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D J Macey

Publications and source records attributed to D J Macey.

At least 37 records · Page 2Linked to original sources

Oxygen consumption by ammocoetes of the lamprey Geotria australis in air.

When covered by moistened lint-free gauze, the larvae (ammocoetes) of the lamprey Geotria australis survived, without apparent discomfort, for 4 days in water-saturated air at 10, 15 and 20 degrees C. In air, the mean standard rates of O2 consumption of medium to large ammocoetes of G. australis (mean = 0.52 g) at 10, 15 and 20 degrees C were 14.5, 35.7 and 52.1 microliters.g-1.h-1, respectively. At 15 degrees C, the slope of the relationship between log O2 consumption (microliter O2.h-1) and log body weight for ammocoetes over a wide range in body weight was 0.987. The Q10s for rate of O2 consumption between 10 and 15 degrees C, 15 and 20 degrees C and 10 and 20 degrees C were 4.9, 2.9 and 3.6, respectively. Our results and observations of the ammocoetes suggest that, when out of water, larval G. australis derives most of its O2 requirements from cutaneous respiration, particularly at lower temperatures. This would be facilitated by the small size and elongate shape (and thus a relatively high surface-to-volume ratio), low metabolic rate, thin dermis, extensive subdermal capillary network and high haemoglobin concentration of larval G. australis.

Animals↗

A radioimmunoimaging and MIRD dosimetry treatment planning program for radioimmunotherapy.

A treatment planning program for radioimmunotherapy employing quantitative Anger camera imaging and the MIRD formalism has been designed and implemented on a clinical nuclear medicine computer. Radionuclide residence times are calculated from linear, mono- and bi-exponential, and cubic spline fits to regional activity versus time curves, and radiation-absorbed dose estimates for all target organs for 131I, 67Cu, and 58 other radionuclides can be calculated. This software has been successfully applied to radioimmunotherapy of B-cell malignancies and breast adenocarcinomas.

Dose-Response Relationship, Radiation↗

Prediction of radiation doses from therapy using tracer studies with iodine-131-labeled antibodies.

UNLABELLED: Tracer pharmacokinetic studies are often used in treatment planning for radionuclide therapy including radioimmunotherapy. This study evaluates the validity of using tracer studies to predict radiation doses from therapy with the same radiolabeled antibody. METHODS: Quantitative imaging and blood radioactivity were used to obtain the pharmacokinetics and radiation doses that were delivered to the total body, blood, marrow, lungs, liver, kidneys, thyroid, spleen and tumors. Tracer and therapy data for eight patients with lymphoma and one patient with breast cancer were compared using linear regression statistics. Doses of 131I-labeled antibody for the tracer studies ranged from 0.1 to 0.4 GBq (2 to 10 mCi), and therapy doses ranged from 0.7 to 5.6 GBq (20 to 150 mCi). RESULTS: Radiation doses to tissues and, in particular, the bone marrow and tumors were reliably predicted from tracer studies. In this group of patients, median dose to marrow from marrow targeting, total body and blood was 9.2 cGy/GBq for tracer studies and 7.6 cGy/GBq for therapy studies with a median difference of 0.5 cGy/GBq. Median dose to tumors was 81.1 cGy/GBq for tracer studies and 70.3 cGy/GBq for therapy studies with a median difference of 5.9 cGy/GBq. CONCLUSION: In these patients, tracer studies were predictive of the radiation doses from therapy for total body, major organs and tumors. The radiation doses to marrow and tumors, which are the usual determinants of the therapeutic index, correlated well between tracer and therapy studies (r > or = 0.95).

Antibodies, Monoclonal↗

Enhanced TAG-72 expression and tumor uptake of radiolabeled monoclonal antibody CC49 in metastatic breast cancer patients following alpha-interferon treatment.

