Biomedical subjects

M C Graham

Publications and source records attributed to M C Graham.

At least 37 records · Page 2Linked to original sources

PubMed1996

Spatial mapping of the percentage cellularity in human bone marrow using magnetic resonance imaging.

A noninvasive assay for the spatial distribution of the percentage cellularity in human bone marrow is presented. Twelve individuals were studied using two magnetic resonance imaging techniques: (1) fast spin echo imaging with frequency selective presaturation, and (2) three-point chemical shift imaging. The data were compared to results obtained using a previously validated stimulated echo spectroscopic method. The results of this study demonstrate that a measure of the percentage cellularity in bone marrow is possible using magnetic resonance imaging techniques provided that high-quality water or lipid suppression is achieved across the region of interest. Since the method is applicable to bone marrow at any anatomic location, it may prove useful in dosimetric calculations during and after a course of internal or external beam radiotherapy.

Adult↗

PubMed1996

Bone marrow dosimetry: regional variability of marrow-localizing antibody.

UNLABELLED: In radiolabeled antibody therapy, imaging and biopsy-based methods are used to estimate marrow activity concentration when the administered antibody localizes to the marrow. Absorbed dose estimates obtained using such measurements may be subject to large variability due to the potential for regional differences in marrow activity concentration. This variability was examined in ten patients with leukemia after administration of 131I-labeled HuM195 antibody. METHODS: Regions of interest were drawn around the head and neck of the humerus and femur (both sides) and around lumbar vertebra 3 (L3) and 4 (L4) on a series of planar images collected at multiple times postadministration of the antibody. A single exponential fit to each attenuation-corrected, time-activity curve was obtained to estimate clearance half-life and the back-extrapolated percent injected activity. RESULTS: The activity concentration in the femoral head and neck (mean and s.d. = 0.04 +/- 0.02 %ID/g) was not significantly different than that measured in L3 and L4 (0.06 +/- 0.02% ID/g) but was not significantly lower than the concentrations measured in the humeral head and neck regions (0.07 +/- 0.03 %ID/g, p < 0.05). Although half-life estimates differing by more than a factor of 2 were observed in half-life between regions overall. S-factors were used for individual marrow regions to determine the mean absorbed dose to marrow in the femoral and humeral heads and the lumbar vertebrae (L3 and L4) which were 0.66 +/- 0.3, 1.0 +/- 0.3 and 2.2 +/- 0.5 mGy/MBq (2.4, 3.8 and 8.3 rad/mCi), respectively. CONCLUSION: A single value is generally quoted for the absorbed dose delivered to the red marrow following marrow-localizing radiolabeled antibody administration. These results suggest that the regional marrow dose may differ significantly from the mean.

Bone Marrow↗

PubMed1996

Quantitative imaging of iodine-124 with PET.

UNLABELLED: PET is potentially very useful for the accurate in vivo quantitation of time-varying biological distributions of radiolabeled antibodies over several days. The short half-lives of most commonly used positron-emitting nuclides make them unsuitable for this purpose. Iodine-124 is a positron emitter with a half-life of 4.2 days and appropriate chemical properties. It has not been widely used because of a complex decay scheme including several high energy gamma rays. However, measurements made under realistic conditions on several different PET scanners have shown that satisfactory imaging and quantitation can be achieved. METHODS: Whole-body and head-optimized scanners with different detectors (discrete BGO, block BGO and BaF2 time-of-flight), different septa and different correction schemes were used. Measurements of resolution, quantitative linearity and the ability to quantitatively image spheres of different sizes and activities in different background activities were made using phantoms. RESULTS: Compared with conventional PET nuclides, resolution and quantitation were only slightly degraded. Sphere detectability was also only slightly worse if imaging time was increased to compensate for the lower positron abundance. CONCLUSION: Quantitative imaging with 124I appears to be possible under realistic conditions with various PET scanners.

Half-Life↗

PubMed1995

A prospective comparison of Synthetic Serum Substitute and human serum albumin in culture for in vitro fertilization-embryo transfer.

