Imaging organic and mineral phases in a biomineral using novel contrast techniques.

Chitons are marine molluscs that mineralize their teeth by the process of matrix-mediated biomineralization. The teeth develop in a continuous manner forming hard minerals, including magnetite, making analysis of the matrix within these mineralized regions difficult. This article describes the use of charge contrast imaging techniques, rarely applied to biological samples, to simultaneously image the organic and mineral phases within the teeth of these animals. Resulting evidence demonstrates the power of this technique in delivering architectural information concerning both the matrix and mineral phases, without the need for removal of the hard mineralized material.

Intraperitoneal radioimmunochemotherapy of ovarian cancer: a phase I study.

A phase I trial was designed to examine the feasibility of combining interferon and Taxol with intraperitoneal radioimmunotherapy (177Lu-CC49). Patients with recurrent or persistent ovarian cancer confined to the abdominal cavity after first line therapy, Karnofsky performance status > 60, adequate liver, renal and hematologic function, and tumor that reacted with CC49 antibody were enrolled. Human recombinant alpha interferon (IFN) was administered as 4 subcutaneous injections of 3 x 10(6) U on alternate days beginning 5 days before RIT to increase the expression of the tumor-associated antigen, TAG-72. The addition of IFN increased hematologic toxicity such that the maximum tolerated dose (MTD) of the combination was 40 mCi/m2 compared to 177Lu-CC49 alone (45 mCi/m2). Taxol, which has radiosensitizing effects as well as antitumor activity against ovarian cancer, was given intraperitoneally (i.p.) 48 hrs before RIT. It was initiated at 25 mg/m2 and escalated at 25 mg/m2 increments to 100 mg/m2. Subsequent groups of patients were treated with IFN + 100 mg/m2 Taxol + escalating doses of 177Lu-CC49. Three or more patients were treated in each dose group and 34 patients were treated with the 3-agent combination. Therapy was well tolerated with the expected reversible hematologic toxicity. The MTD for 177Lu-CC49 was 40 mCi/m2 when given with IFN + 100 mg/m2 Taxol. Interferon increased the effective whole body half-time of radioactivity and the whole body radiation dose. Taxol did not have a significant effect on pharmacokinetic or dosimetry parameters. Four of 17 patients with CT measurable disease had a partial response (PR) and 4 of 27 patients with non-measurable disease have progression-free intervals of 18+, 21+, 21+, and 37+ months. The combination of intraperitoneal Taxol chemotherapy (100 mg/m2) with RIT using 177Lu-CC49 and interferon was well tolerated, with bone marrow suppression as the dose-limiting toxicity.

Both GABA(B) receptor agonist and antagonists decreased brain stimulation reward in the rat.

The present experiments were designed to determine the role of GABA(B) receptor function on brain stimulation reward. Using a discrete-trial current-intensity threshold procedure, dose-effect functions were generated for the GABA(B) receptor agonist CGP 44532 (0-1.0 mg/kg, s.c.) and the GABA(B) receptor antagonists CGP 56433A (0-10.0 mg/kg, s.c.) and CGP 51176 (0-300.0 mg/kg, s.c.) on brain reward thresholds in rats. The GABA(B) receptor antagonists CGP 56433A and CGP 51176 were used also to examine interaction effects with the GABA(B) receptor agonist CGP 44532 on reward thresholds. Administration of the highest doses of both the GABA(B) receptor agonist and antagonists elevated reward thresholds. Thus, both the agonist and antagonists used induced a reward decrement when administered separately. In addition, the co-administration of either of the two receptor antagonists with the agonist induced an additive effect on thresholds, rather than blocking the agonist-induced threshold elevations. These results suggest that activation of GABA(B) receptors modulates intracranial self-stimulation behavior in a complex fashion, possibly through differential effects of GABA(B) agonists and antagonists on pre- and post-synaptic GABA(B) receptors.

Real-time monitoring and verification of in vivo high dose rate brachytherapy using a pinhole camera.

