RIGS: surgery. Talking the talk and (just possibly) walking the walk.
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Antibodies, Monoclonal↗
Biomedical subjects
S M Larson
Publications and source records attributed to S M Larson.
Evaluation of carbon-14-colchicine biodistribution with whole-body quantitative autoradiography in colchicine-sensitive and -resistant xenografts.
UNLABELLED: Quantitative autoradiography (QAR) with radiolabeled monoclonal antibodies in xenografted animals has been extensively described in the past, either on individual tissues or on the whole body. We applied whole-body QAR to identify multidrug resistant tumors using 14C-colchicine (14C-CHC). METHODS: Two groups of five animals each were xenografted with CHC-sensitive and CHC-resistant human neuroblastoma cells. Animals were injected intravenously with 4 microCi/0.11 mumole 14C-CHC per gram of body weight and sacrificed after 60 min. Whole-body QAR was carried out using 25-microns thick sections. RESULTS: Fusion images allowed direct comparison of 14C-CHC uptake in tumor and nontumor tissues. Mean 14C-CHC distribution in sensitive and resistant tumors was 882.0 +/- 43.6 and 399.6 +/- 157.7 nCi/g corresponding to 24.5 +/- 1.21 and 11.1 +/- 4.38 nmole/g, respectively (p < 0.001), with normal tissue distribution in both groups being similar. Three-dimensional QAR showed that the uptake of 14C-CHC was in the cellular zones of the tumor. This method has potential in biodistribution studies of novel radiopharmaceuticals such as 14C-CHC. CONCLUSION: These studies further suggest that PET imaging of 11C-CHC is feasible to distinguish between sensitive and resistant tumor deposits in vivo.
Animals↗
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.
Adult↗
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.
Bone Marrow↗
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.
Antibodies, Monoclonal↗
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↗
Visualization of myocardial metastasis of carcinoid tumor by indium-111-pentetreotide.
We present a case of metastatic carcinoid tumor metastatic to the heart, presenting as ventricular arrhythmia and diagnosed by 111Inpentetreotide scintiscan despite negative endocardial biopsy. The incidence and diagnosis of carcinoid heart disease is discussed, as well as the complementary role of high-resolution anatomical images (CT, MRI) with functional images (SPECT, PET) to determine the correct diagnosis of this rare condition.
Carcinoid Heart Disease↗
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↗
Improving the balance between treatment and diagnosis: a role for radioimmunodetection.
Despite major advances in diagnostic testing, including the introduction and widespread availability of high-resolution computed tomography (CT) and magnetic resonance imaging, inadequate diagnostic information still interferes with proper management of many patients with cancers. This is particularly true for recurrent colorectal cancer, for example. In the course of this symposium, significant advances have been reported which are likely to improve management of this clinical situation. 111In, oncoscint for colorectal and ovarian cancer imaging, has been approved for single use only, and is a product licensed by the Food and Drug Administration. It has been shown to be significantly more effective than CT for detecting the presence of disease that is confined to the abdomen outside the liver. This agent is very useful in a limited role. A larger opportunity awaits other preparations reported at this conference, especially 99mTc-labeled Immu-4 carcinoembryonic antigen, which is significantly better than CT for determining resectability of recurrent cancer (T. Behr et al., Cancer Res. 55 (Suppl.): 5777S-5785S, 1995). The 99mTc-labeled compound preparations offer the advantages of low immunogenicity, excellent imaging energies of 99mTc, and "same-day" imaging. Even the most effective cancer treatment such as surgical resection, if applied to a patient who basically does not need it, can be a needless expense and a trauma to the patient. To date, our emphasis in oncology research has been heavily weighted toward developing new therapies. The success of radioimmunodetection is one indication of why it is time for a paradigm shift, during which we can move toward a more balanced program that emphasizes both diagnosis and therapy. To achieve this we must urge research institutions such as the National Cancer Institute and American Cancer Society to make major investments in the diagnostic aspects of cancer care. With the knowledge base that we have now, we can make improvements in patient care by emphasizing development of improved diagnostic methods and support for cost-effectiveness studies for developed methods, in order that currently available treatments can be more intelligently applied.
Humans↗
Radiolabeled anti-CD33 monoclonal antibody M195 for myeloid leukemias.
