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Biomedical subjects

S M Larson

Publications and source records attributed to S M Larson.

At least 127 records · Page 7Linked to original sources
PubMed1994

Antibody response to murine anti-GD2 monoclonal antibodies: correlation with patient survival.

Clinical strategies which modulate the human anti-mouse antibody response (HAMA) in patients may have a profound influence on the idiotype network inducible by murine monoclonal antibodies (MoAb). Prior to myeloablative chemotherapy (ABMT), 9 patients with Stage IV neuroblastoma were imaged with 131I-3F8, a MoAb specific for the ganglioside GD2. Their serum HAMA, anti-idiotypic, anti-GD2, and anti-anti-idiotypic antibodies were assayed by enzyme-linked immunosorbent assay prior to, and at 3 and 6 months postimaging. HAMA and anti-idiotypic levels remained low, in contrast to the high levels in 10 patients imaged with 131I-3F8 without ABMT. Five of the 9 patients are long-term survivors; all had elevated anti-GD2 and anti-anti-idiotypic levels, significantly higher than those who died of disease. Although 131I-3F8 imaging prior to ABMT detected abnormal sites in 4 of 9 patients, 3 of the 4 patients have continued in remission for 24-63 months after ABMT, and all 3 mounted anti-GD2 and anti-anti-idiotypic antibody responses. We conclude that myeloablative therapy strongly suppressed the HAMA/anti-idiotypic response to murine MoAb and that the prognostic significance of host immune response to ganglioside GD2 MoAb deserves further investigation.

Animals↗
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

Overview of clinical radioimmunodetection of human tumors.

The role of radioimmunodetection in the detection of cancer has been established through the development of high affinity immunoconjugates and recent improvements in radiochemistry. Advances in imaging techniques, particularly single-photon emission computed tomography and image registration, also have dramatically improved the sensitivity and accuracy of tumor detection. Molecular engineering of immune constructs provides promise of enhanced tumor localization properties and reduced immunogenicity, allowing repeated studies to be performed. The role of radioimmunodetection in the evaluation of cancer patients will increase in importance in the future.

Adult↗
PubMed1994

Reovirus exists in the form of 13 particle species that differ in their content of protein sigma 1.

When electrophoresed in 0.7% agarose gels, populations of reovirus particles can be resolved into 13 well-defined bands that possess from 0 to 12 projection/spike-associated trimers of protein sigma 1. This state of affairs is not an artifact of purification, of the techniques used to demonstrate it, of aggregation, or of virus particle instability. Complexes of monoclonal antibody against protein sigma 1 with virus particles that possess only 1, or, to a lesser extent, 2 sigma 1 trimers are less stable (that is, more readily dissociated by sonication) than complexes of antibody and virus particles that possess 3 or more sigma 1 trimers. The specific infectivity of virus particles that possess 3 or more sigma 1 trimers is essentially the same; virus particles that possess only 2 sigma 1 trimers are about two-thirds as infectious; and particles that possess only 1 sigma 1 trimer still possess very significant infectivity (about one-third of maximum). Reovirus particles that possess no sigma 1 trimers (about 1 in 30) are essentially noninfectious. The reason reovirus particles do not possess a full complement of sigma 1 trimers is presumably the fact that only very small amounts of protein sigma 1 are synthesized in infected cells; and since possession of 3 such trimers is sufficient for maximal infectivity, and since the average number of sigma 1 trimers per reovirus particle is 7.1, there is presumably no selection for variants that synthesize larger amounts of sigma 1. On the contrary, such variants may well be at a selective disadvantage.

Capsid Proteins↗
PubMed1994

The value of thallium and three-phase bone scans in the evaluation of bone and soft tissue sarcomas.

Thirty-seven patients with newly diagnosed or treated sarcomas had 47 sets of sequential thallium scans (TS) followed by three-phase bone scan (TPBS) on the same day. The diagnosis in all patients was verified by biopsy (n = 40) or long-term follow-up studies (n = 7). The sensitivity, specificity, and accuracy of TS and TPBS in detecting sarcomatous lesions was calculated: TS sensitivity was 88%, specificity 69%, and accuracy 83%; blood flow (BF) and blood pool (BP) sensitivity was 91%, specificity 54%, and accuracy 81%; delayed bone scan (DB) sensitivity was 88%, specificity 38%, and accuracy 74%. In 17 studies the flow and blood pool parts of the TPBS and TS demonstrated the soft tissue component of sarcomas, which would have been missed if only the delayed bone scan had been performed. The TS lesion to normal tissue ratio alone was not very helpful in differentiating sarcomas from benign conditions because some benign lesions are highly cellular and vascular while some malignant lesions, such as chondrosarcoma, have poor vascularity and a less cellular chondroid matrix. However, when the thallium ratio was correlated with similar ratios calculated from the BP image, it was found that if the TS lesion to normal tissue ratio exceeded the BP lesion to normal tissue ratio (12 patients), the specificity for detecting sarcomatous lesions was 100%. Nevertheless, the reverse was not true. The positive predictive value of this observation was 100% and the negative predictive value was 37%.