We investigated a pinhole imaging system for independent in vivo monitoring and verification of high dose rate (HDR) brachytherapy treatment. The system consists of a high-resolution pinhole collimator, an x-ray fluoroscope, and a standard radiographic screen-film combination. Autofluoroscopy provides real-time images of the in vivo Ir-192 HDR source for monitoring the source location and movement, whereas autoradiography generates a permanent record of source positions on film. Dual-pinhole autoradiographs render stereo-shifted source images that can be used to reconstruct the source dwell positions in three dimensions. The dynamic range and spatial resolution of the system were studied with a polystyrene phantom using a range of source strengths and dwell times. For the range of source activity used in HDR brachytherapy, a 0.5 mm diameter pinhole produced sharp fluoroscopic images of the source within the dynamic range of the fluoroscope. With a source-to-film distance of 35 cm and a 400 speed screen-film combination, the same pinhole yielded well recognizable images of a 281.2 GBq (7.60 Ci) Ir-192 source for dwell times in the typical clinical range of 2 to 400 s. This 0.5 mm diameter pinhole could clearly resolve source positions separated by lateral displacements as small as 1 mm. Using a simple reconstruction algorithm, dwell positions in a phantom were derived from stereo-shifted dual-pinhole images and compared to the known positions. The agreement was better than 1 mm. A preliminary study of a patient undergoing HDR treatment for cervical cancer suggests that the imaging method is clinically feasible. Based on these studies we believe that the pinhole imaging method is capable of providing independent and reliable real-time monitoring and verification for HDR brachytherapy.

The new iron age.

In the last four years there has been a major change in the approach to diagnosis of the iron overload disorder hereditary haemochromatosis (HH) following the discovery of the gene that is mutated in HH called HFE. In the first part of this review we will give a concise overview of the disease. Also the current literature on the role of HFE in iron absorption and transport at a molecular level and how mutations in HFE may lead to the break down in the regulation of iron homeostasis is reviewed. The second part of the review focuses on the molecular aspects of iron storage. Different chemical forms of storage iron deposits such as ferrihydrite and geotite are present in the iron storage proteins ferritin and haemosiderin. The type of iron storage deposits is thought to be an important factor in determining the degree of iron toxicity and tissue damage in patients with iron overload. Variations in the form of iron deposits in different types of iron overload disease e.g. HH or beta-thalessemia, the site of iron deposition and the clinical treatment used will be discussed.

CRF and urocortin decreased brain stimulation reward in the rat: reversal by a CRF receptor antagonist.

The present studies were designed to investigate the effects of corticotropin-releasing factor (CRF) receptor activation and antagonism on intracranial self-stimulation (ICSS) reward using a discrete-trial current-intensity threshold procedure. Bipolar electrodes were implanted in the lateral hypothalamus, and cannula guides were implanted above the lateral ventricle of male Wistar rats. Dose-effect functions were established for the effects on ICSS of the competitive CRF receptor agonist h/rCRF (0-5.0 microg, i.c.v. ), the CRF receptor agonist urocortin (0-5.0 microg, i.c.v.), and the CRF receptor antagonist [D-Phe(12), Nle(21,38), C(alpha) MeLeu(37)] h/rCRF(12-41) (0-5.0 microg, i.c.v.). Administration of h/rCRF or urocortin dose-dependently elevated ICSS thresholds without altering performance measures (latencies to respond to stimulation, extra and time-out responses). CRF was more potent than urocortin in terms of threshold dose-effects on ICSS thresholds compared to vehicle. Despite these apparent potency differences, percent effect sizes on ICSS thresholds were comparable at the highest doses of both peptides. In contrast to the significant threshold elevation effects of CRF and urocortin, the competitive CRF antagonist D-Phe CRF(12-41) had no effect on ICSS thresholds or performance measures. To determine the neuropharmacological specificity of the effect of CRF on brain stimulation reward, D-Phe CRF(12-41) was used to antagonize CRF-induced threshold elevations. Pretreatment with either the 5.0- or 10.0-microg doses of D-Phe CRF(12-41) effectively blocked CRF-induced reward threshold elevations (3.0 microg) without affecting other ICSS performance measures. These results indicate that CRF neurotransmission can modulate ICSS reward processes.

