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D R Fisher

Publications and source records attributed to D R Fisher.

At least 55 records · Page 3Linked to original sources
PubMed1995

Pharmacokinetics and normal organ dosimetry following intraperitoneal rhenium-186-labeled monoclonal antibody.

UNLABELLED: Pharmacokinetics, biodistribution and radiation dose estimates following intraperitoneal administration of a 186Re-labeled murine antibody, NR-LU-10, were assessed in 27 patients with advanced ovarian cancer. METHODS: Quantitative gamma camera imaging and gamma counting of serum and intraperitoneal fluid radioactivity were used to obtain data for dosimetry estimation. The MIRD intraperitoneal model was used to estimate dose to normal organs from radioactivity within the peritoneal cavity. The absorbed dose to normal peritoneum was estimated in two ways: from the gamma camera activity and peritoneal fluid samples. RESULTS: Serum activity peaked at 44 hr and depended on the concentration of radioactivity in the peritoneal fluid. Mean cumulative urinary excretion of 186Re was 50% by 140 hr. Estimates of radiation absorbed dose to normal organs in rad/mCi administered (mean +/- s.d.) were whole body 0.7 +/- 0.3; marrow 0.4 +/- 0.1; liver 1.9 +/- 0.9; lungs 1.3 +/- 0.7; kidneys 0.2 +/- 0.2; intestine 0.2 +/- 0.2. Peritoneal surface dose estimates varied depending on the volume of fluid infused and the method of dose determination. Using gamma camera data, the peritoneal dose ranged from 7 to 36 rad/mCi. Using peritoneal fluid sample data, the dose ranged from 2 to 25 rad/mCi. Significant myelosuppression was observed at marrow doses above 100 rad. CONCLUSION: Noninvasive methods of dose estimation for intraperitoneal administration of radioimmunoconjugates provide reasonable estimates when compared with previously described methods.

Female↗
PubMed1994

Radiation dosimetry for radioimmunotherapy. An overview of current capabilities and limitations.

BACKGROUND. The two major uncertainties associated with absorbed dose calculations involve: (1) measurement errors from assessment of radioactivity in specific organs and tissues by direct counting; and (2) application of standard anthropomorphic and biokinetic models for dose assessment. Uncertainties in direct counting result from the inherent difficulty of measuring radioactivity inside the body. Although the system recommended by the Medical Internal Radiation Dose (MIRD) Committee of the Society of Nuclear Medicine provides a general framework and conceptual basis for the dosimetry of administered radiopharmaceuticals, it does not provide complete methods for assessing some of the more important quantities of interest in radioimmunotherapy, such as dose to tumors and descriptions of spatial dose distributions within tissues. Current MIRD anthropomorphic models are only crude representations of the human body. Generalized biokinetic models used in the MIRD system may vary considerably from the actual biokinetics of radiolabeled compounds in the body. This review describes limitations of the present MIRD system for radioimmunotherapy; they include assumptions used in treatment planning and the lack of specific methods for tumor dosimetry, multi-cellular dosimetry, microdosimetry, small animal dosimetry, and uncertainty analysis. CONCLUSIONS. Treatment planning for radioimmunotherapy requires patient-specific organ models and customized biokinetic parameters. Improvements are also needed in marrow dosimetry to account for the amount and distribution of red marrow relative to that found in adjacent source regions, skeletal structures, and circulating blood. Simplified assumptions with regard to the locally absorbed fraction of beta-particle energy in tissues adjacent to source regions should not be used when depth-dose profiles are needed; for example, radiation absorbed doses to intestinal walls should be calculated over the entire mass of tissue or described by absorbed-dose distributions. Additional research is needed to develop improved measurement techniques and computational methods to assess more accurately internal dose distributions within tumors and normal tissues.

Humans↗
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↗
PubMed1994

Application of the cross-organ beta dose method for tissue dosimetry in tumor-bearing mice treated with a 90Y-labeled immunoconjugate.