OBJECTIVE: To compare the efficacy of a globulin-containing protein source, Synthetic Serum Substitute (Irvine Scientific, Santa Ana, CA) and human serum albumin (HSA) in the early culture of human oocytes and embryos. DESIGN: Oocytes from 31 consecutive IVF cycles were assigned alternately to dishes containing human tubal fluid (HTF) and either Synthetic Serum Substitute or HSA as the protein source. Each semen sample was split for processing in Synthetic Serum Substitute or HSA. Sperm processed in Synthetic Serum Substitute was added to oocytes cultured in Synthetic Serum Substitute, and sperm processed in HSA was added to oocytes cultured in HSA. After determination of fertilization, zygotes were placed in HTF containing the same protein supplement. Before transfer, the embryos were graded morphologically. MAIN OUTCOME MEASURES: Occurrence of normal fertilization and embryo quality as assessed by morphological grading. RESULTS: There was no significant difference in the occurrence of fertilization or in embryo morphological quality between oocytes cultured in Synthetic Serum Substitute as compared with HSA. CONCLUSIONS: The use of a globulin-containing protein source in culture for IVF-ET did not improve the fertilization rate or embryo quality. Our design did not allow for demonstration of an effect on pregnancy rate.

Adult↗

PubMed1995

Image registration of SPECT and CT images using an external fiduciary band and three-dimensional surface fitting in metastatic thyroid cancer.

Image registration of 131I SPECT with CT scans was performed in a patient with metastatic thyroid carcinoma using an external fiduciary band and a three-dimensional surface-fitting algorithim. Areas of metastatic disease taking up 131I were accurately localized to the liver, lungs and vertebral bodies; providing information that could not be obtained by planar or SPECT images alone. Based on these findings, further invasive diagnostic procedures were not performed, therefore considerably altering management in this patient. This approach to image registration has immediate clinical utility in the registration and interpretation of SPECT studies with corresponding CT or MRI scans.

Algorithms↗

PubMed1994

A phase 1B trial of humanized monoclonal antibody M195 (anti-CD33) in myeloid leukemia: specific targeting without immunogenicity.

This trial studied the biodistribution, pharmacology, toxicity, immunogenicity, and biologic characteristics of a trace-labeled, anti-CD33, humanized monoclonal antibody M195 (Hu-M195) in patients with relapsed and refractory myeloid leukemia. Hu-M195 is a computer-modeled, "complementarity-determining region-grafted," IgG1, humanized version of M195. M195 is a murine monoclonal antibody that reacts with CD33, a 67-kD glycoprotein expressed on early myeloid progenitor cells and myeloid leukemia (acute myelogenous leukemia and chronic myelogenous leukemia) cells, but not normal stem cells. 131I-murine-M195 has already shown significant ability to cytoreduce patients with relapsed or refractory myeloid leukemias. Hu-M195 has higher avidity than the original mouse monoclonal antibody and, unlike murine M195, has the capability to mediate antibody-dependent cellular cytotoxicity against leukemia targets. Thirteen patients with relapsed or refractory myelogenous leukemia were treated with Hu-M195 at 4 levels of 0.5, 1.0, 3.0, and 10.0 mg/m2 in a phase I trial. Patients received a total of 6 doses per patient over 18 days. Two patients were retreated for a total of 12 doses. The first dose of Hu-M195 was trace-labeled with 131I to allow detailed pharmacokinetic and biodistribution studies by serial sampling of blood, radioimmunoassays of cells, and whole-body gamma-camera imaging. Cumulative total doses of up to 216 mg of Hu-M195 were administered safely. Reversible fever and rigors were observed after infusion at the highest dose levels. The entire bone marrow was specifically and clearly imaged within hours after infusion, with optimal biodistribution occurring at the 3 mg/m2 level. Adsorption of Hu-M195 onto targets in vivo was demonstrated by flow cytometry; near saturation of available sites occurred at the 3 mg/m2 dose level. Plasma and whole body half lives were 38 and 51 hours, respectively, which may reflect continual replenishment of target sites on new leukemia cells. 131I-Hu-M195 was rapidly internalized into the target cells in vivo within 1 hour. Human antihuman antibody responses were not observed. In conclusion, Hu-M195 can be administered safely in multiple doses, without significant toxicity or any evidence of immunogenicity, and can localize rapidly and efficiently to the bone marrow in patients with myeloid leukemias. Additional phase II trials with this agent alone or in combination with cytokines or isotopes are warranted at the optimal biologic dose.

