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PubMed1994

Comparative toxicity studies of yttrium-90 MX-DTPA and 2-IT-BAD conjugated monoclonal antibody (BrE-3).

BACKGROUND: BrE-3 is monoclonal antibody that has promise for imaging and therapy of human adenocarcinoma. Because of observations in therapeutic trials of yttrium-90 (90Y) escape from radioimmunoconjugates and uptake by the skeleton with resultant bone marrow toxicity, the authors attempted to evaluate the importance of this factor by a comparison of the LD50 in healthy mice treated with 90Y that had been chelated with either of two high affinity chelators, methylbenzyldiethylene-triaminepentaacetic acid (MX-DTPA) or bromoacetamidobenzyl-1,4,7,10-tetraazocyclododecane- N,N',N'',N'''-tetraacetic acid (BAD). METHODS AND RESULTS: Bone marrow hematopoietic toxicity was dose-limiting and the source of death for both chelators. The LD50 for 90Y-BrE-3-MX-DTPA was 220.9 microCi, and that for 90Y-BrE-3-2IT-BAD and was 307.8 microCi. Whole-body autoradiography revealed substantially greater uptake of 90Y in the skeleton when MX-DTPA was used as the chelator. CONCLUSIONS: These observations suggest that 90Y escape to bone is a significant factor in the maximum tolerated dose of radioimmunoconjugate that can be used in therapeutic trials. These results probably underestimate the importance of 90Y escape since 90Y in the skeleton of patients is likely to be more significant than in mice because more of the 90Y energy is absorbed in the marrow of larger species.

Animals↗
PubMed1994

A mouse model for calculating cross-organ beta doses from yttrium-90-labeled immunoconjugates.

BACKGROUND: The organs of laboratory mice used in radioimmunotherapy experiments are relatively small compared to the ranges of high-energy yttrium-90 (Y-90) beta particles. Current Medical Internal Radiation Dose (MIRD) dosimetry methods do not account for beta energy that escapes an organ. A dosimetry model was developed to provide more realistic dose estimates for organs in mice who received Y-90-labeled antibodies by accounting for physical and geometric factors, loss of beta dose due to small organ sizes, and cross-organ doses. METHODS: The dimensions, masses, surface areas, and overlapping areas of different organs of 10 athymic nude mice, each weighing approximately 25 g, were measured to form a realistic geometric model. Major organs in this model include the liver, spleen, kidneys, lungs, heart, stomach, small intestine, large intestine, thyroid, pancreas, bone, marrow, and carcass. A subcutaneous tumor mass also was included in the model. By accounting for small organ absorbed fractions and cross-organ beta doses, the MIRD methodology was extended from humans to mice for beta dose calculations. RESULTS: Absorbed fractions of beta energy were calculated using the Berger's point kernels and the electron transport code EGS4. Except for the tumor and carcass, the self-organ absorbed fractions ranged from 15% to 20% in smaller organs (the marrow and thyroid) to 65%-70% in larger organs (the liver and small intestine). Cross-organ absorbed fractions also were calculated from estimates of the overlapping surface areas between organs. CONCLUSION: The mathematic mouse model presented here provides more realistic organ dosimetry of radiolabeled monoclonal antibodies in the nude mouse, which should, in turn, contribute to a better understanding of the correlation of biodistribution study results and organ-tumor toxicity information.

Animals↗
PubMed2002

Biokinetics of yttrium-90--labeled huBrE-3 monoclonal antibody.

BACKGROUND: This study reports summary biokinetics for 17 patients treated with huBrE-3 antibody labeled with indium-111 ((111)In) and yttrium-90 ((90)Y) in a Phase I dose escalation trial. METHODS: Patients were infused with huBrE-3 antibody conjugated to 1-p-isothiocyanatobenzyl 3-methyl- and 1-p-isothiocyanatobenzyl 4-methyl-diethylenetriamine pentaacetic acid (MX-DTPA). The huBrE-3 was labeled with increasing amounts of (90)Y radioactivity according to the following activity regimen: 10 mCi/m(2), 20 mCi/m(2), 33 mCi/m(2), 50 mCi/m(2), and 70 mCi/m(2). In addition to the (90)Y activity, 3--5 mCi of (111)In was labeled to huBrE-3 to serve as an imaging agent. In characterizing the biokinetics of huBrE-3, serial urine and blood samples were acquired. Additionally, whole-body imaging using a scintillation camera was performed at four time points postinfusion. RESULTS: Cumulative urine data yielded a plot of total-body biologic excretion that was relatively flat. Total body regions of interest derived from nuclear medicine scintigrams decreased according to a monoexponential function with a slope slightly greater than the rate of physical decay. When physical decay was combined with the urine biologic excretion rate, the calculated rate of activity decrease was indistinguishable from the scintigraphic rate of decrease in total-body activity. CONCLUSIONS: The authors concluded from these observations that the radioactivity remains essentially inside the patient, that biologic excretion of activity from the total body is not appreciable, and that the path for biologic excretion of activity that does occur is via the urine. The half-time associated with the beta (slow) phase for extraction from the blood averages 40.5 hours. Since large amounts of radioactivity do not appear in the urine, and total-body activity is decreased approximately according to physical decay (64.1 hours), activity must pool elsewhere after leaving the blood. The logical place is the skeleton, with possible selective binding to the bone marrow. Bone marrow biopsies from 4 of 7 patients who consented to serial biopsies were supportive of this conclusion.

