PET imaging of (86)Y-labeled anti-Lewis Y monoclonal antibodies in a nude mouse model: comparison between (86)Y and (111)In radiolabels.

UNLABELLED: Absorbed doses in (90)Y radioimmunotherapy are usually estimated by extrapolating from (111)In imaging data. PET using (86)Y (beta(+) 33%; half-life, 14.7 h) as a surrogate radiolabel could be a more accurate alternative. The aim of this study was to evaluate an (86)Y-labeled monoclonal antibody (mAb) as a PET imaging agent and to compare the biodistribution of (86)Y- and (111)In-labeled mAb. METHODS: The humanized anti-Lewis Y mAb hu3S193 was labeled with (111)In or (86)Y through CHX-A"-diethylenetriaminepentaacetic acid chelation. In vitro cell binding and cellular retention of radiolabeled hu3S193 were evaluated using HCT-15 colon carcinoma cells, a cell line expressing Lewis Y. Nude mice bearing HCT-15 xenografts were injected with (86)Y-hu3S193 or (111)In-hu3S193. The biodistribution was studied by measurements of dissected tissues as well as by PET and planar imaging. RESULTS: The overall radiochemical yield in hu3S193 labeling and purification was 42% +/- 2% (n = 2) and 76% +/- 3% (n = 6) for (86)Y and (111)In, respectively. Both radioimmunoconjugates specifically bound to HCT-15 cells. When cellular retention of hu3S193 was studied using (111)In-hu3S193, 80% of initially cell-bound (111)In activity was released into the medium as high-molecular-weight compounds within 8 h. When coadministered, in vivo tumor uptake of (86)Y-hu3S193 and (111)In-hu3S193 reached maximum values of 30 +/- 6 and 29 +/- 6 percentage injected dose per gram and tumor sites were easily identifiable by PET and planar imaging, respectively. CONCLUSION: At 2 d after injection of (111)In-hu3S193 and (86)Y-hu3S193 radioimmunoconjugates, the uptake of (111)In and (86)Y activity was generally similar in most tissues. After 4 d, however, the concentration of (86)Y activity was significantly higher in several tissues, including tumor and bone tissue. Accordingly, the quantitative information offered by PET, combined with the presumably identical biodistribution of (86)Y and (90)Y radiolabels, should enable more accurate absorbed dose estimates in (90)Y radioimmunotherapy.

An investigation of the physical characteristics of 66Ga as an isotope for PET imaging and quantification.

Isotopes commonly used for PET imaging and quantification have a straightforward decay scheme involving "pure" positron (beta +) emission, i.e., 95%-100% beta + abundance, with no additional gamma rays. 66Ga (Emax = 4.2 MeV, T1/2 = 9.5 h) is a member of a category of isotopes with a lower abundance of beta +'s (57%) and a more complicated spectrum involving combinations of gamma rays that are emitted in cascade. These additional gamma rays tend to cause a higher singles rate, resulting in more random coincidence events. The most abundant positron (51.5%) in the spectrum has one of the highest energies considered for PET imaging. For the purpose of monoclonal antibody dosimetry using 66Ga, it is important to verify the quantification in phantoms prior to initiating human studies. A series of quantitative phantom measurements were performed on the PC4600, a head-optimized BGO based scanner with multiple detector rings. Count rate linearity was verified over concentrations ranging from 4.0 kBq/cc to 37 kBq/cc (0.11-1.0 microCi/cc); resolution averaged 16 mm full width half-maximum in the x and y directions in both the direct and cross planes. Axial resolution was 14 mm. The range of the energetic positrons (up to 4.153 MeV, range 7.6 mm in tissue) was verified as a primary source of resolution degradation. Within the limits outlined above, 66Ga is a suitable isotope for use as 66Ga citrate or with monoclonal antibodies in the detection and staging of tumors and other lesions. In addition, the energetic positrons have possible therapeutic applications when used as a monoclonal antibody label.

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.

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.

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.

High-resolution positron emission tomography of human ovarian cancer in nude rats using 124I-labeled monoclonal antibodies.

