, K.; Zuzel, G.

    2015-01-01

    SOX (Short distance neutrino Oscillations with BoreXino) is a new experiment that takes place at the Laboratori Nazionali del Gran Sasso (LNGS) and it exploits the Borexino detector to study the neutrino oscillations at short distance. In different phases, by using two artificial sources 51Cr and 144Ce-144Pr, neutrino and antineutrino fluxes of measured intensity will be detected by Borexino in order to observe possible neutrino oscillations in the sterile state. In this paper an overview of the experiment is given and one of the two calorimeters that will be used to measure the source activity is described. At the end the expected sensitivity to determine the neutrino sterile mass is shown.

  14. Psychoneuroimmunology and natural killer cells: the chromium release whole blood assay.

    PubMed

    Fletcher, Mary Ann; Barnes, Zachary; Broderick, Gordon; Klimas, Nancy G

    2012-01-01

    Natural killer (NK) cells are an essential component of innate immunity. These lymphocytes are also sensitive barometers of the effects of endogenous and exogenous stressors on the immune system. This chapter will describe a chromium ((51)Cr) release bioassay designed to measure the target cell killing capacity of NK cells (NKCC). Key features of the cytotoxicity assay are that it is done with whole blood and that numbers of effector cells are determined for each sample by flow cytometry and lymphocyte count. Effector cells are defined as CD3-CD56+ lymphocytes. Target cells are the K562 eyrthroleukemia cell line. Killing capacity is defined as number of target cells killed per effector cell, at an effector cell/target cell ratio of 1:1 during a 4 h in vitro assay.

  15. Observation of Energy-Dependent Electron-Capture Decay in Secondary Galactic Cosmic Rays

    NASA Astrophysics Data System (ADS)

    Niebur, S. M.; Binns, W. R.; Hink, P. L.; Israel, M. H.; Klarmann, J.; Lijowski, M.; Christian, E. R.; von Rosenvinge, T. T.; Cummings, A. C.; George, J. S.; Leske, R. A.; Mewaldt, R. A.; Stone, E. C.; Wiedenbeck, M. E.; Yanasak, N. E.

    2000-04-01

    Secondary galactic cosmic rays are produced at cosmic ray energies by fragmentation of primary cosmic rays during propagation through the interstellar medium; these nuclei carry a signature of the energy at which they were produced. Although electron-capture decay is inhibited at most of the energies typical of cosmic rays, decay is possible at the lower energies for isotopes such as 51Cr and 49V. We have analyzed Titanium, Vanadium, and Chromium isotopic data from the Cosmic Ray Isotope Spectrometer on ACE and found evidence of electron-capture decay at lower energies. We will present a comparison of secondary electron-capture decay isotope abundances and abundances of their decay products with results from improved propagation models in order to discuss the amount of electron-capture decay and subsequent acceleration that may have occurred during propagation.

  16. Influence of cadmium on isolated peritoneal macrophage populations: cadmium inhibits Fc receptor internalization

    SciTech Connect

    Cook, G.B.

    1985-01-01

    In vitro experiments were performed to examine the effect of cadmium on adherent phagocytic cell populations. The authors were able to demonstrate, in vitro, a phagocytic defect that was originally observed in an in vivo system. Using in vitro methodologies, cadmium was found to inhibit opsonin-dependent but not opsonin-independent phagocytosis in two different populations of macrophages. The receptors through which the opsonized /sup 51/Cr-ElgG were internalized were characterized as Fc receptors. They were able to demonstrate that cadmium could reversibly inhibit internalization of Fc receptors. This mechanism, rather than an alteration of the receptors' binding capabilities, was responsible for the observed inhibition of Fc mediated (opsonin-dependent) phagocytosis in both populations of macrophages tested. The defect was not specific for cadmium per se. Zinc treatment caused a similar inhibition of Fc receptor mediated phagocytosis.

  17. Blind confirmation in Leiden of Geczy factor on the cells of Dutch patients with ankylosing spondylitis

    SciTech Connect

    Geczy, A.F.; van Leeuwen, A.; van Rood, J.J.; Ivanyi, P.; Breur, B.S.; Cats, A.

    1986-11-01

    A follow-up blind study, of the ability of cross-reactive antisera to distinguish between the cells of Dutch patients with ankylosing spondylitis (AS) and normal controls, was performed in Leiden. Of the 45 cell samples tested, 29 were fresh peripheral blood mononuclear (PBM) cells while 15 were cryopreserved PBM. No false positives but one false negative was identified among the 45 samples, and the negative was confirmed after the recoded cryopreserved cells from this patient were retested. It is concluded that the cross-reactive antisera raised in Sydney give good discrimination between patients and normals. Factors affecting the success of the /sup 51/Cr-release cytotoxicity assay, and possible reasons for the failure of others to confirm these observations, are briefly discussed.

  18. Whole body and tissue blood volumes of two strains of rainbow trout (Oncorhynchus mykiss )

    USGS Publications Warehouse

    Gingerich, W.H.; Pityer, R.A.; Rach, J.J.

    1990-01-01

    1. Estimates of apparent packed cell, plasma and total blood volumes for the whole body and for 13 selected tissues were compared between Kamloops and Wytheville strains of rainbow trout (Oncorhynchus mykiss) by the simultaneous injection of two vascular tracers, radiolabeled trout erythrocytes (51Cr-RBC) and radioiodated bovine serum albumin (125I-BSA). 2. Whole body total blood volume, plasma volume and packed cell volume were slightly, but not significantly greater in the Wytheville trout, whereas, the apparent plasma volumes and total blood volumes in 4 of 13 tissues were significantly greater in the Kamloops strain. 3. Differences were most pronounced in highly perfused organs, such as the liver and kidney and in organs of digestion such as the stomach and intestines. 4. Differences in blood volumes between the two strains may be related to the greater permeability of the vascular membranes in the Kamloops strain fish.

  19. Studies with Radioactive Endotoxin II. Clearance of 3H-Labelled Endotoxin from the Blood of Calves

    PubMed Central

    Maxie, M. G.; Valli, V. E. O.; Lumsden, J. H.

    1974-01-01

    The clearance of 3H-labelled Pseudomonas endotoxin from the blood was studied in a nontolerant and in an endotoxin tolerant state. Calves were rendered tolerant to the toxic effects of the endotoxin by four daily intravenous injections of endotoxin at the dose rate of 5 µg/kg body weight. Clearance of 3H-endotoxin from the blood of nontolerant calves occurred more slowly than did clearance of 51Cr-endotoxin and was not significantly (P<0.05) affected by the development of tolerance. The lungs and liver were the major organs involved in the clearance of 3H-endotoxin from the blood of calves. Leukocytes and erythrocytes, but not platelets, were shown to participate in endotoxin clearance in calves. 3H2O, the control substance used in calves, was not concentrated within any particular organ but rapidly equilibrated with total body water and was slowly excreted. PMID:4279755

  20. Psychoneuroimmunology and natural killer cells: the chromium release whole blood assay.

    PubMed

    Fletcher, Mary Ann; Barnes, Zachary; Broderick, Gordon; Klimas, Nancy G

    2012-01-01

    Natural killer (NK) cells are an essential component of innate immunity. These lymphocytes are also sensitive barometers of the effects of endogenous and exogenous stressors on the immune system. This chapter will describe a chromium ((51)Cr) release bioassay designed to measure the target cell killing capacity of NK cells (NKCC). Key features of the cytotoxicity assay are that it is done with whole blood and that numbers of effector cells are determined for each sample by flow cytometry and lymphocyte count. Effector cells are defined as CD3-CD56+ lymphocytes. Target cells are the K562 eyrthroleukemia cell line. Killing capacity is defined as number of target cells killed per effector cell, at an effector cell/target cell ratio of 1:1 during a 4 h in vitro assay. PMID:22933153

  1. Improved red blood cell survival after cardiac operations with administration of urea during cardiopulmonary bypass

    SciTech Connect

    Roberts, D.; Bake, B.; William-Olsson, G.

    1985-01-01

    The plasma hemoglobin and red blood cell survival (half-life of /sup 51/Cr) was studied in 48 patients undergoing single valve replacement or coronary artery bypass graft. Urea or placebo was administered during cardiopulmonary bypass in a prospective, randomized, double-blind manner to test the potential effect on mechanical hemolysis. The mean plasma hemoglobin level at the end of extracorporeal circulation was significantly lower in the urea-treated groups (coronary artery bypass 342 mg/L; valve replacement 364 mg/L) than in the control groups (coronary artery bypass 635 mg/L, valve replacement 518 mg/L. The half-life of /sup 51/Cr was significantly longer in the urea-treated patients (coronary artery bypass 18 days; valve replacement 16 days) than in the control groups (coronary artery bypass 12.4 days; valve replacement 12.7 days) but still below the normal reference value (29 +/- 4 days). The plasma hemoglobin returned to near normal values (50 mg/L) the day after operation (day 1) and remained low with no differences between control and urea-treated groups. The total blood hemoglobin was followed for 2 weeks after operation and showed significantly less anemia in the urea-treated group. The lowest mean blood hemoglobin level was noted between days 5 and 9-114 (coronary artery bypass) and 107 (valve replacement) gm/L in the urea-treated patients compared to 92.3 gm/L in the control subjects. The reduction in the severity of the anemia led to less transfusion in the urea-treated patients (approximately 0.5 unit/patient) than in the control subjects (approximately 1 unit/patient) between days 3 and 14.

  2. Cell damage by cytolysin. Spontaneous recovery and reversible inhibition by divalent cations

    SciTech Connect

    Bashford, C.L.; Menestrina, G.; Henkart, P.A.; Pasternak, C.A.

    1988-12-01

    Cytolysin-induced membrane damage (which requires low Ca2+) has been studied 1) in E by assay of hemolysis, 2) in Lettre cells by measurement of transmembrane potential, intracellular content of K+ and Na+, leakage of phosphoryl(3H)choline or 51Cr from (3H)choline-labeled or 51CrO4(2-)-labeled cells and leakage of lactate dehydrogenase, and 3) in phospholipid bilayers by measurement of electrical conductivity changes. In Lettre cells, damage is restricted and reversible: little lactate dehydrogenase leaks from cells that leak substantial amounts of Na+, K+, and phosphoryl(3H)choline; at low amounts of cytolysin, membrane potential and intracellular content of Na+ and K+ recover within minutes. In E and Lettre cells, membrane damage is inhibited by Zn2+, by high Ca2+, or by low pH. Inhibition is reversible: addition of EGTA to Zn2+-protected E or Lettre cells (incubated in the presence of cytolysin, low Ca2+ and Zn2+) initiates leakage; removal of Zn2+ (and cytolysin and Ca2+) by washing also initiates leakage; such leakage is again sensitive to Zn2+, high Ca2+, or H+. In phospholipid bilayers, channels induced by cytolysin (at low Ca2+) are partially closed by negative voltage; Ca2+, Zn2+, or H+ promote channel closure. Channels are re-opened (only partially in the case of Zn2+) by positive voltage. From all these results it is concluded that the action of cytolysin on membranes is similar to that of other pore-forming agents: damage does not necessarily lead to lysis of nucleated cells, and can be prevented by Ca2+, Zn2+, or H+.

  3. [Affinity of the elements in group VI of the periodic table to tumors and organs].

    PubMed

    Ando, A; Hisada, K; Ando, I

    1976-10-01

    In order to investigate the tumor affinity radioisotopes, chromium (51Cr), molybdenum (99Mo), tungsten (181W), selenium (75Se) and tellurium (127mTe)--the elements of group VI in the periodic table--were examined, using the rats which were subcutaneously transplanted with Yoshida sarcoma. Seven preprarations, sodium chromate (Na251CrO4), chromium chloride (51CrCl3), normal ammonium molybdate ((NH4)299MoO7), sodium tungstate (Na2181WO4), sodium selenate (Na275SeO4), sodium selenite (Na275SeO3) and tellurous acid (H2127mTeO3) were injected intravenously to each group of tumor bearing rats. These rats were sacrificed at various periods after injection of each preparation: 3 hours, 24 hours and 48 hours in all preparations. The radioactivities of the tumor, blood, muscle, liver, kidney and spleen were measured by a well-type scintillation counter, and retention values (in every tissue including the tumor) were calculated in percent of administered dose per g-tissue weight. All of seven preparations did not have any affinity for malignant tumor. Na251CrO4 and H2127mTeO3 had some affinity for the kidneys, and Na275SeO3 had some affinity for the liver. Na2181WO4 and (NH4)299MoO4 disappeared very rapidly from the blood and soft tissue, and about seventy-five percent of radioactivity was excreted in urine within first 3 hours.

