Application of an [(18)F]fluorodeoxyglucose-sensitive probe for the intraoperative detection of malignancy.

BACKGROUND: Whole-body positron emission tomography (PET) has been shown to be a highly sensitive method for detecting malignancy not imaged by conventional modalities. We have adapted a hand-held gamma-ray-sensitive probe to detect the radiation emission from the [(18)F]fluorodeoxyglucose (FDG) used in PET imaging. This pilot study was devised to examine the feasibility of using a hand-held probe to intraoperatively differentiate normal from tumor-bearing tissue. MATERIALS AND METHODS: A commercially available gamma probe was adapted to detect the radioactivity released from FDG and examined to determine the in vitro sensitivity for localization of a FDG point source. Eight consecutive patients underwent resection of metastatic colon cancer or melanoma; each received a preoperative injection of 7--10 mCi of FDG. The gamma probe was used to determine radioactive counts per second from tumor and normal tissue, and ratios of tumor to adjacent normal background were calculated. RESULTS: In vitro studies with a FDG point source demonstrated the probe could identify the source with a 50% reduction in maximum counts 1.7 +/- 0.1 cm from the source (full-width half-maximum measurement). Based on the results of their preoperative PET scans 17 tumors were identified from the 8 patients. Of the 17 tumors assessed the in vivo tumor-to-background ratios varied from 1.16:1 to 4.67:1 for the melanoma patients (13 tumors) and from 1.19:1 to 7.92:1 for colon cancer patients (4 tumors). Thirteen tumors were resected; four (2 patients) were unresectable. CONCLUSIONS: This study demonstrates the use of a hand-held gamma-ray-sensitive probe to intraoperatively differentiate the radioactivity released from FDG from tumor-bearing and adjacent normal tissue. While further studies are necessary for us to optimize the use of this probe, the intraoperative detection of FDG-avid malignancies may ultimately improve our ability to completely resect patients with metastatic disease.

Rhenium-186-labeled hydroxyethylidene diphosphonate dosimetry and dosing guidelines for the palliation of skeletal metastases from androgen-independent prostate cancer.

Rhenium-186 (tin)-labeled hydroxyethylidene diphosphonate (186Re-labeled HEDP) was evaluated in 27 men with progressive androgen-independent prostate cancer and bone metastases. Administered activities ranged from 1251 to 4336 MBq (33.8-117.2 mCi). The primary objectives were to assess tumor targeting, normal organ dosimetry, and safety. Antitumor effects were assessed by posttherapy changes in prostate-specific antigen and, when present, palliation of pain. Whole-body kinetics, blood and kidney clearance, skeletal dose, marrow dose, and urinary excretion of the isotope were assessed. Targeting of skeletal disease was observed over the period of quantification (4-168 h). Radiation doses to whole body, bladder, and kidney were well tolerated. The dose-limiting toxicity was myelosuppression (grade III) at 4107 MBq (111 mCi) and grade II at 296 MBq (80 mCi). Probe clearance (whole body) and urinary excretion measurements were highly correlated. Of the six patients treated at the highest dosage schedules (three at 1510 MBq/m2 and three at 1665 MBq/m2), three showed a posttherapy decline in prostate-specific antigen of 50% or more. The declines were not sustained. The determination of total activity retained at 24 h, as well as an estimate of marrow dose, correlated with the amount of myelosuppression observed. These results suggest that a single 24-h measurement of retained activity would allow individualized dosing and an improved therapeutic index relative to fixed dosing schema. Repetitive dosing is required to increase palliation.

Imaging herpes virus thymidine kinase gene transfer and expression by positron emission tomography.

