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8 and 12 weeks after Synovectomy with Yttrium 90, cartilage specimens from the femoral condyle of 8 patients with R.A. were examined. Cellular and matrix damage could be detected. Intracellular particles containing Circonium, an Yttrium decay-product could be found using microprobe X-ray analysis. This was verified in experimentally induced arthritis in the rat.
In this study, we labelled Lipiodol with yttrium-90 and analysed the biodistribution in rats after intrahepatic arterial injection. An RP-18 column (E. Merck) was used to separate 90Y from strontium-90. 90Y was retained on the column, which had been pretreated with yttrium-selective extraction reagent, di(2-ethylhexyl) phosphate, while 90Sr was washed out. A hexadentate nitrogen-donor chelating ligand N,N,N',N'-tetrakis(2-benzymidazolylmethyl)-1,2-ethanediamine (EDTB) was synthesized by condensation of 1,2-benzenediamine and ethylene diamine tetra-acetic acid (EDTA). Lipiodol was covalently conjugated with EDTB. The final product was obtained by eluting the retained 90Y from the RP-18 column with EDTB-Lipiodol. Sixteen male rats (Sprague-Dawley) were sacrificed at 1 h, 24 h, 48 h and 72 h (four rats at each time) after injection of approximately 0.1 mCi 90Y-Lipiodol via the hepatic artery. Samples of liver, spleen, muscle, lung, kidney, bone, whole blood and testis were obtained and counted to calculate the tissue concentrations. In addition, labelling efficiency and in vitro stability were determined by ITLC methods. We found that at 1 h after intrahepatic injection, most of the radiotracer was retained in the liver, but it was eliminated gradually over a few days. The radioactivity level in the lung was fair at 1 h and remained at roughly the same level throughout the study. Radioactivity in the kidney and spleen reached a relatively high level at 24 h, but declined rapidly.(ABSTRACT TRUNCATED AT 250 WORDS)
Although radiosynovectomy (RS) applications have been carried out for many years, clinical indications of this non-invasive procedure is thought to be limited probably due to the lack of information of clinicians. Clinicians' preferential indication for RS is the treatment-resistant synovitis of individual joints, i.e. despite systemic pharmacotherapy and intra-articular steroid injections. We present here a case of "lipoma arborescens" treated by yttrium-90, which is a rare intra-articular lesion characterized by villous proliferation of the synovial membrane and hyperplasia of subsynovial fat. The results of clinical, biochemical and hematological examinations, magnetic resonance (MR) imaging, arthroscopy and histological analysis have shown that the etiology was lipoma arborescens in a female patient, aged 36 having swelling and sometimes associating pain at her right knee for 4 years. We have applied to our patient's right knee RS with 185 MBq yttrium-90 colloid together with 40 mg of methylprednisolone acetate, although in our literature survey we have not met any similar case being treated with such indication. Even a year after the application, the patient has absolutely benefited from the treatment clinically, and this was also confirmed by comparative MR images (pre- and post-treatment). Consequently, we consider that Y-90 treatment might be applicable in suitable cases with lipoma arborescens.
Several yttrium-90 labelled somatostatin analogues are now available for cancer radiotherapy. After injection, a large amount of the compound is excreted via the urinary tract, while a variable part is trapped in the tumour(s), allowing the curative effect. Unfortunately, the compound may also be trapped in critical tissues such as kidney or bone marrow. As a consequence, a method for assessment of individual biodistribution and pharmacokinetics is required to predict the maximum dose that can be safely injected into patients. However, (90)Y, a pure beta(-)particle emitter, cannot be used for quantitative imaging. Yttrium-86 is a positron emitter that allows imaging of tissue uptake using a PET camera. In addition to the positron, (86)Y also emits a multitude of prompt single gamma-rays, leading to significant overestimation of uptake when using classical reconstruction methods. We propose a patient-dependent correction method based on sinogram tail fitting using an (86)Y point spread function library. When applied to abdominal phantom acquisition data, the proposed correction method significantly improved the accuracy of the quantification: the initial overestimation of background activity by 117% was reduced to 9%, while the initial error in respect of kidney uptake by 84% was reduced to 5%. In patient studies, the mean discrepancy between PET total body activity and the activity expected from urinary collections was reduced from 92% to 7%, showing the benefit of the proposed correction method.