  4. The role of apoptosis in bispecific antibody-mediated T-cell cytotoxicity.

    PubMed Central

    Kroesen, B. J.; Wellenberg, G. J.; Bakker, A.; Helfrich, W.; The, T. H.; de Leij, L.

    1996-01-01

    In this report we describe the role of apoptosis in the process of tumour cell killing by bispecific monoclonal antibody (BsMAb)-redirected cytolytic T cells. The BsMAb used, BIS-1, has dual specificity for the CD3 complex on T cells and the pancarcinoma-associated 38 kDa transmembrane antigen EGP-2. BIS-1 allows activated T cells to specifically recognise and kill EGP-2-positive but not EGP-2-negative target cells. An assay was developed to quantify apoptosis in cells by separation of 3H-thymidine-labelled low-molecular, i.e. fragmented, from high-molecular, i.e. non-fragmented DNA. The presence of low molecular weight DNA was measured both within the target cells and in the cell-free supernatant. After exposure to BIS-1-redirected, -activated T cells, apoptosis was observed in EGP-2-positive target cells but not in EGP-2-negative target cells. Also no DNA fragmentation proved to be induced in the activated effector cells during assay. The degree of EGP-2-positive target DNA fragmentation depended on the concentration of BsMAb, the E/T ratio and the incubation time. Using a low E/T ratio (1/1), DNA fragmentation in and 51Cr release from target cells showed similar characteristics and kinetics. At higher E/T ratio (20/1), the 51Cr release from the target cells increased to a greater extent than the percentage fragmented target cell DNA. Inhibitors of DNA fragmentation added to the cytotoxicity assay inhibited not only DNA fragmentation, but also the release of chromium-51 from the target cells, suggesting that apoptosis and cell lysis are closely related in BsMAb-mediated cell killing. Images Figure 1 PMID:8611371

  5. Intratypic and intertypic specificity of lymphocytes involved in the recognition of herpes simplex virus glycoproteins.

    PubMed Central

    Carter, V C; Rice, P L; Tevethia, S S

    1982-01-01

    Cytotoxic T lymphocytes (CTL) were generated in C57BL/6 mice with herpes simplex virus type 1 (HSV-1) (strains KOS, 17, HFEM, and mP) and HSV-2 (strains 186, G, and GP6). Effector lymphocytes were tested for cytotoxicity against syngeneic HSV-1- and HSV-2-infected cells in a 5-h 51Cr release assay. HSV-1 strain HFEM was found to induce CTL efficiently only when 100-fold more virus was used as compared with HSV-1 strains KOS, 17, and mP. All HSV-1 and HSV-2 strains induced cross-reactive populations of CTL. CTL generated by HSV-1 KOS and HSV-2 186 also demonstrated cross-reactivity in an ear-swelling model for delayed-type hypersensitivity. Lymphocytes generated by all HSV-2 strains were highly efficient at lysing HSV-1-infected target cells. However, HSV-2-infected target cells were found to be less susceptible to lysis by either HSV-1 or HSV-2 CTL than were HSV-1-infected target cells. The lowered susceptibility of HSV-2-infected cells was not due to an inefficient infection of BL/6 WT-3 cells as measured by standard growth assays and infectious center assays. Varying the multiplicity of infection or the time of infection did not increase the susceptibility of HSV-2-infected target cells to lysis by CTL. Increasing the effector-to-target-cell ratio resulted in an increased lysis of both HSV-1- and HSV-2-infected target cells by CTL, but the level of HSV-2-infected target cell lysis still did not approach the level of HSV-1-infected target cell lysis. HSV-2-infected cells were as efficient as HSV-1-infected cells in the cold cell competition assay employed in reducing the lysis of 51Cr-labeled, HSV-1-infected target cells. In addition, HSV-2-infected cells were susceptible to lysis by HSV-immune serum and complement. PMID:6286488

  6. Relationship of oxidant-mediated cytotoxicity to phospholipid metabolism in endothelial cells

    SciTech Connect

    Duane, P.G.; Rice, K.L.; Charboneau, D.E.; King, M.B.; Gilboe, D.P.; Niewoehner, D.E. )

    1991-05-01

    Exposure to oxidants permeabilizes cell membranes and liberates unesterified fatty acids (UFA) in a variety of cell types, including endothelial cells. Products of phospholipase activity, particularly UFA and lysophosphatides, possess potent detergent-like properties, and we postulated that oxidant injury might be mediated by the accumulation of these toxic phospholipase products. Several radiolabels were incorporated into defined positions in the phospholipids of cultured, confluent bovine pulmonary endothelial cells (BPAEC). The release of radiolabeled fatty acids and the accumulation of cell-associated phospholipase products were measured and compared to a standard cytotoxicity assay ({sup 51}Cr release) in response to an oxidant stress, in this case 0.1 to 10 mM hydrogen peroxide (H{sub 2}O{sub 2}). H{sub 2}O{sub 2} caused time- and dose-dependent {sup 51}Cr release as well as liberation of saturated (({sup 14}C)stearic acid) and unsaturated (({sup 3}H)arachidonic acid) fatty acids and the accumulation of phospholipase A2 and C products. The ability of BPAEC to incorporate UFA into complex phospholipids was shown to be severely impaired in the presence of H{sub 2}O{sub 2}. Further studies showed that H{sub 2}O{sub 2} caused depletion of BPAEC adenosine triphosphate (ATP) content to undetectable levels, and that the depletion of cellular ATP by iodoacetic acid induced substantial release of ({sup 3}H)arachidonic acid but not ({sup 14}C)stearic acid from BPAEC. This finding suggests that release of UFA in response to an oxidant stress may be due in part to a defect in ATP-dependent reacylation pathways and need not reflect any increase in phospholipase activities. Also unsaturated fatty acids were found to be toxic to BPAEC upon adding them to supernatants of cultured monolayers.

  7. Dual-isotope method for determination of human zinc absorption: the use of a test meal of turkey meat

    SciTech Connect

    Flanagan, P.R.; Cluett, J.; Chamberlain, M.J.; Valberg, L.S.

    1985-01-01

    The percentage of /sup 65/Zn taken up (absorbed) from extrinsically labeled turkey meat was calculated from the amounts of /sup 65/Zn and a nonabsorbed /sup 51/Cr marker present in the body or in a single stool specimen after 1-2 d. /sup 51/CrCl/sub 3/ proved to be a suitable marker for unabsorbed /sup 65/Zn and so the early determination of /sup 65/Zn absorption was possible. With stool counting, /sup 65/Zn absorption data from first stool samples after 1-2 d were accurate as judged by correlation with the amount of /sup 65/Zn in the body 7-10 d later (retention); results from subsequent stools gave lower absorption values due to the early excretion of some absorbed /sup 65/Zn. The dual-isotope method gave reproducible results when four successive tests of zinc absorption were carried out in a group of six subjects. The average (mean +/- SD) /sup 65/Zn absorption from turkey meals containing 31 mumol (2 mg) and 46 mumol (3 mg) of zinc was 39 +/- 8% and 29 +/- 6%, respectively, measured by stool counting; /sup 65/Zn absorption and retention correlated well in both studies. A series of different beverages was given in place of water with the turkey meal. Orange juice significantly reduced /sup 65/Zn absorption and milk also showed this tendency, but tea, whiskey, wine or beer had no significant effect on the absorption of /sup 65/Zn from the turkey meal. In groups of subjects the mean ratio of /sup 65/Zn absorption from extrinsically labeled turkey meat on two occasions (1.06) was not significantly different from that of the absorption of extrinsic to intrinsic /sup 65/Zn labels (1.16). The dual-isotope technique with either stool or body counting is suitable for the rapid determination of /sup 65/Zn absorption from extrinsically labeled turkey within 2 d.

  8. Use of a gamma-labeled bile acid (75SeHCAT) as a test of ileal function. Methods of improving accuracy

    SciTech Connect

    Ferraris, R.; Jazrawi, R.; Bridges, C.; Northfield, T.C.

    1986-05-01

    The object of the present study was to improve the accuracy of measurements of ileal function obtained by abdominal scanning and fecal counting after oral administration of the gamma-labeled bile acid 75seleno-homocholic acid-taurine (75SeHCAT), as current techniques do not distinguish between retention of the bile acid within the enterohepatic circulation from retention within the colon, and are also affected by incomplete stool collection when using the fecal method. We have therefore introduced the following modifications: (a) simultaneous ingestion of 51CrCl3 as a nonabsorbable correction marker for both the abdominal scanning and fecal counting methods; and (b) the use of 75SeHCAT counts over the gallbladder area on abdominal scanning, because these counts should be independent of colonic retention. We have studied 42 subjects, including 6 healthy controls, 6 ileal resection subjects, 15 ulcerative colitis patients, and 15 patients with unresected ileal Crohn's disease. Colonic retention (0%-68% per day) caused a variable overestimate of 75SeHCAT absorption. Corrected measurements of the fecal absorption index determined by a gamma-counter and of the abdominal absorption coefficient determined by a gamma-camera correlated well with each other (r = 0.92, p less than 0.0001), providing an internal validation of the 51CrCl3 modification. The fecal absorption index could also be determined from the carmine-rich stool collection of a single day, and this also correlated well with the abdominal absorption coefficient (r = 0.81, p less than 0.0001). Gallbladder scanning alone was simpler, involving only one isotope, but it correlated less well with the fecal absorption index than did the abdominal absorption coefficient (r = -0.64, p less than 0.001).

  9. Paraquat-induced injury of type II alveolar cells. An in vitro model of oxidant injury

    SciTech Connect

    Skillrud, D.M.; Martin, W.J.

    1984-06-01

    Paraquat, a widely used herbicide, causes severe, often fatal lung damage. In vivo studies suggest the alveolar epithelial cells (types I and II) are specific targets of paraquat toxicity. This study used /sup 51/Cr-labeled type II cells to demonstrate that paraquat (10-5 M) resulted in type II cell injury in vitro, independent of interacting immune effector agents. With /sup 51/Cr release expressed as the cytotoxic index (Cl), type II cell injury was found to accelerate with increasing paraquat concentrations (10(-5) M, 10(-4) M, and 10(-3) M, resulting in a Cl of 12.5 +/- 2.2, 22.8 +/- 1.8, and 35.1 +/- 1.9, respectively). Paraquat-induced cytotoxicity (10(-4) M, with a Cl of 22.8 +/- 1.8) was effectively reduced by catalase 1,100 U/ml (Cl 8.0 +/- 3.2, p less than 0.001), superoxide dismutase, 300 U/ml (Cl 17.4 +/- 1.7, p less than 0.05), alpha tocopherol, 10 micrograms/ml (Cl 17.8 +/- 1.6, p less than 0.05). Paraquat toxicity (10(-3) M) was potentiated in the presence of 95% O2 with an increase in Cl from 31.1 +/- 1.7 to 36.4 +/- 2.3 (p less than 0.05). Paraquat-induced type II cell injury was noted as early as 4 h incubation by electron microscopic evidence of swelling of mitochondrial cristae and dispersion of nuclear chromatin. Thus, this in vitro model indicates that paraquat-induced type II cell injury can be quantified, confirmed by morphologic ultrastructural changes, significantly reduced by antioxidants, and potentiated by hyperoxia.

  10. Bile acid retention after Roux-en-Y biliary reconstruction demonstrated by tauro-23-(75Se)selena-25-homocholic acid. An experimental animal study.