We report a series of studies that assess the feasibility and sensitivity of imaging of herpes virus type one thymidine kinase (HSV1-tk) gene transfer and expression with [124I]-5-iodo-2'-fluoro-1-beta-D-arabinofuranosyluracil ([124I]-FIAU) and positron emission tomography (PET) and the ability of [124I]-FIAU-PET imaging to discriminate different levels of HSV1-tk gene expression. Studies were performed in rats bearing multiple s.c. tumors derived from W256 rat carcinoma and RG2 rat glioma cells. In the first set, we tested the sensitivity of [124I]-FIAU-PET imaging to detect low levels of HSV1-tk gene expression after retroviral-mediated gene transfer. HSV1-tk gene transduction of one of preestablished wild-type W256 tumor in each animal was accomplished by direct intratumoral injection of retroviral vector-producer cells (W256-->W256TK* tumors). Tumors produced from W256 and W256TK+ cells served as the negative and positive control in each animal. Highly specific images of [124I]-FIAU-derived radioactivity were obtained in W256TK* tumors (that were transduced in vivo) and in W256TK+ tumors but not in nontransduced wild-type W256 tumors. The level of "specific" incorporated radioactivity in transduced portions of both W256TK* and W256TK+ tumors was relatively constant between 4 and 50 h. In the second set, we tested whether [124I]-FIAU and PET imaging can measure and discriminate between different levels of HSV1-tk gene expression. Multiple s.c. tumors were produced from wild-type RG2 cells and stably transduced RG2TK cell lines that express different levels of HSV1-tk. A highly significant relationship between the level of [124I]-FIAU accumulation [% injected dose/g and incorporation constant (Ki)] and an independent measure of HSV1-tk expression (sensitivity of the transduced tumor cells to ganciclovir, IC50) was demonstrated, and the slope of this relationship was defined as a sensitivity index. We have demonstrated for the first time that highly specific noninvasive images of HSV1-tk expression in experimental animal tumors can be obtained using radiolabeled 2'-fluoro-nucleoside [124I]-FIAU and a clinical PET system. The ability to image the location (distribution) of gene expression and the level of expression over time provides new and useful information for monitoring clinical gene therapy protocols in the future.

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.

Enhancement of radiation dose to the nucleus by vesicular internalization of iodine-125-labeled A33 monoclonal antibody.

UNLABELLED: In radioimmunotherapy, the emission characteristics of the radioisotope is critical in determining the radiation dose to the tumor compared to normal organs. If antibodies internalize and transport low-energy electron emitting isotopes close to the tumor cell nucleus, an improved therapeutic advantage is achieved. METHODS: Using fluorescent microscopy, we studied the subcellular distribution of an internalizing antibody, A33, which detects a restricted determinant on colon cancer cells. We developed a physical model to assess the dose deposited on the nucleus by electrons emitted from radiolabeled A33 accumulated inside vesicles. This model is based on the energy-range relationship of electrons in water. Similarly, another model was developed to calculate the radiation dose to the nucleus from electrons emitted from extracellular space. The percentage of A33 bound to membrane and internalized was determined in vitro at various time points. Cytotoxicity experiments were performed with 125I- and 131I-labeled A33 at various concentrations and specific activities. RESULTS: A33 accumulates in cytoplasmic vesicles (40% of total bound) which transport the activity close to the nucleus. This increases the radiation dose to the cancer cell nucleus by a factor of 3 compared to the average dose calculated based on the assumption of a uniform distribution on the cell membrane. The cytoplasm of antigen-negative normal cells shields the nucleus from the electrons emitted from extracellular 125I. This shielding is 30 times less for 131I. Cytotoxicity data show 10% cell survival with 10 microCi/ml of 125I-A33, but 90% survival with up to 100 micro/Ci/ml of 125I-A33 in the presence of a blocking dose of 100-fold excess of cold A33. Similar experiments with 131I showed cytotoxicity in both cases. CONCLUSIONS: The results of the cytotoxicity experiment are in agreement with the physical model and suggest a basis for improved tumor-to-marrow radiation dose by clinical use of 125I-A33.

Phase I/II study of iodine 125-labeled monoclonal antibody A33 in patients with advanced colon cancer.