Apatite mineralization in teeth of the chiton Acanthopleura echinata.

Raman spectroscopy has been used to demonstrate, for the first time, that calcium mineralization in the core of the major lateral teeth of the chiton Acanthopleura echinata takes place as an ordered process, with crystalline carbonated apatite being the first mineral deposited. Deposition begins at the top of the tooth core, under the so-called tab region, progresses down the interior surface of the tab and lepidocrocite layer, and then extends outwards to the anterior surface. Mineralization is not initiated until the lepidocrocite layer has isolated the core of the tooth from the magnetite cap. The last region to be infiltrated is the anterior basal region of the tooth cusp, immediately above the junction zone. The junction zone is also a region of high ion density, as determined by energy dispersive spectroscopy (EDS) analysis, but we show here for the first time that it is free of mineral deposits, acting instead as a transfer and storage region.

A strategy to reduce red marrow dose for intraperitoneal radioimmunotherapy.

The aim of this study was to determine whether shorter-lived radionuclides can reduce red marrow (RM) toxicity for i.p. radioimmunotherapy (RIT). The potential radionuclides, which included Lu-177, I-131, Y-90, Re-186, Re-188, and Ho-166, were attached to antibody CC49. Each radiopharmaceutical was assumed to have identical in vivo pharmacokinetics. Blood and whole body retention data acquired from 26 patients who received i.p. RIT with Lu-177 CC49 were used as input. The average biological half-time of Lu-177 CC49 in the whole body was 280 h, and the average Lu-177 concentration in plasma increased to a maximum at 2 days postinfusion, followed by steady clearance. The residence time and RM doses were calculated for each radionuclide. In the current model, Re-188 was found to deliver the lowest RM dose, primarily because it had the shortest half-life, whereas Y-90 delivers the highest dose. Re-188 delivers 60% of the RM dose as compared with Lu-177 and can increase the dose to metastatic sites in the i.p. space by a similar factor. Based on limiting the RM dose to 200 cGy, the maximum administered activity of each radionuclide is as follows: (a) 106 mCi, Lu-177; (b) 58 mCi, I-131; (c) 34 mCi, Y-90; (d) 70 mCi, Re-186; (e) 169 mCi, Re-188; and (f) 110 mCi, Ho-166. Because of the delayed steady leakage of radiopharmaceuticals from the i.p. cavity to the plasma, short-lived radionuclides may offer special advantages for i.p. RIT.

Phase II study of interferon-enhanced 131I-labeled high affinity CC49 monoclonal antibody therapy in patients with metastatic prostate cancer.

Adjuvant Interferon (IFN) was given to increase tumor antigen expression and enhance localization with 131I-labeled CC49 radioimmunotherapy in a Phase II trial for hormone resistant metastatic prostate cancer. Patients received four doses of alpha-IFN (3 x 10(6) IU) s.c. on alternate days, from day -5 to day +1 of 75 mCi/m2 131I-CC49 treatment. Toxicity was well tolerated, with the majority of patients experiencing transient grade 3 or 4 neutropenia and/or thrombocytopenia (maximal at 4-6 weeks). The absorbed dose was >25 Gy in four of eight tumors visualized, which represents an increase of >20 fold over whole body radiation dose. Two patients had radiographic minor responses by 6 weeks post-therapy, whereas five of six patients experiencing pain had symptom relief without radiographic changes. The protocol provided modest antitumor effects (pain relief in five of six patients and two minor radiographic responses). This study suggests that the addition of IFN enhanced tumor uptake and antitumor effects as compared to a prior Phase II trial of 131I-CC49 alone.

Factors affecting 131I-Lym-1 pharmacokinetics and radiation dosimetry in patients with non-Hodgkin's lymphoma and chronic lymphocytic leukemia.