The IFNs, alpha and gamma, have been shown to enhance the tumor-associated glycoprotein (TAG-72) on adenocarcinoma cells in vitro and in mice with human breast cancer xenografts, resulting in improved targeting of monoclonal antibody CC49. To determine the effect of IFN-alpha on biodistribution and tumor uptake of 131I-labeled CC49, patients with metastatic breast cancer were randomized to either receive or not receive IFN-alpha (3 million units daily for 14 days) by s.c. injection. Three days after beginning IFN-alpha, all patients received 10-20 mCi of 131I-CC49 (specific activity, 16.7 mCi/mg) i.v. Total-body Anger camera scans, along with total-body blood and plasma pharmacokinetics, were performed. Tumor biopsies were taken in all patients before and 48 h after IFN-alpha treatment. There were no significant differences in number of metastases imaged or whole-body, blood and plasma pharmacokinetics between IFN-alpha-treated and untreated patients. Quantitative immunohistochemistry on biopsy specimens from IFN-alpha-treated patients demonstrated a significant increase in mean +/- SEM TAG-72 expression (45.7 +/- 19.4%) compared to patients that were not given IFN-alpha (1.3 +/- 0.95%; P < 0.05). Although slight increases in the percent injected dose of 131I-CC49 in tumor occurred after IFN-alpha-treatment, the changes were not significant at the P < 0.05 level. These data suggest that IFN-alpha may be useful in enhancing TAG-72 antigen expression in vivo in humans, despite modest improvement in tumor uptake of CC49, possibly because of limited tumor access or other unknown factors.

Adenocarcinoma↗

Hepatic molecular conversion and detoxification of ferritin iron in adult lampreys (Geotria australis), following natural and induced iron loading.

Weekly intramuscular injections of 3 mg of iron as horse spleen ferritin into adult Geotria australis over 10 weeks, resulted in a progressive increase in that form of iron in the serum. However, as with control animals, the ferritin in the liver of injected lampreys consisted of one subunit type, whose M(r) (20,300) differed from those of the two subunit types of horse spleen ferritin. Thus, lampreys had converted horse spleen ferritin iron into endogenous ferritin iron, presumably in their liver. Marked rises in hepatic non-haem iron during the first 2 weeks and between weeks 8 and 10 of iron injections were accompanied by pronounced increases in superoxide dismutase (SOD) activity. This rise, which parallels the rise in SOD activity that occurs as iron increases during the very protracted upstream migration of G. australis, is consistent with the view that SOD protects against iron-mediated damage by removing the superoxide radical, which facilitates the formation of the highly toxic hydroxyl radical. A levelling off of the iron concentration between weeks 2 and 8 was accompanied by a decline in SOD activity, even though nonhaem iron levels were well above those of control animals. Enhanced SOD activity may therefore only be required when there is an elevated flux of iron in the liver through low-molecular-mass intermediates. A small amount of ferritin iron was converted into the more inert haemosiderin iron.

Animals↗

Validation of a dose-point kernel convolution technique for internal dosimetry.

The objective of this study was to validate a dose-point kernel convolution technique that provides a three-dimensional (3D) distribution of absorbed dose from a 3D distribution of the radionuclide 131I. A dose-point kernel for the penetrating radiations was calculated by a Monte Carlo simulation and cast in a 3D rectangular matrix. This matrix was convolved with the 3D activity map furnished by quantitative single-photon-emission computed tomography (SPECT) to provide a 3D distribution of absorbed dose. The convolution calculation was performed using a 3D fast Fourier transform (FFT) technique, which takes less than 40 s for a 128 x 128 x 16 matrix on an Intel 486 DX2 (66 MHz) personal computer. The calculated photon absorbed dose was compared with values measured by thermoluminescent dosimeters (TLDS) inserted along the diameter of a 22 cm diameter annular source of 131I. The mean and standard deviation of the percentage difference between the measurements and the calculations were equal to -1% and 3.6%, respectively. This convolution method was also used to calculate the 3D dose distribution in an Alderson abdominal phantom containing a liver, a spleen, and a spherical tumour volume loaded with various concentrations of 131I. By averaging the dose calculated throughout the liver, spleen, and tumour the dose-point kernel approach was compared with values derived using the MIRD formalism, and found to agree to better than 15%.

Animals↗

Estimation of radiation absorbed doses to the red marrow in radioimmunotherapy.

