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Biomedical subjects

J L Klein

Publications and source records attributed to J L Klein.

At least 109 records · Page 6Linked to original sources
PubMed1987

Hepatoma: model for radiolabeled antibody in cancer treatment.

Hepatocellular cancer, due to its size and location, allows tumor volume reconstruction and dosimetric determination when radiolabeled antibodies are administered during therapy. Factors identified in the treatment of this cancer may have general applicability for the radiolabeled antibody treatment of other malignancies. These factors include antibody preparations, labeling levels, and toxic effects. New findings regarding tumor volume saturation and altered tumor vascular permeability following radiation have important implications and should be investigated in other tumor systems. Another important development is the use of a new radiolabel, 90Y, in cyclic therapy, which is the sequential use of antibodies derived from different species. This therapy has increased the radiation dose to the tumor.

Antibodies↗
PubMed1986

The role of steroid metabolic profiling as an aid in the diagnosis of familial precocious puberty, a subgroup of true precocious puberty.

We report the results of a study of a rare form of true precocious puberty in a family with a history of the condition. Only the male members manifest the trait, whereas it appears to be carried by both males and females. Routine urinary steroid analysis rapidly eliminated most of the classical enzyme defects associated with premature sexual maturation. Further investigation of urinary steroid extracts using gas chromatography and gas chromatography-mass spectrometry revealed essentially normal prepubertal androgen values for the proband A at 4 years of age, and for his affected and carrier relatives when compared with healthy age-matched individuals. While his plasma gonadotropin levels were in the prepubertal range, his plasma testosterone value was significantly elevated with values just below the normal range for an adult male. This is the fourteenth reported family with a vertical pattern of familial sexual precocity, but the first to have a steroid profile. Analysis suggests sex-limited autosomal dominance with a greater than 90% penetrance. The elevated plasma testosterone concentration, prepubertal plasma gonadotropin concentration, minimal histopathologic evidence of gametogenesis and only moderate increase in testicular volume over the five-year course of follow-up support a diagnosis of the recently described condition of familial gonadotropin independent sexual precocity. The gas chromatography-mass spectrometry urinary profiling shows elevated cortisol output but otherwise normal adrenal function.

17-Hydroxycorticosteroids↗
PubMed1986

Myocardial perfusion changes following 1 year of exercise training assessed by thallium-201 circumferential count profiles.

The effect of exercise training on myocardial perfusion was assessed using initial and 1-year thallium-201 (Tl-201) exercise studies in 56 patients with stable coronary artery disease (CAD). Subjects had been randomized into a trained group participating in supervised exercise three times per week and a control group. Indices (non-dimensional units) based on computer-analyzed circumferential count profile from nine regions of the heart, assessed in three projections, were used to eliminate observer bias and more accurately quantitate Tl-201 distribution and 4-hour washout. There was serial improvement of the global distribution count profiles in 21 of 27 (77.8%) of the trained and in 9 of 29 (31.0%) of the control subjects (p less than 0.001). The mean interval change in global initial distribution over the year period was 5 +/- 13 (mean +/- SD) in the trained and -6 +/- 14 in the control groups (p less than 0.003). The mean initial distribution of the trained group had improvement in all nine regions (significant in three), while the control group showed mean improvement in only one of nine regions. Additionally, the trained group showed improvement in the mean washout in five of nine regions (significant in three), while no mean regional washout improvement occurred in the control group. Thus, in this group of patients with stable CAD, exercise training resulted in apparently improved cardiac perfusion evidenced by enhance Tl-201 uptake and washout.

Coronary Circulation↗
PubMed1986

90Yttrium antiferritin--a new therapeutic radiolabeled antibody.

A new radiolabel 90Yttrium has been chelated to antiferritin antibodies for the treatment of hepatocellular cancer. The isotope 90Yttrium has the advantage of no significant external radiation to other individuals, that is, outpatient therapy and potentially more therapeutic power with an increase from 0.3 Mev 131I beta radiation to 0.9 Mev 90Yttrium pure beta radiation. Six patients treated in the Phase I study have had modest hematologic toxicity and two have had partial remissions of their primary tumors. One of these patients has had complete remission of a pulmonary metastasis. The use of external radiation (900 rad) to the primary tumor in advance of radiolabeled antibody administration has increased antibody uptake and increased tumor dose rate and total dose. An extensive study of 90Yttrium antiferritin is planned.