An antibody has been labelled with generator produced yttrium-90 (90Y) via a chelating group (DTPA) covalently attached to the protein. An average yield for protein labelling of 76% was obtained. The blood clearance of iodinated and 90Y labelled antibody is similar in rats and mice. However, in contrast to iodine, the yttrium label accumulates in the liver after release from the protein.
Studies were initiated at Oak Ridge National Laboratory (ORNL) in 1982 for the radiolabeling of resin microspheres with yttrium-90 (90Y) for liver cancer therapy. Yttrium-90 is the decay product of strontium-90 (90Sr). Subsequently, 90Y became a major radioisotope of choice for labeling antibodies for therapeutic trials in the treatment of other forms of cancer. A 25-Ci 90Y 90Y generator or 90Sr cow was placed in service to supply the anticipated needs of customers. In vivo use of 90Y required that the 90Sr contamination levels be kept below 10 muCi/Ci 90Y (corrected to preparation time). Also, it was necessary to remove trace metals that interfered in the 90Y antibody radiolabeling process, giving low radiolabeling yields. Di-(2-ethylhexyl) phosphoric acid (HDEHP) in dodecane has been used routinely at ORNL to extract 90Y and thereby give a product that meets the radiochemical purity required with respect to 90Sr. Methods were also developed to remove interfering trace elements to provide acceptable labeling yields.
The influence of the ligands ethylenediaminetetramethylene phosphonic acid (EDTMP) and citrate (CIT) on the biodistribution of radio-yttrium in rats bearing a DS-carcinosarcoma was compared. 88Y-EDTMP and 87Y-CIT were i.v. injected into the same animals. Faster blood clearance and higher renal excretion were observed for the EDTMP-ligand. Of high practical interest is the reduced liver uptake of radio-yttrium (by one order of magnitude) with the EDTMP complex. Since bone and tumour accumulation is only weakly influenced, high tumour-to-liver ratios (up to 14) were observed. We propose to use EDTMP or similar complex ligands for liver blocking when radionuclides like 90Y, 169Yb, 225Ac or other group 3 elements are to be applied in endoradionuclide therapy technique.
We report a case of a patient with end-stage liver disease secondary to hepatitis C, complicated by a large hepatocellular carcinoma. Because of the size of the tumor exceeded the Milan criteria, he was not a candidate for liver transplantation. However, after two treatments with yttrium-90 glass microsphere infusions, the tumor became smaller and the patient's alpha-fetoprotein level dropped to normal range. He was listed for transplantation and subsequently received a deceased donor liver transplant. Two years after his transplantation, he remains tumor free and has normal alpha-fetoprotein levels. This is the first reported case in the literature of using yttrium-90 microspheres as a bridge to liver transplantation in a patient with a large hepatocellular carcinoma. This therapy should be considered in patients with cirrhosis and large hepatocellular carcinomas exceeding current size criterion, who would otherwise be good candidates for transplantation.
The picosecond neodymium:yttrium lithium fluoride laser, a high-power, short-pulse laser that uses low energy per pulse and has a high repetition rate and a highly coherent energy source of 1,053 nm, was used to perform sclerectomies by an ab externo approach in human cadaver eyes. We evaluated laser settings with regard to full-thickness scleral perforation and thermal damage to surrounding tissue. We studied energy per pulse, depth per burst (a present number of spots), spot and line separation of the pattern (spacing between spots of the laser in length [spot separation] and width [line separation]), and total energy required to perforate the sclera. Efficiency was determined by evaluating which settings required the fewest spots and least total energy to perforate the sclera. We studied histologic sections of the sclerectomy sites to determine thermal damage to the surrounding sclera. The picosecond neodymium:yttrium lithium fluoride laser is effective in performing full-thickness sclerectomy with minimal thermal damage to the surrounding tissue. The anterior chamber could be penetrated with an average total energy of 13.3 +/- 0.4 (SEM) J. The sclerectomy size was 545 +/- 11 microns externally and 163 +/- 4 microns internally. Successful sclerectomies were performed with as little as 3 to 5 microns of thermal damage to the surrounding scleral tissue with 250 microJ per pulse.