Myelotoxicity is the dose-limiting factor in radioimmunotherapy. Traditional methods most commonly used to estimate the radiation adsorbed dose to the bone marrow of patients consider contributions from radionuclide in the blood and/or total body. Targeted therapies, such as radioimmunotherapy, add a third potential source for radiation to the bone marrow because the radiolabeled targeting molecules can accumulate specifically on malignant target cells infiltrating the bone marrow. A non-invasive method for estimating the radiation absorbed dose to the red marrow of patients who have received radiolabeled monoclonal antibodies (MoAb) has been developed and explored. The method depends on determining the cumulated activity in three contributing sources: 1) marrow; 2) blood; and 3) total body. The novel aspect of this method for estimating marrow radiation dose is derivation of the radiation dose for the entire red marrow from radiation dose estimates obtained by detection of cumulated activity in three lumbar vertebrae using a gamma camera. Contributions to the marrow radiation dose from marrow, blood, and total body cumulated activity were determined for patients who received an I-131 labeled MoAb, Lym-1, that reacts with malignant B-lymphocytes of chronic lymphocytic leukemia and nonHodgkin's lymphoma. Six patients were selected for illustrative purposes because their vertebrae were readily visualized on lumbar images. The radiation doses to the marrow contributed by nonpenetrating emissions in the marrow blood and penetrating emissions in the total body were similar in these patients with a mean of 0.2 and 0.3 rads per administered mCi from the blood and total body, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone Marrow↗

Improved conjugate view quantitation of I-131 by subtraction of scatter and septal penetration events with a triple energy window method.

The majority of radiation absorbed dose estimates for radioimmunotherapy (RIT) with I-131 labeled antibodies have been calculated based on in vivo quantitation of activity using the conjugate view approach with planar Anger camera images. Scatter and septal penetration events contributed by a small fraction of high-energy photons emitted by I-131 with an energy exceeding 600 KeV lead to a significant degradation of I-131 images acquired with an Anger camera, which blurs the images of uptake sites and complicates the definition of background regions. The objective of this study was to evaluate a triple energy window (TEW) subtraction method that has been used to remove these interfering events from I-131 images. In the method, a primary photopeak image for I-131 is obtained after sequential subtraction of septal penetration and scatter events by using scatter multipliers derived from a photopeak window and two adjacent scatter window images. Qualitative improvement in image contrast was demonstrated with this technique, together with more accurate and reproducible quantitation for I-131 in the organs of an abdominal phantom. This TEW scatter subtraction method can be used to provide more precise dosimetry estimates for radionuclide therapy and RIT with I-131.

Abdomen↗

Radiation dose distribution within the bone marrow of patients receiving holmium-166-labeled-phosphonate for marrow ablation.

The primary objective of this work was to estimate the absorbed dose distribution to the bone marrow of six multiple myeloma patients who received holmium-166 (166Ho) DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonic acid) for the purpose of bone marrow ablation. A methodology based on gamma camera images was developed to estimate the regional absorbed dose distributions delivered to the bone marrow, and this was compared with values calculated from the MIRD technique and bone marrow biopsies. The activity concentration in various skeletal regions was calculated from the activity in the region of interest (ROI) drawn on whole body gamma camera images, and the mass of bone in each ROI was derived from a dual x-ray absorptiometry image. The radiation absorbed dose to the bone marrow was calculated from this activity concentration using an adaptation of Bragg-Gray cavity theory. The radiation absorbed dose delivered to the bone marrow in the six patients calculated from the MIRD "S" factors ranged from 15.0 to 46.3 Gy. The gamma camera measured activity concentration in skeletal regions predominantly composed of trabecular bone was approximately five to six times higher than that in cortical regions. The skeletal activity concentration in each patient ranged from highs in such regions as the ribs to lows in such regions as the shin and foot by a factor of nearly 20, producing a heterogeneous distribution of absorbed dose within the marrow. Dose volume histograms calculated for these patients indicated that 15%-20% of the marrow received an absorbed dose significantly larger than the average value, while 5%-10% of the marrow received a substantially lower dose. Weighted mean dose estimates from the regional technique were typically 30% greater than the average dose estimates calculated with the MIRD "S" factors. Finally, absorbed dose estimates for the marrow calculated from the regional technique correlated more closely with the clinical response of blood cells and abnormal proteins measured in bone marrow aspirates and peripheral blood samples than estimates from the MIRD "S" factors.