UNLABELLED: Lym-1, a monoclonal antibody that preferentially targets malignant lymphocytes, has induced therapeutic responses in patients with non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) when labeled with 131I. Responders had statistically significant prolongation of survival compared with nonresponders. The nonmyeloablative, maximum tolerated dose for each of two doses of 131I-Lym-1 was 3.7 GBq/m2 (total 7.4 GBq/m2 [100 mCi/m2, total 200 mCi/m2]) of body surface area. The purpose of this study was to determine the pharmacokinetics and radiation dosimetry for the initial 131I-Lym-1 therapy dose in patients with NHL and CLL and to compare tumor dosimetry with 131I-Lym-1 dosing and other patient parameters. METHODS: Fifty-one patients with stage 3 or 4 lymphoma were treated with 131I-Lym-1 (0.74-8.04 GBq [20-217 mCi]) in either a maximum tolerated dose (MTD) or low-dose (LD) trial. Total Lym-1 given to each patient was sufficient in all instances to exceed the threshold required for stable pharmacokinetics. Quantitative imaging and physical examination, including caliper and CT measurement of tumor size and analysis of blood, urine and feces, were performed for a period of 7 to 10 d after infusion to assess pharmacokinetics and radiation dosimetry. Clinical records were reviewed to obtain data required for comparative assessments. RESULTS: The concentration (%ID/g) and biologic half-time of 131-Lym-1 in tumor were about twice those in normal tissues, although tumor half-time was similar to that of the thyroid. Pharmacokinetics were similar for patients in the MTD and LD trials, and for NHL and CLL patients in the LD trial, except that the latter group had less tumor concentration of 131I. Mean tumor radiation dose per unit of administered 131I was 1.0 Gy/GBq (3.7 rad/mCi) for patients with NHL whether in MTD or LD trials, about nine times greater than that for body or marrow. Tumor radiation dose was less and liver radiation dose was more in patients with CLL. Otherwise, radiation dosimetry was, on average, remarkably similar among groups of patients and among individual patients. Pharmacokinetics and dosimetry did not appear to be influenced by the amount of 131I or Lym-1 within the ranges administered. Tumor concentration of 131I and radiation dose per gigabecquerel were inversely related to tumor size but did not seem to be related to histologic grade or type, tumor burden or therapeutic response. CONCLUSION: The therapeutic index of 131I-Lym-1 was favorable, although the index for patients with CLL was less than that for patients with NHL. Pharmacokinetics and radiation dosimetry were, on average, remarkably similar among patients and groups of patients in different trials.

Effects of prolonged iron loading in the rat using both parenteral and dietary routes.

Female Porton rats have been treated with either parenteral iron (intraperitoneal red cells) or dietary iron (carbonyl iron) for up to 12 months or 22 months respectively. In the parenteral iron loaded animals, the liver iron concentration rose from approximately 2 mg g-1 dry wt at 2 months to 21 mg g-1 dry wt at 12 months, while for the dietary iron loaded animals, this value rose from 14 to 48 mg g-1 dry wt at 12 months to over 60 mg g-1 dry wt after 22 months. In contrast, splenic iron concentrations rose more in the parenterally loaded animals (up to 66 mg g-1 dry wt after 12 months) than in the dietary loaded animals (approx. 34 mg g-1 dry wt after 24 months). This study yielded hepatic iron concentrations comparable to those seen in human thalassaemia patients with comparative low hepatotoxicity. Splenic iron concentrations in the parenteral iron loaded group generally exceeded those reported in thalassaemia. Iron concentrations derived from computer assisted morphometry of liver iron deposits correlated well (r = 0.88, p < 0.001) with chemical analysis data. The fraction of iron in the non-parenchymal cells correlated positively with the duration of iron loading (r = 0.86, p < 0.001).

The effect of prolonged iron loading on the chemical form of iron oxide deposits in rat liver and spleen.