PURPOSE: A phase I/II study was designed to determine the maximum-tolerated dose (MTD) of iodine 125-labeled monoclonal antibody A33 (125I-mAb A33), its limiting organ toxicity, and the uptake and retention of radioactivity in tumor lesions. PATIENTS AND METHODS: Patients (N = 21) with advanced chemotherapy-resistant colon cancer who had not received prior radiotherapy were treated with a single 125I-mAb A33 dose. 125I doses were escalated from 50 to 350 mCi/m2 in 50-mCi/m2 increments. Radioimmunoscintigrams were performed for up to 6 weeks after 125I-mAb A33 administration. RESULTS: All 20 patients with radiologic evidence of disease showed localization of 125I to sites of disease. Twelve of 14 patients, who underwent imaging studies 4 to 6 weeks after antibody administration, had sufficient isotope retention in tumor lesions to make external imaging possible. No major toxicity was observed, except in one patient with prior exposure to mitomycin who developed transient grade 3 thrombocytopenia. Although the isotope showed variable uptake in the normal bowel, gastrointestinal symptoms were mild or absent, and in no case did stools become guaiac-positive. The MTD was not reached at 125I doses up to 350 mCi/m2. However, cytotoxicity assays demonstrated that patients treated with the highest dose had sufficiently high serum levels of 125I-mAb A33 to lyse colon cancer cells in vitro. Among 21 patients, carcinoembryonic antigen (CEA) levels returned to normal in one patient and decreased by 35% and 23%, respectively, in two patients; one additional patient had a mixed response on computed tomography. Additional, significant responses were observed in those patients treated with chemotherapy [carmustine [BCNU], vincristine, flourouracil, and streptozocin [BOF-Strep]) after completion of the 125I-mAb A33 study. CONCLUSION: Low-energy emission radioimmunotherapy with doses of up to 350 mCi/m2 of 125I-mAb A33 did not cause bowel or bone marrow toxicity. The modest antitumor activity in these heavily pretreated patients is encouraging because of lack of toxicity at the doses studied. The long radioactivity retention in tumors suggests that isotopes with a long half-life may have a therapeutic advantage, based on calculated dose delivery to tumor versus normal tissue. Due to the low bone marrow dose, further 125I trials with humanized mAb A33 are warranted, and controlled studies must be conducted to evaluate the combination of radioimmunotherapy and chemotherapy.

Pharmacokinetics and dosimetry of iodine-125-IUdR in the treatment of colorectal cancer metastatic to liver.

UNLABELLED: The radiotoxicity of 125I is highly sensitive to the site of decay relative to nuclear DNA. This paper describes a new approach, based upon pharmacokinetic clearance of radioactivity from the tumor, with which to quantify the fraction of [125I]IUdR incorporated within the DNA of tumor cells. METHODS: Patients were injected with [125I]IUdR through the hepatic artery. Iodine-131-IUdR was used as a tracer for imaging and quantitation. Both conventional and DNA-level dosimetry were performed. RESULTS: We calculated that if 15% of the tumor cells were in S phase at the time of injection, there would be 250 decays of 125I in the DNA per tumor cell after an infusion of 5 mCi [125I]IUdR. According to in vitro data based on 5 x 10(8) cells per g tumor, 99% of these cells in S phase would be killed. CONCLUSION: The estimate of cell inactivation is strongly dependent on the number of cells per gram and the fraction of cells in S phase at the time of injection, which indicates that repeat injections would be necessary to achieve a therapeutic effect.

Pilot clinical trial of 5-[125I]iodo-2'-deoxyuridine in the treatment of colorectal cancer metastatic to the liver.