Adult↗

PubMed1994

Murine and humanized constructs of monoclonal antibody M195 (anti-CD33) for the therapy of acute myelogenous leukemia.

Long-term survival rates of patients with acute myelogenous leukemia treated with intensive chemotherapy are 15-20%, despite efforts to develop new treatment strategies. Murine M195 (131I-M195), an anti-CD33, immunoglobulin (Ig) G2a monoclonal antibody has reactivity restricted to early myeloid cells and myeloid leukemic blasts but not hematopoietic progenitors. Previous trials in patients with relapsed or refractory myeloid leukemia showed that 131I-M195 rapidly targeted to the bone marrow and internalized into target cells. This article describes a therapeutic dose escalation study in which 24 patients received from 50 mCi/m2 to 210 mCi/m2 of 131I-M195 in divided doses. Cytoreduction of peripheral cell counts and bone marrow blasts occurred without nonhematopoietic toxicity. Doses of 131I-M195 greater than 135 mCi/m2 were associated with marrow cytoreduction sufficient to necessitate bone marrow transplant. However, 37% of the patients developed human anti-mouse antibody, preventing retreatment. To decrease immunogenicity and improve effector function, chimeric IgG1 and IgG3, and complementarity-determining region-grafted, humanized IgG1 and IgG3 versions of mouse M195 were developed by genetic engineering techniques. The new versions maintained specificity and biologic function, and they were superior to the mouse M195 in their ability to perform antibody-dependent cellular cytotoxicity against leukemia cells. Humanized M195, but not chimeric M195, showed a 4-8.6 times higher avidity than its mouse counterpart. Because effector function of IgG depends to a large extent on Fc clustering, a homodimeric HuG1 also was developed. Homodimeric HuG1 showed an ability to cause additional dramatic improvements in effector functions, as well as an ability to internalize and retain radioisotope in target leukemia cells. Monomeric and dimeric forms of humanized M195 may be advantageous in the therapy of acute myelogenous leukemia.

Adult↗

PubMed1994

Clinical applications of fusion imaging in oncology.

Recent developments in tumor imaging, made possible by advances in instrumentation and radiopharmaceuticals, has led to an increasing need for accurate anatomic correlation of single photon emission computed tomography (SPECT) and positron emission tomography (PET) images. Fusion imaging permits the functional strengths of SPECT and PET to be combined with the anatomic resolution of computed tomography (CT) and magnetic resonance imaging (MRI). Clinical applications of fusion imaging include the evaluation of brain tumors, lymphoma, hepatic lesions and monoclonal antibody studies. The continued development of these techniques will eventually allow fusion imaging to become a routine part of nuclear medicine practice.

Antibodies, Monoclonal↗

PubMed1994

Current status of radioimmunotherapy.

Radioimmunotherapy with radiolabeled monoclonal antibodies is increasingly effective for hematopoietic tumors, with a number of investigators reporting persistent major responses. Radioimmunotherapy for solid tumors has been more difficult and only an occasional major response has been reported and these have so far not been persistent. Toxicity is predominantly hematopoietic, with platelets being most sensitive to the effects of radiation. Even at ultra-high doses (up to 28 mCi/kg of 131I), second organ toxicity has not been reached. Rational approaches to dose planning are becoming possible with improvements in dosimetry, based on quantitative SPECT and PET imaging. Current therapeutic indices for tumor/marrow, the most radiosensitive organ, are in the range of 5-10 to 1. This is probably still too low for curative treatment of solid tumors, and further refinements, perhaps based on novel antibody formulations, are needed.

Clinical Trials as Topic↗

PubMed1994

Estradiol and progesterone production by cultured granulosa cells cryopreserved from in vitro fertilization patients.