BACKGROUND: Radioimmunotherapy of nude mice bearing human tumor xenografts using 90Y-labeled monoclonal antibodies has resulted in slower tumor growth, decreased tumor burden, and increased survival times. Dosimetry estimates in the murine model usually were based on biodistribution data and standard Medical Internal Radiation Dose approaches. A new dosimetric model for the mouse that takes into consideration the small dimensions, mass, and proximity of murine organs has been developed based on self-organ absorbed and cross-organ doses. METHODS: Nude mice bearing carcinoembryonic antigen-expressing WiDr human colon cancer xenografts were injected with 240 microCi 90Y-anti-carcinoembryonic-antigen monoclonal antibodies and then killed at 12, 24, 72, 120, and 168 hours. Tumors and major organs were removed, weighed, and counted on a gamma counter. Using the resulting biodistribution data, the radiation doses to tumor and normal organs were calculated using the new dosimetric model for the mouse. RESULTS: Three organs (the liver, kidneys, and large bowel) directly received > 50% of the total absorbed beta dose from radioactivity. Lungs, stomach, and marrow received the highest percentage (70-75%) of the total absorbed dose from adjacent organs. Tumor absorbed dose, estimated with the new dosimetric model, was three times less than that obtained with a MIRD-style calculation without correction for self-absorbed and cross-organ doses. CONCLUSIONS: The new dosimetric model, which accounts more accurately for self-organ absorbed and cross-organ beta dose fraction, allows the calculation of tumor and organ doses in the murine model. Accurate estimation of radiation doses to tumor and critical organs, such as the marrow, spleen and kidneys, is important in determining the efficacy and toxicity of radioimmunotherapy regimens in animals and in subsequent human applications.

Animals↗
PubMed1994

An internal dosimetry intercomparison study.

Pacific Northwest Laboratory performed a study to evaluate the consistency of internal dosimetry assessments. A total of eleven laboratories, including DOE sites and NRC licensees, participated in this intercomparison study. Participants were asked to respond to five actual exposure scenarios, previously used in a similar European study. The participating dosimetrists assessed the data of the test scenarios and calculated results in terms of estimated radionuclide intake and the resulting internal doses. To maintain confidentiality, results are given without identifying any site. Except for one scenario, the results showed that the standard deviation of the final results on committed effective dose equivalent for each exposure scenario was about 30-50% of the mean value, giving a consistency slightly greater variant than that of the European study. The discrepancies can be attributed to variations in 1) the interpretation and statistical treatment of the bioassay data; 2) the biokinetic models applied; and 3) the computational tools used. This represents a preliminary study; further intercomparison testing is needed to fully evaluate the problem of dose-assessment inconsistency.

Administration, Inhalation↗
PubMed1993

Dosimetry of rhenium-186-labeled monoclonal antibodies: methods, prediction from technetium-99m-labeled antibodies and results of phase I trials.

Rhenium-186 is a beta-emitting radionuclide that has been studied for applications in radioimmunotherapy. Its 137 keV gamma photon is ideal for imaging the biodistribution of the immunoconjugates and for obtaining gamma camera data for estimation of dosimetry. Methods used for determining radiation absorbed dose are described. We have estimated absorbed dose to normal organs and tumors following administration of two different 186Re-labeled immunoconjugates, intact NR-LU-10 antibody and the F(ab')2 fragment of NR-CO-02. Tumor dose estimates in 46 patients varied over a wide range, 0.4-18.6 rads/mCi, but were similar in both studies. Accuracy of activity estimates in superficial tumors was confirmed by biopsy. Prediction of 186Re dosimetry from a prior 99mTc imaging study using a tracer dose of antibody was attempted in the NR-CO-02 (Fab')2 study. Although 99mTc was an accurate predictor of tumor localization and the mean predicted and observed radiation absorbed doses to normal organs compared favorably, 186Re dosimetry could not be reliably predicted in individual patients. The methods described nevertheless provide adequate estimates of 186Re dosimetry to tumor and normal organs.

Humans↗
PubMed1992

Specific marrow ablation before marrow transplantation using an aminophosphonic acid conjugate 166Ho-EDTMP.

166Holmium ethylenediaminetetramethylene phosphonic acid (166Ho-EDTMP) is a short-lived beta-emitting radionuclide complexed to an aminophosphonate ligand that we have investigated in a canine model as a potential agent for specific marrow ablation before marrow transplantation. After intravenous injections, 166Ho-EDTMP distributed principally to bone and after 24 hours the concentrations of 166Ho-EDTMP in bone were more than 200-fold higher than in any other organ. Increasing dosages of 166Ho-EDTMP led to increasingly prolonged and severe myelosuppression, but myeloablation was not achieved. Histologic examination of recovering animals suggested that the spleen may have acted as a reservoir for circulatory hematopoietic precursors. Four splenectomized animals administered 20 to 30 mCi/kg 166Ho-EDTMP without marrow transplantation died with marrow aplasia, while four splenectomized animals administered similar dosages of 166Ho-EDTMP followed by autologous transplantation recovered. The dose-limiting toxicity of 166Ho-EDTMP appeared to be marrow stromal damage resulting in myelofibrosis, which was reversible. These results suggest that 166Ho-EDTMP can be used to specifically ablate marrow function before marrow transplantation.