Absorptiometry, Photon↗

Development of a SPECT-based three-dimensional treatment planning system for radioimmunotherapy.

UNLABELLED: Two major obstacles in the development of improved methods for more accurate dose estimates for radioimmunotherapy have been the difficulty in obtaining an accurate patient-specific three-dimensional activity map in vivo and calculating the resulting absorbed dose. We propose a method for three-dimensional internal dosimetry that integrates the three-dimensional activity map from SPECT with a dose-point kernel convolution technique to provide the three-dimensional distribution of absorbed dose. METHODS: Accurate activity quantitation was achieved with appropriate methods. The count density map from SPECT images was converted into an activity concentration map with a calibration phantom approach. This map was then convolved with an 131I dose-point kernel and three-dimensional fast Fourier transform to yield three-dimensional distribution of absorbed dose, which was then processed to provide the absorbed dose distribution in regions of interest. RESULTS: The accuracy of quantitative SPECT was validated to be within 16%. The calculated penetrating radiation absorbed dose was verified with thermoluminescent dosimeter measurements to be within 8%. With standard organs and configuration, the method calculated absorbed dose in good agreement with the MIRD formalism (less than 14%). CONCLUSION: This method overcomes the limitations of planar imaging techniques and the current routine implementation of the MIRD formalism. The results can be processed to provide the absorbed dose distribution in regions of interest and parameters for treatment optimization. Absorbed dose distribution from any plane can be graphically displayed in various ways.

Calibration↗

Pharmacokinetics, dosimetry and toxicity of holmium-166-DOTMP for bone marrow ablation in multiple myeloma.

UNLABELLED: In this Phase I clinical trial, six multiple myeloma patients who had not responded to conventional therapy and were scheduled for bone marrow transplantation received a bone-seeking radiopharmaceutical for bone marrow ablation. The pharmacokinetics, dosimetry, and toxicity of this radiopharmaceutical were studied. METHODS: Patients received from 519 mCi to 2.1 Ci (19.2 GBq to 77.7 GBq) of holmium-166 (166Ho) complexed with a bone-seeking agent, DOTMP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonic acid). The reproducibility of pharmacokinetics from multiple injections of 166Ho-DOTMP administered to these myeloma patients was demonstrated from blood (r2 = 0.926) and whole-body retention (r2 = 0.983), which allowed therapeutic parameters to be determined from a diagnostic study. RESULTS: Over 50% of the 166Ho-DOTMP injected dose was excreted within 2-3 hr postinjection, increasing to 75%-85% over a 24-hr period. Rapid blood clearance minimized radiation dose to nontarget tissue: less than 10% of the injected activity was retained in the blood pool at 1 hr postinjection, and less than 2% remained after 5 hr. The total radiation absorbed dose delivered to the bone marrow for the six patients ranged from 7.9 Gy to 41.4 Gy. CONCLUSION: All patients demonstrated severe bone marrow toxicity with a white blood cell (WBC) count < 1,000 cells/microliters, two patients exhibited marrow ablation (WBC count < 100 cells/microliters), and no other toxicity > or = grade 2 was observed in any of the patients.

Bone Marrow↗

Iron release from ferritin and its sensitivity to superoxide ions differs among vertebrates.

The influence of the superoxide-generating system, xanthine oxidase, on the release of iron from various vertebrate ferritins was determined both in the presence and absence of superoxide dismutase. The initial rate of iron release in the presence of this system was higher for ferritins from human, trout and rat liver than for those from lamprey liver and horse spleen. The proportion of this iron release that was superoxide-dependent in the case of rat, human and trout ferritins was 92, 86 and 84% respectively, whereas no such superoxide-dependent iron release occurred from the ferritins of lamprey liver and horse spleen. On the other hand, the rate of superoxide-independent iron release was of comparable magnitude for all of the species examined. The rate of superoxide-dependent iron release was related neither to the iron: protein ratios nor to the subunit size of the ferritins. However, it is significant that the ferritins with a high rate of superoxide-dependent iron release came from tissues known to be susceptible to iron damage. It is thus proposed that the resistance of lamprey liver ferritin to the mobilization of iron by superoxide ions accounts in part for the tolerance of the lamprey liver to high iron loads.