Antibodies↗
PubMed1986

Detection of specific anti-antibodies in patients treated with radiolabeled antibody.

Over 100 patients have received cyclic treatment with polyclonal 131I labeled anti-ferritin and anti-carcinoembryonic antigen (CEA) antibodies from different animal species (rabbit, pig, cynomolgous monkey, bovine, and baboon). Because survival was prolonged from original cyclic treatment, retreatment with original antibodies (recycling) became a necessary consideration. An assay using autoradiography of Ouchterlony gels, with diffusion of patients' sera against the varied radiolabeled antibodies, was developed to detect anti-antibody precipitin bands. Anti-antibody could be detected with a sensitivity to the 60 ng level. Sera from 35 patients given from 1 to 7 separate cycles (2 injections/week, total antibody 6 mg/cycle) of radiolabeled foreign antibody were studied for the production of anti-antibodies. Anti-antibodies were detected in 11 of 22 primary hepatoma patients studied, 3 of 4 intrahepatic biliary cancer patients, and 0 of 9 Hodgkin's disease patients. In all but two of the patients, the anti-antibodies produced were specific for the species used in the treatment of the patient. Eight patients were reinjected (recycled) with previously used antibodies and the presence or absence of precipitin bands correlated with the ability of these antibodies to deposit in the tumor or to be rapidly degraded. The importance of this assay is its simplicity, sensitivity, and the rapid detection of anti-antibody activity for patients requiring treatment with radiolabeled antibodies.

Antibodies, Anti-Idiotypic↗
PubMed1986

Ferritin concentration and 131I-antiferritin tumor localization in an experimental hepatoma.

Polyclonal 131I-labeled rabbit anti-rat ferritin was shown to specifically localize in the H4IIe rat hepatoma model. Tumor targeting was shown to be maximal in primary tumors or metastatic lesions less than 1 gram. Radiolabeled antiferritin tumor targeting decreased with increasing tumor size. In this study, ferritin levels were measured in H4IIe tumors grown both in vitro and in vivo. In vitro tumor cells synthesized and secreted ferritin into the medium as measured by radioimmunoassay, and confirmed by the incorporation of 14C-leucine into ferritin synthesis. The concentration of ferritin in the tumor cells as measured by radioimmunoassay remained relatively constant over this same time period. In vivo tumor ferritin levels in whole tumor extracts were highest in small tumors (less than 1 gram) and decreased as the tumors became larger. Serum ferritin levels of tumor-bearing animals paralleled the level in the tumors themselves. The elevated serum ferritin levels in animals with small tumors did not inhibit tumor targeting with radiolabeled antiferritin antibody. These findings are a foundation for understanding the selective tumor targeting of tumor associated proteins by radiolabeled antibodies, which includes factors such as tumor size, vascularity, antigen content, and circulating antigen.

Animals↗
PubMed1986

Limitations of indium-111 leukocyte scanning in febrile renal transplant patients.

Indium-111-labeled leukocyte scanning was evaluated as a technique for investigating possible abscess as the cause of fever in 10 renal allograft recipients under therapy for rejection, acute tubular necrosis, or urinary infection. The usefulness of the method in this setting was found to be limited by marked nonspecificity of renal, pulmonary, and other focal leukocyte accumulation. Although wound infections were correctly identified, false-positive scans resulted in multiple nonproductive consultations and radiologic procedures (some invasive) and contributed to the decision to perform one negative exploratory laparotomy. Such generalized nonspecificity in this patient population is in distinct contrast to the experience with this diagnostic test in nontransplant patients, and has not previously been reported. Possible explanations and implications of these findings are discussed. Consequently, great caution is recommended in the use of indium-111 leukocyte scans to diagnose infection in febrile renal transplant patients who present in a similar clinical setting.

Adolescent↗
PubMed1985

A model system that predicts effective half-life for radiolabeled antibody therapy.