Antibodies, Monoclonal↗
PubMed2006

Recommendations for the use of yttrium-90 ibritumomab tiuxetan in malignant lymphoma.

Radioimmunotherapy (RIT) with Yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin) combines the tumor targeting attributes of a monoclonal antibody against the CD20 antigen and the pure beta-radiation of 90Y. High efficacy and a favorable safety profile have been demonstrated in Phase II and III clinical trials enrolling patients with CD20+ B-cell non-Hodgkin lymphoma (B-NHL). On the basis of these results, 90Y-ibritumomab tiuxetan was approved in the United States for the treatment of patients with follicular lymphoma (FL) or transformed B-NHL. In the European Union its use was restricted to FL, refractory to or relapsed after rituximab. There are a number of important clinical trials currently evaluating 90Y-ibritumomab tiuxetan in other subtypes of lymphoma such as diffuse large-cell and mantle-cell lymphoma, as consolidation therapy or as part of myeloablative regimens. In light of the constantly increasing clinical experience with RIT, clinicians face the challenge of how to best integrate this promising new treatment option into existing established treatment algorithms. By incorporating the most recent data in this rapidly developing field, this review article focuses on current recommendations for the use of 90Y-ibritumomab tiuxetan in patients with malignant lymphoma, outlines future perspectives, and provides practical recommendations for patient management.

Antibodies, Monoclonal↗
PubMed2002

Hydroxylapatite with substituted magnesium, zinc, cadmium, and yttrium. II. Mechanisms of osteoblast adhesion.

The present in vitro study investigated osteoblast adhesion on hydroxylapatite (HA) doped with either cadmium (Cd), zinc (Zn), magnesium (Mg), or yttrium (Y). Compared with any other dopant tested in the present study, osteoblast adhesion was significantly (p < 0.05) greater on HA doped with Y after 4 h; in addition, osteoblast adhesion increased with concentration (2-7 mol%) of Y in HA. The findings that HA doped with greater amounts of Y adsorbed higher concentrations of calcium and, subsequently, of vitronectin and collagen (proteins known to mediate osteoblast adhesion), but not of albumin, laminin, and fibronectin, may explain the observed enhanced adhesion of osteoblasts on these substrates. Interactions (i.e., adsorption and configuration/bioactivity) of vitronectin and collagen may have been promoted by increased porosity of doped HA. Through doping with Y, the present study provided the first evidence that HA can be synthesized and processed with improved cytocompatibility properties for osteoblast adhesion, and thus offered essential information for the design of novel proactive bioceramics. Proactive bioceramics which elicit specific, timely, and desired responses from surrounding cells and tissues are necessary for improving bonding of orthopaedic/dental implants to juxtaposed bone; such osseointegration will, undoubtedly, enhance implant efficacy.

Adsorption↗
PubMed1989

Mechanical properties and short-term in-vivo evaluation of yttrium-oxide-partially-stabilized zirconia.

Yttrium-oxide-partially-stabilized zirconia (YPSZ) belongs to a new class of ceramics exhibiting an improved toughness when compared to alumina. The toughening mechanism is related to a martensitic-like transformation of tetragonal metastable grains into a monoclinic state occurring at the crack tip. Specific tests showed that YPSZ exhibited a high bending strength (900-1200 MPa), a low Young's modulus (200 GPa), and a high toughness (KIC = 9-10 MN/m3/2). Its average grain size of 0.5 microns allows a surface roughness as low as 0.008 microns. Sterilization or aging in saline solution at room temperature for 100 days did not affect the toughness of this material. Cylindrical YPSZ samples, manufactured by cold isostatic pressing and sintering, were implanted in the paraspinal muscles in the rat up to 12 weeks. The tissue reaction was evaluated with reference to alumina (ISO requirements) by means of quantitative histomorphometry. No significant differences were found between YPSZ and alumina for both the membrane thickness and cell distributions surrounding the implants.