Adolescent↗
PubMed1994

Simultaneous gallium-67 citrate and technetium-99m sestamibi SPET in a case of myocardial lymphoma: comparison with echocardiography before and after chemotherapy.

A patient with diffuse large cell lymphoma involving the interventricular septum and the inferior ventricular wall was imaged with a simultaneous dual-isotope single-photon emission tomography (SPET) acquisition technique, using the radiotracers technetium-99m hexakis 2-methoxyisobutylisonitrile (sestamibi) and gallium-67 citrate, in conjunction with echocardiography, prior to and following the first course of chemotherapy. Simultaneous acquisition--with the advantage of displaying corresponding sets of SPET slices without any need for position correction--, supplemented by echocardiography, increased the accuracy of evaluation of the extent of disease and response to treatment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

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.

Clinical Trials as Topic↗
PubMed1994

Gallium-67-citrate imaging in nuclear oncology.

Gallium-67-citrate is one of the most useful radiopharmaceuticals to detect tumors, stage extent of the disease, monitor response to treatment and distinguish recurrent disease from post-treatment changes. Gallium is likewise very sensitive to detect and locate infections and inflammatory foci. This application is extremely important in the management of immunocompromised cancer patients. Image interpretation should be tempered with full knowledge of the patients clinical condition, anatomic alterations due to prior surgery and correct timing of image acquisition. Early imaging at 4-6 h is useful to detect gastrointestinal infections, whereas 24 h imaging is used to evaluate chest infections. Although gallium-67 is a non-specific agent, the identification of the etiology of the inflammation may be improved by adequate clinical and laboratory information as well as correlation with other imaging modalities such as sonography and computerized x-ray tomography (CT). High dose (10 mCi) gallium-67 single photon emission computed tomography (SPECT) imaging with image co-registration is important for accurate uptake localization.

Citrates↗
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

Antibody targeting in metastatic colon cancer: a phase I study of monoclonal antibody F19 against a cell-surface protein of reactive tumor stromal fibroblasts.

PURPOSE: To define the toxicity, imaging, and biodistribution characteristics of iodine 131-labeled monoclonal antibody F19 (131I-mAbF19). MAbF19 recognizes the fibroblast activation protein (FAP), a cell-surface glycoprotein not present in most normal tissues, but abundantly expressed by reactive stromal fibroblasts of epithelial cancers, including more than 95% of primary and metastatic colorectal carcinomas. PATIENTS AND METHODS: 131I-mAbF19 was administered intravenously to 17 patients with hepatic metastases from colorectal carcinoma who were scheduled for resection of localized metastases or insertion of hepatic artery catheter for regional chemotherapy. Seven to 8 days before surgery, patients received 131I-mAbF19 at three dose levels, with at least four patients entered at each level. RESULTS: No toxicity associated with intravenous 131I-mAbF19 administration was observed. Tumor images were obtained on planar and single-photon emission tomography (SPECT) scans in 15 of 17 patients with hepatic metastases, tumor-infiltrated portal lymph nodes, and/or recurrent pelvic disease. The smallest lesion visualized was 1 cm in diameter. The optimal time for tumor imaging was 3 to 5 days after 131I-mAbF19 administration. The use of image registration techniques allowed precise anatomic localization of 131I-mAbF19 accumulation. Immunohistochemical analysis of biopsy tissues showed expression of FAP in the tumor stroma (but not in normal liver) in all patients studied and confirmed that the FAP-positive tumor stromal fibroblasts were interposed between the tumor capillaries and the malignant colon epithelial cells. At the time of surgery, tumor-to-liver ratios up to 21:1 and tumor-to-serum ratios up to 9:1 were obtained. The fraction of the injected 131I-mAbF19 dose per gram tumor (%ID/g tumor) localized to hepatic metastases at the time of surgery ranged from 0.001% to 0.016%. CONCLUSION: The FAP tumor fibroblast antigen is highly expressed in primary and metastatic colorectal carcinomas and shows limited expression in normal adult tissues. This highly selective expression pattern allows imaging of colorectal carcinoma lesions as small as 1 cm in diameter on 131I-mAbF19 scans. Because of the consistent presence of FAP in the stroma of epithelial cancers and the accessibility of FAP-positive tumor stromal fibroblasts to circulating monoclonal antibodies (mAbs), this study suggests possible diagnostic and therapeutic applications of humanized mAbF19 and mAbF19 constructs with novel immune and nonimmune effector functions.