M195, a mouse monoclonal antibody reactive with the early myeloid antigen CD33, has been shown to target leukemia cells in patients and to reduce large leukemic burdens when labeled with 131I. A complementarity-determining region-grafted, humanized version (HuM195) has demonstrated similar targeting of leukemia cells without immunogenicity. We have studied two applications of therapy with 131I-M195. First, to intensify therapy prior to bone marrow transplantation (BMT), we combined 131I-M195 with busulfan and cyclophosphamide. Fifteen patients received first BMT for relapsed or refractory acute myelogenous leukemia or accelerated or blastic chronic myelogenous leukemia; four received second BMT for relapsed chronic or accelerated chronic myelogenous leukemia. Doses of 131I-M195 ranged from 120 to 230 mCi/m2. Few toxicities could be attributed to 131I-M195 therapy, and all patients engrafted. Eighteen patients achieved complete remission. Among those patients receiving first BMT, three have remained in unmaintained remission for 18+ to 29+ months. Six patients relapsed, including one with isolated central nervous system disease 32 months after BMT. Ten patients died in complete remission of transplant-related complications. Second, we studied whether 131I-M195 could reduce minimal residual disease and prolong remission and survival durations safely in patients with relapsed acute promyelocytic leukemia after they attained remission with all-trans-retinoic acid. Seven patients were treated with either 50 or 70 mCi/m2 131I-M195. Toxicity was limited to myelosuppression. As a measure of minimal residual disease, we monitored PML/RAR-alpha mRNA by reverse transcription PCR. Six patients had positive reverse transcription PCR assays prior to receiving 131I-M195; two converted transiently to negative. Median disease-free survival and overall survival of the seven patients were 8 (range, 3-14.5) months and 28 (range, 5.5-43+) months, respectively. This regimen compares favorably with others for relapsed acute promyelocytic leukemia. In an effort to avoid nonspecific cytotoxicity associated with 131I in future trials for minimal residual disease, we have conjugated short-range, alpha particle-emitting radioisotopes to HuM195 using a bifunctional chelate, 2-(p-isothiocyanatobenzyl)-cyclohexyldiethyl-enetriaminep entaacetic acid, with high efficiency and specific activities. 212Bi-HuM195 has demonstrated dose- and specific activity-dependent killing of HL60 cells in vitro. Injection of 213Bi-HuM195 into healthy BALB/c mice produced no effects on weight or viability.
Adult↗
The Hubble Space Telescope (HST) observing campaign on comet Shoemaker-Levy 9.
The Hubble Space Telescope made systematic observations of the split comet P/Shoemaker-Levy 9 (SL9) (P designates a periodic comet) starting in July 1993 and continuing through mid-July 1994 when the fragments plunged into Jupiter's atmosphere. Deconvolutions of Wide Field Planetary Camera images indicate that the diameters of some fragments may have been as large as approximately 2 to 4 kilometers, assuming a geometric albedo of 4 percent, but significantly smaller values (that is, < 1 kilometer) cannot be ruled out. Most of the fragments (or nuclei) were embedded in circularly symmetric inner comae from July 1993 until late June 1994, implying that there was continuous, but weak, cometary activity. At least a few nuclei fragmented into separate, condensed objects well after the breakup of the SL9 parent body, which argues against the hypothesis that the SL9 fragments were swarms of debris with no dominant, central bodies. Spectroscopic observations taken on 14 July 1994 showed an outburst in magnesium ion emission that was followed closely by a threefold increase in continuum emission, which may have been caused by the electrostatic charging and subsequent explosion of dust as the comet passed from interplanetary space into the jovian magnetosphere. No OH emission was detected, but the derived upper limit on the H2O production rate of approximately 10(27) molecules per second does not necessarily imply that the object was water-poor.
Atmosphere↗
Correlation of the findings of thallium-201 chloride scans with those of other imaging modalities and histology following therapy in patients with bone and soft tissue sarcomas.
We performed a retrospective [corrected] study to evaluate the imaging potential of thallium-201 as compared with other imaging modalities in differentiating residual/recurrent tumors from post-therapy changes in patients with musculoskeletal sarcomas. 201Tl scans, magnetic resonance imaging (17), X-ray computed tomography (6) or contrast angiography (6) studies in 29 patients previously treated for musculoskeletal sarcomas were correlated with either histopathologic findings (26 patients) or 2-year clinical follow-up (three patients). All imaging studies were acquired within 2 weeks. Ratios of 201Tl tumor uptake to the contralateral (28 patients) or adjacent region of interest were calculated. When qualitative interpretation was in doubt, only those cases with a ratio of 1.5 or more were considered suggestive of recurrent of residual viable tumor tissue. Residual or recurrent tumor tissue was verified in 21 patients by biopsy. All had true-positive 201Tl scans while the other imaging modalities were true-positive in 20 and equivocal in one. In eight patients, there was no evidence of viable tumor tissue as proven by biopsy in five and long-term clinical follow-up in three. 201Tl scan was false-positive (ratio 1.5) in one patient and true-negative in seven while the other imaging modalities had four false-positives. The average 201Tl ratios were 2.8+/-1.1 in the true-positive cases and 1.3+/-0.3 in the true-negative cases. The percentage sensitivities, specificities, and accuracy for 201Tl were 100%, 87.5%, and 96.5% versus 95%, 50%, and 82.7% respectively for other imaging modalities. These results indicate that 201Tl scintigraphy is more accurate than other imaging modalities in differentiating residual/recurrent musculoskeletal sarcomas from post-therapy changes.
Adolescent↗
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.
Adolescent↗
Targeting cancer with radiolabeled antibodies.
