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PubMed1984

Phase I study of the adoptive immunotherapy of human cancer with lectin activated autologous mononuclear cells.

In previous in vitro studies, the authors showed that phytohemagglutinin (PHA) stimulated peripheral blood lymphocytes (PBL) from cancer patients to generate cells that were lytic for fresh autologous tumor but not for lymphocytes or lymphoblasts. Thus, after IRB approval, a phase I clinical protocol was instituted in cancer patients who had failed all other therapy to determine the toxicity and effects, in vivo, of the infusion of large numbers of such PHA activated autologous PBL. Ten patients were treated on the protocol, six with sarcoma, one with melanoma, and three with colorectal cancer. Up to a total of 1.7 X 10(11) PBL were obtained from 7 to 15 successive leukaphereses, the cells from each leukapheresis being incubated in vitro in medium containing PHA and human AB serum for 2 days and then reinfused following the next leukapheresis 2 days later. Toxicity encountered included fever and chills in 10/10 patients, headaches in 5/10, nausea and vomiting in 3/10, and requirement for erythrocyte transfusion in 8/10. No evidence for autoimmune disease, abnormal serum chemical or coagulation studies, or pulmonary emboli was found. 111Indium trafficing studies showed distribution of infused cells mainly to the spleen and liver, with some accumulation in the lungs and tumor especially after repeated infusions. In 9/10 patients, activated PBL were detected in the peripheral circulation by the sixth leukapheresis. Evidence for this was found by assaying the incorporation of tritiated thymidine (3H-Tdr) into, and lysis of fresh tumor cells by, unstimulated PBL from successive leukaphereses. No tumor regression was seen in these patients with bulk disease. These studies demonstrated that large numbers of PHA-activated PBL can be safely obtained and infused into humans, achieving an increase in the number of circulating activated cells with evidence of migration of cells to tumor, lungs, liver and spleen. Further studies of the use of activated lymphocyte infusion in conjunction with chemotherapy in humans are in progress.

Adult↗
PubMed1994

Captopril-enhanced 99Tcm-MAG3 renal scintigraphy in subjects with suspected renovascular hypertension.

This pilot study was undertaken to generate preliminary data on the accuracy of captopril-enhanced renal scintigraphy with a relatively new radiopharmaceutical, 99Tcm-mercaptoacetyltriglycine (99Tcm-MAG3) for detecting significant renal artery stenosis. Truth data was based either on arteriographic or outcome criteria (blood pressure response to therapy). Twenty-seven subjects with suspected renovascular hypertension were studied with baseline and captopril-enhanced 99Tcm-MAG3 renal scintigraphy and renal arteriography. Scan interpretations were expressed as a probability of a significant renal artery stenosis. Scan interpretations were compared with renal arteriographic results, renal vein renin levels, blood pressure values after renal artery repair, and blood pressure control after 4-26 months of clinical follow-up. Using > or = 50% luminal obstruction on arteriography as the reference standard for renal artery stenosis and a high probability scan representing a positive test, the test sensitivity and specificity were 33 and 97%, respectively (using high or indeterminate probability to represent a positive scan, the test sensitivity and specificity were 67 and 83%, respectively). The negative predictive value of a low probability scan for renal artery stenosis was 80%. However, including a measure of renovascular hypertension (blood pressure response to renal artery repair) as the reference standard, the accuracy of the scan improves, with the negative predictive value of a low probability scan for renovascular hypertension increasing to 97%. Scintigraphic results were also positively correlated with renal vein renin values in a statistically significant fashion (two-tailed Fisher exact test statistic = 6.43, P = 0.0219). Captopril-enhanced 99Tcm-MAG3 renal scintigraphy is a moderately accurate technique for detecting renal artery stenosis. More importantly, our preliminary findings suggest that the scintigraphic technique using 99Tcm-MAG3 appears to predict the blood pressure response to renal artery repair in subjects with suspected renovascular hypertension, thereby separating subjects with haemodynamically insignificant renal artery stenosis from those with renovascular hypertension.

Angiography↗
PubMed2005

Uncertainty analysis of (99m)Tc-HEPIDA liver clearance determination.

