G. J. J. Teule

The 67gallium pulmonary leak index in assessing the severity and course of the adult respiratory distress syndrome.

OBJECTIVE To establish the value of the 67Gallium (Ga) pulmonary leak index, a marker of increased permeability edema of the lungs, in assessing the severity and course of the adult respiratory distress syndrome (ARDS). DESIGN Prospective observational study. SETTING Medical intensive care unit of a university hospital. PATIENTS Seventeen consecutive, mechanically-ventilated ARDS patients. Eleven patients (recovering from ARDS) improved, as defined by the ability to taper the level of positive end-expiratory pressure (PEEP) to 0 cm H2O at a median of 7 days after admission. Ten patients survived. Six patients did not recover and died a median of 3.5 days after admission. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS The pulmonary leak index (i.e., upper limit of normal 14.1 x 10(-3)/min) was measured within 72 hrs after admission, and repeated within 48 hrs at the time of recovery in recovering patients. At admission and recovery, respiratory variables were recorded and a lung injury score was calculated. At admission, the pulmonary leak index was increased in each patient to 32.3 (range 15.6 to 52.4) and 28.7 (range 26.0 to 40.8) x 10(-3)/min in recovering and nonrecovering patients, respectively (NS). Groups did not differ with respect to the oxygenation ratio, the level of PEEP, radiographic abnormalities, and the lung injury score. At recovery, the pulmonary leak index in recovering patients had decreased in each patient and had normalized in four patients, averaging 15.2 (range 5.6 to 25.9) x 10(-3)/min, concomitantly with an increased oxygenation ratio, less radiographic abnormalities, and a decreased lung injury score (p < .01 vs. admission). For pooled recovering and nonrecovering patient data, the pulmonary leak index directly related to the lung injury score (p < .005). CONCLUSIONS The 67Ga pulmonary leak index may be a clinically useful tool to quantify the severity and course of ARDS, since clinical recovery from the syndrome may be characterized by amelioration of increased microvascular permeability.

Gallium-67 radiotoxicity in human U937 lymphoma cells

Promising clinical results have been obtained with radiolabeled antibodies in lymphoma patients. The higher uptake by lymphomas of 67Gallium (67Ga) compared with monoclonal antibodies makes selective radiotherapy by the widely available 67Ga appealing. However, the gamma radiation of 67Ga used in scintigraphy is considered to be almost non-toxic to lymphoma cells. However, in addition to photon radiation 67Ga emits low energy Auger electrons and 80-90 keV conversion electrons which could be cytotoxic. The objective of the present study was the assessment of radiotoxicity of 67Ga on a lymphoid cell line: U937. Proliferation (MTT-assay) and clonogenic capacity (CFU-assay) were measured after 3 and 6 days incubation with 10, 20 and 40 microCi ml-1 67Ga. Growth inhibition was 36% after 3 days incubation and 63% after 6 days incubation with 40 microCi 67Ga ml-1. Clonogenic capacity was reduced by 51% after 3 days and 72% after 6 days incubation with 40 microCi ml-1 67Ga. A survival curve showed an initial shoulder and became steeper beyond 200-250 pCi cell-1 (low linear energy transfer type). Iso-effect doses of 67Ga and 90Yttrium (90Y) were determined. The iso-effect dose of 40 microCi 67Ga ml-1 (cumulative dose of conversion electrons 306 cGy) was 2.5 microCi 90Y ml-1 (cumulative dose 494 cGy) and the iso-effect dose of 80 microCi 67Ga ml-1 was 5.0 microCi 90Y/ml. The main cytotoxic effect of 67Ga seems to be induced by the 80 keV conversion electrons. We conclude that the conversion electrons of 67Ga have a cytotoxic effect on U937 cells and that in our experiments a 16-fold higher microCi-dose of 67Ga than of 90Y was needed for the same cytotoxic effect. We believe that 67Ga holds promise for therapeutic use.

Transport of 67Ga and 111In across a membrane. Role of plasma binding and concentration gradients.