    PubMed

    Bolder, U; Bares, R; Arlt, G; Hojabri, K; Schumpelick, V

    1990-07-01

    In this study of 65 laboratory rats the influence of biliary Roux-en-Y anastomosis on the enterohepatic circulation was investigated. Three different types of Roux-en-Y limbs were studied and compared with sham-operated controls. To collect information about the influence of the length and motility of the Roux limb, 10-cm and 3-cm isoperistaltic Roux segments and 10-cm anisoperistaltic Roux limbs were investigated. 75SeHCAT, a tau-labelled synthetic bile acid, was used for assessment of enterohepatic circulation. Intestinal transit time was evaluated by measuring the decrease of whole-body counts of 51Cr-labelled ethylenediamintetraacetic acid (EDTA), an inert marker of intraluminal contents. 99mTc-labelled dimethyl-iminodiacetic acid (HIDA) was used to detect possible alterations of bile flow. 75SeHCAT results showed marked retention of bile acids in all Roux-en-Y animals compared with controls. Results of short and long Roux limbs did not differ significantly from each other (t1/2 10 cm, 59.8 h; 3 cm, 59.3 h; control, 42.6 h; p less than or equal to 0.001). The anisoperistaltic Roux limbs showed prolonged retention even when compared with isoperistaltic limbs (t1/2 98.6 h; p less than or equal to 0.001). 51Cr-EDTA results did not show significant differences between all groups. 99mTc-HIDA showed undelayed excretion in all animals but increase of radioactivity at the site of the Roux-en-Y enteroanastomosis, indicating marked stasis in the biliodigestive Roux limb. The results demonstrate the impact of biliary Roux-en-Y anastomosis on bile acid retention due to stasis in the defunctioning jejunal segment.

  11. Deletion of the Platelet-Specific Alloantigen PlA1 from Platelets in Glanzmann's Thrombasthenia

    PubMed Central

    Kunicki, Thomas J.; Aster, Richard H.

    1978-01-01

    Expression of a Platelet-specific alloantigen (PlA1) was studied in five unrelated patients with Glanzmann's thrombasthenia using immunologic techniques based on release of 51Cr from tagged platelets by PlA1-specific antibody. Less than 1% of the normal quantity of PlA1 could be detected on platelets of patients 1, 2, and 3; platelets from patients 4 and 5 contained 22 and 12% of normal levels, respectively. After treatment with bromelain, platelets from patients 4 and 5, but not those from patients 1, 2, and 3, released 51Cr as well as normal PlA1-positive platelets when exposed to anti-PlA1. Platelets from each of the five patients reacted normally with drug-dependent antibodies and with autoantibodies specific for platelets. Polyacrylamide gel electrophoresis of thrombasthenic platelets showed marked deficiencies of glycoproteins IIbα and III (P < 0.0005), confirming recent reports of others. Deficiency of the two proteins as determined by gel scanning was more pronounced in patients 1, 2, and 3 than in patients 4 and 5. Normal levels of glycoproteins IIbα and III were found in platelets from normal subjects negative for PlA1. These observations are consistent with the possibility that the PlA1 antigen is located on one or both of the glycoproteins lacking in Glanzmann's thrombasthenia, although other explanations are possible. They further suggest that patients with thrombasthenia may be heterogeneous in respect to the degree to which these glycoproteins are deleted. The PlA1 antigen can be measured with considerable precision and may provide a marker useful for the diagnosis and study of Glanzmann's disease. PMID:566280

  12. Favism: divicine hemotoxicity in the rat.

    PubMed

    McMillan, D C; Jollow, D J

    1999-10-01

    Favism is an acute hemolytic anemia known to occur in susceptible individuals who ingest fava beans. Susceptibility to favism is conferred by a genetic deficiency in erythrocytic glucose-6-phosphate dehydrogenase (G6PD) activity. Although the fava bean pyrimidine aglycones, divicine and isouramil, have been implicated in the onset of favism in humans, the lack of a well-defined experimental animal model for favism has hampered progress in elucidating the mechanism underlying hemotoxicity. We have examined whether a favic-like response could be provoked in G6PD-normal rats treated with synthetic divicine. Intraperitoneal administration of divicine to rats preloaded with 51Cr-tagged erythrocytes resulted in a severe, dose-dependent decrease in blood radioactivity (TD50 approximately 0.5 mmol/kg) within 24 h. The increased rate of removal of blood radioactivity was accompanied by a rapid decline in reduced glutathione levels in the blood, decreased hematocrits, marked hemoglobinuria, splenic enlargement, and reticulocytosis. In vitro exposure of 51Cr-tagged red cells to divicine before their re-administration to isologous rats also resulted in a sharp, concentration-dependent decrease in erythrocyte survival in vivo (TC50 approximately 1.5 mM), and these divicine-damaged red cells were removed from the circulation by the spleen. These data demonstrate that a favic response can be induced in G6PD-normal rats treated with divicine, and that hemolytic activity can be reproduced in isolated red cells under conditions that will allow a direct examination of the mechanism underlying this hemotoxicity. PMID:10543033

  13. Chromium absorption in the vascularly perfused rat intestine

    SciTech Connect

    Dowling, H.J.; Offenbacher, E.G.; Pi-Sunyer, F.X.

    1986-03-01

    The mechanism of chromium (Cr) absorption by the rat small intestine was investigated using a double perfusion technique wherein the luman of the small intestine and the vasculature supplying it were separately perfused. The intestinal perfusate (IP) was a nutrient-rich tissue culture medium (TCM) with added inorganic Cr and /sup 51/Cr. The vascular perfusate (VP) was a Krebs-Ringer bicarbonate solution (KRB) containing 4.7% dextran, 0.1% glucose and 5% human serum. Cr absorption was calculated by the amount of /sup 51/Cr detected in the VP. To determine the transport mechanism for Cr, its absorption into the VP was measured at various Cr concentrations of the IP ranging from 10-400 ppb CrCl/sub 3/. The amount of Cr absorbed into the blood rose linearly with the intestinal Cr concentration suggesting a process of simple diffusion. Manipulations of the VP and IP constituents were made to investigate their effects on Cr absorption. When serum was omitted from the VP, Cr adsorption was suppressed, suggesting that serum component(s) are necessary for optimal Cr absorption. When either of 2 plasma transport proteins (apo-transferrin, albumin) were added to the serum-free VP at physiological levels, Cr absorption returned to, but did not exceed, control levels. When the TCM was replaced with a KRB solution; Cr absorption was suppressed indicating that there are nutrient(s) of the TCM which facilitate Cr absorption. Further suppression occurred when a Cr concentration gradient opposing Cr absorption was created (IP at 100 ppb Cr, VP at 400 ppb Cr).

  14. A novel one-step, highly sensitive fluorometric assay to evaluate cell-mediated cytotoxicity.

    PubMed

    Nociari, M M; Shalev, A; Benias, P; Russo, C

    1998-04-15

    In this study, a fluorometric method using alamarBlue has been developed for detecting cell-mediated cytotoxicity in vitro. AlamarBlue is a non-toxic metabolic indicator of viable cells that becomes fluorescent upon mitochondrial reduction. Specific lysis of targets by effector cells is quantified by comparing the total number of viable cells in wells containing effector and targets together, with wells where target and effector cells were separately seeded. Cell-mediated cytotoxic activity by alloreactive T cells and natural killer cells has been detected using a novel application of the alamarBlue technique. The assay that we have developed to detect cell-mediated cytotoxicity is extremely sensitive and specific and requires a significant lower number of effector cells than the standard 51Cr assay. Since alamarBlue reagent is non-toxic to cells and the assay can be performed under sterile conditions, effector cells may be recovered at the end for further analysis or cell expansion, if desired. Direct comparison of cell-mediated cytotoxicity measured by the alamarBlue method with the standard 51Cr release assay revealed that the former method is as specific and more sensitive than the conventional assay. Moreover, very small inter and intra-assay variations have been observed for alamarBlue cytotoxicity assays. In conclusion, this study shows that the alamarBlue assay is an extremely sensitive, economical, simple and non-toxic procedure to evaluate cell-mediated cytotoxicity that yields accurate results using a limited number of effector cells. Furthermore, since this assay is a one-step procedure, and does not involve any risk for the personnel, it may be useful to analyze automatically cell-mediated cytotoxicity in a large number of samples.

  15. Effects of adenosine derivatives on cytotoxic T lymphocyte (CTL) and primary antibody responses in mice

    SciTech Connect

    Kandil, O.; Nakic, M.; Nelson, J.A.

    1986-03-05

    Accumulation of adenosine (Ado) and/or deoxyadenosine (dAdo) in adenosine deaminase deficiency is thought to mediate the immunodeficiency associated with the genetic disease in humans. To study the mechanism by which immune function is impaired, we are using analogs which are not substrates for the deaminase. The analogs and their doses (mg/kg/day, IP) are: an Ado analog, Tubercidin (2); and two dAdo analogs, 2-chlorodeoxy-adenosine (50) and 2-fluoro, arabinosyl AMP (250). CTL were generated by injecting C57B1/6 mice with 2.5 x 10/sup 7/ P815 mastocytoma cells, IP. Groups of mice were then treated once daily on days 9-11 with the analogs. On day 12, the animals were sacrificed and spleen cell suspensions were enriched for CTL by passage through nylon wool columns. CTL were measured against /sup 51/Cr-labeled P815 targets using a standard /sup 51/Cr-release assay. Primary antibody response was assessed in AKR mice following immunization with a T-dependent (sheep erythrocytes) or T-independent (TNP-Ficoll) antigen. Animals were treated with the analogs on days 1-3. On day 4, spleen cells were removed and assayed for antibody response in a plaque-forming assay. The dAdo analogs, but not tubercidin, inhibited the immune functions at these near-maximally tolerated doses. Treatment of the mice with the deaminase inhibitor, deoxycoformycin (1 mg/kg/day), was not inhibitory to these responses.

  16. Entamoeba histolytica: target cells killed by trophozoites undergo DNA fragmentation which is not blocked by Bcl-2.

    PubMed

    Ragland, B D; Ashley, L S; Vaux, D L; Petri, W A

    1994-11-01

    Amebic destruction of neutrophils and macrophages is contact-dependent. Adherence is mediated by a galactose-specific surface lectin on the amebic membrane. The pathway by which contact-dependent cytolysis of the target cell occurs is unknown. We hypothesized that target cell death is due to the triggering of apoptosis (programmed cell death) by the amebae. The purpose of this study was to determine whether target cell DNA is fragmented into a ladder pattern characteristic of apoptosis and to test whether overexpression of Bcl-2, a protein that confers resistance to apoptotic death from some stimuli, blocks target cell killing. The murine myeloid cell line FDC-P1 transfected with a retrovirus construct expressing the Bcl-2 protein was shown to be resistant to the apoptotic death that the parental line undergoes upon growth factor deprivation. 51Cr-labeled FDC-P1 control or bcl-2-transfected cells were incubated with Entamoeba histolytica (4:1 cell/ameba ratio) and killing of the cells was assessed by 51Cr release. Both cell lines were susceptible to contact-dependent killing. Death induced by the amebae in the bcl-2-transfected cells resulted in a DNA ladder fragmentation pattern (using [125I]iododeoxyuridine-labeled target cell DNA) identical to that seen in the control cells undergoing apoptosis upon growth factor withdrawal. Target cell DNA fragmentation was inhibited by blocking adherence with galactose. Our data suggest that target cell killing by E. histolytica can occur via Bcl-2-independent apoptotic mechanism. PMID:7957763

  17. Biphasic effect of duodenal ulcerogens cysteamine (C), mepirizole (M) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropryridine (MPTP) on gastric emptying in the rat

    SciTech Connect

    Pihan, G.; Kline, T.J.; Szabo, S.