PET has inherently high resolution and excellent contrast imaging and accurately measures radioactivity concentrations in vivo. When combined with specific immunological targeting it might provide a highly specific and sensitive radioimmunoscintigraphic tool. To investigate this we injected 124I-labeled MAb MX35 or MAb MH99 monoclonal antibodies (doses 200-400 mu Ci) intravenously into nude rats bearing subcutaneous human ovarian cancer xenografts (SK-OV-7 and SK-OV-3 cell lines). A melanoma cell line (SK-MEL-30) was used as a control tumor. These murine monoclonal antibodies react with cell-surface antigens expressed by most ovarian cancer cells, including the ovarian cell line used. Imaging was performed at 1-6 days using a high-resolution positron emission tomograph (PCR-I) with a spatial resolution of 4.5 mm. The slice thicknesses were 0.5 and 1.0 cm. Forty to seventy thousand coincident pulses were obtained per frame. The PET results were compared with those of autopsy and histology. Samples of blood, tumor, and normal tissues were obtained at various time points. PET calculation of isotope uptake ratios demonstrated specific localization of the antibodies in tumor, with ratios of tumor to normal tissue uptake as high as 6:1. Subcutaneous ovarian cancer nodules as small as 7 mm were identified with PET imaging. The results corresponded well with tissue sampling. Our findings suggest that PET imaging of tumors with 124I-labeled monoclonal antibodies may be useful in human diagnostic and therapeutic applications in ovarian cancer as well as other diseases.

Radiation dose in CT.

The energy deposited in the patient by the rotating x-ray beam in computed tomography produces more uniform absorbed dose values within the section of imaged tissue than those produced in conventional radiologic procedures. The dose values within a specific section are determined by factors such as voltage, current, scan time, scan field, rotation angle, filtration, collimation, and section thickness and spacing. For routine dose determinations, a pencil ionization chamber is usually employed with a plastic phantom. Dose for a specific patient can be determined with thermoluminescent dosimeters placed on the patient. Multiple-scan procedures normally increase the dose in a specific section by less than a factor of two. Typical multiple-scan average doses are in the range of 40-60 mGy for head scans and 10-40 mGy for body scans. Integral dose, however, is directly proportional to the number of sections in an examination. When examination factors are changed to reduce dose, the image noise increases. An optimum protocol is one that results in a balance between dose and image quality.

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.

Quantitative imaging of I-124 using positron emission tomography with applications to radioimmunodiagnosis and radioimmunotherapy.

Positron emission tomography (PET) is potentially useful for the quantitative imaging of radiolabeled antibodies, leading in turn to improved dosimetry in radioimmunotherapy. Iodine-124 is a positron-emitting nuclide with appropriate chemical properties and half-life (4.2 days) for such studies since the radiolabeling of antibodies with iodine is well understood and the half-life permits measurements over several days. Unfortunately, I-124 has a complex decay scheme with many high-energy gamma rays and a positron abundance of only 25%. It has therefore been largely ignored as a PET-imaging nuclide. However, measurements made with phantoms and animals under realistic conditions using a BGO-based PET scanner have shown that satisfactory imaging and quantitation can be achieved. Investigations of spatial resolution, the linearity of regional observed count rate versus activity in the presence of other activity, and the visualization and quantitation of activity in spheres with different surrounding background activities were carried out with phantoms up to 22 cm in diameter. Compared with F-18, spatial resolution was only slightly degraded (13.5 mm FWHM vs 12 mm FWHM) while linearity was the same over a 10:1 activity range (0.015 to 0.15 MBq/ml for I-124). The visualization and quantitation of spheres was also slightly degraded when using similar imaging times. Increasing the imaging time for I-124 reduced the difference. To verify that the technique would work in vivo, measurements were made of human neuroblastoma tumors in rats which had been injected with I-124 labeled 3F8 antibody. Although the number of samples was small, good agreement was achieved between image-based measurements and direct measurements of excised 4-g tumors. Thus quantitative imaging of I-124 labeled antibodies appears to be possible under realistic conditions.