If i.v. injected radiogallium does not firmly bind to circulating transferrin in plasma, the transvascular transport of the radionuclide may be affected by diffusion of unbound radionuclide and interstitial transferrin, and may therefore not be specific for transferrin transport. Using equilibrium dialysis, the avidity of 67Ga and 111In to bind to plasma transferrin was compared by evaluating transport of unbound radionuclide across a semipermeable membrane, as a function of the plasma (transferrin) concentration gradient. One chamber of a dialysis cell was filled with human plasma and 67Ga or 111In, and the other, separated by the membrane, with increasing concentrations of plasma in normal saline. The half-time (mean +/- S.D.) for reaching equilibrium between the chambers decreased (P less than 0.05) for 67Ga from 13.1 +/- 3.3 to 4.9 +/- 1.6, 3.7 +/- 1.2 and 3.0 +/- 0.5 h, at plasma concentrations of 0, 25, 50 and 100%, respectively. The equilibrium half-time for 111In did not fall at increasing plasma concentrations and was higher (P less than 0.005) than for 67Ga at 25 to 100% plasma. Hence, 67Ga is not as avidly bound to plasma transferrin as 111In, since, in contrast to 111In, dissociation of the 67Ga-transferrin complex and transmembrane diffusion of unbound 67Ga increases when the plasma transferrin concentration gradient decreases. In vivo, the transvascular transport of 67Ga may be influenced by diffusion of unbound radionuclide, depending on the interstitial transferrin concentration, and may not be a specific indicator of transvascular protein transport.

Increased systemic microvascular albumin flux in septic shock

Lymph/plasma (L/P) albumin ratios were followed in a patient with a traumatic thoracic duct lymph fistula, during septic shock when lymph flow was high and at recovery when lymph flow was low. Higher albumin ratios were found during the former. On both occassions, the P-L difference of radioactive counts/min per gram was followed for 6 h after i.v. injection of 51Cr human serum albumin (HSA). Equilibration half times between plasma and lymph amounted to 0.85 h during septic shock and 2.49 h at recovery. The data indicate that systemic microvascular albumin flux had increased during shock in our patient. Increased permeability may have been responsible.

Radioimmunotargeting in ovarian carcinoma patients with indium‐111 labeled monoclonal antibody OV‐TL 3 F(ab′)2: pharmacokinetics, tissue distribution, and tumor imaging

Safety and feasibility of tumor targeting with radiolabeled monoclonal antibodies was studied in 28 patients suspected of having ovarian carcinoma, after i.v. administration of 1 mg F(ab′)2 fragments of the murine monoclonal antibody OV-TL 3, labeled with 150 MBq Indium-111. There were no adverse reactions, hematological and biochemical serum parameters were stable. In one patient a (subclinical) HAMA-response was found. Plasma clearance of the immunoconjugate was biphasic with half lives of t½}α = 1.4±0.8 h and t½}β = 25.1±3.7 h, resulting in an optimal time period for immunoscintigraphy at 24–48 h after administration. In 20 patients, undergoing extensive explorative surgery, a total of 271 samples of tumorous and normal tissues were analyzed for radiolabel uptake and tumor presence. The mean uptake in tumor deposits was 5.6 times (range 2.2–19.3) as high as the uptake in normal tissues (fat, peritoneum, muscle, skin). The diagnostic accuracy of immunosctigraphy was compared with that obtained with computer tomography, magnetic resonance imaging, ultrasonography and physical examination. While pelvic localizations were equally well detected by all methods, 48% of the abdominally located tumor deposits were correctly diagnosed by immunoscintigraphy, with only 12% detected by ultrasonography, 8% by CT-scanning and physical examination, and 6% by MRI. Immunoscintigraphy has potential as a diagnostic tool in ovarian cancer patients and biolocalization results justify further research into the therapeutic application of labeled monoclonal antibodies.

Absorbed dose distribution of the auger emitters 67Ga and 125I and the β-emitters 67Cu, 90Y, 131I, and 186Re as a function of tumor size, uptake, and intracellular distribution

PURPOSE The influence of tumor volume, uptake of radioactive compounds in cells of tumors and normal tissues, and characteristics of the emitted ionizing particles on the efficacy of systemic radiation were studied. METHODS AND MATERIALS The influence of these variables was assessed using a point kernel approach combined with a distance histogram technique. Simulation calculations were performed to assess dose distributions for three tumor sizes (phi = 200 microns, 2 mm, or 2 cm) and six radionuclides: 67Ga, 125I, 67Cu, 90Y, 131I, and 186Re. RESULTS The energy deposition patterns depended on the relation of the tumor size and range of the emitted particles. Selective uptake was especially important in cases where the range was short compared to the dimension of the tumor. CONCLUSION To attain a high dose for treatment of micrometastases, the use of Auger and conversion electron emitters (67Ga and 125I) or beta-emitters with emission spectra including low energetic electrons (67Cu and 131I) was recommended. The results demonstrated the complementary nature of selectivity of energy deposition and crossfire. This implied that for tumor cells or areas with reduced uptake, crossfire from radioactivity in surrounding cells or areas with selective uptake would be provided by intermediate (conversion electrons) or long-range (beta-particles) emissions.

High-dose gallium-67 therapy in patients with relapsed acute leukaemia: a feasibility study.