BACKGROUND: The aim of the study was to obtain information on the accuracy and precision of (99m)Tc-HEPIDA hepatic (Cl(Hp)) and plasma (Cl(Pl)) clearances and selection of an appropriate estimator of the measurement uncertainty of a single determination of these quantities. MATERIAL AND METHODS: In a simulation (Monte Carlo) experiment, it was assumed that the recorded results of plasma and hepatic clearances, as obtained from 185 patients, provided authentic information about (99m)Tc-HEPIDA behaviour in the body over a wide range of the clearances studied. The time course (99m)Tc-HEPIDA concentration in blood plasma has been described by means of biexponential function with parameter values derived for each patient. For each patient, using these data and urinary excretion data, there had been 5000 simulations performed; in each of the latter, the directly measured numbers have been substituted by simulated ones, obtained by means of varying the real ones, using random generated values. These reflected errors of plasma and radioactive standard pipetting (from 1 to 5%) and stochasticity of counting radioactive decay (1%). The time of blood sampling and urine voiding was also varied, assuming realistic uncertainty. The varied values were then used for computation of the simulated clearances. From the 5,000 calculated clearances for each patient, mean-values were calculated, as well as mean standard errors, standard deviations and mean uncertainty of measurements using a widely accepted rule of partial error propagation, and, in addition, a modified rule of the latter. Accuracy of clearance (Cl(Pl), Cl(Hp), Cl(Ur)) determination was assessed on the basis of comparison of mean values from simulations with those from directly recorded values. Precision was identified with standard deviation of each of the 5000 simulations. The uncertainty thus obtained was compared with results of calculated traditional and modified uncertainty. There was good agreement between standard deviation of the simulations with results of the modified calculation of total differential. Therefore, a coefficient of variation from simulation computations and a modified means of calculation of the propagated errors was accepted as a measure of uncertainty of a single determination. RESULTS/CONCLUSIONS: There was a very high correlation between the mean values from simulations and those from direct determinations (r > 0.98 in each case). The regression lines practically corresponded to the lines of identity. These correlations were not affected by the assumed range of pipetting uncertainty. In conclusion, the methods of (99m)Tc-HEPIDA clearance determination are satisfactory. Precision of clearance measurements depends substantially upon uncertainty of pipetting. For plasma clearance, the coefficients of variations at Cl(Pl) > 350 ml/min and at ab.80 ml/min amounted to 2 and 11% respectively, at pipetting uncertainty of 2%. Similarly, for hepatic clearances of (99m)Tc-HEPIDA of 300 ml/min and 30 ml/min, CV was 2.5 and 25%, respectively (at the same uncertainty of pipetting).

Algorithms↗
PubMed1995

Stabilisation of high-activity 99mTc-d,l-HMPAO preparations with cobalt chloride and their biological behaviour.

It has been reported that the stability of a 1.11-GBq (30 mCi) technetium-99m d,l-hexamethyl-propylene amine oxime (HMPAO) preparation can be improved to up to 5 h by the addition of 200 micrograms CoCl2.6H2O within 2 min after reconstitution. However, it is not clear whether this method is also efficient for high-activity preparations (5.55 GBq) and whether this modified 99mTc-d,l-HMPAO has the same biological properties and can safely be used. We have now studied CoCl2-stabilised 99mTc-d,l-HMPAO preparations containing different amounts of "in-house" HMPAO ligand and SnCl2 and reconstituted with activities from 1.11 GBq to 5.55 GBq 99mTc. The characteristics of the generator eluates were also divergent, ranging from fresh eluates from a generator eluted less than 2 h previously to 4-h-old eluates from a generator not eluted during the preceding 72 h. Preparations containing up to 5.55 GBq 99mTc and as low as 2 micrograms SnCl2.2H2O can be efficiently stabilised for at least 6 h by the addition of CoCl2 shortly after reconstitution. Interestingly, it was found that the stabilisation method is not efficient if the cobalt ions are added prior to reconstitution of the preparation. This implies that the cobalt chloride cannot be incorporated in the labelling kit. Also, preparations with amounts of the ligand lower or higher than 0.5 mg formed the 99mTc-d,l-HMPAO complex with low radiochemical yield or showed rapid degradation. Therefore, combination of a subdivision and storage of Ceretec kits in fractions (as reported in the literature) is contra-indicated with this CoCl2 stabilisation method. CoCl2-stabilised Ceretec kits reconstituted with 5550 MBq 99mTcO4- and used 4-5 h after preparation retain the diagnostic usefulness of the fresh 1110-MBq preparation with regard to leucocyte labelling and brain imaging. Although baboon brain uptake of the stabilised preparation was 6%-9% lower, this small difference could not be distinguished in the tomographic images. The data obtained with both inhouse prepared d,l-HMPAO and Ceretec kits suggest that the eluate restrictions recommended by the Ceretec manufacturer can be neglected if the preparation is stabilised with Co2+ ions. Studies with 57Co-spiked CoCl2 added to d,l-HMPAO preparations demonstrated that the Co2+ ions clearly interact with the d,l-HMPAO ligand, probably to form one or more complexes. From biodistribution studies in mice it became evident that the toxicological profile of the Co2+ ions in the presence of d,l-HMPAO should be more favourable than that of cobaltous ions. For these reasons, it seems justifiable that CoCl2-stabilised 99mTc-d,l-HMPAO preparations should undergo rigorous studies to elucidate their clinical usefulness and pharmacological safety.

Animals↗
PubMed2002

New bone-seeking agent: animal study of Tc-99m-incadronate.