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Animals↗
In vivo imaging and specific targeting of P-glycoprotein expression in multidrug resistant nude mice xenografts with [125I]MRK-16 monoclonal antibody.
Multidrug resistance (MDR) in tumors is associated with P-glycoprotein (Pgp) expression. In vivo quantitation of Pgp may allow MDR to be evaluated noninvasively prior to treatment planning. The purpose of this study was to radiolabel MRK-16, a monoclonal antibody that targets an external epitope of P-glycoprotein, and perform in vivo quantitation of P-glycoprotein in a MDR xenograft nude mouse model. MRK-16 was labeled with 125I by the iodogen method, with subsequent purification by size exclusion chromatography. Groups of 10 Balb c mice were each xenografted with colchicine-resistant or sensitive neuroblastoma cell lines, respectively. Whole body clearance and tumor uptake over time was quantitated by gamma camera imaging, and biodistribution studies were performed with [125I]MRK-16 and an isotype matched control antibody, A33. Quantitative autoradiography and immunohistochemistry analysis of tumors was also evaluated to confirm specific targetting of [125I]MRK-16. Peak tumor uptake was at 2-3 days post-injection, and was significantly greater in resistance compared to sensitive tumors (mean % injected dose/g +/- SD) (18.76 +/- 2.94 vs 10.93 +/- 0.96; p < 0.05). Quantitative autoradiography verified these findings (19.13 +/- 0.622 vs 12.08 +/- 0.38, p < 0.05). Specific binding of [125I]MRK-16 was confirmed by comparison to [131I]A33 in biodistribution studies, and localized to cellular components of tissue stroma by comparison of histologic and autoradiographic sections of sensitive and resistant tumors. Immunoblot analysis demonstrated a 4.5-fold difference in P-glycoprotein expression between sensitive and resistant cell lines without colchicine selective pressure. We conclude that in vivo quantitation of P-glycoprotein in MDR tumors can be performed with [125I]MRK-16.(ABSTRACT TRUNCATED AT 250 WORDS)
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Extramedullary hematopoiesis assessment in a patient with osteopetrosis.
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Adult↗
Sequential targeted therapy for relapsed acute promyelocytic leukemia with all-trans retinoic acid and anti-CD33 monoclonal antibody M195.
Acute promyelocytic leukemia (APL) provides a model to examine the sequential use of selective oncogene product-targeted and lineage-targeted agents. All-trans retinoic acid (RA) has been shown to produce brief remissions by a novel differentiating mechanism in most patients with APL. M195, a mouse monoclonal antibody (moAb) reactive with the cell-surface antigen CD33, can target myeloid leukemia cells in patients and reduce large leukemic burdens when labeled with 131I. We studied whether 131I-M195 could safely reduce minimal residual disease and prolong remission and survival durations in patients with relapsed APL after they had attained remission with all-trans RA. Seven patients with relapsed APL in second remission were treated with either 70 (n = 2) or 50 (n = 5) mCi/m2 of 131I-M195. As a measure of minimal residual disease, we serially monitored PML/RAR-alpha mRNA by a reverse transcription polymerase chain reaction (RT-PCR) assay. There was no immediate toxicity. Late toxicity was limited to myelosuppression, but no episodes of febrile neutropenia were seen. Six patients had detectable PML/RAR-alpha mRNA after all-trans RA therapy; two had single negative RT-PCR determinations following 131I-M195. Median disease-free survival of the seven patients was 8 months (range 3-14.5). Four patients with median follow-up of 24 months remain alive, and median overall survival exceeds 21+ months (range 5.5-33+). This regimen based on targeted therapy compares favorably to other approaches for the treatment of relapsed APL, including that used in the immediately preceding trial in which patients were induced into remission and maintained with all-trans RA, as well as other chemotherapy-based regimens. These data support further study of moAb-based therapy for minimal residual disease in acute leukemia.
Adult↗
Tumor receptor imaging: proceedings of the National Cancer Institute workshop, review of current work, and prospective for further investigations.
In February 1994, the National Cancer Institute held a workshop to evaluate the current and future role of emission tomographic imaging methods, positron emission tomography and single-photon emission computed tomography, in improving the accuracy of cancer diagnosis and the effectiveness of treatment and in elucidating basic aspects of human cancer biology. Reviews covered many of the receptor and transport systems for hormones and growth factors, as well as metabolic changes important in human cancer, and topical presentations reviewed the current status of receptor-based imaging in the most well-characterized systems: somatostatin receptor imaging of neuroendocrine tumors, estrogen receptor imaging of breast cancer, and epidermal growth factor receptor and tumor metabolic imaging. A critical analysis was made of the current research and of new directions for the future development and use of receptor-imaging methods in oncology. In each area, recommendations were made for further investigation, where emerging understanding of tumor cell biology and defined molecular targets might be combined with the methods of radiopharmaceutical design and evaluation, to develop new approaches to critical issues in the diagnosis, staging, and treatment of cancer through tumor receptor imaging.
Humans↗