    1986-03-01

    The effect of acute or chronic administration of duodenal ulcerogens on gastric emptying (GE) of a liquid meal was investigated. In Sprague-Dawley rats (150-200g) 2 ml of /sup 51/Cr in 2% dextrose (5000 CPM) was given intragastrically and the GE half life was established as 7.6 min (controls). In acute experiments, C (30mg/100g), M (40mg/100g) or MPTP (4mg/100g) injected subcutaneously all delayed GE at 1, 2, 4, 8 and 24 hr by 15-77%. Maximal GE delay (p<0.05) by 77, 48 or 71% was found 1, 1 or 2 hr after C, M or MPTP, respectively. In chronic experiments, C (22mg/100g) was given x3 on the first day and once daily (25mg/100g) for 3 or 10 additional days. M (20mg/100g) once daily and MPTP (4mg/100g) x3 daily were given for 4 or 11 days. GE was measured on the 5th and 12th day. Chronically, MPTP accelerated GE by 63 and 31% at 5 and 12 days (p<0.05) and C and M did not change GE. The severity of duodenal ulcers correlated (p<0.05) with the amount of /sup 51/Cr remaining in the stomach: r=-0.68, -0.74 and -0.70 after C, M and MPTP, respectively. Acute administration of duodenal ulcerogens delay GE in rats. Chronic treatment with duodenal ulcerogens either accelerates or does not change GE. The most severe chronic ulcers exhibit the most rapid emptying. The authors data suggest that rapid GE might be a secondary rather than a primary alteration in duodenal ulceration.

  18. Modulation of distal colonic epithelial barrier function by dietary fibre in normal rats

    PubMed Central

    Mariadason, J; Catto-Smith, A; Gibson, P

    1999-01-01

    BACKGROUND—Dietary fibre influences the turnover and differentiation of the colonic epithelium, but its effects on barrier function are unknown. 
AIMS—To determine whether altering the type and amount of fibre in the diet affects paracellular permeability of intestinal epithelium, and to identify the mechanisms of action. 
METHODS—Rats were fed isoenergetic low fibre diets with or without supplements of wheat bran (10%) or methylcellulose (10%), for four weeks. Paracellular permeability was determined by measurement of conductance and 51Cr-EDTA flux across tissue mounted in Ussing chambers. Faecal short chain fatty acid (SCFA) concentrations were assessed by gas chromatography, epithelial kinetics stathmokinetically, and mucosal brush border hydrolase activities spectrophotometrically. 
RESULTS—Body weight was similar across the dietary groups. Conductance and 51Cr-EDTA flux were approximately 25% higher in animals fed no fibre, compared with those fed wheat bran or methylcellulose in the distal colon, but not in the caecum or jejunum. Histologically, there was no evidence of epithelial injury or erosion associated with any diet. The fibres exerted different spectra of effects on luminal SCFA concentrations and pH, and on mucosal indexes, but both bulked the faeces, were trophic to the epithelium, and stimulated expression of a marker of epithelial differentiation. 
CONCLUSIONS—Both a fermentable and a non-fermentable fibre reduce paracellular permeability specifically in the distal colon, possibly by promoting epithelial cell differentiation. The mechanisms by which the two fibres exert their effects are likely to be different. 

 Keywords: colon; differentiation; epithelium; fibre; paracellular permeability; proliferation PMID:10026327

  19. The induction of cytotoxicity by a bispecific antibody against CEA positive cell line, in vitro.

    PubMed

    Hideshima, T; Iwasaki, A; Baba, M; Yamashita, Y; Shirakusa, T; Okada, H

    1996-01-01

    A mouse anti-human carcinoembryonic antigen (CEA) x anti-human CD3 bispecific antibody, AB5C10*UCHT1, was developed. This antibody-heteroconjugate was chemically prepared by cross-linking the AB5C10 monoclonal antibody reactive with human CEA with the monoclonal antibody, UCHT1, which binds to CD3 on human T-lymphocytes. The AB5C10*UCHT1 recognized both CEA expressed on the KATOIII cell line and CD3 expressed on T-lymphocytes, as determined using flowcytometry. Next, AB5C10*UCHT1-mediated cytolysis was analyzed by 51Cr-release assay. When 51Cr-labeled target KATOIII cells were incubated for 6 h with effector cells that had been pretreated with AB5C10*UCHT1 for 60 min at 4 degrees C, the percentage specific lysis was significantly increased compared to that of untreated effector cells. Using peripheral blood mononuclear cells (PBMC) and lymphokine-activated killer (LAK) cells pretreated with AB5C10*UCHT1 for effector cells, the percentage specific lysis was determined to be 16.3% and 57.4% at effector: target (E:T) ratios of 100:1 and 12.5:1, respectively. On the other hand, the percentage specific lysis of untreated PBMC and LAK cells determined to be 3.0% and 35.8% at E:T ratios of 100:1 and 12.5:1, respectively. The minimum effective dose of AB5C10*UCHT1 required for antibody-mediated cytotoxicity was 0.1 mu g/ml. The results of this study suggest that AB5C10*UCHT1 could be useful for augmenting the cytotoxicity of CD3-positive T-cells against CEA-positive target cells in vitro. PMID:8919276

  20. New flow cytometric assays for monitoring cell-mediated cytotoxicity.

    PubMed

    Zaritskaya, Liubov; Shurin, Michael R; Sayers, Thomas J; Malyguine, Anatoli M

    2010-06-01

    The exact immunologic responses after vaccination that result in effective antitumor immunity have not yet been fully elucidated and the data from ex vivo T-cell assays have not yet defined adequate surrogate markers for clinical efficacy. A more detailed knowledge of the specific immune responses that correlate with positive clinical outcomes should help to develop better or novel strategies to effectively activate the immune system against tumors. Furthermore, clinically relevant material is often limited and, thus, precludes the ability to perform multiple assays. The two main assays currently used to monitor lymphocyte-mediated cytoxicity in cancer patients are the (51)Cr-release assay and IFN-gamma ELISpot assay. The former has a number of disadvantages, including low sensitivity, poor labeling and high spontaneous release of isotope from some tumor target cells. Additional problems with the (51)Cr-release assay include difficulty in obtaining autologous tumor targets, and biohazard and disposal problems for the isotope. The ELISpot assays do not directly measure cytotoxic activity and are, therefore, a surrogate marker of cyotoxic capacity of effector T cells. Furthermore, they do not assess cytotoxicity mediated by the production of the TNF family of death ligands by the cytotoxic cells. Therefore, assays that allow for the simultaneous measurement of several parameters may be more advantageous for clinical monitoring. In this respect, multifactor flow cytometry-based assays are a valid addition to the currently available immunologic monitoring assays. Use of these assays will enable detection and enumeration of tumor-specific cytotoxic T lymphocytes and their specific effector functions and any correlations with clinical responses. Comprehensive, multifactor analysis of effector cell responses after vaccination may help to detect factors that determine the success or failure of a vaccine and its immunological potency.

  1. Cytolytic activity of Naegleria fowleri cell-free extract.

    PubMed

    Fulford, D E; Marciano-Cabral, F

    1986-11-01

    The cytotoxic activity of a cell-free extract of Naegleria fowleri amebae on B103 rat nerve cells in culture was investigated. The cell-free extract was prepared by subjecting lysed amebae to centrifugation at 100,000 g for 1 h, precipitation of the supernatant fluid with 30-60% saturated ammonium sulfate, and desalting by group exclusion chromatography utilizing Sephadex G-25. The supernatant fluid recovered from this procedure was termed the soluble fraction. The Naegleria cytotoxic activity present in the soluble fraction was assayed by 51Cr released from labeled B103 cells. The Naegleria soluble fraction, when added to nerve cells, elicited blebs on the B103 target cell surface within 5 min after exposure to the fraction. Later, holes were observed in the B103 cell plasma membrane. These alterations were never observed on untreated B103 cells. Phospholipase A, phospholipase C, and protease activities were associated with the desalted ammonium sulfate-precipitable cytotoxic activity of N. fowleri cell-free lysate. The cytotoxic activity was impaired by ethylenediamine-tetraacetate (EDTA), phospholipase A inhibitor (Rosenthal's reagent), heating at 50 degrees C for 15 min, or incubation at pH 10 for 60 min. Repeated freeze-thawing and inhibitors of proteolytic enzymes had no effect on the cytotoxic activity. Small amounts of ethanol (5% v/v) enhanced cytotoxic activity of the fraction. Phospholipases A and C, as well as other as yet unidentified cytolytic factors may be responsible for producing 51Cr release from target cells by the soluble fraction of N. fowleri extracts.

  2. Interaction of the Pseudomonas aeruginosa secretory products pyocyanin and pyochelin generates hydroxyl radical and causes synergistic damage to endothelial cells. Implications for Pseudomonas-associated tissue injury.

    PubMed Central

    Britigan, B E; Roeder, T L; Rasmussen, G T; Shasby, D M; McCormick, M L; Cox, C D

    1992-01-01

    Pyocyanin, a secretory product of Pseudomonas aeruginosa, has the capacity to undergo redox cycling under aerobic conditions with resulting generation of superoxide and hydrogen peroxide. By using spin trapping techniques in conjunction with electron paramagnetic resonance spectrometry (EPR), superoxide was detected during the aerobic reduction of pyocyanin by NADH or porcine endothelial cells. No evidence of hydroxyl radical formation was detected. Chromium oxalate eliminated the EPR spectrum of the superoxide-derived spin adduct resulting from endothelial cell exposure to pyocyanin, suggesting superoxide formation close to the endothelial cell plasma membrane. We have previously reported that iron bound to the P. aeruginosa siderophore pyochelin (ferripyochelin) catalyzes the formation of hydroxyl free radical from superoxide and hydrogen peroxide via the Haber-Weiss reaction. In the present study, spin trap evidence of hydroxyl radical formation was detected when NADH and pyocyanin were allowed to react in the presence of ferripyochelin. Similarly, endothelial cell exposure to pyocyanin and ferripyochelin also resulted in hydroxyl radical production which appeared to occur in close proximity to the cell surface. As assessed by 51Cr release, endothelial cells which were treated with pyocyanin or ferripyochelin alone demonstrated minimal injury. However, endothelial cell exposure to the combination of pyochelin and pyocyanin resulted in 55% specific 51Cr release. Injury was not observed with the substitution of iron-free pyochelin and was diminished by the presence of catalase or dimethyl thiourea. These data suggest the possibility that the P. aeruginosa secretory products pyocyanin and pyochelin may act synergistically via the generation of hydroxyl radical to damage local tissues at sites of pseudomonas infection. PMID:1469082

  3. Study of the Impact of Tissue Density Heterogeneities on 3-Dimensional Abdominal Dosimetry: Comparison Between Dose Kernel Convolution and Direct Monte Carlo Methods

    PubMed Central

    Dieudonné, Arnaud; Hobbs, Robert F.; Lebtahi, Rachida; Maurel, Fabien; Baechler, Sébastien; Wahl, Richard L.; Boubaker, Ariane; Le Guludec, Dominique; Sgouros, Georges; Gardin, Isabelle

    2014-01-01

    Dose kernel convolution (DK) methods have been proposed to speed up absorbed dose calculations in molecular radionuclide therapy. Our aim was to evaluate the impact of tissue density heterogeneities (TDH) on dosimetry when using a DK method and to propose a simple density-correction method. Methods This study has been conducted on 3 clinical cases: case 1, non-Hodgkin lymphoma treated with 131I-tositumomab; case 2, a neuroendocrine tumor treatment simulated with 177Lu-peptides; and case 3, hepatocellular carcinoma treated with 90Y-microspheres. Absorbed dose calculations were performed using a direct Monte Carlo approach accounting for TDH (3D-RD), and a DK approach (VoxelDose, or VD). For each individual voxel, the VD absorbed dose, DVD, calculated assuming uniform density, was corrected for density, giving DVDd. The average 3D-RD absorbed dose values, D3DRD, were compared with DVD and DVDd, using the relative difference ΔVD/3DRD. At the voxel level, density-binned ΔVD/3DRD and ΔVDd/3DRD were plotted against ρ and fitted with a linear regression. Results The DVD calculations showed a good agreement with D3DRD. ΔVD/3DRD was less than 3.5%, except for the tumor of case 1 (5.9%) and the renal cortex of case 2 (5.6%). At the voxel level, the ΔVD/3DRD range was 0%–14% for cases 1 and 2, and −3% to 7% for case 3. All 3 cases showed a linear relationship between voxel bin-averaged ΔVD/3DRD and density, ρ: case 1 (Δ = −0.56ρ + 0.62, R2 = 0.93), case 2 (Δ = −0.91ρ + 0.96, R2 = 0.99), and case 3 (Δ = −0.69ρ + 0.72, R2 = 0.91). The density correction improved the agreement of the DK method with the Monte Carlo approach (ΔVDd/3DRD < 1.1%), but with a lesser extent for the tumor of case 1 (3.1%). At the voxel level, the ΔVDd/3DRD range decreased for the 3 clinical cases (case 1, −1% to 4%; case 2, −0.5% to 1.5%, and −1.5% to 2%). No more linear regression existed for cases 2 and 3, contrary to case 1 (Δ = 0.41ρ − 0.38, R2 = 0.88) although