Intersellar implantation of yttrium-90 rods was a common treatment for a variety of pituitary tumours in the 1960s and 1970s. The magnetic resonance (MR) imaging features in three patients with implants (two for growth hormone-secreting and one for prolactin-secreting pituitary adenomas) are presented: the implants appeared as low signal cylinders with no image distortion, in contradistinction to CT where the implants generate beam hardening and back projection artefacts. Confident evaluation of the pituitary fossa for residential tumour and sequelae of therapy could be made on MR. It is the imaging technique of choice in the follow-up of patients treated with yttrium-90 implants.
We investigated pulmonary clearance of yttrium (Y) and acute lung injury following intratracheal instillation (i.t.) of yttrium chloride (YCl3) in saline- or YCl3-pretreated rats (30 days before the second challenge). About 67% of the initial dose of Y remained in the lung even 31 days after the i.t. treatment. The pretreatment with YCl3 significantly reduced i.t.-YCl3-induced increases in biochemical inflammatory indicators in bronchoalveolar lavage fluid (BALF), such as lactate dehydrogenase, beta-glucuronidase, and alkaline phosphatase activities and protein concentration, while the pretreatment increased the number of polymorphonuclear leukocyte (PMN) in BALF. These results suggest that the augmentation of PMN infiltration does not play an important role, if any, in i.t. YCl3-induced increases in biochemical indicators in BALF. The reduction of the increases in those biochemical inflammatory indicators may be due, at least in part, to the increase of manganese-superoxide dismutase (Mn-SOD) activity in the lung tissue, because the lung Mn-SOD activity in the YCl3-pretreated group was two times higher than that of the saline-pretreated group.
An investigation into the in vitro behaviour of two yttrium-90-labelled somatostatin analogues was performed. Further in vivo characterisation was performed with the most promising agent. A new DTPA-octreotide analogue (Bz-DTPA-oct) was synthesised by coupling a bifunctional DTPA chelator to the N-terminal amine of the D-Phe1 of Tyr3-octreotide. This new SRIF analogue and DTPA-octreotide (OctreoScan) were radiolabelled with 90Y prior to serum stability being evaluated. Receptor binding assays were also performed on the two radioligands using rat cortex membranes. The [90Y]-Bz-DTPA-oct was further evaluated in vivo using tumour-bearing rats. The first conjugate (DTPA-octreotide) bound with a high affinity to SRIF receptors and the 90Y complex was relatively stable in human serum (t1/2 3.8 d for 90Y lost to serum proteins). The second conjugate (Bz-DTPA-oct) also exhibited a high binding affinity to SRIF receptors, but it demonstrated an even slower loss of 90Y to serum proteins (t1/2 12.1 d). The in vivo evaluation of the more stable [90Y]-Bz-DTPA-oct showed a very rapid and high accumulation in somatostatin receptor-positive tumours, which after 1 h resulted in tumour/nontumour ratios of 3.8, 21, and 4.9 (for blood, muscle, and liver, respectively). These tumour/nontumour ratios increased, and were by 24 h postinjection 138, 285, and 6.1 (for blood, muscle, and liver). Yttrium-90-labelled Bz-DTPa-oct is rapidly and selectively accumulated in somatostatin receptor-positive tissue. Octadentate Bz-DTPA-oct could be ligand for 90Y radiotherapy of somatostatin receptor-positive tumours and their metastases.