Female Porton rats were loaded with iron either by supplementing the diet with 2.5% carbonyl iron for up to 22 months (18 rats) or by regularly injecting rat blood cells intraperitoneally for up to 10 months (eight rats). 57Fe Mössbauer spectroscopy of freeze-dried samples of liver and spleen was used to analyse the chemical forms of iron deposited in these tissues over the period of iron loading. A sextet signal in the Mössbauer spectra was identified as being due to a form of haemosiderin based on the structure of the mineral goethite. The spectral parameters of the sextet signal in the rat tissues indicate that the goethite-like haemosiderin particles are less crystalline than those found in iron-loaded human tissues. For the dietary-iron-loaded rat livers, the fraction (Fs) of the Mössbauer signal in the form of this sextet was found to increase significantly (from approx 0.04 to 0.09) with the age of the rats (r=0.77, P<0.0005). This indicates that the fraction of liver iron in the form of the goethite-like haemosiderin increases with age of the rat and hence with the duration of iron loading. In addition, Fs for these livers was found to increase significantly with the fraction of iron in non-parenchymal cells as measured by computer-assisted morphometric analysis of histological sections (r=0.71, P<0.005).

Planar gamma camera quantitation of 123I, 99mTc or 111In in the liver and spleen of an abdominal phantom.

Three planar, gamma camera methods for quantitating radiopharmaceuticals, such as radiolabeled antibodies, were investigated. Iodine-123 (123I), technetium-99m (99mTc) or indium-111 (111In) in the liver and spleen of an abdominal phantom were assessed in this study. In the first approach, the number of counts detected in a "single image" of the liver or spleen was used to measure radionuclide content using an attenuation correction factor (ACF) calculated from data obtained without radionuclide in the background volume of the phantom. In the other two methods, radionuclide content was derived from either the geometric mean (GM) of counts in conjugate, opposed images ("global conjugate") or in individual, opposed pixels of the conjugate, opposed images ("pixel conjugate") of the liver and spleen. Both of the conjugate image methods were corrected for attenuation with a first order ACF derived from a transmission image. The influence of background radionuclide on the accuracy of quantitation was studied by filling the background volume of the phantom with water containing 7 or 14 percent of the concentration of the radioactive water placed in the liver and spleen. The best estimates of radionuclide content were obtained by quantitation from the GM of counts in conjugate images of the liver and spleen. Radionuclide content of the liver and spleen could be determined from a single image if correction for attenuation was available. In all instances, measurements were less accurate for the spleen and for either organ when 111In was used. These results further validate and extend observations reported by others and provide a basis for radiation dosimetry for these and similar radionuclides and organs in patients.

Dissociation of consummatory and vocal components of feeding in squirrel monkeys treated with benzodiazepines and alcohol.

The primary aim of the current experiments was to develop methods that engender vocalizations associated with positive social situations comprising affiliative behavior and feeding that could be quantified under controlled laboratory conditions and were sensitive to anxiolytic drugs. Classical conditioning procedures were used to elicit vocalizations during presentation of stimulus lights (i.e., CS condition) previously paired with either preferred foods (e.g., grapes, peanuts, bananas) or standard foods (e.g., monkey chow) as well as during presentation of both food types (i.e., UCS condition). When compared to the period before stimulus light presentation (i.e., Pre-CS condition), the rate, duration and number of elemental units of food-related "twitter" vocalizations were increased during the CS conditions regardless of food type. Monkeys spent significantly more time oriented toward the food box during the light stimulus that preceded preferred food than for the light stimulus that preceded standard food. However, twitter vocalizations were higher for standard food regardless of the stimulus conditions (i.e., Pre-CS, CS and UCS). Administration of the benzodiazepine full agonist chlordiazepoxide (CDP, 1-10 mg/kg), the partial agonist bretazenil (BRZ, 1-10 mg/kg), the antagonist flumazenil (FLZ, 1-10 mg/kg) and ethyl alcohol (EtOH, 0.1-1.0 g/kg) differentially altered vocalizations. Although CDP and BRZ increased feeding of standard food, twitters were reduced across stimulus conditions. CDP and BRZ did not alter other social contact calls (i.e., "peeps"). FLZ also reduced twitters without altering peeps, but did not increase feeding. In contrast, EtOH did not increase feeding or peeps, but did increase food-related twitters. These results indicate that there is a dissociation between food-related behaviors, such as food consumption and orientation towards the food source, and vocal behaviors associated with group communication during feeding.