  4. Ga-68 DOTANOC PET/CT imaging in detection of primary site in patients with metastatic neuroendocrine tumours of unknown origin and its impact on clinical decision making: experience from a tertiary care centre in India

    PubMed Central

    Pankaj, Promila; Verma, Ritu; Jain, Anjali; Belho, Ethel S.; Mahajan, Harsh

    2016-01-01

    25.1±18.0 (median: 16.25; range, 2.1–150). Significant positive correlation was found between SUVmax of detected primary site and SUVmax of the histopathologically proven sites of metastasis (r=0.662; P<0.0001). Based on the findings of the Ga-68 DOTANOC PET/CT scan, 3 out of 40 patients underwent definitive treatment for their primary tumour (1 gastric, 1 ileal and 1 prostatic tumour). One patient was being planned for resection of primary rectal lesion at the time of data-collection. Thirty-six out of 68 patients were started on long-acting somatostatin analogues or chemotherapy or targeted therapy. Two patients underwent multiple cycles of peptide receptor radionuclide therapy (PRRNT) using 90Y and 177Lu labeled somatostatin analogues. Conclusions Our findings indicate that Ga-68 DOTANOC PET/CT is a promising imaging modality in patients with metastatic NETs of unknown origin for detection of the primary site and in guiding their therapeutic management. PMID:27284479

  5. 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 procedure of

  6. 3D modeling of effects of increased oxygenation and activity concentration in tumors treated with radionuclides and antiangiogenic drugs

    SciTech Connect

    Lagerloef, Jakob H.; Kindblom, Jon; Bernhardt, Peter

    2011-08-15

    Purpose: Formation of new blood vessels (angiogenesis) in response to hypoxia is a fundamental event in the process of tumor growth and metastatic dissemination. However, abnormalities in tumor neovasculature often induce increased interstitial pressure (IP) and further reduce oxygenation (pO{sub 2}) of tumor cells. In radiotherapy, well-oxygenated tumors favor treatment. Antiangiogenic drugs may lower IP in the tumor, improving perfusion, pO{sub 2} and drug uptake, by reducing the number of malfunctioning vessels in the tissue. This study aims to create a model for quantifying the effects of altered pO{sub 2}-distribution due to antiangiogenic treatment in combination with radionuclide therapy. Methods: Based on experimental data, describing the effects of antiangiogenic agents on oxygenation of GlioblastomaMultiforme (GBM), a single cell based 3D model, including 10{sup 10} tumor cells, was developed, showing how radionuclide therapy response improves as tumor oxygenation approaches normal tissue levels. The nuclides studied were {sup 90}Y, {sup 131}I, {sup 177}Lu, and {sup 211}At. The absorbed dose levels required for a tumor control probability (TCP) of 0.990 are compared for three different log-normal pO{sub 2}-distributions: {mu}{sub 1} = 2.483, {sigma}{sub 1} = 0.711; {mu}{sub 2} = 2.946, {sigma}{sub 2} = 0.689; {mu}{sub 3} = 3.689, and {sigma}{sub 3} = 0.330. The normal tissue absorbed doses will, in turn, depend on this. These distributions were chosen to represent the expected oxygen levels in an untreated hypoxic tumor, a hypoxic tumor treated with an anti-VEGF agent, and in normal, fully-oxygenated tissue, respectively. The former two are fitted to experimental data. The geometric oxygen distributions are simulated using two different patterns: one Monte Carlo based and one radially increasing, while keeping the log-normal volumetric distributions intact. Oxygen and activity are distributed, according to the same pattern. Results: As tumor pO{sub 2

  7. Extracorporeal adsorption therapy: A Method to improve targeted radiation delivered by radiometal-labeled monoclonal antibodies.

    SciTech Connect

    Nemecek, Eneida R.; Green, Damian J.; Fisher, Darrell R.; Pagal, John M.; Lin, Yukang; Gopal, A. K.; Durack, Lawrence D.; Rajendran, Joseph G.; Wilbur, D. S.; Nilsson, Rune; Sandberg, Bengt; Press, Oliver W.

    2008-04-01

    antibody labeled with indium-111 (111In), seven patients received RIT with anti-CD20 antibody labeled with indium-111 for biokinetics and dosimetry, and therapeutic doses of antibody labeled with yttrium-90 (90Y). Performing the ECAT procedure at a rate that such that one blood volume per hour were circulated for 3 hours, resulted in mean radioactivity depletion of 96% in whole blood, 49% in whole body 49%, 62% in the lungs and 40% in liver and kidneys. There was no sufficient data to determine whether there was an improvement in the relative delivery of radiation to the tumor compared to normal organs by performing ECAT, but pharmacokinetic modeling studies suggested a potential therapeutic advantage using this approach. [refs] To evaluate the potential therapeutic advantages of ECAT, we performed biodistribution studies in nonhuman primates comparing the therapeutic ratios of radiation delivered using this approach to those delivered by conventional RIT alone. In addition, we evaluated lutetium-177 (177Lu) as an alternative isotope to optimize the delivery of RIT by improving the therapeutic index (target to non-target ratio)

  8. 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

  9. Regulation of the complement-mediated elimination of red blood cells modified with biotin and streptavidin.

    PubMed

    Muzykantov, V R; Murciano, J C; Taylor, R P; Atochina, E N; Herraez, A

    1996-10-01

    molecules per cell, and the resulting SA/b23-RBC bound 5 x 10(4) molecules of biotinylated IgG (b-IgG) per cell. About 60% of the injected dose of b-IgG/SA/b23-RBC labeled with 51Cr was detected in the rat blood cells 1 day after iv injection. To assess whether b-IgG/SA/b23-RBC circulate in the bloodstream as a stable complex, we have injected 125I-labeled b-IgG/ SA/51Cr-labeled b23-RBC in rats. Up to 60 min after injection, both radiolabels display similar level in bloodstream. Up to 3 h after injection, about 70% of 125I was detected in the blood cells. In contrast, 100% of 125I was detected in plasma after injection of nonconjugated 125I-labeled b-IgG. Thus, major portion of SA/b23-RBC-attached b-IgG circulates as a complex with RBC. About 30% of RBC-bound b-IgG undergoes detachment from the carrier b-RBC, probably in the pulmonary capillaries, because lung level of 125I was twice as high as that of 51Cr. Therefore, the surface density of biotin on the b-RBC membrane appears to play a key role in regulating complement-mediated clearance of bn-RBC and SA/bn-RBC from the bloodstream. Modest biotinylation generates b-IgG/SA/b23-RBC circulating for several hours as stable immunoerythrocytes without detectable lysis or marked elimination, and it may be possible to use these RBC in a drug delivery system.

  10. Platelet accumulation and turnover on de-endothelialized aortae in rats.

    PubMed Central

    Winocour, P. D.; Kinlough-Rathbone, R. L.; Richardson, M.; Mustard, J. F.

    1989-01-01

    Previous studies indicate that the subendothelium of rabbit aortae de-endothelialized with a balloon catheter rapidly becomes covered with a monolayer of platelets; after 60 min few additional platelets accumulate and although most platelets are lost from the injured surface by 4 days, there is a substantial delay before re-endothelialization. We examined the dynamics of platelet accumulation on rat aortae de-endothelialized with a balloon catheter to determine if the response to this type of injury is similar to rabbit aortae. When 51Cr-platelets were injected prior to aortic de-endothelialization, 25,500 +/- 2,750 platelets/mm2 accumulated on rat subendothelium in the first 15 min. After 60 and 92 h, fewer platelets remained on the surface (13,740 +/- 2,400 and 5,020 +/- 1,330 platelets/mm2, respectively). When 51Cr-platelets were injected into rats 30 min after injury, platelet accumulation in a 30-min period was 8,610 +/- 1,230 platelets/mm2. By 4 days rat aortae did not accumulate newly injected platelets significantly in a 30-min period, but in a 24-h period 20,600 +/- 3,490 platelets/mm2 accumulated. Morphologically, the non-endothelialized areas of rat aortae were almost completely covered with platelets 4 days after injury. Fourteen days after injury, rat aortae did not accumulate newly injected platelets and, morphologically, no platelets were present on the surface which was almost re-endothelialized. Thus, in rats, as with rabbits, platelets rapidly accumulate on de-endothelialized aortae and the ability to attract newly introduced platelets is considerably reduced shortly after injury. In contrast to rabbits, however, de-endothelialized aortae in rats remain attractive to new platelets up to 4 days following injury, but less so than at the time of injury. Also, in contrast to rabbits, 14 days after injury to rat aortae the surface is almost completely re-endothelialized. Thus, there are species differences in platelet interactions with de

  11. Probiotics Prevent Intestinal Barrier Dysfunction in Acute Pancreatitis in Rats via Induction of Ileal Mucosal Glutathione Biosynthesis

    PubMed Central

    Lutgendorff, Femke; Nijmeijer, Rian M.; Sandström, Per A.; Trulsson, Lena M.; Magnusson, Karl-Eric; Timmerman, Harro M.; van Minnen, L. Paul; Rijkers, Ger T.; Gooszen, Hein G.; Akkermans, Louis M. A.; Söderholm, Johan D.

    2009-01-01

    Background During acute pancreatitis (AP), oxidative stress contributes to intestinal barrier failure. We studied actions of multispecies probiotics on barrier dysfunction and oxidative stress in experimental AP. Methodology/Principal Findings Fifty-three male Spraque-Dawley rats were randomly allocated into five groups: 1) controls, non-operated, 2) sham-operated, 3) AP, 4) AP and probiotics and 5) AP and placebo. AP was induced by intraductal glycodeoxycholate infusion and intravenous cerulein (6 h). Daily probiotics or placebo were administered intragastrically, starting five days prior to AP. After cerulein infusion, ileal mucosa was collected for measurements of E. coli K12 and 51Cr-EDTA passage in Ussing chambers. Tight junction proteins were investigated by confocal immunofluorescence imaging. Ileal mucosal apoptosis, lipid peroxidation, and glutathione levels were determined and glutamate-cysteine-ligase activity and expression were quantified. AP-induced barrier dysfunction was characterized by epithelial cell apoptosis and alterations of tight junction proteins (i.e. disruption of occludin and claudin-1 and up-regulation of claudin-2) and correlated with lipid peroxidation (r>0.8). Probiotic pre-treatment diminished the AP-induced increase in E. coli passage (probiotics 57.4±33.5 vs. placebo 223.7±93.7 a.u.; P<0.001), 51Cr-EDTA flux (16.7±10.1 vs. 32.1±10.0 cm/s10−6; P<0.005), apoptosis, lipid peroxidation (0.42±0.13 vs. 1.62±0.53 pmol MDA/mg protein; P<0.001), and prevented tight junction protein disruption. AP-induced decline in glutathione was not only prevented (14.33±1.47 vs. 8.82±1.30 nmol/mg protein, P<0.001), but probiotics even increased mucosal glutathione compared with sham rats (14.33±1.47 vs. 10.70±1.74 nmol/mg protein, P<0.001). Glutamate-cysteine-ligase activity, which is rate-limiting in glutathione biosynthesis, was enhanced in probiotic pre-treated animals (probiotics 2.88±1.21 vs. placebo 1.94±0.55 nmol/min/mg protein; P<0

  12. Tumoricidal effector mechanisms of murine Bacillus Calmette-Guérin-activated macrophages: mediation of cytolysis, mitochondrial respiration inhibition, and release of intracellular iron by distinct mechanisms.