OBJECTIVE: Disodium cycloheptylaminomethylenediphosphonate monohydrate (incadronate disodium) is a third-generation bisphosphonate compound which potently inhibits bone resorption, and a highly effective drug in the treatment of metastatic bone disease. We first labeled incadronate disodium with 99mTc, and examined its biodistribution and bone uptake after intravenous injection in rats to assess its potential for clinical use as a bone-seeking agent for judgment of the therapeutic effect of incadronate on bone metastases. Bone scan with 99mTc-labeled incadronate (99mTc-incadronate) may yield important information prior to the use of incadronate for treatment of bone metastases. METHODS: Synthesis of 99mTc-incadronate was carried out by reduction of 99mTc-pertechnetate in the presence of SnCl2 and N2 gas. Normal rats were injected with 18.5 MBq (0.5 mCi) 99mTc-incadronate in a volume of 0.1 ml intravenously and then sacrificed at 15 min, 30 min, 1 h or 2 h (six rats at each time point) after injection. Samples of muscle, stomach, small intestine, kidney, liver and bone (femur) were taken and weighed. In addition, a 1-ml sample of blood was drawn from the heart, and urine was taken from the urinary bladder immediately after sacrifice. Samples were measured for radioactivity and expressed as percent uptake of injected dose per gram or per milliliter (% ID/g or ml). Bone-to-blood and bone-to-muscle uptake ratios were determined from the % ID/g or ml values for these organs. RESULTS: The greatest accumulation of 99mTc-incadronate was found in bone. Radioactivity in bone was as high as 3.22 +/- 0.68% ID/g at 2 hours after injection. Scintigraphic images of 99mTc-incadronate in normal rats revealed highly selective skeletal uptake. CONCLUSION: 99mTc-incadronate exhibited high uptake in bone, and relatively low uptake in soft tissue, suggesting that it may be useful as a bone-seeking agent for judgment of the therapeutic effect of incadronate on bone metastases, by determining the degree of its accumulation in metastatic bone lesions.

Animals↗
PubMed1996

Clinical evaluation of tumor targeting with the anticarcinoembryonic antigen murine monoclonal antibody fragment, MN-14 F(ab)2.

BACKGROUND: The initial clinical experience with the second-generation, high-affinity, MN-14 immunoglobulin (IgG) anticarcinoembryonic antigen (CEA) monoclonal antibody (MoAb) in patients with CEA-producing tumors was reported previously. A bivalent fragment of this MoAb, MN-14 F(ab)2, was prepared, and its pharmacokinetics, targeting properties, dosimetry, and immunogenicity were investigated. METHODS: MN-14 F(ab)2(0.6-29 mg) was labeled with 131I(7.7-269 millicuries and injected into 28 patients with CEA-producing cancers. External scintigraphy was used to evaluate tumor targeting. Quantitative external scintigraphy methods were used to determine the organ and tumor radiation doses. RESULTS: The overall sensitivity of tumor targeting on a lesion basis was 86%, similar to that reported previously for MN-14 whole IgG. The biologic T1/2's for the fragment in the blood and total body (in hours) were 16.8 +/- 4.1 and 59.4 +/- 9.4, respectively, compared with 27.3 +/- 15.7 and 69.6 +/- 32.2 reported for MN-14 IgG. Depending on the protein dose given, high plasma CEA levels (>100ng/ML) resulted in a significant alteration of MoAb pharmacokinetics and organ dosimetry. Individual tumors received an average dose of 10.7 +/- 7.3 centigray [cGy]/mCi, and the tumor-to-total body, red marrow, lung, liver, and kidney dose ratios were 16.8 +/- 11.1, 5.6 +/- 3.6, 5.1 +/- 3.9, 6.0 +/- 3.8, and 3.1 +/- 2.0, respectively (mean + standard deviation [SD]). Only 9 of 18 patients (50%) injected with >4 mg (range: 4-52.1 mg) of MN-14 F(ab)2 developed significant levels of human antimouse antibodies, suggesting that the F(ab)2 may be less immunogenic than the intact IgG. CONCLUSIONS: MN-14 F(ab)2 exhibits a similar targeting sensitivity and tumor dose as reported previously for the IgG form. The lower red marrow doses combined with lower immunogenicity expected for this agent, may make it a suitable alternative for future imaging and therapeutic applications.

Adolescent↗
PubMedDate not supplied

Preliminary study of sentinel node identification with 99mTc colloid and blue dye in patients with endometrial cancer.

AIMS AND BACKGROUND: Intraoperative lymphatic mapping and sentinel node (SLN) biopsy have generated a tremendous amount of interest and are already established as part of the standard practice in the surgical management of breast cancer and melanoma. To reduce extensive radical procedures and decrease the morbidity in the treatment of gynecologic malignancies, much effort is being made to use less aggressive interventions. The purpose of our study was to determine the feasibility of SLN mapping in a group of patients with endometrial cancer at early stages. METHOD AND STUDY DESIGN: Between September 2000 and May 2001 11 patients with endometrial cancer FIGO stage Ib (n = 10) and IIa (n = 1) underwent laparoscopic SNL detection during laparoscopy-assisted vaginal hysterectomy with bilateral salpingo-oophorectomy and bilateral systematic pelvic lymphadenectomy. Radioactive isotope injection was performed 24 hours before surgery and blue dye injection was performed just before surgery in the cervix at 3,6, 9 and 12 hours. A 350 mm laparoscopic gamma scintyprobe MR 100 type 11, 99mTc settled (Pol Hi Tech), was used intraoperatively for SLN detection. RESULTS: Seventeen (17) SLNs were detected with lymphoscintigraphy (six bilateral and five unilateral). At laparoscopic surgery we found the same locations belonging at internal iliac lymph nodes (the so-called Lebeuf-Godard area, lateral to the inferior vesical artery, ventral to the origin of the uterine artery and medial or caudal to the external iliac vein). Fourteen (14) SLNs were negative on histological analysis and three were positive for micrometastases (mean SLN sections = 60). All other pelvic lymph nodes were negative at histological analysis. The same SLN locations detected with the gamma scintyprobe were observed at laparoscopy after patent blue dye injection. CONCLUSIONS: Our preliminary data suggest that combined 99mTc-labeled colloid and vital blue-dye techniques are feasible for SLA detection in endometrial cancer; they represent a very promising tool to transform the management of early-stage endometrial cancer. The clinical validity of this combined technique should be evaluated prospectively.