Low-dose, fractionated radioimmunotherapy for B-cell malignancies using 131I-Lym-1 antibody.

PURPOSE: This trial was conducted to assess the toxicity and efficacy of 131I-Lym-1 in patients with either malignant B-cell non-Hodgkin's lymphoma (NHL) or chronic lymphocytic leukemia (CLL) using low-dose, fractionated radioimmunotherapy (RIT). MATERIALS AND METHODS: Thirty adult patients who had advanced B-cell malignancies (25 NHL and 5 CLL) had progressed despite standard therapy; 12 patients entered the trial with Karnofsky performance status (KPS) of equal to or greater than 60. Patients were treated with a series of intravenous doses of 131I-Lym-1 with a goal of reaching a cumulative dose in each patient of at least 300 mCi. All patients were Lym-1 reactive. Clinical responses and immediate toxicity were evaluable in all 30 patients and delayed toxicity in 26. RESULTS: Toxicity to Lym-1 antibody occurred with 28% of the 176 doses and was transient. Human antimouse antibodies (HAMA) were generated in 30% after a mean of 4 doses, but interrupted therapy in only 10% of the patients. Thrombocytopenia was dose-limiting; there were no deaths due to toxicity. Tumor regression occurred in 25 (83%) of the patients and was great enough, and durable enough, in 17 (57%) to qualify them as responders; 13 NHL patients and 4 CLL patients. Advanced disease often interrupted therapy prematurely. However, 18 patients received at least 180 mCi of 131I-Lym-1; 17 (94%) of these responded to the therapy. CONCLUSION: Although advanced disease often interrupted therapy prematurely, the results from 131I-Lym-1 therapy are clearly promising and warrant additional trials.

Oxygen consumption, carbon dioxide excretion and respiratory quotient of larval lampreys (Mordacia mordax) in air.

The standard rates of O2 consumption of larval Mordacia mordax (weight range 1.3-2.3 g), after these ammocetes had been in humidified air for 18 hr, were 26.8, 46.3 and 71.2 microL x g(-1) x hr(-1) at 10, 15 and 20 degrees C, respectively. The corresponding rates of CO2 excretion were 20.7, 35.6 and 54.1 microL x g(-1) x hr(-1). The RQs at the three temperatures were essentially identical (0.76 or 0.77) and similar to that of adults of the lamprey Geotria australis in air at 15 degrees C. The above RQs for ammocoetes, which are probably similar to those that would be recorded in water, are consistent with the view that the aerobic respiration of these animals relies predominantly on lipid as an energy source, but that some energy is derived from carbohydrate and/or protein. The RQs for larval and adult lampreys in air lie well within the range recorded for amphibious fishes in air.

Practical determination of organ S values for individual patients for therapy.

Radiation dose calculations using S values of a reference man can introduce substantial errors for individuals patients. We found that all non target sources can be included in the remainder of the body estimate for therapeutic radionuclides. A practical method to derive organ S values based on MIRD data and the mass of the organ and total body of individual patients is proposed.

The effect of histological processing on the form of iron in iron-loaded human tissues.

Iron-loaded human spleen tissue was immersed in neutral buffered formalin over a period of 200 days. Over the first 60 days, iron leached steadily from the tissue until 3% had been lost. Thereafter, no further iron leaching was detected. Comparisons of Mossbauer spectra of freeze-dried tissue and tissue freeze-dried after immersion in formalin for 200 days showed no evidence of chemical transformation of the iron remaining in the tissue. The spectra indicated a difference in the heme-iron to non-heme iron ratio between the two samples probably reflecting inhomogeneity of the ratio throughout the spleen as measured on the centimetre scale. Mossbauer spectra of freeze-dried samples of iron-loaded human liver and pancreas tissue were compared with those for samples from the same patient that had been processed by routine hospital procedures for histology and archival. These spectra showed no evidence for chemical transformation of the iron present in the tissues. These results demonstrate that it is feasible to use archived fixed and embedded human tissue samples for studies aimed at gauging the relative fraction of goethite-like hemosiderin present in the tissue.