    PubMed

    Klostergaard, J; Leroux, M E; Ezell, S M; Kull, F C

    1987-04-15

    Murine Bacillus Calmette-Guérin-activated macrophages mediate discrete cytotoxic effects in cocultured tumor target cells in vitro. These effects include: the loss of intracellular iron, in part associated with reversible inhibition of the Kreb's cycle enzyme, aconitase; cytostasis, associated with reversible lesions inflicted in the electron transport chain (ETC) of the mitochondria resulting in reversible loss of proliferative capacity; and cytolysis, manifested by eventual gross perturbation of the integrity of the plasma membrane. We demonstrate that these manifestations of cytotoxicity are the result of three independent mechanisms employing apparently distinct macromolecules for their commission. Analysis of target cells that are highly susceptible (L-929), highly resistant (L-1210), or have incomplete resistance (EMT-6) to the cytolytic effects of cocultured activated macrophages indicates that there is no consistent relationship between the release of intracellular 59Fe and 51Cr. Thus, perturbation of intracellular iron pools did not appear to be an obligatory step on the pathway to cytolysis. Further evidence for this dissociation was obtained by employing a specific heteroantiserum reactive with cytolytic molecule(s). This antiserum could block the cytolytic response (51Cr release of cocultured L-929 and EMT-6 targets) but had no effect on the extent of iron release from viable EMT-6 or L-1210 targets. Furthermore, the cytolytic factor itself was incapable of mediating effects on the ETC or in causing release of intracellular iron. Two lines of evidence suggested that effects on the ETC are not linked with loss of intracellular iron. First, the monokine respiration inhibitory factor was incapable of causing release of intracellular iron from target cells in which the mitochondria were strongly suppressed. Second, the kinetics of release of respiration inhibitory factor from endotoxin-triggered Bacillus Calmette-Guérin-activated macrophages indicate a

  13. Hepatic or splenic targeting of carrier erythrocytes: a murine model

    SciTech Connect

    Zocchi, E.; Guida, L.; Benatti, U.; Canepa, M.; Borgiani, L.; Zanin, T.; De Flora, A.

    1987-10-01

    Carrier mouse erythrocytes, i.e., red cells, subjected to a dialysis technique involving transient hypotonic hemolysis and isotonic resealing were treated in vitro in three different ways: (a) energy depletion by exposure for 90 min at 42 degrees C; (b) desialylation by incubation with neuroaminidase; and (c) oxidative stress by incubation with H/sub 2/O/sub 2/ and NaN3. Procedure (c) afforded maximal damage, as shown by analysis of biochemical properties of the treated erythrocytes. Reinfusion in mice of the variously manipulated erythrocytes following their /sup 51/Cr labeling showed extensive fragilization as indicated by rapid clearance of radioactivity from the circulation. Moreover, both the energy-depleted and the neuraminidase-treated erythrocytes showed a preferential liver uptake, reaching 50 and 75%, respectively, within 2 h. On the other hand, exposure of erythrocytes to the oxidant stress triggered a largely splenic removal, accounting for almost 40% of the reinjected cells within 4 h. Transmission electron microscopy of liver from mice receiving energy-depleted erythrocytes demonstrated remarkable erythrocyte congestion within the sinusoids, followed by hyperactivity of Kupffer cells and by subsequent thickening of the perisinusoidal Disse space. Concomitantly, levels of serum transaminase activities were moderately increased. Each of the three procedures of manipulation of carrier erythrocytes may prove applicable under conditions where selective targeting of erythrocyte-encapsulated chemicals and drugs to either the liver or the spleen has to be achieved.

  14. [Relations between location of elements in periodic table and affinity for the kidneys (author's transl)].

    PubMed

    Ando, A; Hisada, K; Ando, I

    1977-10-01

    The distribution of many inorganic compounds in rats was investigated in order to evaluate kidney affinity of inorganic compounds. In these experiments, 30%, 10-20% and 4-10% of administered dose was localized in the kidneys in 203Hg-acetate and 203 Bi-acetate, in H198AuCl4, 103PdCl2, 201TlCl, 210Pd(NO3)2 and H2(127M)TeO3, and in Na2(51)CrO4, 54MnCl2, (114m)InCl3 and 7BeCl2, respectively. Some bipositive ions and anions was hardly taken up into the kidneys. And in many hard acids according to classification of Lewis acids, the uptake rate into the kidneys was usually small. On the other hand, Hg, Au and Bi, which have strong binding power to the protein, showed high uptake rate in the kidneys. As Hg++, Au+ and Bi+++ was soft acids according to classification of Lewis acids, it was thought that these elements would bind strongly to soft base (RSH, RS-) present in the kidney.

  15. Familial hypercatabolic hypoproteinemia. A disorder of endogenous catabolism of albumin and immunoglobulin.

    PubMed Central

    Waldmann, T A; Terry, W D

    1990-01-01

    The metabolism of albumin and IgG was investigated in two siblings, products of a first-cousin marriage, a female aged 34 yr and a male aged 17, who had a marked reduction in their respective serum concentrations of IgG (1.3 and 3.1 mg/ml) and albumin (19 and 21 mg/ml). The metabolism of radioiodinated IgG and albumin was studied in the two patients. The total circulating and body pools of IgG were less than 28% of normal. The IgG synthetic rates were within the normal range. However, the IgG survival was short, with their respective fractional catabolic rates increased fivefold to 31% and 36% of the intravenous pool per day (normal, 6.7 +/- 2%/d). Furthermore, the patients had reduced total body pools, normal synthetic rates, and increased fractional catabolic rates for albumin. There was no proteinuria or abnormality of renal or liver function. In addition, the patients did not have circulating antibodies directed toward IgG, IgA, or albumin. Furthermore, both patients had normal fecal 51Cr-labeled albumin tests, thus excluding excessive gastrointestinal protein loss. We propose that these siblings have a previously unrecognized familial disorder characterized by reduced serum concentrations of IgG and albumin caused by a defect in endogenous catabolism, leading to a short survival of these proteins that is associated in this family with chemical diabetes and a skeletal deformity. Images PMID:2254461

  16. Experimental Anomalies in Neutrino Physics

    NASA Astrophysics Data System (ADS)

    Palamara, Ornella

    2014-03-01

    In recent years, experimental anomalies ranging in significance (2.8-3.8 σ) have been reported from a variety of experiments studying neutrinos over baselines less than 1 km. Results from the LSND and MiniBooNE short-baseline νe /νe appearance experiments show anomalies which cannot be described by oscillations between the three standard model neutrinos (the ``LSND anomaly''). In addition, a re-analysis of the anti-neutrino flux produced by nuclear power reactors has led to an apparent deficit in νe event rates in a number of reactor experiments (the ``reactor anomaly''). Similarly, calibration runs using 51Cr and 37Ar radioactive sources in the Gallium solar neutrino experiments GALLEX and SAGE have shown an unexplained deficit in the electron neutrino event rate over very short distances (the ``Gallium anomaly''). The puzzling results from these experiments, which together may suggest the existence of physics beyond the Standard Model and hint at exciting new physics, including the possibility of additional low-mass sterile neutrino states, have raised the interest in the community for new experimental efforts that could eventually solve this puzzle. Definitive evidence for sterile neutrinos would be a revolutionary discovery, with implications for particle physics as well as cosmology. Proposals to address these signals by employing accelerator, reactor and radioactive source experiments are in the planning stages or underway worldwide. In this talk some of these will be reviewed, with emphasis on the accelerator programs.

  17. Involvement of endogenous opiates in regulation of gastric emptying of fat test meals in mice

    SciTech Connect

    Fioramonti, J.; Fargeas, M.J.; Bueno, L.

    1988-08-01

    The role of endogenous opioids and cholecystokinin (CCK) in gastric emptying was investigated in mice killed 30 min after gavage with /sup 51/Cr-radiolabeled liquid meals. The meals consisted of 0.5 ml of milk or one of five synthetic meals containing arabic gum, glucose and/or arachis oil and/or casein. Naloxone (0.1 mg/kg sc) significantly (P less than 0.01) accelerated gastric emptying of milk and meals containing fat but did not modify gastric emptying of nonfat meals. The CCK antagonist asperlicin (0.1 mg/kg ip) increased by 25% gastric emptying of milk. The gastric emptying of meals containing glucose and casein but not fat was reduced after administration of the COOH-terminal octapeptide of cholecystokinin (CCK-8, 4 micrograms/kg ip). This decrease was antagonized by both asperlicin (10 mg/kg ip) and naloxone (0.1 mg/kg sc). Intracerebroventricular (icv) administration of an opiate antagonist that poorly crosses the blood-brain barrier, methyl levallorphan (10 micrograms/kg), did not modify gastric emptying of milk but accelerated it when peripherally administered (0.1 mg/kg sc). Similarly, asperlicin (icv) administered at a dose of 1 mg/kg did not affect milk emptying. These results indicate that endogenous opiates are involved at peripheral levels in the regulation of gastric emptying of fat meals only and that such regulation involves release of CCK.

  18. The clearance kinetics of autologous RhD-positive erythrocytes coated ex vivo with novel recombinant and monoclonal anti-D antibodies

    PubMed Central

    Chapman, G E; Ballinger, J R; Norton, M J; Parry-Jones, D R; Beharry, N A; Cousins, C; Dash, C H; Peters, A M

    2007-01-01

    Anti-D is given routinely to pregnant RhD-negative women to prevent haemolytic disease of the fetus and newborn. To overcome the potential drawbacks associated with plasma-derived products, monoclonal and recombinant forms of anti-D have been developed. The ability of two such antibodies, BRAD-3/5 monoclonal anti-D IgG (MAD) and rBRAD-3/5 recombinant anti-D IgG (RAD), to clear RhD-positive erythrocytes from the circulation was compared using a dual radiolabelling technique. Six RhD-positive males received autologous erythrocytes radiolabelled with 99mTc and 51Cr and coated ex vivo with MAD and RAD. Blood samples were collected up to 1 h following intravenous injection, and percentage dose of radioactivity in the samples determined. Three different levels of coating were used on three separate occasions. No significant differences between MAD and RAD were observed in the initial clearance rate constant at any dose level. The log[activity]-time clearance plots were curved, showing a reduction in the clearance rate constant with time. This reduction was more marked for RAD than for MAD. The results support a dynamic model for the clearance of antibody-coated erythrocytes that may have wider relevance for the therapeutic use of antibodies. PMID:17680827

  19. Cholinergic mediation of small intestinal transit in the rat

    SciTech Connect

    Nemeth, P.R.; Ems, B.L.; Pepple, S.C

    1986-03-05

    It has been reported that small intestinal transit (SIT) in the rat is not cholinergically mediated. The geometric mean of a marker may be a more powerful method for SIT studies. Therefore, it was their goal to evaluate the effect of muscarinic blockade in normal and prostaglandin E/sub 2/ (PGE/sub 2/)-enhanced SIT using this method. Male, food-fasted rats (190 to 240 g) were first dosed subcutaneously with atropine. 30 min after the atropine the rats received an oral dose of PGE/sub 2/ at 5.0 mg/kg. 5 min after PGE/sub 2/, a /sup 51/Cr-labeled marker was dosed intraduodenally, and a 25 min transit period followed. The results are: (1) 5.0 mg/kg of PGE/sub 2/ significantly stimulates the geometric mean of the marker in agreement with previous findings and (2) atropine is inhibitory at doses as low as 0.20 mg/kg for basal SIT and 0.10 mg/kg for PGE/sub 2/-stimulated SIT. This indicates (1) the rat has cholinergically mediated SIT, and (2) cholinergic activation may be important for PGE/sub 2/ effects on SIT in the rat.