Aluminum Oxide↗
PubMed2005

Macro-structural effect of metal surfaces treated using computer-assisted yttrium-aluminum-garnet laser scanning on bone-implant fixation.

Porous coatings have been applied to the surface of prosthetic devices to foster stable device fixation. The coating serves as a source of mechanical interlocking and may stimulate healthy bone growth through osseointegrated load transfer in cementless arthroplasty. Joint arthroplasty by porous-coated prostheses is one of the most common surgical treatments, and has provided painless and successful joint mobility. However, long-term success is often impaired by the loss of fixation between the prosthesis and bone. Porous-coated prostheses are associated with several disadvantages, including metal debris from porous coatings (third body wear particles) and irregular micro-texture of metal surfaces. Consequently, quantitative histological analysis has been very difficult. These issues arise because the porous coating treatment is based on addition of material and is not precisely controllable. We recently developed a precisely controllable porous texture technique based on material removal by yttrium-aluminum-garnet laser. Free shapes can be applied to complex, three-dimensional hard metal surfaces using this technique. In this study, tartan check shapes made by crossing grooves and dot shapes made by forming holes were produced on titanium (Ti6A14V) or cobalt chrome (CoCr) and evaluated with computer-assisted histological analysis and measurement of bone-metal interface shear strength. Width of grooves or holes ranged from 100 to 800 mum (100, 200, 500, and 800 microm), with a depth of 500 microm. When the cylindrical porous-texture-treated metal samples (diameter, 5 mm; height, 15 mm) were implanted into a rabbit femoral condyle, bone tissue with bone trabeculae formed in the grooves and holes after 2 or 4 weeks, especially in 500-microm-wide grooves. Abundant osteoconduction was consistently observed throughout 500-microm-wide grooves in both Ti6A14V and CoCr. Speed of osteoconduction was faster in Ti6A14V than in CoCr, especially in the tartan check shape made of 500-microm-wide grooves. In pushout testing, the tartan check shape made of 500-microm-wide grooves had significantly higher bone-metal interface shear strength than the dot shape or commercial porous coating. These results indicate that the tartan check shape made of 500-microm-wide grooves on metal surfaces has potential for clinical application in artificial prosthesis design.

Aluminum↗
PubMed2007

Microtensile bond strength of composite resin to human enamel prepared using erbium: Yttrium aluminum garnet laser.

The Erbium: Yttrium Aluminum Garnet (YAG) laser used for preparation of cavity can alter the substrate and it could influence the bond strength of enamel. The aim of this in vitro study was to evaluate the influence of Er:YAG laser's energy using microtensile bond test. Three groups were obtained (cavity preparation) and each group was divided into two subgroups (adhesive system). After that the adhesive protocol was performed, sections with a cross-sectional area of 0.8 mm2 (+/-0.2 mm2) were obtained. The specimens were mounted in a universal testing machine (0.5 mm/min). Statistical analysis showed a decrease in bond strength for lased groups (p < 0.01) and when the total-etching adhesive system was used the laser 300 mJ subgroup showed higher bond strength compared to the laser 250 mJ (p < 0.01). It was concluded that the cavities prepared using laser appear less receptive to adhesive procedures than conventional bur-cut cavities.

Adhesives↗
PubMed1992

Feasibility of skin deepithelialization using the contact neodymium-yttrium-aluminum-garnet laser.

In a manner similar to laserbrasion, the carbon dioxide (CO2) laser has a proven role for expediting skin deepithelialization, which is an essential component of many reconstructive procedures. However, the contact Neodymium-Yttrium-Aluminum-Garnet (Nd:YAG) laser has many additional attributes such as tactile feedback and less plume that theoretically offer an advantage over the CO2 laser for this adjunctive maneuver. In rat experimental models and clinical applications, removal of the epidermis necessary for skin deepithelialization may indeed be achieved using a rounded probe for vaporization with the contact Nd:YAG laser. Unfortunately, the length of time necessary for skin deepithelialization with the Nd:YAG laser exceeded even conventional methods, such that this role with the present technology, although possible, is inefficient and impractical.

Aluminum Silicates↗
PubMed2005

Use of yttrium-90 microspheres (TheraSphere) in a patient with unresectable hepatocellular carcinoma leading to liver transplantation: a case report.