Adult↗
PubMed2005

A human transferrin-vascular endothelial growth factor (hnTf-VEGF) fusion protein containing an integrated binding site for (111)In for imaging tumor angiogenesis.

UNLABELLED: Our objective was to synthesize a recombinant protein (hnTf-VEGF [VEGF is vascular endothelial growth factor]) composed of VEGF(165) fused through a flexible polypeptide linker (GGGGS)(3) to the n-lobe of human transferrin (hnTf) for imaging angiogenesis. The hnTf domain allowed labeling with (111)In at a site remote from the VEGF receptor-binding domain. METHODS: DNA encoding hnTf, peptide linker (GGGGS)(3), and VEGF(165) genes were cloned into the Pichia pastoris vector pPICZalphaB to generate the pPICZalphaB-hnTF-VEGF plasmid. The expression vector was transformed into P. pastoris KM71H strain. The protein was purified using Co(2+) metal affinity resin. The growth-stimulatory effects of hnTf-VEGF on human umbilical vascular endothelial cells (HUVECs) and its binding to porcine aortic endothelial cells (PAECs) transfected with VEGF receptors were evaluated. hnTf-VEGF protein was labeled with (111)InCl(3) in 10 mmol/L HEPES/15 mmol/L NaHCO(3) buffer, pH 7.4 (HEPES is N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid). The loss of (111)In in vitro from (111)In-hnTf-VEGF to transferrin in human plasma and to diethylenetriaminepentaacetic acid (DTPA) in buffer was determined. Tumor and normal tissue distributions of (111)In-hnTf-VEGF were evaluated in athymic mice implanted subcutaneously with U87MG human glioblastoma xenografts. Tumor imaging was performed. RESULTS: Sodium dodecylsulfate-polyacrylamine gel electrophoresis under reducing and nonreducing conditions showed bands for hnTf-VEGF monomer (M(r) of 65 kDa) and dimer (M(r) of 130 kDa). hnTf-VEGF stimulated the growth of HUVECs 3-fold and demonstrated binding to PAECs displaced by a 50-fold excess of VEGF(165) but not by apotransferrin. There was 21.3% +/- 3.4% loss of (111)In per day from (111)In-hnTf-VEGF to transferrin in plasma, but <5% loss to DTPA over 4 h. (111)In-hnTf-VEGF accumulated in U87MG tumors (6.7% injected dose per gram at 72 h after injection) and its tumor uptake decreased 15-fold by coadministration of a 100-fold excess of VEGF but not by apotransferrin. The tumor-to-blood ratio was 4.9:1 at 72 h after injection and tumors were imaged at 24-72 h after injection. CONCLUSION: (111)In-hnTf-VEGF is a promising radiopharmaceutical for imaging tumor angiogenesis and represents a prototypic protein harboring the metal-binding site of transferrin for labeling with (111)In without introducing DTPA metal chelators.

Animals↗
PubMed2003

A novel monoclonal antibody design for radioimmunotherapy.

The generation of chimeric and complementary-determining region (CDR) grafted monoclonal antibodies (MAb) have reduced the immunogenicity problem in the clinical application of radioimmunotherapy with monoclonal antibodies. However, humanization (Hu) has prolonged the circulation (plasma T1/2) of radiolabeled antibodies, resulting in an increased normal tissue exposure to radioactivity and greater dose-limiting bone marrow suppression. To overcome this problem, a tumor-associated glycoprotein (TAG)-72-specific CDR grafted MAb with C(H)2 domain deletion (DeltaC(H)2) was developed from the MAb CC49. Preclinical studies have demonstrated that HuCC49 DeltaC(H)2 clears more rapidly from the plasma of mice than HuCC49. This preliminary report describes the initial human experience with HuCC49 DeltaC(H)2 radiolabeled with 131I and administered to patients with metastatic colorectal carcinoma. In this pilot study we enrolled four patients who received a single infusion of 20 mg of HuCC49 DeltaC(H)2 (total protein dose) labeled with 10 mCi of 131I. Pharmacokinetics, biodistribution, dosimetry, and immune response were evaluated over 2-6 weeks. No toxicity was observed in this group of patients. A one-compartment bolus model using the non-linear (NLIN) procedures in Statistical Analysis Software (SAS; SAS, Incorporated, Cary, NC) best describes the pharmacokinetics of the 131I-HuCC49 DeltaC(H)2 with a plasma mean T1/2 of 20 +/- 3 hours, a mean residence time (MRT) of 29 +/- 4 hours and a clearance rate (Cl) of 1.5 +/- 0.1 mL/hours/kg. The whole body and marrow radiation dose estimates were 0.55 +/- 0.06 rad/mCi and 1.00 +/- 0.14 rad/mCi, respectively. All patients had positive localization of antibody to metastatic tumor sites. The 131I-HuCC49 DeltaC(H)2 biodistribution was similar to murine CC49. Three patients had no evidence of antibody response to HuCC49 DeltaC(H)2 over 6 weeks of observation, and one patient had a marginal response by week 6. Intravenous administration of HuCC49 DeltaC(H)2 is safe and well tolerated. The deleted C(H)2 construct has a shorter half-life compared with prior studies of murine CC49 but with similar biodistribution and low immunogenicity. These studies support the further clinical investigation of this agent in phase I trials by intravenous and intraperitoneal routes.