  20. Gamma-ray spectrometry of LDEF samples

    SciTech Connect

    Winn, W.G.

    1991-01-01

    A total of 31 samples from the Long Duration Exposure Facility (LDEF), including materials of aluminum, vanadium, and steel trunnions were analyzed by ultra-low-level gamma spectroscopy. The study quantified particle induced activations of (sup 22)Na, {sup 46}Sc, {sup 51}Cr, {sup 54}Mn, {sup 56}Co, {sup 57}Co, {sup 58}Co, and {sup 60}Co. The samples of trunnion sections exhibited increasing activity toward the outer end of the trunnion and decreasing activity toward its radial center. The trunnion sections did not include end pieces, which have been reported to collect noticeable {sup 7}Be on their leading surfaces. No significant {sup 7}Be was detected in the samples analyzed. The Underground Counting Facility at Savannah River Laboratory (SRL) was used in this work. The facility is 50 ft. underground, constructed with low-background shielding materials, and operated as a clean room. The most sensitive analyses were performed with a 90%-efficient HPGe gamma-ray detector, which is enclosed in a purged active/passive shield. Each sample was counted for one to six days in two orientations to yield more representative average activities for the sample. The non-standard geometries of the LDEF samples prompted the development of a novel calibration method, whereby the efficiency about the samples surfaces (measured with point sources) predicted the efficiency for the bulk sample.

  1. Interaction of a mouse macrophage cell line with homologous erythrocytes.

    PubMed

    Singer, J A; Walker, W S; Morrison, M

    1982-06-01

    The interaction of the IC-21 murine macrophage cell line and homologous red blood cells (RBC) was assessed in the absence of exogenous opsonins. These results were used to evaluate this system as a potential model for macrophage-mediated clearance of old or damaged RBC. The binding and ingestion of density-separated and unseparated RBC by IC-21 cells were quantitated in assays that involved both 51Cr-labeled RBC and direct microscopy. The number of unseparated RBC that bound to IC-21 macrophages depended on the number of RBC added. Macrophages phagocytized an appreciable proportion of RBC within 3 hours with the ratio of RBC:macrophage of 10, a point at which the RBC-binding was not rate limiting. The mouse RBC were separated into dense- and less-dense fractions which are presumably enriched for old and young cells, respectively. When these RBC fractions were incubated with the IC-21 macrophage, significantly more of these dense cells were phagocytized. These results show that IC-21 macrophage cell line is a useful model for defining the processes whereby aged or damaged RBC are recognized and removed from circulation by macrophages. PMID:7120230

  2. Induction of persistent autoimmune haemolytic anaemia in mice by combined use of rat erythrocyte preimmunization and chronic GVHR.

    PubMed Central

    Negoro, S; Takashima, T; Toba, H; Kishimoto, S

    1985-01-01

    Female F1 mice (BDF1: C57BL/6 x DBA/2, BCF1: C57BL/6 x C3H/HeN, BBF1: C57BL/6 x BALB/c) were preimmunized with rat erythrocytes and then received splenic T cells from parental female C57BL/6 mice injected with hydrocortisone acetate before killing. In BDF1 and BCF1 mice, direct Coombs' test (DCT) positivity persisted for more than 4 months in almost all mice. They also showed haematological sign of anaemia, and the survival of infused 51Cr-labelled parental C57BL/6 erythrocytes was reduced. In BBF1 mice, DCT positivity returned to negative within 2 months. Autoantibodies were eluted from DCT-positive erythrocytes and their specificities were examined. They were capable of binding equally well to erythrocytes from all strains of mice tested, including the donor mice. They also cross-reacted with rat erythrocytes but not with sheep, rabbit or human erythrocytes. Isotypes of the autoantibodies eluted were also examined. Interestingly, isotypes of the autoantibodies obtained from individual mice were confined to one or other subclass of IgG isotype: IgG1, IgG2a or IgG2b. PMID:3878325

  3. Effect of bacterial inoculation of strains of Pseudomonas aeruginosa, Alcaligenes feacalis and Bacillus subtilis on germination, growth and heavy metal (Cd, Cr, and Ni) uptake of Brassica juncea.

    PubMed

    Ndeddy Aka, Robinson Junior; Babalola, Olubukola Oluranti

    2016-01-01

    Bacterial inoculation may influence Brassica juncea growth and heavy metal (Ni, Cr, and Cd) accumulation. Three metal tolerant bacterial isolates (BCr3, BCd33, and BNi11) recovered from mine tailings, identified as Pseudomonas aeruginosa KP717554, Alcaligenes feacalis KP717561, and Bacillus subtilis KP717559 were used. The isolates exhibited multiple plant growth beneficial characteristics including the production of indole-3-acetic acid, hydrogen cyanide, ammonia, insoluble phosphate solubilization together with the potential to protect plants against fungal pathogens. Bacterial inoculation improved seeds germination of B. juncea plant in the presence of 0.1 mM Cr, Cd, and Ni, as compared to the control treatment. Compared with control treatment, soil inoculation with bacterial isolates significantly increased the amount of soluble heavy metals in soil by 51% (Cr), 50% (Cd), and 44% (Ni) respectively. Pot experiment of B. juncea grown in soil spiked with 100 mg kg(-1) of NiCl2, 100 mg kg(-1) of CdCl2, and 150 mg kg(-1) of K2Cr2O7, revealed that inoculation with metal tolerant bacteria not only protected plants against the toxic effects of heavy metals, but also increased growth and metal accumulation of plants significantly. These findings suggest that such metal tolerant, plant growth promoting bacteria are valuable tools which could be used to develop bio-inoculants for enhancing the efficiency of phytoextraction. PMID:26503637

  4. Activation cross sections of longer-lived radionuclides produced in germanium by alpha particle irradiation

    NASA Astrophysics Data System (ADS)

    Takács, S.; Takács, M. P.; Ditrói, F.; Aikawa, M.; Haba, H.; Komori, Y.

    2016-09-01

    The cross sections of alpha particles induced nuclear reactions on natural germanium were investigated by using the standard stacked foil target technique, the activation method and high resolution gamma spectrometry. Targets with thickness of about 1 μm were prepared from natural Ge by vacuum evaporation onto 25 μm thick polyimide (Kapton) backing foils. Stacks were composed of Kapton-Ge-Ge-Kapton sandwich target foils and additional titanium monitor foils with nominal thickness of 11 μm to monitor the beam parameters using the natTi(α,x)51Cr reaction. The irradiations were done with Eα = 20.7 and Eα = 51.25 MeV, Iα = 50 nA alpha particle beams for about 1 h. Direct or cumulative activation cross sections were determined for production of the 72,73,75Se, 71,72,74,76,78As, and 69Ge radionuclides. The obtained experimental cross sections were compared to the results of theoretical calculations taken from the TENDL data library based on the TALYS computer code. A comparison was made with available experimental data measured earlier. Thick target yields were deduced from the experimental cross sections and compared with the data published before.

  5. Bioavailability and toxicity after oral administration of m-iodobenzylguanidine (MIBG)

    PubMed Central

    Kuin, A; Rutgers, M; Valk, M A van der; Beijnen, J H; Smets, L A

    1999-01-01

    meta-iodobenzylguanidine (MIBG) radiolabelled with iodine-131 is used for diagnosis and treatment of neuroadrenergic neoplasms such as phaeochromocytoma and neuroblastoma. In addition, non-radiolabelled MIBG, administered i.v., is used in several clinical studies. These include palliation of the carcinoid syndrome, in which MIBG proved to be effective in 60% of the patients. Oral MIBG administration might be convenient to maintain palliation and possibly improve the percentage of responders. We have, therefore, investigated the feasibility of oral administration of MIBG in an animal model. Orally administered MIBG demonstrated a bioavailability of 59%, with a maximal tolerated dose of 60 mg kg−1. The first and only toxicity encountered was a decrease in renal function, measured by a reduced clearance of [51Cr]EDTA and accompanied by histological tubular damage. Repeated MIBG administration of 40 mg kg−1for 5 sequential days or of 20 mg kg−1for two courses of 5 sequential days with a 2-day interval did not affect renal clearance and was not accompanied by histological abnormalities in kidney, stomach, intestines, liver, heart, lungs, thymus, salivary glands and testes. Because of a sufficient bioavailability in absence of gastrointestinal toxicity, MIBG is considered suitable for further clinical investigation of repeated oral administration in patients. 1999 Cancer Research Campaign PMID:10070872

  6. Cell-mediated immunity in F 344 rats bearing intraocular tumors derived from human adenovirus 12-induced retinal tumor.

    PubMed

    Kobayashi, M; Mukai, N; Solish, S P; Sawada, T; Pomeroy, M E

    1983-10-01

    The eyes of 10 F344 rats were inoculated with retinal tumor cells (EXP-5 cell line) induced by human adenovirus 12. The animals were killed at 4 weeks thereafter, and the cytotoxicity of their lymphocytes was investigated by using 51Cr-releasing assay. The percentage of EXP-5 cells killed in vitro by lymphocytes was higher in 10 rats with ocular tumors (24.6% +/- 6.1%, mean +/- SD) than in 10 control rats (6.2% +/- 1.8%). Morphologic investigation using syngeneic spleen cells confirmed the presence of lymphoid cells, resembling T-lymphocytes, adhering to EXP-5 cells. The influence of subcutaneous injection of EXP-5 cells on the growth of intravitreously injected tumor cells was investigated. Cells injected subcutaneously prior to intravitreous injection elicited an immune response that was capable of controlling vitreous tumor growth. These findings suggest that the rats with transplanted retinal tumors develop a cell-mediated immune response in the early stage of tumor bearing, and that a state of pre-existing specific immunity can overcome so-called "immunologic privilege" of the vitreous body.

  7. /sup 125/I-hippuran absorption from the human renal pelvis

    SciTech Connect

    Bratt, C.G.; Granerus, G.

    1986-09-01

    The absorption of /sup 125/I-hippuran from human renal pelvis was studied peroperatively in 18 patients with obstruction at the pelviureteric junction. Three types of experiment were included: absorption during induced diuresis, absorption at a constant intrapelvic pressure of 30 cm. H/sub 2/O, and excretion of the indicator by the contralateral kidney. Total and separate glomerular filtration rate were measured using /sup 51/Cr-EDTA clearance technique and isotope renography. Distal tubular function was evaluated as maximum concentration ability. During induced diuresis the intrapelvic pressure increased to an average maximum value of 31.6 cm. H/sub 2/O. The excretion of isotope from the contralateral kidney varied from one to 44% of the given dose. A significant correlation (r = 0.87) between the maximum intrapelvic pressure obtained and the amount of isotope excreted from the contralateral kidney was demonstrated. At a constant intrapelvic pressure of 30 cm. H/sub 2/O the excretion of isotope from the contralateral kidney varied from two to 26% of the dosage given. The low value probably depended on the impaired function of the obstructed kidney. Our results show the existence of a significant reflux from the renal pelvis of small molecules, which was affected by renal function, intrapelvic pressure and volume.

  8. Production of human anti-HLA monoclonal antibodies

    SciTech Connect

    Walker, M.C.; Mercier, F.; Roger, J.; Varin, M.

    1986-03-01

    Only 40% of the several hundred anti-HLA murine monoclonal antibodies (MAbs) that have been made detect HLA-A,B,C or DR specificities previously defined by human alloantisera, the range of recognized specificities is very narrow, and few of the MAbs have proven useful as tissue typing reagents. In hopes of obtaining HLA typing reagents, the authors are developing a protocol for the production of human anti-HLA MAbs from HLA-antigen (Ag) immunized peripheral blood B cells of volunteering renal patients, immunized to one or more HLA Ags through therapeutic blood transfusions. A simple enrichment of the donor B cells has not been sufficient for anti-HLA MAb production, the authors are currently delineating the conditions necessary for increasing the number of HLA-specific donor B cells by in vitro stimulation with cells expressing the HLA Ag to which the B cell donor is immunized. For the production of MAbs, the stimulated B cells are transformed with Epstein-Barr virus and subsequently fused with KR-4 lymphoblastoid cells. Hybridomas are selected by HAT and Ouabain. Supernatants are screened for anti-HLA activity against lymphocyte targets expressing the original immunizing HLA Ag by complement mediated /sup 51/Cr release assay. Antibody specificity is determined by the complement-dependent microcytotoxicity test used for HLA typing.