Radiation dosimetry survey of computed tomography systems from ten manufacturers.

Profiles of the absorbed dose delivered throughout cylindrical and anthropomorphic phantoms during single scans by computed tomography systems from ten manufacturers were measured using LiF thermoluminescent dosemeters (TLD) and X-ray therapy verification film. The dose profiles demonstrate that a significant portion of the dose is delivered outside the imaged volume of a single scan. The doses measured in cylindrical Plexiglas phantoms were similar to those measured in anthropomorphic cross sections of tissue substitute materials except near the centre of the thorax section. The film results, obtained using a single calibration curve, agreed with the TLD results to within 25% for most systems.

An evaluation of CT systems from ten manufactures.

During the past three years, 23 computerized tomography (CT) machines from ten different manufacturers located in Europe and the USA have been evaluated. Using the same set of phantoms and measurement techniques, performance data have been derived including noise, uniformity of CT numbers, low contrast detectability, spatial resolution, modulation transfer function, effective photon energy and linearity of CT numbers. Thermoluminescent and film dosimetry were used to determine single-slice dose profiles at the periphery and centre of specialized anthropomorphic phantoms. The results of this study are presented in tabular and graphical form together with some general conclusions on their implications.

A method of correcting for linear drift in computed tomography brain scans.

Linear drift of X-ray attenuation coefficients must be corrected if quantitative comparisons are to be made between computed tomography (CT) brain scans of the same individual performed at different times. Such a correction is accomplished by comparing the low (cerebrospinal fluid) end of the attenuation coefficient frequency histograms using a percentile--percentile plot. A "drift correction" permits serial quantitative assessments of the progression or regression of white matter hypodensity, such as occurs in drug induced leukoencephalopathy.

Partial volume summation: a simple approach to ventricular volume determination from CT.

The accurate determination of ventricular volume from computed tomography (CT) is not a trivial problem. The direct approach of measuring the area within a visually determined boundary or contour level and multiplying by the nominal slice thickness may be subject to large errors because such boundaries are not, in general, well defined. When the ventricles are filled with a high-contrast material such as metrizamide, we may use the technique of 'partial volume summation,' a simple but accurate, clinically applicable method which may be performed on a standard DeltaScan-50 or similar system.

Determination of ventricular volume following metrizamide CT ventriculography.

Volume averaging, relatively slight differences in the mean attenuation coefficients of CSF and white/grey matter, and the irregular contours of the human ventricular system have so far seriously limited the accuracy of CT estimation of ventricular volume. Taking advantage of the high attenuation of metrizamide-containing CSF, we have developed three methods for computing ventricular volume after metrizamide CT ventriculography; these methods depend upon computer analysis of X-ray absorption data obtained from contiguous CT brain slices. All three methods were validated by CT scanning a formalin-fixed cadaver brain containing an apoxy-resin cast of the ventricular system. Calculated ventricular volumes were compared with the actual measured volume of the ventricular cast.

Distribution and retention of 35S-sodium sulfate in man.

Measurements were made of the 35S content of tissues obtained from biopsies and autopsies made during and up to 6 months after treatment of chondrosarcoma or chordoma with carrier-free Na235SO4. Usually 70--90% of an intravenous dose was excreted in the urine during the first 3 days. The major component of the blood concentration had a biologic half-time of 0.4--0.7 days. The initial uptakes in chondrosarcoma, chordoma, and red bone marrow were high and nearly equal, but the rates of loss differed greatly. Uptake in epiphyseal cartilage was comparable to that in chondrosarcoma; uptake in other types of cartilage was lower, but subsequent loss was very slow. For an administered dose of 1 mCi per kilogram of body weight, the integrated radiation doses were 2.4 rads for blood, 33 rads for red bone marrow, 155 rads for chondrosarcoma, 49 rads for chordoma, and 135 rads for normal cartilage. Doses to muscle, skin, and fibrous tissue were 7--15 rads.