Animals↗
PubMed1992

Selective radiation of hematolymphoid tissue delivered by anti-CD45 antibody.

The ability to deliver radiation selectively to lymphohematopoietic tissues may have utility in conditions treated by myeloablative regimens followed by bone marrow transplantation. Since the CD45 antigen is the most broadly expressed of hematopoietic antigens, we examined the biodistribution of radiolabeled anti-CD45 monoclonal antibodies in normal mice. Trace 125I or 131I-labeled monoclonal antibodies 30G12 (rat IgG2a), 30F11 (rat IgG2b), and F(ab')2 fragments of 30F11 were injected i.v. at doses of 5 to 1000 micrograms. For both intact antibodies, a higher percentage of injected dose/g (% ID/g tissue) in blood was achieved with higher antibody doses. However, as the dose of antibody was increased, the % ID/g in the target organs of spleen, marrow, and lymph nodes decreased. At doses between 5 and 10-micrograms, % ID/g in these tissues exceeded that in lung, the normal organ with the highest concentration of radiolabel. In contrast, thymus was the only hematopoietic organ in which the % ID/g increased with increasing antibody dose, although at high dose the % ID/g was still far below that achieved in the other hematopoietic organs. Antibody 30F11 F(ab')2 fragments were cleared more quickly than intact antibody from blood and from both target and nontarget organs, although the relationship between increasing antibody dose and decreasing % ID/g in spleen, marrow, and lymph nodes was observed. The time-activity curves for each dose of antibody were used to calculate estimates of radiation absorbed dose to each organ. At the 10-micrograms dose of 30G12, the spleen was estimated to receive a radiation dose that was 13 times more than lung, the lymph nodes 3 to 4 times more, and the bone marrow 3 times more than lung. For each antibody fragment dose, the radiation absorbed dose per MBq 131I administered was lower because the residence times of the fragments were shorter than those of the intact antibody. Thus these estimates suggested that the best "therapeutic ratio" of radiation delivered to target organ as compared to lung was achieved with lower doses of intact antibody. We have demonstrated that radiolabeled anti-CD45 monoclonal antibodies can deliver radiation to lymphohematopoietic tissues with relative selectivity and that the relative uptake and retention in different hematolymphoid tissues change with increasing antibody dose.

Animals↗
PubMed1992

Magnetic resonance imaging of myositis ossificans: analysis of seven cases.

Myositis ossificans typically presents as soft tissue swelling with progressive ossification on radiographs. Since magnetic resonance imaging (MRI) is commonly used to evaluate soft tissue masses, we analyzed eight MR examinations in seven patients with myositis ossificans to determine if typical patterns were present. One acute lesion had homogeneous intermediate signal intensity on T1-weighted images and high signal intensity on T2-weighted images. Two subacute lesions had low signal intensity margins with slightly increased signal intensity centers on T1-weighted images and very high signal intensity on T2-weighted images. Five chronic lesions had two different patterns. All five were well-defined with low signal intensity borders. Three had signal intensity patterns characteristic of fat on T1-weighted and T2-weighted images. The other two lesions had intermediate signal intensity on T1-weighted images and slightly increased signal intensity on T2-weighted images. We conclude that typical MR appearances of myositis ossificans do exist. A low signal intensity rim is a common finding. However, these patterns are not unique to myositis ossificans and resemble those that have been reported in other lesions. It is important to be aware of the spectrum of MR findings of myositis ossificans when considering the differential diagnosis of a soft tissue mass.

Acute Disease↗
PubMed1992

Signs of patellar chondromalacia on sagittal T2-weighted magnetic resonance imaging.

We incidentally noted distinctive high signal defects or fissures in the patellar articular cartilage on sagittal T2-weighted magnetic resonance (MR) images in 4 patients. At subsequent arthroscopy all 4 patients were found to have patellar chondromalacia. To determine the reliability of these signs, we retrospectively evaluated, in a blinded manner, sagittal T2-weighted MR images of the knee in 75 patients who were undergoing arthroscopic assessment of their patellar articular cartilage. We identified high signal defects or fissures in the patellar cartilage of 5 patients. Patellar chondromalacia was noted at arthroscopy in all 5 patients. Arthroscopy demonstrated patellar chondromalacia in an additional 21 patients with normal MR images. We conclude that high signal defects or fissures on sagittal T2-weighted images are useful signs of patellar chondromalacia. This single imaging sequence will, however, detect only a small number of the cartilage lesions that may be present.