Effect of recombinant alpha-interferon on pharmacokinetics, biodistribution, toxicity, and efficacy of 131I-labeled monoclonal antibody CC49 in breast cancer: a phase II trial.

Preclinical studies have demonstrated that recombinant IFN-alpha (rIFN-alpha) can enhance the tumor associated glycoprotein 72 (TAG-72) on tumors. To determine whether rIFN-alpha could enhance TAG-72 expression in vivo in patients, 15 women with breast cancer were randomized to receive daily injections of rIFN-alpha (3 x 10(6) units/m2 for 14 days) beginning on day 1 (group 1 = 7 patients) or on day 6 (group 2 = 8 patients). On day 3, all patients received a 10-20-mCi tracer dose of 131I-CC49, a high-affinity murine monoclonal antibody reactive against TAG-72, followed by a therapy dose of 60-75 mCi/m2 of 131I-CC49 on day 6. Whole body and single-photon emission computed tomography scans along with whole blood pharmacokinetics were performed following tracer and treatment phases. Hematological toxicity was considerable; reversible grade 3-4 neutropenia and thrombocytopenia was observed in 12 of 15 patients. Twelve of 14 patients tested developed human antimouse antibodies 3-6 weeks after treatment. For group 1 patients, whole blood residence time increased significantly between that predicted from the tracer doses and therapy doses (42.6 +/- 4.7 versus 51.5 +/- 4.8 h, respectively; P < 0.01). The calculated radiation absorbed dose to red marrow from therapy compared to tracer activity was also significantly higher for this group (1.25 +/- 0.35 versus 1. 07 +/- 0.26 cGy/mCi; P < 0.05). Treatment with rIFN-alpha was found to enhance TAG-72 expression in tumors from patients receiving rIFN-alpha (group 1) by 46 +/- 19% (P < 0.05) compared to only 1.3 +/- 0.95% in patients not initially receiving IFN (group 2). The uptake of CC49 in tumors was also significantly increased in rIFN-alpha-treated patients. One partial and two minor tumor responses were seen. In summary, rIFN-alpha treatment altered the pharmacokinetics and tumor uptake of 131I-CC49 in patients at the expense of increased toxicity.

Prediction of radiation doses from therapy using tracer studies with iodine-131-labeled antibodies.

UNLABELLED: Tracer pharmacokinetic studies are often used in treatment planning for radionuclide therapy including radioimmunotherapy. This study evaluates the validity of using tracer studies to predict radiation doses from therapy with the same radiolabeled antibody. METHODS: Quantitative imaging and blood radioactivity were used to obtain the pharmacokinetics and radiation doses that were delivered to the total body, blood, marrow, lungs, liver, kidneys, thyroid, spleen and tumors. Tracer and therapy data for eight patients with lymphoma and one patient with breast cancer were compared using linear regression statistics. Doses of 131I-labeled antibody for the tracer studies ranged from 0.1 to 0.4 GBq (2 to 10 mCi), and therapy doses ranged from 0.7 to 5.6 GBq (20 to 150 mCi). RESULTS: Radiation doses to tissues and, in particular, the bone marrow and tumors were reliably predicted from tracer studies. In this group of patients, median dose to marrow from marrow targeting, total body and blood was 9.2 cGy/GBq for tracer studies and 7.6 cGy/GBq for therapy studies with a median difference of 0.5 cGy/GBq. Median dose to tumors was 81.1 cGy/GBq for tracer studies and 70.3 cGy/GBq for therapy studies with a median difference of 5.9 cGy/GBq. CONCLUSION: In these patients, tracer studies were predictive of the radiation doses from therapy for total body, major organs and tumors. The radiation doses to marrow and tumors, which are the usual determinants of the therapeutic index, correlated well between tracer and therapy studies (r > or = 0.95).