Gonadotropin-stimulated steroidogenesis was studied in cultured human granulosa-lutein cells obtained from patients undergoing procedures for in vitro fertilization. The impact of cryopreservation on cell function in vitro was studied. Granulosa cells obtained from in vitro fertilization patients were cultured in serum-supplemented medium or cryopreserved at -135 degrees C for 2-22 months. Fresh (unfrozen) cells (10(5) produced estradiol at a rate of 1320 pmol/l (over 72 h) and progesterone at about 2500 nmol/l. Estradiol production by either fresh or cryopreserved granulosa cells in culture was unaffected by physiological concentrations of follicle-stimulating hormone (7 IU/l). Adding testosterone (10(-7) mol/l) to the medium increased estradiol secretion approximately sixfold. In contrast, progesterone production was not affected by follicle-stimulating hormone or testosterone. No significant differences were observed in cultures of cryopreserved granulosa cells compared to cultures of unfrozen cells with respect to estradiol secretion, the effects of follicle-stimulating hormone or testosterone on estradiol secretion, or progesterone production. Progesterone production by fresh and cryopreserved cells was stimulated by human chorionic gonadotropin. These data indicate that cryopreservation offers the potential to facilitate prospective studies utilizing large numbers of human granulosa-lutein cells in culture.

Aromatase↗

PubMed1994

Clinical validation of SPECT and CT/MRI image registration in radiolabeled monoclonal antibody studies of colorectal carcinoma.

UNLABELLED: Registration methods combine the anatomic localizing ability of CT or MRI with SPECT images of radiolabeled monoclonal antibodies (Mabs), allowing the accurate staging of patients prior to surgery or following treatment. METHODS: Twenty-four patients (15 males and 9 females, mean age 55 yr, range 29-70 yr) were studied with this technique. Ten patients had suspected colorectal cancer recurrence and were infused with 10 mCi of 131I-CC49 prior to staging laparotomy. Fourteen patients treated in a Phase I radioimmunotherapy study with 131I-CC49 were also studied. All patients underwent SPECT imaging of the abdomen and pelvis 5-7 days following infusion of Mab. RESULTS: Phantom studies demonstrated a 3.6-mm surface fitting mean accuracy of datasets for the liver and 1.8 mm for an intrahepatic tumor. In the presurgical group, SPECT and CT/MRI registration allowed more accurate identification of uptake abnormal sites. Areas of metastatic disease > 1 cm confirmed at surgery were found in six of nine patients with liver lesions and in two patients with extrahepatic (including one patient with pelvic) disease. In patients imaged following radioimmunotherapy, all lesions > 1.5 cm seen on CT/MRI were identified, and activity distribution in tumor and normal tissue could be more accurately assessed. CONCLUSIONS: Routine registration of SPECT and CT/MRI images is feasible and allows more accurate anatomic assessment of sites of abnormal uptake in radiolabeled Mab studies.

Adrenal Gland Neoplasms↗

PubMed1993

Development of a method to measure kinetics of radiolabelled monoclonal antibody in human tumour with applications to microdosimetry: positron emission tomography studies of iodine-124 labelled 3F8 monoclonal antibody in glioma.

We present a method to assess quantitatively the immunological characteristics of tumours using radiolabelled monoclonal antibody and positron emission tomography (PET) to improve dosimetry for radioimmunotherapy. This method is illustrated with a glioma patient who was injected with 96.2 MBq of iodine-124 labelled 3F8, a murine antibody (IgG3) specific against the ganglioside GD2. Serial PET scans and plasma samples were taken over 11 days. A three-compartment model was used to estimate the plasma to tumour transfer constant (K1), the tumour to plasma transfer constant k2, the association and dissociation constants (k3, k4) of antibody binding, and the binding potential. Tumour radioactivity peaked at 18 h at 0.0045% ID/g. The kinetic parameters were estimated to be: K1 = 0.048 ml h-1 g-1, k2 = 0.16 h-1, k3 = 0.03 h-1, k4 = 0.015 h-1 and BP = 2.25. Based on these kinetic parameters, the amount of tumour-bound radiolabelled monoclonal antibody was calculated. This method permits estimates of both macrodosimetry and microdosimetry at the cellular level based on in vivo non-invasive measurement.

Brain↗

PubMed1993

Dose-escalation trial of M195 labeled with iodine 131 for cytoreduction and marrow ablation in relapsed or refractory myeloid leukemias.