Adolescent↗
PubMed1992

The use of radiolabeled anti-CD33 antibody to augment marrow irradiation prior to marrow transplantation for acute myelogenous leukemia.

Disease recurrence remains a major limitation to the use of marrow transplantation to treat leukemia. Previous transplant studies have demonstrated that higher doses of total-body irradiation result in less disease recurrence, but more toxicity. In this study, the possibility of delivering radiotherapy specifically to marrow using a radiolabeled anti-CD33 antibody (p67) was explored. Biodistribution studies were performed in nine patients using .05-.5 mg/kg p67 trace-labeled with 131I. In most patients initial specific uptake of 131I-p67 in the marrow was seen, but the half-life of the radiolabel in the marrow space was relatively brief, ranging from 9-41 hr, presumably due to modulation of the 131I-p67-CD33 complex with subsequent digestion and release of 131I from the marrow space. In four of nine patients these biodistribution studies demonstrated that with 131I-p67 marrow and spleen would receive more radiation than any normal nonhematopoietic organ, and therefore these four patients were treated with 110-330 mCi 131I conjugated to p67 followed by a standard transplant regimen of cyclophosphamide plus 12 Gy TBI. All four patients tolerated the procedure well and three of the four are alive in remission 195-477 days posttransplant. This study demonstrates the feasibility of using a radiolabeled antimyeloid antibody as part of a marrow transplant preparative regimen and also highlights a major limitation of using conventionally labeled anti-CD33--namely, the short residence time in marrow. Strategies to overcome this limitation include the use of alternative labeling techniques or the selection of cell surface stable antigens as targets.

Adolescent↗
PubMed1991

Biodistribution and dosimetry following infusion of antibodies labeled with large amounts of 131I.

Dosimetry and treatment planning for therapeutic infusions of radiolabeled antibodies are usually performed by extrapolation from the biodistribution of trace-labeled antibody. This extrapolation assumes that the biodistribution of high specific activity antibody will be similar to that seen with trace-labeled antibody. However, high doses of radiation result in rapid depletion of lymphoid and hematopoietic cells in lymph nodes, spleen, and marrow with replacement by blood and plasma. If radiolabeled antibody is cleared slowly from blood, this replacement may result in increased radionuclide concentrations in these tissues following infusions of antibody labeled with large amounts of radionuclide. To examine the influence of deposited radiation on the biodistribution of radiolabeled antibody, we treated mice with a constant amount of antibody that was labeled with varying amounts of 131I. Survival was determined in normal specific pathogen-free AKR/Cum mice (Thy1.2+) after infusion of anti-Thy1.1 antibody labeled with 10 to 6500 muCi of 131I, to determine an appropriate range of 131I doses for further study. The dose producing 50% lethality within 30 days following infusion of 131I-labeled antibody was 530 muCi 131I. Biodistribution, bone marrow histology, and dosimetry were subsequently determined after infusion of 500 micrograms of antibody labeled with 10, 250, 500, or 3500 muCi 131I. The amount of 131I did not influence uptake or retention of antibody in blood, liver, lung, or kidney. In contrast, infusion of antibody labeled with 250 to 3500 muCi of 131I led to a dose-related increase in the concentration of 131I in marrow, spleen, lymph node, and thymus. For example, at 96 h after infusion of antibody labeled with 500 or 3500 muCi 131I, concentrations in marrow were 3- to 4-fold higher than after infusion of trace-labeled antibody. The increase in marrow 131I concentrations was associated with depletion of cells and hemorrhage within the marrow space. As a result, estimated mean absorbed doses to marrow, lymph node, spleen, and thymus were 1.2 to 3.1 times higher than would have been predicted from the biodistribution of trace-labeled antibody. These results suggest that the biodistribution of trace-labeled antibody should be an accurate predictor of the behavior of high specific activity antibody in blood and solid organs such as liver and kidney. In contrast, radiation from antibody labeled with large amounts of radionuclide can result in an alteration of the concentration of radiolabeled antibody in rapidly responding tissues such as marrow.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Radiolabeled anti-CD45 monoclonal antibodies target lymphohematopoietic tissue in the macaque.