Radiolabeled antibodies to tumor associated proteins localize in both experimental and clinical cancers. In the therapeutic applications of radiolabeled antibody, tumor effective half-life (composite of biological and physical half-lives), along with the concentration of isotope deposited and energies of the isotope used, determine the tumor dose. Antibodies directed against the same antigenic specificity but derived from different species have varied tumor and whole body effective half-lives and as a result, achieve different tumor doses. In vitro testing does not evaluate the in vivo differences in effective half-life that affect tumor dose. We have developed an animal model to evaluate the effective half-life and biodistribution of radiolabeled immunoglobulin (IgG) from diverse species. To determine the relevance of such a model, the effective half-lives and tissue distributions of the different immunoglobulins in the model were compared to those obtained from the clinical program using the same radiolabeled antibody preparations. In both the experimental model and in the clinical trials, radiolabeled immunospecific and normal IgG derived from monkey, rabbit, and porcine sources had the longest effective half-lives, goat and sheep had intermediate effective half-lives, and chicken and turkey had the shortest effective half-lives. Prescreening of bovine and baboon normal IgG predict long half-lives and similar organ distributions. These species have been immunized for clinical use. Bovine IgG has a long clinical half-life and has been added to our other successful antibodies. Baboon IgG is now ready for clinical testing. The value of this model system is that it appears to be an effective in vivo preclinical screen for tumor effective half-life of antibodies and IgG from diverse species, thus guiding potential clinical use.

Animals↗
PubMed1985

Factors that affect antiferritin localization in four rat hepatoma models.

The effect of tumor size, vascularity, ferritin content and the amount of injected 131I-antiferritin on tumor localization was studied in four hepatoma models with varying growth rates, histology, vascularity, and ferritin content. Separate groups of 12 animals with the H-4-II-E, 7800, 7777, and 3924A rat hepatomas with less than 2 g or greater than 2 g tumors were injected with escalating doses of 131I-antiferritin or 131I nonspecific IgG (control). Tumor vascularity was measured by 51Cr-labeled erythrocyte injection, ferritin content of tumors by radioimmunoassay and immunoperoxidase staining, and the histological location of 131I-antiferritin by autoradiography. 131I-antiferritin specifically localized in the H-4-II-E and 7800 models and correlated with the tumor size, vascular content, and amount of injected antiferritin. No localization took place in the 7777 or 3924A tumors despite the presence of ferritin in these models. The only factor that correlated with localization in the models was vascularity. The vascularity of 3924A and 7777 tumors was significantly reduced in comparison to the H-4-II-E and 7800 tumors. The dependence of targeting on vascularity was demonstrated with autoradiography as well. These findings indicate the correlation of vascularity and tumor localization with 131I-antiferritin.

Animals↗
PubMed1985

The effect of iron dextran on ferritin content and 131I-antiferritin localization in experimental hepatomas.

Polyclonal 131I rabbit antirat ferritin localizes in certain hepatoma models. The effect of intraperitoneal iron dextran on tumor and sera ferritin content and tumor and normal tissue localization with 131I antiferritin was studied. Separate groups of 10-12 animals were injected with escalating doses of 131I-antiferritin IgG, or nonspecific IgG, one week after injection with iron dextran or normal saline. The results demonstrate that tumor, serum, and normal tissue ferritin content was increased after iron dextran administration but tumor localization increased after administration of 131I-antiferritin in the H4II-E and 7800 models. The 3924A and 7777 models showed no tumor localization with or without iron dextran but did show an increase in normal tissue localization after iron dextran. Immunoperoxidase staining of tissues with antiferritin revealed increased staining in the liver and spleen and only a slight increase in the tumors after iron dextran was administered. The results demonstrate that tumor localization is a complex phenomenon that depends on normal tissue, sera, and tumor-antigen distribution.

Animals↗
PubMed1985

Computed tomography assisted volumetric analysis of primary liver tumor as a measure of response to therapy.

Serial computed tomography assisted volumetric analyses were made in 33 patients with hepatoma. Thirteen of 27 patients with tumor volumes less than 2,290 cc had a partial response to experimental therapy. However, only three of these patients also demonstrated a significant change in liver volume. Tumor volume determinations made by the method described are an accurate (+/- 10%) and reproducible way to measure response to therapy. In spite of small changes in total liver volume, there may be concomitantly substantial changes in tumor volume.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1985

Iodine 131 antiferritin, a new treatment modality in hepatoma: a Radiation Therapy Oncology Group study.