Gallium-67 (67Ga) accumulates in malignant tissues via the transferrin receptor without need for a monoclonal antibody and emits cytotoxic low-energy electrons. In this study we investigated the feasibility, pharmacokinetics, toxicity and preliminary efficiency of high-dose 67Ga injected intravenously (i.v.) in patients with acute leukaemia not responding to conventional therapy. Twelve doses of 36-105 mCi of Gallium67 citrate were administered as a push injection to eight patients with resistant leukaemia in a pilot study. All five patients with acute myeloid leukaemia (AML) and three patients with acute lymphoblastic leukaemia (ALL) had resistant disease or resistant relapse. No (sub)acute toxicity was observed. Independent of the administered dose, whole-blood radioactivity levels 10 min after administration measured only 1.25 +/- 1.39 microCi ml-1, indicating a large volume of distribution. Urine excretion in the first 24 h ranged from 18% to 51.5% (median 29.5%) of the administered dose. Cellular uptake of 67Ga was less than in previous in vitro studies. Whole-body radiation dose was estimated to be 0.25 +/- 0.03 cGy mCi-1. Red marrow dose was estimated to be between 0.18 +/- 0.02 and 0.97 +/- 0.12 cGy mCi-1. One definite response was observed in an ALL patient with disappearance of skin lesions, normalisation of the enlarged spleen and profound leucopenia. Three other patients showed transient reductions in white blood cell counts without disappearance of blasts from the peripheral blood. We conclude that high-dose i.v. 67Ga can be safely administered but that the uptake of 67Ga in blast cells must increase to make 67Ga therapeutically useful in patients with relapsed leukaemia.

What is the cause of pulmonary oedema after acute myocardial infarction? A case study

A patient is described with an acute myocardial infarction (AMI) and pulmonary oedema, necessitating mechanical ventilation, at a mean pulmonary capillary wedge pressure (PCWP) below 13 mmHg. The67Ga-transferrin pulmonary leak index (PLI), a measure of microvascular permeability, was normal. A study of the course of the PCWP revealed intermittent elevations up to 22 mmHg, owing to intermittent mitral regurgitation. Pulmonary oedema after an AMI can thus be caused by pressure factors, even at sporadic elevations of PCWP, following intermittent, ischaemia-induced dysfunction of the posterior papillary muscle. Conversely, the measurement of a normal67Ga-PLI may help to diagnose hydrostatic as opposed to permeability pulmonary oedema, if sporadic elevations of the PCWP are not recognised.

Reproducibility of ejection fraction measurements by gated equilibrium blood pool scintigraphy

The reproducibility of ejection fraction measurements has been studied using gated equilibrium blood pool scintigraphy. The use of appropriate statistical tests is proposed and commented upon. The intra-observer variability for our group of patients has a standard deviation of 6.4%, the interobserver variability of 3.2% and sequential studies done on the same and different days give standard deviations (due to “time” alone) of 1.0% and 1.9%, respectively. Different factors and sources involved in variability are mentioned. Variability values reported in the literature are discussed.

Evaluation of heart-to-organ ratios of 123I-BMIPP and the dimethyl-substituted 123I-DMIPP fatty acid analogue in humans.

Radioiodinated fatty acid analogues modified by methyl-substitution are used for single photon emission tomography (SPET) imaging of the heart. The effect of mono- and dimethyl-substitution on heart-to-organ ratios was investigated in humans to evaluate their relative merits for SPET image quality. Planar total body scans were performed in fasting patients with coronary artery disease, but without heart failure, 1 h after administration of 111 MBq 15-(p-[I-123]-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP, n = 7) or 111 MBq 15-(p-[I-123]-iodophenyl)-3,3-dimethylpentadecanoic acid (DMIPP, n = 4). Because these branched fatty acids are used for cardiac imaging, we focused on heart-to-organ (heart/organ) ratios by comparing small regions of interest in heart, liver, lung, muscle and bladder. Both tracers showed good visualization of the heart. DMIPP showed a relatively high liver uptake: the heart/liver ratios for DMIPP and BMIPP were 0.39 +/- 0.05 and 1.00 +/- 0.12, respectively (P < 0.0001). Increased lung activity was found for BMIPP, with a heart/lung ratio of 1.63 +/- 0.17 versus 2.32 +/- 0.28 for DMIPP (P < 0.001). In contrast to DMIPP, BMIPP also showed increased activity in the bladder. In conclusion, BMIPP and DMIPP show different distribution patterns. Despite the more favourable heart/lung ratios for DMIPP, the high liver uptake affects cardiac SPET image quality and therefore BMIPP appears to provide superior cardiac SPET image quality in humans.