Animals↗

Overview of radiation myelotoxicity secondary to radioimmunotherapy using 131I-Lym-1 as a model.

The radiation dose-limiting toxicity from radioimmunotherapy has been myelotoxicity in the absence of bone marrow reconstitution (transplantation). Myelotoxicity can be assessed directly by biopsy examination of the bone marrow and indirectly by peripheral blood counts. In patients with B-cell malignancies, thrombocytopenia has been the initial and most severe manifestation of 131I-Lym-1 radiation toxicity from treatment. Manifestations of myelotoxicity varied greatly among the patients and from one treatment dose to another in the same patient, suggesting that additional factors were present. There was an increased likelihood of Grade 3-4 hematopoietic toxicity after 131I-Lym-1 treatment if the patient had peripheral blood cell abnormalities before undergoing 131I-Lym-1 treatment. Fractionation of the total 131I-Lym-1 dose was associated with less toxicity. In many patients, myelotoxicity could not be explained by marrow radiation dose (0.36 +/- 0.13 rads per administered mCi) from 131I-Lym-1 in the blood and body alone. Bone marrow examination and 131I-Lym-1 imaging usually provided evidence for additional marrow radiation from 131I-Lym-1-targeting of marrow malignancy and also for residual toxic effects from prior treatment in these patients. Immunohistologic and imaging examination of the bone marrow performed with the intended treatment antibody allowed assessment of extent of marrow malignancy and prediction of degree of myelotoxicity from subsequent treatment. Treatment programs (and protocols) for radioimmunotherapy should incorporate these methods into the decision process. Larger amounts of 131I-Lym-1 can be used in patients selected to have relatively normal peripheral blood cell counts and normocellular bone marrows uninvolved by the malignancy. These observations appear to be relevant to the maximum tolerated dose in radioimmunotherapy for other malignancies as well.

Antibodies, Monoclonal↗

Phase II radioimmunotherapy trial with 131I-CC49 in colorectal cancer.

BACKGROUND: Radiolabeled CC49, a second generation high affinity monoclonal antibody (MoAb) reactive with tumor-associated glycoprotein 72 (TAG72) has undergone previous Phase I testing in patients with colon cancer. Based on this report, the authors treated 15 refractory metastatic colon cancer patients with 131I-CC49 to determine its overall toxicity and the response to therapy of patients treated with it. METHODS: Patients received 75 mCi/m2 131I-CC49 (20 mg MoAb) intravenously for a period of 30-60 minutes. Whole body retention was derived from the measured dose-rate of I-131 monitored daily at 1 m using an ion chamber. Two whole-body and static-gamma camera images were taken of patients on days 4 and 7 after the infusion. RESULTS: Nonhematologic toxicity (Grade 1-2) consisted of nausea (two patients), arthralgias (three patients), transient fever and chills (two patients), and transient blood pressure changes (two patients). At 4-5 weeks posttreatment, reversible Grade 3-4 thrombocytopenia was observed in 7 of 15 patients, and reversible Grade 3-4 granulocytopenia was observed in 6 of 15 patients. Twelve of 13 patients tested developed human anti-mouse antibody (range, 161 to > 20,000 ng/ml) at 6-8 weeks postinfusion. Mean +/- SD whole-body half-life (whole-body retention) of 131I-CC49 was 57.3 +/- 13.4 hours. Tumors were seen in all patients. In two of three patients treated a second time, an increased whole body clearance rate correlated with elevated human anti-mouse antibody, reduced uptake in tumor, and enhanced uptake in the thyroid. Estimated tumor doses ranged from 19-667 rads. Red marrow dose estimated from whole body retention ranged from 60 to 117 rads and correlated with decreases in platelet count. No objective tumor responses (i.e., partial or complete) were observed. CONCLUSIONS: Despite minimal toxicity and favorable tumor uptake, efficacy has been limited at this dose and schedule.