Prior to therapy, model for end stage liver disease (MELD) scoring, diagnostic imaging and tumor staging were performed in a patient with T3 HCC. The patient received an orthotopic liver transplant (OLT) 42 days after treatment. The explant specimen showed complete necrosis of the target tumor. Follow-up of this patient has demonstrated no evidence of recurrence. There was no life threatening or fatal adverse experiences related to treatment. This case report documents the natural course, history and outcome of a patient treated with yttrium-90 for unresectable HCC. The patient was downstaged from T3 to T2 and was subsequently transplanted.

Adult↗
PubMed2004

Quality of life in patients diagnosed with primary hepatocellular carcinoma: hepatic arterial infusion of Cisplatin versus 90-Yttrium microspheres (Therasphere).

BACKGROUND: The aims of the study were to test the difference in health-related quality (HRQL) of life and survival in patients diagnosed with primary hepatocellular carcionma (HCC) and treated with either hepatic arterial infusion (HAI) of Cisplatin or 90-Yttrium microspheres (Therasphere). METHOD: The design of the study was a non-randomized parallel cohort study. Twenty-eight patients participated in the present study. HRQL was assessed by administration of the Functional Assessment of Cancer Therapy-Hepatobiliary. Survival was measured using Kaplan Meier methods. RESULTS: The results of present study suggest treatment with Therasphere) had an advantage in regard to HRQL and survival when compared to Cisplatin. At 3-month follow-up, patients who were treated with Therasphere had a higher level of functional well-being as well as overall quality of life when compared to patients treated with Cisplatin. At 6-month follow-up patients (treated with Therasphere) continued to have better functional well-being when compared to patients being treated with HAI of Cisplatin. At 6-month follow-up, survival was found to be similar for patients treated with Therasphere when compared to patients being treated with Cisplatin. CONCLUSIONS: Preliminary data suggest that treatment with Therasphere has a modest advantage in regard to HRQL when compared patients treated with HAI of Cisplatin. Future research with Therasphere, that includes a larger sample size and longer follow-up, is necessary to make definitive conclusions regarding the efficacy and effect on HRQL.

Adolescent↗
PubMed1994

Continuous infusion chemotherapy as a radiation-enhancing agent for yttrium-90-radiolabeled monoclonal antibody therapy of a human tumor xenograft.

Radioimmunotherapy using monoclonal antibodies is a promising investigational treatment modality for solid tumors. Use of radiation-enhancing agents could significantly impact on the therapeutic response of this treatment. We evaluated the potential interaction of a known radiation-enhancing agent, 5-fluorouracil (5-FU), with the radioimmunotherapeutic effect of a yttrium-90 (90Y)-labeled monoclonal antibody in a human adeno-carcinoma xenograft. Athymic mice were inoculated subcutaneously with the human colon carcinoma cell line LS-174T. All mice had intraperitoneal 3-day osmotic infusion pumps placed by laparotomy. Half of the pumps were filled with 0.9% saline solution and half were filled with a solution containing 5-FU. Three activity levels of 90Y-radiolabeled CC49 antibody were injected into tail veins of the mice. Each activity level was injected into a group of animals with saline-filled pumps and a group with 5-FU-filled pumps. A significant interaction between treatment group and time was found suggesting that the rate of tumor growth for the group of animals receiving 90Y at 100 microCi plus 5-FU compared to the group of animals receiving 90Y alone was significantly delayed (P = 0.0055), showing a radiation enhancing effect by 5-FU. These results suggest that the addition of the radiation-enhancing agent 5-FU to radiolabeled antibody may increase the ability to treat solid tumors. Further investigations with other antibodies, radionuclides, and tumor models are indicated.

Adenocarcinoma, Mucinous↗
PubMed1987

Long-term follow-up of patients who underwent yttrium-90 pituitary implantation for treatment of proliferative diabetic retinopathy.