We evaluated the in vivo biodistribution of indium- and yttrium-labeled second-generation polyamidoamine dendrimer (PAMAM) conjugated with 2-(p-isothiocyanatobenzyl)-6-methyl-diethylenetriaminepentaacetic acid (1B4M), a derivative of DTPA. In addition, we conjugated PAMAM-1B4M to humanized anti-Tac IgG (HuTac) and evaluated its in vitro and in vivo properties. PAMAM-1B4M was labeled with 111In at 37-48 MBq/mg (1.0-1.3 mCi/mg) or with 88Y at 3.7-4.8 MBq/mg (0.1-0. 13 mCi/mg), and an aliquot of radiolabeled conjugate was saturated with the corresponding stable yttrium or indium. Nontumor-bearing nude mice were injected intravenously with 55.5-66.6 kBq (1.5-1.8 microCi) of 88Y-labeled PAMAM-1B4M or with 185 kBq (5 microCi) of 111In-labeled PAMAM-1B4M. The mice were then sacrificed at 15 min, 90 min, 1 day, and 4 days postinjection. Then the PAMAM-1B4M was conjugated with HuTac and labeled with 111In at 111-259 MBq/mg (3-7 mCi/mg). Another preparation of 111In-labeled HuTac-PAMAM-1B4M was saturated with stable indium. Immunoreactivity of both preparations and biodistribution in normal mice 1 h after injection and in ATAC4 and A431 tumor-bearing mice 18 h after injection were evaluated and compared with those of 111In-labeled 1B4M-HuTac. We noted significantly higher accumulations (p < 0.05) of 111In-labeled and 88Y-labeled unsaturated PAMAM-1B4M than saturated preparations in the liver, kidney, spleen, and bone at most time points. The whole-body clearance times of unsaturated preparations were significantly slower than those of saturated preparations at all time points, with the exception of 168 h for 111In-labeled PAMAM-1B4M. The saturated preparation of 111In-labeled HuTac-PAMAM-1B4M showed lower hepatic uptake (27 +/- 2%ID/g) than the unsaturated (32 +/- 2%ID/g), but greater than the HuTac-1B4M control (10 +/- 0%ID/g). The splenic uptake showed 15 +/- 1, 38 +/- 5, and 8 +/- 1%ID/g for the saturated, unsaturated, and control, respectively. The biodistribution of the dendrimer conjugated HuTac in normal organs of tumor-bearing mice was similar to nontumor-bearing mice. Specific tumor (ATAC4) uptake was higher than that in nonspecific tumor (A431). In conclusion, we evaluated the biodistribution of radiolabeled PAMAM-1B4M. We noted high accumulation in the liver, kidney, and spleen, which significantly decreased when the chelates were saturated with the stable element. A similar phenomenon was observed between unsaturated and saturated 111In-labeled HuTac-PAMAM-1B4M, indicating that the PAMAM dendrimer had a detrimental effect on biodistribution.
Novel 1,4,7-triazacyclononane-N,N',N' '-triacetic acid (NOTA) based octadentate ligands [2-(4,7-biscarboxymethyl[1,4,7]triazacyclononan-1-ylethyl)carbonylmethylamino]acetic acid tetrahydrochloride (1) and [3-(4,7-biscarboxymethyl[1,4,7]triazacyclononan-1-yl-propyl)carbonylmethylamino]acetic acid tetrahydrochloride (2) with pendent donor groups as potential yttrium chelators for radioimmunotherapy (RIT) have been prepared via a convenient and high-yield cyclization route. The complexation kinetics of the novel chelates with Y(III) was investigated and compared to that of 1,4,7,10-tetraazacyclododecane-N,N',N' ',N" '-tetraacetic acid (DOTA), a macrocyclic chelating agent well recognized as forming very stable complexes with yttrium but also limited in usage because of slow Y(III) complex formation rates. The in vitro stability of the corresponding (88)Y-labeled complexes in human serum was assessed by measuring the release of (88)Y from the complexes over 14 days. The in vivo biodistribution of (86)Y-labeled 1 in mice was evaluated and compared to that of the (86)Y-DOTA complex. Formation of the Y complex of 1 was significantly more rapid than that of either 2 or DOTA. Serum stability of the (88)Y complex formed with 1 was equivalent to the DOTA complex, while the complex formed with 2 proved to be significantly unstable. The results obtained from a biodistribution study indicate that the (86)Y-1 complex possesses in vivo stability comparable to the analogous DOTA complex.