  9. Depressed natural killer cell function in thermally injured adults: successful in vivo and in vitro immunomodulation and the role of endotoxin.

    PubMed Central

    Bender, B S; Winchurch, R A; Thupari, J N; Proust, J J; Adler, W H; Munster, A M

    1988-01-01

    Natural killer (NK) cells mediate host defense against infections and are regulated by interleukin 2 (IL-2) and other factors. We studied NK cell function in burn patients using a 51Cr release assay with K562 target cells. We found that peripheral blood lymphocytes from burn patients had depressed NK activity (target cell lysis = 22.0 +/- 3.1% vs 39.8 +/- 3.2% in healthy volunteers, P less than 0.001) and also a lower response to IL-2 (28.9 +/- 3.8% vs 53.2 +/- 4.3%, P less than 0.001). Thirteen burn patients were randomly assigned to receive either standard therapy or 5 days of intravenous polymyxin B in addition to standard therapy. After 2 weeks, the patients not receiving polymyxin B had a significant decline in peripheral blood NK activity (P less than 0.01) and response to IL-2 (P less than 0.05), while no decline in NK cell activity was seen in patients who received polymyxin B. Sera from burn patients was found to suppress the NK activity of lymphocytes from healthy adults by 5-75%. After using affinity chromatography to remove endotoxin, the sera from burn patients no longer suppressed NK cell activity. Circulating endotoxin appears to be involved in the suppression of NK activity in burn patients. PMID:3258200

  10. Hypothalamic circuit regulating colonic transit following chronic stress in rats.

    PubMed

    Yoshimoto, Sazu; Cerjak, Diana; Babygirija, Reji; Bulbul, Mehmet; Ludwig, Kirk; Takahashi, Toku

    2012-03-01

    Although acute stress accelerates colonic transit, the effect of chronic stress on colonic transit remains unclear. In this study, rats received repeated restraint stress (chronic homotypic stress) or various types of stress (chronic heterotypic stress) for 5 and 7 days, respectively. Vehicle saline, oxytocin (OXT), OXT receptor antagonist or corticotropin-releasing factor (CRF) receptor antagonists were administered by intracerebroventricular (ICV) injection prior to restraint stress for 90 min. Immediately after the stress exposure, the entire colon was removed and the geometric center (GC) of Na51CrO4 (a nonabsorbable radioactive marker; 0.5 μCi) distribution was calculated to measure the transit. Gene expression of OXT and CRF in the paraventricular nucleus (PVN) was evaluated by in situ hybridization. Accelerated colonic transit with the acute stressor was no longer observed following chronic homotypic stress. This restored colonic transit was reversed by ICV injection of an OXT antagonist. In contrast, chronic heterotypic stress significantly accelerated colonic transit, which was attenuated by ICV injection of OXT and by a CRF receptor 1 antagonist. OXT mRNA expression in the PVN was significantly increased following chronic homotypic stress, but not chronic heterotypic stress. However, CRF mRNA expression in the PVN was significantly increased following acute and chronic heterotypic stress, but not chronic homotypic stress. These results indicate that central OXT and CRF play a pivotal role in mediating the colonic dysmotility following chronic stress in rats.

  11. Mechanisms of impurity diffusion in rutile

    SciTech Connect

    Peterson, N.L.; Sasaki, J.

    1984-01-01

    Tracer diffusion of /sup 46/Sc, /sup 51/Cr, /sup 54/Mn, /sup 59/Fe, /sup 60/Co, /sup 63/Ni, and /sup 95/Zr, was measured as functions of crystal orientation, temperature, and oxygen partial pressure in rutile single crystals using the radioactive tracer sectioning technique. Compared to cation self-diffusion, divalent impurities (e.g., Co and Ni) diffuse extremely rapidly in TiO/sub 2/ and exhibit a large anisotropy in the diffusion behavior; divalent-impurity diffusion parallel to the c-axis is much larger than it is perpendicular to the c-axis. The diffusion of trivalent impurity ions (Sc and Cr) and tetravalent impurity ions (Zr) is similar to cation self-diffusion, as a function of temperature and of oxygen partial pressure. The divalent impurity ions Co and Ni apparently diffuse as interstitial ions along open channels parallel to the c-axis. The results suggest that Sc, Cr, and Zr ions diffuse by an interstitialcy mechanism involving the simultaneous and cooperative migration of tetravalent interstitial titanium ions and the tracer-impurity ions. Iron ions diffused both as divalent and as trivalent ions. 8 figures.

  12. The role of macrophages in the cytotoxic killing of tumour cells in vitro

    PubMed Central

    Zembala, M.; Ptak, W.; Hanczakowska, Maria

    1973-01-01

    Lymph node and spleen cells from normal mice were cultured for 3 days with polyoma virus-induced tumour, Ehrlich's ascites tumour or leukaemia L 1210 cells. This resulted in in vitro immunization of the lymphocytes, which were then transferred to irradiated target cells labelled with 51Cr. Normal, i.e. non-immune thioglycollate-stimulated peritoneal macrophages were also added to some tubes. Non-immune macrophages mixed with immunized lymphocytes showed a significantly increased ability to destroy tumour cells as compared with macrophages in the absence of immunized lymphocytes. The immunized lymphocytes were almost entirely inactive alone. When the number of macrophages was kept constant the cytotoxicity was dependent on the number of viable immunized lymphocytes placed on the target cells. Immunized lymphocytes, in the presence of macrophages, only exhibited strong killing of the target cells against which they had been immunized; some lysis of `bystander' cells was, however, seen provided specific target cells were present. Macrophage monolayers exposed to immunized lymphocytes upon contact with specific antigen became `armed' and showed a significant cytotoxicity for specific target cells. When immunized lymphocytes and normal macrophages were treated with actinomycin D and puromycin, cytotoxicity was inhibited in the immunized lymphocytes but not in the macrophages. The possible mechanism of normal macrophage cooperation with immunized lymphocytes in the cytotoxic killing reaction is discussed. Results presented in this paper favour the view that immunologically specific cytophilic factor (presumptive cytophilic antibody) is involved in the macrophage-mediated cytotoxicity in the system studied. PMID:4356674

  13. Human prealbumin fraction: effects on cell-mediated immunity and tumor rejection

    SciTech Connect

    Leung, K.H.; Ehrke, M.J.; Bercsenyi, K.; Mihich, E.

    1982-02-01

    The effect of human prealbumin fraction as allogeneic cell-mediated immunity in primary sensitization cultures of murine spleen cells was studied by 3H-thymidine uptake and specific 51Cr release assays. Prealbumin caused a dose-dependent augmentation of these responses. Human serum albumin, bovine serum albumin, and calf-thymosin fraction 5 had little effect. Prealbumin was active when added on day 0 or 1 but not thereafter. Prealbumin added to effector cells from immunized mice did not change their lytic activity. Prealbumin, but not human serum albumin or thymosin fraction 5, augmented secondary cell-mediated immunity in culture after primary immunization in mice. A slow growing mammary tumor line, which originated as a spontaneous mammary tumor in a DBA/2 HaDD breeder mouse, initially grows in 100% of DBA/2J mice but is then rejected in 10 to 20% of them. When prealbumin (59 microgram/day) was given subcutaneously for 2 weeks to DBA/2J mice and the tumor implanted 2 weeks later. 78% of the mice rejected the tumor and were then resistant to a rechallenge.

  14. Augmentation by transferrin of IL-2-inducible killer activity and perforin production of human CD8+ T cells.

    PubMed Central

    Nakamura, A; Sone, S; Nabioullin, R; Sugihara, K; Munekata, M; Nishioka, Y; Nii, A; Ogura, T

    1993-01-01

    The effects of human transferrin (Tf) on lymphokine (IL-2)-activated killer (LAK) induction from blood lymphocytes of healthy donors was examined. LAK cells were induced by 6-day incubation in medium with recombinant human IL-2 of lymphocytes, and their cytotoxic activity was assessed by measuring 51Cr release from NK-resistant Daudi cells. Tf alone did not induce any LAK activity, but in combination with IL-2, it augmented LAK induction dose- and time-dependently. This augmenting effect was completely abolished by pretreatment with anti-Tf antiserum. Tf augmented the proliferative response of lymphocytes to IL-2 and their expressions of receptors for IL-2 and Tf. CD8+ T cells were isolated from purified blood lymphocytes using antibody-bound magnetic beads. Addition of Tf to cultures of CD8+ cells resulted in significant augmentation of killer cell induction and perforin (PFP) production after 4 days stimulation with IL-2. These results indicate that Tf is important in generation of IL-2-inducible killer properties and PFP activity of human CD8+ T cells. PMID:8467561

  15. Relative role of pore water versus ingested sediment in bioavailability of organic contaminants in marine sediments

    SciTech Connect

    Forbes, T.L.; Hansen, R.; Kure, L.K.; Forbes, V.E.; Giessing, A. |

    1998-12-01

    Experimental data for fluoranthene and feeding selectivity in combination with reaction-diffusion modeling suggest that ingestion of contaminated sediment may often be the dominant uptake pathway for deposit-feeding invertebrates in sediments. A dietary absorption efficiency of 56% and accompanying forage ratio of 2.4 were measured using natural sediment that had been dual-labeled ({sup 14}C:{sup 51}Cr) with fluoranthene and fed to the marine deposit-feeding polychaete Capitella species I. Only 3 to 4% of the total absorption could be accounted for by desorption during gut passage. These data were then used as input into a reaction-diffusion model to calculate the importance of uptake from ingested sediment relative to pore-water exposure. The calculations predict a fluoranthene dietary uptake flux that is 20 to 30 times greater than that due to pore water. Factors that act to modify or control the formation of local chemical gradients, boundary layers, or dietary absorption rates including particle selection or burrow construction will be important in determining the relative importance of potential exposure pathways. From a chemical perspective, the kinetics of the adsorption and desorption process are especially important as they will strongly influence the boundary layer immediately surrounding burrowing animals or irrigated tubes. The most important biological factors likely include irrigation behavior and burrow density and size.

  16. Diffusion of chromium and manganese in γ-TiAl

    NASA Astrophysics Data System (ADS)

    Prasad Tiwari, Gyanendra; Iijima, Yoshiaki; Lee, Chan-Gyu; Koo, Bon-Heun

    2011-02-01

    The γ-TiAl intermetallic compound with suitable alloying additions has shown considerable promise as a material for high-temperature applications. Diffusion studies in this alloy system are useful in assessment of their creep behaviour and structural stability in service conditions. Tracer diffusion coefficients of 51Cr and 54Mn in a γ-TiAl intermetallic compound containing 54.1 at. % aluminium were determined in the temperature range from 1095 to 1470 K. The temperature dependence of both the diffusing species follows a linear Arrhenius behaviour and can be expressed as D Cr = 4.4 × 10-3exp(-350 kJ mol-1/RT) m2 s-1 and D Mn = 1.2 × 10-3 ×exp(-326 kJ mol-1/RT) m2 s-1. The data are analysed on the basis of empirical correlations between the diffusion and melting parameters applicable for conventional mono-vacancy diffusion mechanism in metals. It is concluded that impurity diffusion in γ-TiAl occurs through the migration of thermal vacancies via nearest-neighbour or next-nearest neighbour jumps.

  17. Natural killer (NK) activity of pit cells perfused from livers of rats treated with ethanol

    SciTech Connect

    Albornoz, L.; Jones, J.M.; Crutchfield, C.; Veech, R.L. Univ. of Arkansas Medical Sciences, Little Rock )

    1991-03-11

    The liver is the major site of ethanol (ETOH) metabolism. Liver sinusoids contain lymphocytes with NK activity. The authors treated LEW rats for 2 weeks with i.p. injection of 1.25 ml 25% ETOH/kg