UNLABELLED: The thymidine analog, 5-iodo-2'-deoxyuridine (IUdR), is incorporated in the DNA of cells in the S phase. When incorporated into DNA, short-range Auger electrons emitted by 125I-labeled IUdR can cause double-strand breaks, delivering a lethal radiation dose to the cell. We conducted therapeutic trial to evaluate[125I/131I]IUdR pharmacokinetics in liver metastases from colorectal cancer. Dosimetry, safety, and therapeutic potential were assessed. METHODS: Four patients were each infused with 5 mCi [125I]IUdR and 10 mCi [131I]IUdR through the sideport of a hepatic artery pump. Iodine-131 images were quantitated and used for pharmacokinetic studies. The radioactivity in the DNA of biopsy samples of tumor, normal liver and bone marrow, obtained 24 or 48 hr after injection, was counted. RESULTS: All patients had [125I]IUdR and [131I]IUdR uptake in tumor, with a biexponential clearance. Repeat injections in individual patients showed little variation in tumor uptake, especially in the slow clearance component. On planar images, no long-term retention was seen in bone marrow or other actively dividing normal tissues. Radioactivity in all tumor DNA samples was greater than background, while that in normal liver cell DNA was at background levels. Radioactivity in the DNA of one marrow sample taken at 24 hr was above background, but in another taken at 48 hr it was equal to background levels. No side effects were noted, no hematologic toxicity was observed in any patients and no tumor responses were seen. CONCLUSION: There is persistent uptake of [125I]IUdR in hepatic tumors, thereby making hepatic artery infusion a suitable mode of delivery for therapy. Repeat injections will be needed because only 15%-50% of tumor cells are in the S phase. Based on results from this pilot study, a therapeutic regimen is being planned.

Pilot radioimmunotherapy trial with 131I-labeled murine monoclonal antibody CC49 and deoxyspergualin in metastatic colon carcinoma.

An antimouse immune response is invariable following administration of murine monoclonal antibody (mAb), precluding effective multidose therapy. In advanced colorectal cancer patients, we carried out a pilot study with multiple doses of 131I-labeled CC49 administered with deoxyspergualin (DSG), an immunomodulator, to determine its effect on immune response. Cumulative toxicity and efficacy were also evaluated. Six patients with tumor-associated glycoprotein 72-expressing colorectal cancer were treated i.v. with 15 mCi/m2 131I-labeled to 20 mg mAb CC49 biweekly, along with concurrent DSG 200 mg/m2 daily for 5 days, for a maximum of four courses. None had received prior murine mAbs. All patients had targeting of radioactivity to known tumor sites following initial infusion. Four of six patients received all four courses of therapy, three without any acute side effects. In these patients, there was no change in serum clearance with variable tumor targeting following repeat infusions. Two patients had

Quantitative studies of monoclonal antibody targeting to disialoganglioside GD2 in human brain tumors.

Iodine-131 3F8, a murine IgG3 monoclonal antibody that targets to GD2-bearing tumors, was administered intravenously to 12 patients with brain tumors. Six patients received 2 mCi (0.74 Bq) of 131I-3F8, five patients 10 mCi (3.7 Bq)/1.73 m2 of 131I-3F8, and one patient 2.6 mCi (0.96 Bq) of 124I-3F8, with no side-effects. Nine of 11 malignant gliomas and the single metastatic melanoma showed antibody localization, with the best tumor delineation on single-photon emission tomography (SPET) following 10 mCi (3.7 Bq)/1.73 m2 dose. No nonspecific uptake in the normal craniospinal axis was detected. There was no difference in the pharmacokinetics of low-dose versus the higher-dose antibody groups; plasma and total-body half-lives were 18 h and 49 h, respectively. Surgical sampling and time-activity curves based on quantitative imaging showed peak uptake in high-grade glioma at 39 h, with a half-life of 62 h. Tumor uptake at time of surgery averaged 3.5 x 10(-3) %ID/g and peak activity by the conjugate view method averaged 9.2 x 10(-3) %ID/g (3.5-17.8). Mean radiation absorption dose was 3.9 rad per mCi injected (range 0.7-9.6) or 10.5 cGy/Bq (range 1.9-26). There was agreement on positive sites when immunoscintigraphy was compared with technetium-99m glucoheptonate/diethylene triamine penta-acetic acid planar imaging, thallium-201 SPET, and fluorine-18 fluorodeoxyglucose positron emission tomography. Taken together, these data suggest that quantitative estimates of antibody targeting to intracranial tumors can be made using the modified conjugate view method.

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.

Imaging of brain tumor proliferative activity with iodine-131-iododeoxyuridine.