Adult↗
PubMed2006

PET imaging of the dopamine transporter with 18F-FECNT: a polar radiometabolite confounds brain radioligand measurements.

UNLABELLED: 18F-2beta-Carbomethoxy-3beta-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane (18F-FECNT), a PET radioligand for the dopamine transporter (DAT), generates a radiometabolite that enters the rat brain. The aims of this study were to characterize this radiometabolite and to determine whether a similar phenomenon occurs in human and nonhuman primate brains by examining the stability of the apparent distribution volume in DAT-rich (striatum) and DAT-poor (cerebellum) regions of the brain. METHODS: Two rats were infused with 18F-FECNT and sacrificed at 60 min. Extracts of brain and plasma were analyzed by high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometric (LC-MS) techniques. Two human participants and 3 rhesus monkeys were injected with 18F-FECNT and scanned kinetically, with serial arterial blood analysis. RESULTS: At 60 min after the injection of rats, 18F-FECNT accumulated to levels about 7 times higher in the striatum than in the cortex and cerebellum. The radiometabolite was distributed at equal concentrations in all brain regions. The LC-MS techniques identified N-dealkylated FECNT as a major metabolite in the rat brain, and reverse-phase HPLC detected an equivalent amount of radiometabolite eluting with the void volume. The radiometabolite likely was 18F-fluoroacetaldehyde, the product expected from the N-dealkylation of 18F-FECNT, or its oxidation product, 18F-fluoroacetic acid. The distribution volume in the cerebellum increased up to 1.7-fold in humans between 60 and 300 min after injection and 2.0 +/- 0.1-fold (mean +/- SD; n = 3) in nonhuman primates between 60 and 240 min after injection. CONCLUSION: An 18F-fluoroalkyl metabolite of 18F-FECNT originating in the periphery confounded the measurements of DAT in the rat brain with a reference tissue model. Its uniform distribution across brain regions suggests that it has negligible affinity for DAT (i.e., it is an inactive radiometabolite). Consistent with the rodent data, the apparent distribution volume in the cerebellum of both humans and nonhuman primates showed a continual increase at late times after injection, a result that may be attributed to entry of the radiometabolite into the brain. Thus, reference tissue modeling of 18F-FECNT will be prone to more errors than analysis with a measured arterial input function.

Animals↗
PubMed2001

Inhalation of [123I]alpha1-protease inhibitor: toward a new therapeutic concept of alpha1-protease inhibitor deficiency?

UNLABELLED: The alpha1-protease inhibitor (alpha1-Pi) is separated from human serum and is therefore extremely expensive. Because only 2%-3% concentrates in the lung after intravenous administration, inhalational therapy for alpha1-Pi deficiency would seem likely to be better. The aims of this study were therefore to determine the pattern of deposition of inhaled alpha1-Pi labeled with 123I and measure the amount deposited in the lungs. METHODS: Eighteen patients with congenital severe alpha1-Pi deficiency were enrolled in the study. The low-specific-activity 123I-labeled alpha1-Pi aerosol (median particle size +/- SD, 3.9 +/- 2.5 microm) was generated by an air pressure-driven nebulizer. The patients inhaled for an average of 23.6 +/- 8.9 min. Static scintigrams in two projections were acquired immediately after (T1) and 1 (T2), 4 (T3), and 24 h (T4) after inhalation. The patients were divided into the following three groups according to their forced expiratory volume in 1 s (FEV1): group I, < or =40% of predicted normal (n = 8); group II, 40% < FEV1 < or = 60% of predicted normal (n = 4); group III, >60% of predicted normal (n = 6). RESULTS: The absolute percentage uptake values of alpha1-Pi in group I were 12.4 for T1, 7.3 for T2, 4.6 for T3, and 1.2 for T4; in group II the values were 13.0, 9.6, 6.2, and 2.0, respectively; and in group III, 14.6, 11.4, 6.5, and 3.6, respectively. Differences between the groups were generally statistically significant. Between T1 and T2, the probability value was <0.05 for group I versus group II, <0.006 for group I versus group III, and <0.39 for group II versus group III. Between T1 and T3, the probability value was <0.29 for group I versus group II, <0.22 for group I versus group III, and <0.94 for group II versus group III. Retention (between T1 and T4) was also dependent on the grade of the disease: P < 0.2 for group I versus group II, P < 0.001 for group I versus group III, and P < 0.02 for group II versus group III. Grading of the uptake pattern by three independent experienced investigators (87% agreement) revealed a peripheral deposition that was group dependent. We found that greater peripheral deposition corresponded with lower lung functional impairment: P < 0.5 for group I versus group II, P < 0.01 for group I versus group III, and P < 0.08 for group II versus group III. Degradation also corresponded with functional impairment: P < 0.05 for group I versus group II, P < 0.006 for group I versus group III, and P < 0.3 for group II versus group III. CONCLUSION: The results of this study show that sufficient amounts of alpha1-Pi can be deposited in the periphery of the lung by inhalation at least in patients with low-grade disease. Inhalation of alpha1-Pi may thus represent a new and more convenient route of drug administration.