One hundred five patients with hepatoma were treated with iodine 131 antiferritin in three sequential protocols in phase 1-2 trials. Therapy began in all trials with external beam irradiation and chemotherapy. The dosimetric results with 131I antiferritin indicated that 30 mCi (8 to 10 mCi/mg immunoglobulin G [IgG]) was sufficient to saturate the tumor. Tumor-effective half-life of the radioactive antibody was 3 to 5 days and was dependent on the species of animal from which the antibody was derived. This led to a 30 mCi on day 0 and 20 mCi on day 5 treatment schedule. Toxicity was predominantly thrombocytopenia. Due to clinical remission, cyclic therapy was next developed with antibodies from different species of animals. Rabbit, pig, monkey, and bovine antibodies were determined to produce the longest tumor-effective half-life and therefore the highest dose of radiation. Integration of 15 mg doxorubicin and 500 mg 5-fluorouracil (5-FU) with 131I antiferritin was accomplished next. Remission to external beam radiation was evaluated by computed tomography (CT) scan tumor volume computations that indicated that 22% of the patients had a partial remission (PR) from initial presentation to 1 month following external irradiation and chemotherapy. From the time of radioactive antibody administration, 48% of the patients (7% complete response [CR] and 41% PR) achieved remission to 131I antiferritin. Of 79 patients evaluated by CT scan tumor volumetrics 50% of the patients (7% CR and 43% PR) remitted to the entire treatment regimen. Patients not previously treated and without metastasis who were alpha fetoprotein positive (AFP+) had a 5-month median survival compared with AFP- median survival of 10 1/2 months. There were four CRs with one being 3 years and 6 months. The longest PR was 5 years and 8 months. These studies have demonstrated the toxicity and therapeutic activity of 131I antiferritin and the emerging role of radiolabelled antibody in cancer therapy.

Adolescent↗
PubMed1985

Gallium-67 uptake by hepatoma: studies in cell cultures, perfused livers, and intact rats.

In this investigation, the effect of transferrin on 67Ga uptake by rat hepatoma was studied at three levels: at the level of individual tumor cells in culture; at the level of isolated, perfused livers with implanted intrahepatic tumors; and in intact animals bearing intrahepatic tumors. This approach was possible using H-4-II-E hepatoma cells which grew into discrete tumors when implanted intrahepatically. Transferrin at low concentrations (0.05-0.5 mg/ml) stimulated, while at a higher concentration (1.0 mg/ml) it inhibited 67Ga uptake by tumor cells in culture. In contrast, in isolated, perfused livers with intrahepatic tumors, transferrin at concentration levels of 0.05 and 0.1 mg/ml had no effect, while at 0.25-1.0 mg/ml transferrin inhibited 67Ga uptake by intact tumors. Administration of transferrin which markedly enhanced the serum unsaturated iron binding capacity, had no effect on 67Ga accumulation in the intrahepatic tumors in vivo. These results indicate that, although transferrin at low concentration promotes the uptake of 67Ga by individual tumor cells in culture, it does not do so in intact tumors in isolated rat liver preparations or in tumor bearing rats. We conclude that the mechanism of 67Ga uptake by intact tumors is different from that of tumor cells growing in culture.

Animals↗
PubMed1984

Distribution of and physiologic factors that affect 131I-antiferritin tumor localization in experimental hepatoma.

Polyclonal 131I rabbit anti-rat ferritin localizes in the H-4-II-E hepatoma model. The effect of tumor size, vascularity, and ferritin content on tumor localization was examined. The extravascular and intravascular quantity and location of 131I non-specific IgG and 131I-antiferritin IgG in tumors were determined by gamma counter analysis of tissue samples and autoradiography. Separate groups of 8-10 tumor bearing rats with 0.6-1 g, 1-3 g, 4-8 g, 8-14 g, and greater than 14 g tumors were injected with 500 microCi (200 micrograms) of 131I non-specific IgG or 131I-antiferritin. Tumor targeting with antiferritin occurred maximally in primary or metastatic lesions less than 1 g in size. Decreased localization occurred with increasing tumor size and no localization took place in tumors greater than 8 g in size. This finding is independent of administered dose because increasing the amount of injected antiferritin from 2- to 10-fold did not increase the antiferritin/normal IgG targeting ratio in any group of tumors greater than 4 g. The quantity and physical characteristics of the tumor vasculature may in part explain selective tumor localization. Tumor vascularity per gram as measured by 51Cr labeled erythrocytes decreased as tumor size increased. Decreased localization was evident in the necrotic portions of large tumors. Autoradiography of tumor sections revealed that most of the 125I-IgG activity is deposited perivascularly with decreased deposition of antibody in necrotic areas of tumors and at increasing distance from the lumen of vessels. These findings have clinical importance since this non-homogeneous distribution of antibody could result in the delivery of low doses of radiation to large necrotic areas of tumors. These results help to demonstrate some of the complex physiologic factors that affect tumor localization and antibody distribution.