Despite bone marrow transplantation, many patients with advanced leukemia subsequently relapse. If an additional increment of radiation could be delivered to lymphohematopoietic tissues with relative specificity, the relapse rate may decrease without a marked increase in toxicity. We have examined the biodistribution of two 131I-labeled monoclonal antibodies reactive with the CD45 antigen in Macaca nemestrina. Three animals received 0.5 mg/kg BC8, an IgG1 of low avidity (6 x 10(7) L/mol). Three received 0.5 mg/kg AC8, an IgG2a of moderate avidity (5 x 10(8) L/mol), and two received 4.5 mg/kg AC8. Estimates of radiation absorbed dose demonstrated that these antibodies could deliver up to five times more radiation to lymph nodes, and up to 2.6 times more to bone marrow, than to lung or liver. The higher avidity AC8 antibody at 0.5 mg/kg was cleared more rapidly from blood and resulted in lower antibody uptake in lymph nodes than did BC8 at 0.5 mg/kg. Increasing the dose of AC8 to 4.5 mg/kg resulted in slower blood clearance and higher lymph node uptake. These studies suggest that radiolabeled anti-CD45 antibodies can deliver radiation with relative specificity to lymphohematopoietic tissues. This approach, in combination with marrow transplantation, may improve treatment of hematologic malignancies.

Animals↗
PubMed1991

Integrated microscopic-macroscopic pharmacology of monoclonal antibody radioconjugates: the radiation dose distribution.

Accurate dosimetry is essential for the assessment of radioimmunotherapy. Most often studied to date has been the macroscopic dosimetry related to organ and tumor distribution of the radiolabeled antibody, but the question of microscopic dose heterogeneity is also important. To address the latter issue, we have taken an integrated approach to the pharmacology, taking into account whole-body distribution, transcapillary transport, percolation through the tumor interstitial space, antigen-antibody interaction, and antibody metabolism. The first step is to simulate the spatial antibody concentration profile in a tumor as a function of time after i.v. (e.g., bolus) injection, using reasonable values for the parameters involved. The second step is to calculate, also as a function of time, the absorbed radiation dose distribution resulting from each concentration profile. Parameter values for IgG pharmacology and a radiation point source function for 131I are used to explore the effect of antibody distribution profiles on absorbed dose in the tumor. The geometry simulated corresponds to a spherical nodule of densely packed tumor cells. Absorbed doses are calculated for radiation from a single nodule (e.g., a micrometastasis or prevascular primary tumor) and for a cubic lattice of such nodules (e.g., corresponding to nodular lymphoma). As noted in our previous studies, there is a "binding site barrier." Binding to antigen retards antibody percolation into the nodules; high antibody affinity tends to decrease percolation and give a higher absorbed dose near the surface of each nodule. Heterogeneous antibody distribution results in a heterogeneous absorbed dose. This is more apparent in the case of radiation from a single nodule than it is for radiation from within an array of nodules. Dehalogenation results in a lower absorbed dose over time, and the effect is more apparent at later times after injection. PERC-RAD, the computer program package developed for these analyses, provides a convenient and flexible way to assess the impact of macroscopic and microscopic parameters on the distribution of radioimmunoconjugates and on the consequent profile of absorbed radiation dose in tumors. This mathematical model and the general principles developed here can be applied as well to other radiolabeled biological ligands.

Antibodies, Monoclonal↗
PubMed1991

Modified biokinetic model for uranium from analysis of acute exposure to UF6.

Urinalysis measurements from 31 workers acutely exposed to uranium hexafluoride (UF6) and its hydrolysis product UO2F2 (during the 1986 Gore, Oklahoma UF6-release accident) were used to develop a modified recycling biokinetic model for soluble U compounds. The model is expressed as a five-compartment exponential equation: yu(t) = 0.086e-2.77t + 0.0048e-0.116t + 0.00069e-0.0267t + 0.00017 e-0.00231t + 2.5 x 10(-6) e-0.000187t, where yu(t) is the fractional daily urinary excretion and t is the time after intake, in days. The excretion constants of the five exponential compartments correspond to residence half-times of 0.25, 6, 26, 300, and 3,700 d in the lungs, kidneys, other soft tissues, and in two bone volume compartments, respectively. The modified recycling model was used to estimate intake amounts, the resulting committed effective dose equivalent, maximum kidney concentrations, and dose equivalent to bone surfaces, kidneys, and lungs.

Accidents, Occupational↗