Administration, Inhalation↗
PubMed2002

Hepatobiliary scintigraphy for evaluating the hepatotoxic effect of halothane and the protective effect of catechin in comparison with histo-chemical analysis of liver tissue.

Halothane and its metabolites cause liver damage by decreasing liver blood flow and generating free-radical species. Catechin suppresses lipid peroxidation and increases enzyme activity, therefore it seems to be capable of protecting liver parenchyma against the direct toxic effect of halothane. The aim of this study was to investigate the role of hepatobiliary scintigraphy in detecting liver damage after halothane anaesthesia and the protective effect of catechin in comparison with histo-chemical analysis. Thirty rabbits, divided into three groups (A, controls; B, halothane; and C, catechin+halothane), were investigated. In group A no anaesthesia was administered. Group B only received halothane, while group C was pretreated with catechin and halothane anaesthesia was administered for 2 h. Dynamic scintigrams were taken for 60 min after injecting 99mTc-mebrofenin, and the time of peak uptake (TPU) and the time for half of the activity to clear from the liver (T(1/2)) were calculated. Rabbits were killed, and malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) levels were measured in hepatic tissue. The TPU and T(1/2) values of group A is significantly lower than in groups B and C (P<0.0002 and P<0.0002, respectively, for TPU; and P<0.0002 and P<0.0003, respectively, for T(1/2)). The TPU and T(1/2) values of group B were significantly higher than in group C (P<0.0003 and P<0.0003, respectively). The hepatic MDA level of group A was significantly lower than in groups B and C (P<0.0002 and P<0.0002, respectively). SOD, GSH-Px and CAT levels of group A were significantly higher than in groups B and C (P<0.0002, P<0.0001 and P<0.003, respectively, for group A vs group B; and P<0.0005, P<0.0002 and P<0.03, respectively, for group A vs group C). The MDA level of group B was significantly higher than that in group C (P<0.0002). SOD, GSH-Px and CAT levels of group B were significantly lower than in group C (P<0.0002, P<0.0002 and P<0.003, respectively). According to these results, we suggest that catechin protects liver parenchyma against the toxic effect of halothane and its metabolites, and that, compared to invasive histo-chemical analysis, hepatobiliary scintigraphy is a useful and alternative non-invasive method for detecting the protective effect of catechin on liver parenchyma after halothane anaesthesia.

Anesthesia↗
PubMed2006

Cross-camera comparison of SPECT measurements of a 3-D anthropomorphic basal ganglia phantom.

PURPOSE: SPECT examinations of neurotransmitter systems in the brain have to be comparable between centres to generate a comprehensive data pool, e.g. for multicentre studies. Equipment-specific effects on quantitative evaluations and corresponding methods for compensation, however, have been insufficiently examined. Previous studies have shown that quantitative results may vary significantly according to the imaging equipment used, thereby affecting clinical interpretation of the data. The aim of this study was to determine correction factors for common camera/collimator combinations based on standardised measurements of an anthropomorphic 3D basal ganglia phantom to compensate for the effects of different SPECT camera/collimator equipment. The latter may serve as a model for human studies of the dopaminergic system. METHODS: The striatum and background chambers of a commercially available phantom (RSD Alderson) were filled with various( 123)I concentrations encompassing specific striatum/background ratios from 0.6 to 16.1. This setup was imaged with the following four camera/collimator combinations: Siemens Multispect 3 fitted with LEHR and( 123)I parallel-hole collimators, Siemens ECAM with LEHR parallel-hole collimators and Philips Prism 3,000 fitted with LEHR fanbeam collimators, using standardised protocols for acquisition and reconstruction. All scans were automatically co-registered to a SPECT template of the phantom and quantified using a 3D volume of interest (VOI) map based on a CT scan of the phantom. All striatal/background ratios calculated by SPECT were compared with the true ratios calculated from the measurements in a well counter. Regression analyses were performed and recovery correction factors between measured and true ratios determined. RESULTS: The relation between true and measured ratios could be sufficiently described by a linear regression for each camera/collimator combination without relevant improvement when using second-order polynomial regression models. The recovery correction factors and standard errors were 2.04+/-0.04 for the Philips Prism 3,000, 2.67+/-0.03 for the Siemens Multispect 3/LEHR parallel-hole collimators, 2.15+/-0.03 for the Siemens Multispect 3/(123)I collimators and 2.81+/-0.03 for the Siemens ECAM. Percentage recovery ranged from 36% to 49%. CONCLUSION: Measurements of a 3D basal ganglia phantom with various imaging devices revealed linear correlations between measured and true striatal/background ratios. Based on these findings, adjustment of quantitative results between different equipment seems possible, provided that acquisition, reconstruction and evaluation are adequately standardised. The use of identical evaluation methods in phantom and patient studies (comparable shape, size and location of the VOIs) might allow transfer of the calculated correction factors from phantom to studies of the dopaminergic system in patients.