Between 1960 and 1976 117 patients underwent pituitary implantation with yttrium-90 (90Y) for treatment of proliferative retinopathy at the Hammersmith Hospital, London. Mean age at operation was 35 +/- 11 years (mean +/- SD), and mean duration of diabetes 18.6 +/- 10.0 years. Mean insulin dosage prior to implant was 67.2 +/- 24 units, falling to 30.4 +/- 14.9 units post-implant. Thirty-two per cent of patients are still living, 60% are deceased and 8% are lost to follow-up. The 5-year survival rate was 82%. Of the causes of death, 21% died of infection, adrenal insufficiency or hypoglycaemia, 12% of renal failure, and 47% of myocardial or cerebral vascular disease. Ophthalmological follow-up was carried out on the 100 patients operated on between 1965 and 1976. The mean age of this group at implant was 35 +/- 10.5 years, and mean duration of diabetes 17.2 +/- 8.7 years. Visual acuity in the better eye at operation was 6/12 or better in 84% of patients, and this percentage remained similar at the time of the 5 and 10 year follow-up. Blindness (6/60 or worse) in both eyes was present in 12% of patients at the time of 5 and 10 year assessments. By 5 years new vessels on the disc had improved from a mean grading of 2.7 +/- 1.6 to 0.8 +/- 1.2 (p less than 0.001), and by 10 years there was no disc neovascularisation in any eye. There was a similar improvement in the grading of hard exudates, microaneurysms and haemorrhages, but there was an increase in fibrous retinitis proliferans.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

An approach to the mechanism of the asymmetrical radical formation in yttrium-90-beta-irradiated D- and L-alanines.

Several attempts were made to investigate the mechanism of the asymmetrical radical formation in yttrium-90-beta-irradiated D- and L-alanines which was reported in the preceding paper (1). The experiments demonstrated that the magnitude of the asymmetry was dependent on beta-ray dose, namely the lower the dose the larger the observed difference was, and that no difference could be detected when the alanines were irradiated in aqueous state. The results in the present study seem to that different interaction between the crystal structure of the two enantiomers and polarized beta-rays may be responsible for the observed phenomenon.

Alanine↗
PubMed1996

Partition model for estimating radiation doses from yttrium-90 microspheres in treating hepatic tumours.

A uniform distribution of yttrium-90 (90Y) microspheres throughout the entire liver has always been assumed for dose calculation in treating hepatic tumours. A simple mathematical model was formulated which allows estimation of the activities of a therapeutic dose of 90Y microspheres partitioned between the lungs, the tumour and the normal liver, and hence the radiation doses to them. The doses to the tumour and normal liver were verified by intra-operative direct beta-probing. The percentage of activity shunted to the lung and the tumour-to-normal tissue ratio (T/N) were obtained from gamma scintigraphy using technetium-99m-labelled macroaggregated albumin (MAA) which simulates the 90Y microspheres used in subsequent treatment. The intrahepatic activity was partitioned between the tumour and the normal liver based on the T/N and their masses determined from computerized tomography slices. The corresponding radiation doses were computed using the MIRD formula. The estimated radiation doses were correlated with the doses directly measured using a calibrated beta-probe at laparotomy by linear regression. The radiation doses to the tumour and the normal liver, estimated using the partition model, were close to that measured directly with coefficients of correlation for linear regression: 0.862 for the tumours and 0.804 for the normal liver compartment (P<0.001). The partition model permits a distinction between the radiation doses received by the tumour and the normal liver to be made and the doses thus estimated are close to the actual doses received. The optimal doses to the tumour and normal liver and hence the required quantity of 90Y microspheres to be administered can be easily predetermined.

Brachytherapy↗
PubMed1997

Clinical evaluation of the partition model for estimating radiation doses from yttrium-90 microspheres in the treatment of hepatic cancer.

Radiation doses to the tumour and non-tumorous liver compartments from yttrium-90 microspheres in the treatment of hepatic cancer, as estimated by a partition model, have been verified by correlation with the actual doses measured with a beta probe at open surgery. The validity of the doses to the lungs, the tumour and non-tumorous liver compartment as estimated by the partition model was further evaluated in clinical settings. On the basis of the observation that one of three patients who received more than 30 Gy from a single treatment and one of two patients who received more than 50 Gy from multiple treatments developed radiation pneumonitis, it was deduced that an estimated lung dose < 30 Gy from a single treatment and a cumulative lung dose < 50 Gy from multiple treatments were probably the tolerance limits of the lungs. Three of five patients who received lung doses > 30 Gy as estimated by the partition model and were predicted to develop radiation pneumonitis, did so despite the use of partial hepatic embolization to reduce the degree of lung shunting. Furthermore, a higher radiological response rate and prolonged survival were found in the group of patients who received higher tumour doses, as estimated by the partition model, than in the group with lower estimated tumour doses. Thus the radiation doses estimated by the partition model can be used to predict (a) complication rate, (b) response rate and (c) duration of survival in the same manner as the actual radiation doses measured with a beta probe at open surgery. The partition model has made selective internal radiation therapy using 90Y microspheres safe and repeatable without laparotomy.

Adult↗