Animals↗

Quantitative imaging of holmium-166 with an Anger camera.

The objective of this study was to develop a quantitative Anger camera imaging approach for 166Ho in the skeletal system of patients. A dual energy window method was designed to subtract the interference from septal penetration and bremsstrahlung events in Anger camera images acquired with the 80 keV x-rays emitted by 166Ho. The validity of this scatter subtraction method for 166Ho images was demonstrated as improvements of the line spread function and modulation transfer function. Camera sensitivity was found to be nearly independent of source-to-collimator distance only for images acquired with a high-energy collimator. Studies in an Alderson abdominal water phantom demonstrated scatter subtraction can provide quantitative Anger camera images of 166Ho with a scatter multiplier of k = 1.0 and a correction for attenuation. Attenuation correction factors derived from a transmission image were measured for the phantom and verified with water-equivalent blocks of known thickness. Whole-body scan images of 166Ho localized in the skeletal system of patients were significantly improved with this simple scatter subtraction method, and when used to estimate the activity distribution within separate bone regions of the skeleton.

Bone and Bones↗

Dosimetry and toxicity of samarium-153-EDTMP administered for bone pain due to skeletal metastases.

UNLABELLED: Palliation of bone pain in patients with cancer metastatic to bone is being evaluated in several cancer centers by the administration of the bone-seeking phosphonate ethylenediaminetetramethylenephosphonic acid (EDTMP) chelated with the beta particle-emitting radionuclide 153Sm. METHODS: In this study, 153Sm-EDTMP was intravenously injected into 19 patients over a 1-min period. Patients received up to four injections of 18.5 MBq (0.5 mCi) or 37 MBq (1.0 mCi) per kilogram of body weight. Skeletal retention was calculated from urinary excretion. RESULTS: No uptake of 153Sm-EDTMP in nonskeletal tissues was observed in whole-body gamma camera images. The mean skeletal uptake for all patients was 54% +/- 16% of the injected dose (%ID). This resulted in the bone marrow receiving 89 cGy/GBq +/- 27 cGy/GBq (3.28 cGy/mCi +/- 0.99 cGy/mCi), with calculated marrow doses ranging from 27 cGy to 338 cGy. For each patient, the estimated radiation absorbed dose to the marrow was correlated to the percent decrease in platelet number, ranging from 7.4% to 78.9%. CONCLUSION: Since the deviation of uptake between the four injections for a given patient (7.6% ID) was less than the deviation for all patients (16% ID), the initial dose may be used to estimate the skeletal uptake for the remaining doses. These radiation dose estimates permit patients at risk to be identified prior to reaching myelotoxicity and develop dose-response models. Thirteen patients (68%) reported significant pain relief from this radionuclide therapy. Bone pain appears to be alleviated by 153Sm-EDTMP with limited red marrow doses and no toxic effects in other organs.

Bone Marrow↗

Body and blood clearance and marrow radiation dose of 131I-Lym-1 in patients with B-cell malignancies.

Fifty-eight per cent of patients with B-cell malignancies had durable responses to treatment with 131I-Lym-1. Myelosuppression manifested by peripheral blood cytopenia was the radiation dose-limiting toxicity. The mean biologic half-times were 3.3 and 31.2 h for the fast and slow phases, respectively, of the blood clearance and 33.5 h for the clearance from the total body. Nonpenetrating radiation from the blood contributed 0.18 rad and penetrating radiations from the total body contributed 0.18 rad per administered mCi to the bone marrow. The average total contribution from both of these sources was 0.36 +/- 0.14 rad mCi-1. Clearances and marrow radiation doses were remarkably constant among different patients and among different therapy doses for the same patient. These results are potentially useful as an initial approximation for other mouse monoclonal antibodies of the same isotype. While radiation to normal marrow from 'spill-over' incident to specific targeting of 131I-Lym-1 on malignant B-cells in the marrow is not addressed in this publication because it is unique for each patient, it should be considered in the case of individual patients.

Adult↗