METHODS: Iodine-131-iododeoxyuridine (IUdR) uptake and retention was imaged with SPECT at 2 and 24 hr after administering a 10-mCi dose to six patients with primary brain tumors. The SPECT images were directly compared to gadolinium contrast-enhanced MR images as well as to [18F]fluorodeoxyglucose (FDG) PET scans and 201Tl SPECT scans. RESULTS: Localized uptake and retention of IUdR-derived radioactivity was observed in five of six patients. The plasma half-life of [131I]IUdR was short (1.6 min) in comparison to the half-life of total plasma radioactivity (6.4 hr). The pattern of [131I]IUdR-derived radioactivity was markedly different in the 2-hr compared to 24-hr images. Radioactivity was localized along the periphery of the tumor and extended beyond the margin of tumor identified by contrast enhancement on MRI. The estimated levels of tumor radioactivity at 24 hr, based on semiquantitative phantom studies, ranged between < 0.1 and 0.2 microCi/cc (< 0.001% and 0.002% dose/cc); brain levels were not measurable. CONCLUSIONS: Iodine-131-IUdR SPECT imaging of brain tumor proliferation has low (marginal) sensitivity due to low count rates and can detect only the most active regions of tumor growth. Imaging at 24 hr represents a washout strategy to reduce 131I-labeled metabolites contributing to background activity in the tumors, and is more likely to show the pattern of [131I]IUdR-DNA incorporation and thereby increase image specificity. Iodine-123-IUdR SPECT imaging at 12 hr and the use of [124I]IUdR and PET will improve count acquisition and image quality.

Current status of radioimmunodetection.

Radioimmunodetection is a nuclear medicine technique that depends on in vivo detection of localization of antibodies and antibody forms carrying radioactivity for the purpose of diagnosis in patients with cancer. Current methods take advantage of tracers suitable for high resolution gamma-camera imaging, such as 99mTc and 111In, for common tumors, such as colon and lung cancers. In addition, tracers such as 125I have been used for the intraoperative detection of metastatic deposits. These methods detect from 75 to 90% of metastatic deposits with high specificity, and typically contribute important diagnostic information, even in 25-40% of patients with occult disease.

Intraoperative beta probe: a device for detecting tissue labeled with positron or electron emitting isotopes during surgery.

An intraoperative beta probe was designed, built, and tested for detection of radio-labeled malignant tissues that has the advantage of being selectively sensitive to beta while insensitive to gamma radiation. Since beta radiation (electrons or positrons) has a short range in tissue, this probe is ideal for detecting tracers in tumors at the surface of the surgical field. This probe contains a plastic scintillation detector sensitive to beta rays and to a lesser degree some background gamma rays. A second detector counts spurious gamma rays and allows for their subtraction from the activity measured by the first detector. Sensitivity of the dual probe for I-131 and F-18 was measured to be 108 counts/s/kBq (4000 counts/s/microCi). The dual-detector probe faithfully measured the 10:1 "tumor" to background ratio of radioactivity concentrations in a simulated environment of a tumor in the presence of intense background 511 keV photons. In another phantom experiment, simulating abdominal tumor deposits with various realistic I-131 radioactive concentrations, the probe was able to accurately identify tumors of approximately 50 mg with a tumor/normal radioactivity concentration of 3/1 in 10 s.

Clinical comparison of radiolocalization of two monoclonal antibodies (mAbs) against the TAG-72 antigen.

Ten patients with colorectal cancer metastases received 125I-B72.3 and 131I-CC49 prior to laparotomy (five patients received 1 mg, and five 20 mg of each mAb). Tumor:serum ratios of 131I-CC49 were better than those of 125I-B72.3 (P < 0.01 at 1 mg; P = 0.05 at 20 mg; P < 0.01 at both doses). All known lesions > or = 1 cm in diameter were visualized at the 20 mg dose. There was no difference in absolute tumor uptake of 125I-B72.3 or 131I-CC49. We conclude that mAb CC49 has better relative uptake in colorectal cancers than mAb B72.3.

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.

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.