Algorithms↗
PubMed1999

Radiation safety with breast sentinel node biopsy.

BACKGROUND: Sentinel lymph node biopsy with Technetium 99m sulfur colloid (Tc99m) is an evolving technique that offers the potential for improved staging of breast cancer with decreased morbidity. However, the use of radioactive materials in the operating room generates significant concern about radiation exposure. The purpose of this study was to evaluate radiation exposure to operating room personnel, pathologist, and equipment from specimens during breast sentinel lymph node biopsy. METHODS: Twenty patients were injected with 0.7 to 1.1 mCi of Tc99m sulfur colloid 1.5 to 3 hours before sentinel lymph node biopsy. A calibrated Geiger counter was used to measure dose rates from the breast injection site before skin incision (n = 20), lumpectomy specimens (n = 8), and sentinel nodes (n = 20) at distances of 3, 30, and 300 cm. This represented exposure to the surgeon's hands, surgeon's torso, and scrub nurse, respectively. Exposure to the pathologist's hands and torso was represented as dose-rate measurements from lumpectomy and nodal specimens. The operative instruments, trash receptacles, suction canisters, pathology slides, and cryostat machines were measured at 3 cm at the conclusion of each procedure. Specimens or equipment emitting radiation doses equal to background levels (0.04 mRem/h) were exempt from special handling and disposal. RESULTS: The highest exposure rate was to the surgeon's hands from the breast injection site before skin incision (34.25 mRem/h). Exposure to the surgeon's torso measured 1.33 mRem/h, and exposure to the scrub nurse's torso measured 0.15 mRem/h from the injection site. Exposure to the pathologist's hands was 18.62 and 0.06 mRem/h from the lumpectomy specimen and sentinel node, respectively. Exposure to the pathologist's torso measured 0.34 and 0.04 mRem/h from the lumpectomy specimen and sentinel node, respectively. One hundred percent of lumpectomy specimens measured above the exempt level. Thirty-two of 46 (70%) sentinel lymph nodes emitted radiation equal to the exempt background level. Seventeen of 20 trash receptacles (85%) and 4 of 12 (33%) suction canisters measured equal to background levels. All operative instruments, pathology slides, and cryostat machines were equal to background levels. CONCLUSIONS: Radiation exposure to operating room personnel, pathologists, and operative equipment during a breast sentinel node biopsy using Tc99m is minimal. A primary surgeon can perform 2,190 hours, a scrub nurse 33,333 hours, and a pathologist 14,705 hours of procedural work before surpassing Occupational Safety and Health Administration limits. Operative instruments, pathology slides, and cryostat machines do not require special handling. All lumpectomy specimens should be stored for decontamination until the dose rate equals background levels. Intraoperative dose-rate monitoring allows selective decontamination of nodal specimens, trash receptacles, and suction canisters, which decreases disposal time and cost.

Air Pollutants, Radioactive↗
PubMed1994

Gamma-scintigraphy and early hepatocellular dysfunction during posttraumatic sepsis.

BACKGROUND: To determine whether the hepatic conjugation-detoxification function was altered during sepsis, the metabolism of bilirubin was measured with gamma-scintigraphy. METHODS: Time-activity curves were generated after a radiolabeled bilirubin analog (technetium 99m-mebrofenin, hepatoiminodiacetic acid [HIDA]) was administered to anesthetized (fentanyl) mongrel pigs in the following conditions: control (n = 16); 30 minutes after 5 micrograms/kg intravenous Escherichia coli endotoxin (LPS; n = 6); 30 minutes after trauma (40% arterial hemorrhage plus soft tissue injury, n = 9); 72 hours after sham trauma (n = 6); 72 hours after fluid resuscitated trauma either before (n = 9) or 30 minutes after (n = 10) LPS administration. All were ventilated with 65% O2 and instrumented with pulmonary artery oximetric catheters. RESULTS: After trauma plus LPS, the rate of HIDA uptake was depressed 20% to 30% (p < 0.05), whereas its elimination half-time was increased almost threefold (p < 0.05) relative to before LPS administration. At the corresponding time after trauma alone or LPS alone, uptake was not altered and elimination was prolonged less than twofold (p < 0.05) relative to control. Perfusion differences could not explain these data because cardiac index (CI, ml/min/kg) was reduced to the same extent after trauma alone (62 +/- 10), LPS alone (79 +/- 6), or trauma plus LPS (71 +/- 6) compared with control (102 +/- 5), sham (112 +/- 11), or pre-LPS (120 +/- 10) (p < 0.05, respectively). Levels of serum alanine aminotransferase and creatine kinase were both elevated (p < 0.05) 72 hours after resuscitation, but there were no added increments caused by LPS administration. Levels of other enzymes and plasma bilirubin were not increased by trauma or LPS alone or in combination. Changes in HIDA uptake-excretion within 30 minutes of LPS after resuscitated trauma coincided with neutropenia and pulmonary hypertension and preceded a hyperdynamic inflammatory state characterized by increased CI (194 +/- 19 ml/min/kg, p < 0.05) at 90 +/- 13 minutes, decreased systemic vascular resistance (0.48 +/- 0.04 mm Hg per ml/min/kg, p < 0.05 relative to 1.08 +/- 0.07 for control or 0.88 +/- 0.08 for pre-LPS) at 81 +/- 8 minutes, and increased systemic O2 consumption (6.96 +/- 0.93 vs 4.16 +/- 0.23 ml O2/min/kg, p < 0.05 relative to pre-LPS) at 96 +/- 12 minutes. CONCLUSIONS: (1) A prior episode of resuscitated traumatic shock exhausts hepatic reserve and this occult dysfunction in the conjugation-detoxification system or bilirubin metabolism is unmasked by LPS; (2) hepatic dysfunction could have a role in the pathogenesis of the hyperdynamic circulatory response evoked by LPS because HIDA clearance was reduced before CI increased or systemic vascular resistance decreased; (3) HIDA clearance is a rapid, reliable, and inexpensive estimate of bilirubin metabolism that may have a practical application in patients with septic trauma or others with occult liver dysfunction.