Aged↗
PubMed1994

Phase I/II study of iodine 131-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 131-labeled monoclonal antibody (mAb) A33 (131I-mAb A33) administered intravenously, its limiting organ toxicity, and its radioisotope retention in tumors, and to develop preliminary evidence of antitumor activity. PATIENTS AND METHODS: Patients (N = 23) with colorectal cancer who had failed to respond to conventional chemotherapy but had not received prior radiotherapy were treated with escalating doses of 131I-mAb A33. Three or more patients were entered at each dose level, starting at 30 mCi/m2, with increments of 15 mCi/m2 to a maximal dose of 90 mCi/m2. Radiolabeling was performed to maintain a specific activity of 30 mCi/m2/4 mg mAb A33 (projected maximum, 15 mCi/mg). Patients were under strict isolation precautions until whole-body radiation levels decreased to less than 5 mrem/h at 1 m. Serial radioimmunoscintigrams were performed in some cases for up to 3 weeks after 131I-mAb A33 administration. RESULTS: All 20 patients with radiologic evidence of disease showed localization of radioisotope to sites of disease. Two patients with elevated carcinoembryonic antigen (CEA) levels and negative radiologic tests did not have positive antibody scans. One patient with a small-bowel cancer also had a negative antibody scan. The major toxicity was hematologic and was more pronounced in patients with compromised bone marrow due to prior chemotherapy. Of five patients who received 78 to 84 mCi/m2 131I-mAb A33, one had grade 3 and one grade 4 toxicity; of six patients treated with 86 to 94 mCi/m2 131I-mAb A33, two had grade 4 and one grade 1 toxicity. The MTD was determined to be 75 mCi/m2 in these heavily pretreated patients. Although the isotope showed variable uptake in the normal bowel, gastrointestinal symptoms were mild (n = 8) or absent. No major responses were observed; however, three patients had evidence of mixed responses, and CEA levels decreased in two patients without clinical or radiologic measurable disease. Immunoreactivity of radiolabeled mAb A33 decreased at the highest dose levels in preparations in which specific activity exceeded 18 mCi/mg. CONCLUSION: The A33 antigen appears to be a promising target for radioimmunotherapy of colon cancer. The modest antitumor activity of 131I-mAb A33 in heavily pretreated patients is encouraging because of its lack of toxicity in the bowel, the only antigen-positive normal tissue.

Adult↗
PubMed1994

Preselection of patients with high TAG-72 antigen expression leads to targeting of 94% of known metastatic tumor sites with monoclonal antibody I-131-CC49.

We studied 18 consecutive patients with advanced colorectal cancer where primary tumors were preselected for high expression of TAG-72 antigen and who underwent a phase I radioimmunotherapy trial with an intravenously administered monoclonal antibody CC49, 20 mg, labeled with I-131 in amounts varying from 15 mCi/m2 to 75 mCi/m2. Whole-body images and SPECT of the abdomen obtained 1 week after infusion were compared with pretreatment CT scans. A total of 66 lesions were evaluated. SPECT revealed 2/66 lesions (3%) that were not detected by CT; 4/66 were only detected by CT: lungs (1.8 cm and < 1 cm), axilla (1.5 cm), adrenal (2.5 cm). Thus, based on immunohistopathological testing in paraffin-embedded tissue blocks of primary tumors stained for TAG-72 antigen, we have selected a subset of patients (about 70% of referrals) with colorectal cancer for whom I-131-CC49 was shown to target to 62/64 CT positive lesions (97%) and 62/66 (94%) of all known positive lesions. We conclude that in patients with significant TAG-72 tumor expression there is excellent targeting of I-131-CC49 in therapeutic doses to colorectal cancer with respect to lesions detected with CT scanning. It should be noted that this study was not designed as a comparison of the sensitivity of CT versus I-131-CC49 SPECT/planar imaging. Instead, the observed results are consistent with a biological hypothesis that in general, the primary tumor histology vis-à-vis TAG-72 expression reflects the TAG-72 expression of the metastatic sites.

Aged↗
PubMed1994

Flare on bone scintigraphy following Taxol chemotherapy for metastatic breast cancer.

UNLABELLED: Our goal was to determine if a healing flare response seen on bone scintigraphy occurs following chemotherapy with Taxol (paclitaxel; Bristol-Myers Squibb Co., Princeton, NJ), a novel antimicrotubule agent for metastatic breast cancer. METHODS: We performed 74 bone scans on 21 females with breast cancer and bone metastases entering a Phase II trial of Taxol chemotherapy with granulocyte colony stimulating factor (G-CSF). All patients had baseline scans within 6 wk prior to therapy, after the second cycle (4-6 wk) of Taxol, and then after 6-12 mo. All bone scans were reviewed by two nuclear medicine physicians, without knowledge of the patients' clinical history. Skeletal radiographs, CT and MRI scans, as well as clinical history were compared with scan findings. RESULTS: Seven of the 21 patients showed improvement in bone scan findings. Of these seven, three had a flare response following two cycles (4-6 wk) of Taxol, characterized by increased activity in baseline lesions and the appearance of new lesions, followed by improvement on follow-up scans. Evidence of clinical response (> or = 50% reduction in tumor mass) was seen in all of these patients. Seven patients showed no change in baseline findings on follow-up bone scans. Seven patients had post-Taxol scans showing new lesions, with no overall improvement on later follow-up. CONCLUSION: Flare on bone scintigraphy may be seen shortly after commencing Taxol chemotherapy. Bone scans done within the first 3 mo must be interpreted with caution and should be correlated with clinical and radiological findings to avoid inappropriate discontinuation of Taxol chemotherapy.

Adenocarcinoma↗