Animals↗
PubMed1984

Comparative tumor dose from 131I-labeled polyclonal anti-ferritin, anti-AFP, and anti-CEA in primary liver cancers.

Results of dosimetric studies are reported for 30 patients with hepatoma and 5 patients with primary hepatic cholangiocarcinoma who received treatment with 131I-labeled polyclonal antibodies. Studies included liver and tumor volume computations from X-ray CT scans, in vivo quantitation of the activity of radiolabeled antibodies in hepatic tumors and normal liver tissue, and effective half-life measurements. Twenty-two patients with hepatoma were administered 131I-labeled polyclonal anti-ferritin. Five hepatoma patients, who were AFP-positive, were administered anti-alpha-fetoprotein (AFP). Three patients with AFP-positive hepatomas received both 131I-labeled anti-ferritin and anti-AFP in a bolus. The five cholangiocarcinoma patients were treated with 131I-labeled anti-carcinoembryonic antigen (CEA). For administered activities of 30 mCi on day 0 and 20 mCi on day 5, mean values of the radiation dose to hepatomas were approximately 1100 rads for anti-ferritin, 350 rads for anti-AFP, and 960 rads for the combination of anti-ferritin and anti-AFP. Polyclonal anti-ferritin has, therefore, become the antibody of choice in the treatment of hepatoma. The radiation dose to cholangiocarcinomas from 131I-labeled anti-CEA and administered activities of 20 mCi on day 0 and 10 mCi on day 5 was approximately 620 rads. Total-body irradiation for these injection schedules ranged from 30 to 50 rads.

Adenoma, Bile Duct↗
PubMed1984

Variables affecting the tumor localization of 131I-antiferritin in experimental hepatoma.

Ferritin is both a normal tissue- and tumor-associated protein. The in vivo localization of 131I-radiolabeled antitumor ferritin and normal IgG antibodies in the H-4-II-E rat hepatoma model was investigated in both tumor and normal tissues over a dose range of 0.67 micrograms to 5 mg of normal and antiferritin IgG and at labeling ratios (microCi 131I per micrograms IgG) of 15:1, 5:1, and 1:10. The total dose from nonpenetrating radiation in rads was calculated and demonstrated a maximum of 2.9 times greater dose deposition (rads) of antiferritin than normal IgG in hepatoma without specific increase in binding in normal tissues. The maximum tumor targeting achieved was dependent on the amount of injected IgG and not on the labeling ratio or procedure. The binding in tumor could be inhibited by unlabeled antiferritin but not by unlabeled normal rabbit IgG and demonstrated the requirement of specificity for tumor binding. Normal tissues did not target with antiferritin. Most normal tissues have a capacity to bind normal and antiferritin IgG nonspecifically that is linear in relationship to the amount of injected IgG. The results demonstrate that 131I-antiferritin selectively targets ferritin-secreting hepatoma over normal tissues and that the amount of targeting is dependent on the amount of antiferritin injected. The physiologic reasons for such selective localization is not known, but the term "biologic window" has been used to describe the differential availability of tumor ferritin for binding.

Animals↗
PubMed1983

Selective tumor localization in experimental hepatoma by radiolabeled antiferritin antibody.

The in vivo localization of 131I-radiolabeled antiferritin and normal IgG in the H-4-II-E rat hepatoma model was investigated by serial necropsy. Groups of 14 to 18 animals were injected with 500 microCi (200 micrograms) of normal and antiferritin IgG. The total dose from the nonpenetrating beta radiation was calculated for tumor and normal tissue, and expressed as a targeting ratio of antiferritin to normal IgG for each organ studied. The results demonstrate 2.9 times greater dose deposition in tumors of animals treated with 131I-antiferritin than with 131I-normal IgG. 131I-antiferritin deposited equivalently in primary tumors and metastatic lesions of similar size. The specific binding in tumors could be competitively inhibited by the addition of unlabeled antiferritin but not unlabeled normal IgG. Specific targeting with 131I-antiferritin comparison to 131I-normal IgG did not occur in any normal tissue. There was considerable variation in the dose deposition in different normal tissues.

Animals↗