Aniline Compounds↗
PubMed1995

Noninvasive localization of experimental atherosclerotic lesions with mouse/human chimeric Z2D3 F(ab')2 specific for the proliferating smooth muscle cells of human atheroma. Imaging with conventional and negative charge-modified antibody fragments.

BACKGROUND: A murine monoclonal antibody designated Z2D3 (IgM) generated against homogenized human atherosclerotic plaques was demonstrated to be highly specific for proliferating smooth muscle cells. The primary clone subsequently was genetically engineered to provide a mouse/human chimeric antibody with human IgG1 constant region expressed in a rat myeloma cell line. The resulting Z2D3-73.30 chimeric retained the immunoreactivity relative to the parent Z2D3-IgM and was pepsin-digested to yield F(ab')2. 111In-labeled chimeric Z2D3 F(ab')2 was then used for noninvasive imaging of experimental atherosclerotic lesions. To improve the imaging characteristics, we modified chimeric Z2D3 F(ab')2 fragments to carry a high negative charge. Improved visualization of targets with 111In-labeled, negatively charged, polymer-modified antibodies most probably is the result of faster blood clearance and a decrease in nontarget background activity. METHODS AND RESULTS: Experimental atherosclerotic lesions were induced in rabbits by deendothelialization of the infradiaphragmatic aorta followed by a 6% peanut oil-2% cholesterol diet. After 12 weeks, localization of the conventionally labeled 111In-Z2D3 F(ab')2 (24 Mbq [650 microCi]/500 to 750 micrograms) (n = 4) was compared with 111In-labeled, negatively charged, polymer-modified Z2D3 F(ab')2 (24 Mbq [650 microCi]/25 to 50 micrograms) in eight atherosclerotic rabbits. Three control rabbits also received radiolabeled polymer-modified Z2D3. Ten rabbits with atherosclerotic lesions received 111In-labeled nonspecific human IgG1 F(ab')2 with (n = 6) or without (n = 4) negative charge modification. Atherosclerotic lesions were visualized in all rabbits with the conventional Z2D3 F(ab')2 at 48 hours. However, unequivocal lesion visualization was possible at 24 hours only with negatively charged, polymer-modified Z2D3 F(ab')2. Quantitative uptake of F(ab')2 fragments was essentially determined by the presence of atherosclerotic lesions (F1.37 = 69.8; P < .0001) and the specificity of the antibody (F1.37 = 36.6; P < .0001). Uptake of the conventional Z2D3 in atherosclerotic lesions (mean +/- SEM percent injected dose per gram, 0.112 +/- 0.024%) was six times higher than background activity in the normal aortic segments (nondenuded thoracic aorta; mean percent injected dose per gram, 0.019 +/- 0.003%). Uptake of the conventional Z2D3 was also significantly higher than that of nonspecific human IgG1 F(ab')2 (0.027 +/- 0.004%). Specific uptake of the conventional Z2D3 in the lesions was comparable to the charge-modified Z2D3 uptake (0.084 +/- 0.017; P = .20). Uptake of negative charge-modified Z2D3 in the lesions was significantly higher than in the corresponding background activity in normal thoracic aorta (0.021 +/- 0.002). Uptake of negative charge-modified Z2D3 F(ab')2 in the lesions was higher than the uptake of negative charge-modified nonspecific IgG1 F(ab')2 (0.020 +/- 0.002) in the lesions. Uptake of charge-modified Z2D3 in the atherosclerotic lesions was also significantly higher than the corresponding regions of the aorta of the control rabbits (0.017 +/- 0.002; F1.18 = 27.9; P = .0001). There was, however, no difference in the specific lesion uptake of negative charge-modified Z2D3 at 24 hours (0.079 +/- 0.014) and 48 hours (0.084 +/- 0.0017; P = .99) after intravenous administration. Nontarget organ activities were lower with negative charge-modified 111In-labeled Z2D3 F(ab')2 than with the conventional Z2D3 F(ab')2. Mean kidney activity was fourfold less with the modified (0.45 +/- 0.06) than with the conventionally radiolabeled (1.67 +/- 0.264; P = .001) Z2D3 F(ab')2.

Animals↗