PURPOSE: Mouse monoclonal antibody (mAb) M195 (anti-CD33) is reactive with most myeloid leukemia cells, monocytes, and hematopoietic progenitors, but not with other hematopoietic cells or stem cells nor with nonhematopoietic human tissues. A therapeutic dose-escalation study of M195 labeled with iodine 131 was conducted in patients with relapsed or refractory myeloid leukemias. METHODS: Twenty-four patients (16 relapsed or refractory acute myeloid leukemias, five blastic myelodysplastic syndromes [MDS], two chemotherapy-related secondary leukemias, and one blastic chronic myelogenous leukemia [CML]), including seven who had failed to respond to prior bone marrow transplantation (BMT), received from 50 mCi/m2 to 210 mCi/m2 of 131I-M195 in divided doses. RESULTS: In 22 patients, whole-body gamma-imaging demonstrated marked uptake of antibody into all areas of bone marrow. Twenty-three patients (96%) demonstrated decreases in peripheral-blood cell counts, with decreased percentage of bone marrow blasts seen in 83% of cases. Eighty-nine percent of bone marrow biopsies examined quantitatively demonstrated substantial decreases in the number of blasts, with greater than 99% of blasts killed in some patients. The two cases that failed to demonstrate leukemic cytoreduction occurred in the first two dose levels. For 131I doses of 135 mCi/m2 or greater, pancytopenia was profound and lasted for at least 12 days. Eight patients had sufficient marrow cytoreduction to proceed to BMT. Three of these achieved marrow remission, one of 6+, and one of 9 months' duration. Two patients in blastic phase temporarily reverted to their original myelodysplastic states. Thirty-seven percent of assessable patients developed human anti-mouse antibody (HAMA). In two patients with HAMA who were re-treated, plasma 131I-M195 levels could not be maintained and no therapeutic effect resulted. Significant nonhematologic toxicity (hepatic) was seen in one patient and the maximum-tolerated dose (MTD) was not reached. CONCLUSION: These data suggest that safe leukemic cytoreduction can be achieved with 131I-M195 even in multiply relapsed or chemotherapy-refractory leukemias. This agent may be useful as part of a preparative regimen for BMT.

Adolescent↗

PubMed1993

Three-dimensional dosimetry for radioimmunotherapy treatment planning.

Absorbed-dose calculations for radioimmunotherapy are generally based on tracer imaging studies of the labeled antibody. Such calculations yield estimates of the average dose to normal and target tissues assuming idealized geometries for both the radioactivity source volume and the target volume. This work describes a methodology that integrates functional information obtained from SPECT or PET with anatomical information from CT or MRI. These imaging modalities are used to define the actual shape and position of the radioactivity source volume relative to the patient's anatomy. This information is then used to calculate the spatially varying absorbed dose, depicted in "colorwash" superimposed on the anatomical imaging study. By accounting for individual uptake characteristics of a particular tumor and/or normal tissue volume and superimposing resulting absorbed-dose distribution over patient anatomy, this approach provides a patient-specific assessment of the target-to-surrounding normal tissue absorbed-dose ratio. Such information is particularly important in a treatment planning approach to radioimmunotherapy, wherein a therapeutic administration of antibody is preceded by a tracer imaging study to assess therapeutic benefit.

Brain Neoplasms↗

PubMed1993

Modeling and dosimetry of monoclonal antibody M195 (anti-CD33) in acute myelogenous leukemia.

Individual patient response to radioimmunotherapy is influenced by each patient's tumor burden, antibody clearance kinetics and the antibody-antigen interaction. In hematologic malignancies, wherein antibody access to tumor-cell associated antigen is rapid, mathematical modeling may provide a quantitative basis for assessing the impact of patient variability on a particular therapeutic protocol. Compartmental modeling analysis of antibody pharmacokinetics from a Phase I trial of 131I-labeled monoclonal antibody, M195 (anti-CD33), was used to estimate tumor burden in cases of acute myelogenous leukemia and the absorbed dose in liver, spleen and red marrow. The suitability of a nonlinear, two-compartment model for simulating M195 distribution in leukemia patients was evaluated by comparing model predictions with patient measurements. The results demonstrate that for directly accessible, hematologically distributed tumor cells, a two-compartment model fits observed patient biodistribution data and may provide information regarding both total tumor burden and tumor burden in the liver, spleen and red marrow. The model also provides biodistribution information for absorbed dose calculations to tissues that are not directly sampled. Such information is important in determining the optimum therapeutic dose of radiolabeled antibody for a given patient.