Eighteen patients with inoperable hepatocellular carcinoma (HCC) were treated with intrahepatic arterial yttrium-90 microspheres. All these patients showed a lung shunting below 15% and a tumour-to-normal ratio higher than 2 as determined by diagnostic technetium-99m macroaggregated albumin (Tc-MAA) gamma scintigraphy. The treatment was given through an arterial port placed during laparotomy. The radiation doses to the liver and tumour were determined intraoperatively with a beta probe and liquid scintillation counting of multiple liver biopsies. The treatment was well tolerated without major complications. In all patients the tumour marker fell to a level which ranged from 41% to 0.2% of the pretreatment level. Tumour regression was found to be dose related. Progressive or static disease occurred in a higher proportion of patients whose tumours received < 120 Gy (P = 0.005). Survival was better in those whose tumours received > 120 Gy (median survival = 55.9 weeks) than those whose tumours received lower doses (median survival = 26.2 weeks). This difference is statistically significant with P = 0.005. We conclude that yttrium-90 microsphere therapy is safe and that tumour response is dose related. A tumour dose of > 120 Gy is recommended.
Patients with low-grade, follicular non-Hodgkin's lymphoma usually present with advanced disease, which is not considered curable with conventional therapies. New approaches are needed to improve the outcomes in patients with this disease. Yttrium 90 ibritumomab tiuxetan (Zevalin; Biogen Idec Inc, Cambridge, MA), is highly effective, with overall response rates of 73% to 83% and complete response rates of 15% to 51%, with a median duration of response in complete responders of 23 months. The response rates tend to be higher in patients who have been treated with fewer prior therapies, and (90)Y ibritumomab tiuxetan may be suitable for use early in the course of therapy. Delayed myelosuppression is the most common adverse effect, and it is predictable, reversible, and manageable. Yttrium 90 ibritumomab tiuxetan has less nonhematologic toxicity than chemotherapy, with only minimal alopecia, mucositis, nausea, or vomiting, and a lower incidence of infections. The ibritumomab tiuxetan regimen is routinely and safely given in an outpatient setting and is completed in 7 to 9 days, and is thus more convenient for patients than chemotherapy.
OBJECTIVES: To detail recent developments pertaining to the efficacy and safety of radioimmunotherapy with yttrium 90 (90Y) ibritumomab tiuxetan for patients with B-cell non-Hodgkin's lymphoma (NHL). DATA SOURCES: Published clinical trials of 90Y ibritumomab tiuxetan and secondary literature on radioimmunotherapy and NHL. CONCLUSION: Yttrium 90 ibritumomab tiuxetan is safe and effective in the indicated population. It has a good safety profile and is generally well tolerated. It is not associated with the adverse events from conventional chemotherapy and external beam radiation therapy. IMPLICATIONS FOR NURSING PRACTICE: Nursing professionals who are aware of the efficacy and safety data associated with 90Y ibritumomab tiuxetan can optimize efficacy and educate patients and their caregivers about the regimen.
Radioimmunotherapy (RIT) is a promising new treatment option for patients with relapsed/refractory non-Hodgkin's lymphoma. Clinical trials have demonstrated that both iodine-131 (131I) and yttrium-90 (90Y) are suitable radionuclides for RIT. Iodine-131 and 90Y differ markedly in their physical properties including half-life, path length, type of energy emissions, intracellular stability, and the organs targeted by the free radionuclide. Both radionuclides can be safely administered in the outpatient setting under current Nuclear Regulatory Commission guidelines. Potential advantages of 131I for RIT include availability, stable chemistry, longer half-life, and an emission spectrum that allows for dosimetric studies and therapy with the same immunoconjugate. By contrast, 90Y has a longer path length and superior intracellular stability compared with 131I. Yttrium-90 may therefore be preferable to 131I for patients with bulky disease, poorly vascularized solid tumors, or when targeting internalized antigens. Although 90Y emits no gamma photon, dosimetry studies for 90Y RIT can be performed using a surrogate radionuclide such as indium-111. Both 131I- and 90Y-labeled anti-CD20 antibodies have demonstrated efficacy in treating relapsed/refractory non-Hodgkin's lymphoma. Further studies are needed, however, to determine if the differences in the pharmacology of 131I and 90Y are clinically relevant.