Antibodies, Monoclonal↗

PubMed1992

PET scanning of iodine-124-3F9 as an approach to tumor dosimetry during treatment planning for radioimmunotherapy in a child with neuroblastoma.

A patient with advanced neuroblastoma who had failed chemotherapy presented with a large abdominal mass and virtually total bone marrow replacement by tumor on repeated marrow biopsies. She was considered a candidate for a Phase I 131I-3F8 radioimmunotherapy trial, (MSKCC 89-141A). As a potential aid to treatment planning, a test dose of 124I-3F8 was injected and the patient was imaged over the 72 hr postinjection using two BGO based PET scanners of different designs. Time activity curves were obtained, and the cumulated activity concentration of radiolabeled 3F8 in tumor was determined. Based on MIRD, an estimated radiation absorbed dose for 131I-3F8 was 7.55 rad/mCi, in the most antibody avid lesions. Because of low uptake and unfavorable dosimetry in some bulky tumor sites, it was decided not to treat the patient with radiolabeled antibody. Positron emission tomography of 124I-labeled antibodies can be used to measure cumulated activity or residence time in tumor for more accurate estimates of radiation absorbed tumor dose from radioiodinated antibodies and can help guide management decisions in patients who are candidates for radioimmunotherapy.

Adrenal Gland Neoplasms↗

PubMed1991

In vivo measurements of bone marrow cellularity using volume-localized proton NMR spectroscopy.

Volume-localized proton NMR spectroscopy was used to estimate bone marrow cellularity in the posterior iliac crests of patients undergoing treatment with hematopoietic growth factors for a variety of hematologic and neoplastic disorders. Twelve patients were accrued, six of whom were studied more than once, yielding a total of 25 measurements. These data were compared to cellularity assessments derived from conventional bone marrow core biopsies obtained within a 24-h period before or after the NMR exam. The results obtained by the two methods are well correlated (R = 0.94, P less than 0.001), suggesting that this noninvasive technique may preclude the need for biopsies in some cases.

Adult↗

PubMed1991

A phase I trial of monoclonal antibody M195 in acute myelogenous leukemia: specific bone marrow targeting and internalization of radionuclide.

Ten patients with myeloid leukemias were treated in a phase I trial with escalating doses of mouse monoclonal antibody (mAb) M195, reactive with CD33, a glycoprotein found on myeloid leukemia blasts and early hematopoietic progenitor cells but not on normal stem cells. M195 was trace-labeled with iodine-131 (131I) to allow detailed pharmacokinetic and dosimetric studies by serial sampling of blood and bone marrow and whole-body gamma-camera imaging. Total doses up to 76 mg were administered safely without immediate adverse effects. Absorption of M195 onto targets in vivo was demonstrated by biopsy, pharmacology, flow cytometry, and imaging; saturation of available sites occurred at doses greater than or equal to 5 mg/m2. The entire bone marrow was specifically and clearly imaged beginning within hours after injection; optimal imaging occurred at the lowest dose. Bone marrow biopsies demonstrated significant dose-related uptake of M195 as early as 1 hour after infusion in all patients, with the majority of the dose found in the marrow. Tumor regressions were not observed. An estimated 0.33 to 1.0 rad/mCi 131I was delivered to the whole body, 1.1 to 6.1 rad/mCi was delivered to the plasma, and up to 34 rad/mCi was delivered to the red marrow compartment. 131I-M195 was rapidly modulated, with a majority of the bound immunoglobulin G (IgG) being internalized into target cells in vivo. These data indicate that whole bone marrow ablative doses of 131I-M195 can be expected. The rapid, specific, and quantitative delivery to the bone marrow and the efficient internalization of M195 into target cells in vivo also suggest that the delivery of other isotopes such as auger or alpha emitters, toxins, or other biologically important molecules into either leukemia cells or normal hematopoietic progenitor cells may be feasible.

Adult↗