Clinical Assessment of 177Lu-DOTATATE Quantification by Comparison of SUV-Based Parameters Measured on Both Post-PRRT SPECT/CT and 68Ga-DOTATOC PET/CT in Patients With Neuroendocrine Tumors: A Feasibility Study.

PATIENTS AND METHODS: Patients with WD-GEP-NET who benefited from a pretherapeutic 68Ga-DOTATOC PET/CT and a 177Lu-DOTATATE SPECT/CT after the cycle 1 of peptide receptor radionuclide therapy were prospectively included. SPECT/CT acquisitions were performed on a system calibrated with a conversion factor of 9.48 counts/MBq per second and were reconstructed with an iterative algorithm allowing quantification using the SPECTRA Quant software (MIM Software, Cleveland, OH). For each patient, different SUV parameters were recorded on both PET/CT (Ga parameters) and SPECT/CT (Lu parameters) for comparison: physiological uptakes (liver/spleen), tumor uptake (1-10/patient; SUVmax, SUVmean, SUVpeak, MTV), tumor-to-liver and tumor-to-spleen ratios according to liver/spleen SUVmax and SUVmean (TLRmax, TLRmean, TSRmax, and TSRmean, respectively). RESULTS: Ten patients (8 female; 2 male) aged from 50 to 83 years presenting with a metastatic progressive WD-GEP-NET (7 small intestine, 2 pancreas, 1 rectum) were included. Median values of lesional Lu-SUV were significantly lower than the corresponding Ga-SUV (P < 0.001), whereas median values of lesional Lu-MTV, Lu-TLR, and Lu-TSR were significantly higher than the corresponding Ga-MTV, Ga-TLR, and Ga-TSR (P < 0.02). Pearson correlation coefficients were strong for both SUV and MTV parameters (0.779-0.845), weak for TLR parameters (0.365-0.394), and moderate-to-strong for TSR parameters (0.676-0.750). CONCLUSIONS: Our results suggest the feasibility of 177Lu-DOTATATE SPECT/CT quantification in clinical practice and show a strong correlation of several SUV-based parameters with the corresponding in 68Ga-DOTATOC PET/CT.

Synthesis, characterization, and binding assessment with human serum albumin of three bipyridine lanthanide(III) complexes.

In this work, the terbium(III), dysprosium(III), and ytterbium(III) complexes containing 2, 2'-bipyridine (bpy) ligand have been synthesized and characterized using CHN elemental analysis, FT-IR, UV-Vis and 1H-NMR techniques and their binding behavior with human serum albumin (HSA) was studied by UV-Vis, fluorescence and molecular docking examinations. The experimental data indicated that all three lanthanide complexes have high binding affinity to HSA with effective quenching of HSA fluorescence via static mechanism. The binding parameters, the type of interaction, the value of resonance energy transfer, and the binding distance between complexes and HSA were estimated from the analysis of fluorescence measurements and Förster theory. The thermodynamic parameters suggested that van der Waals interactions and hydrogen bonds play an important role in the binding mechanism. While, the energy transfer from HSA molecules to all these complexes occurs with high probability, the order of binding constants (BpyTb > BpyDy > BpyYb) represents the importance of radius of Ln3+ ion in the complex-HSA interaction. The results of molecular docking calculation and competitive experiments assessed site 3 of HSA, located in subdomain IB, as the most probable binding site for these ligands and also indicated the microenvironment residues around the bound mentioned complexes. The computational results kept in good agreement with experimental data.

Assessment of tumor hypoxia by 62Cu-ATSM PET/CT as a predictor of response in head and neck cancer: a pilot study.

OBJECTIVE: In radiotherapy and chemotherapy tumor hypoxia is recognized as a major obstacle to effective treatment. We undertook a pilot study in patients with locally advanced head and neck cancer to determine whether there is a relationship between tumor uptake of (62)Cu-ATSM and response to chemoradiotherapy. METHODS: Seventeen patients were studied using PET/CT with (62)Cu-ATSM and (18)F-FDG prior to the initiation of radiotherapy and chemotherapy. All patients had locally advanced head and neck cancer (stage III or IV). Tumor uptake in all patients was measured by region of interest analysis using the maximal standardized uptake value (SUVmax). A total dose of 50.4-70.2 Gy (median 70.2 Gy) was delivered in 29-39 fractions (median 39 fractions) to tumor. In patients with (non CR) and without (CR) residual/recurrent tumors at 2-year post irradiation, the statistical significance of the differences in tumor (62)Cu-ATSM SUVmax, T/M ratio, (18)F-FDG SUVmax and tumor volume were analyzed using Student's t test and Welch test. The relationship between clinical outcome and (62)Cu-ATSM/(18)F-FDG uptake patterns was analyzed using Kruskal-Wallis test. The correlation between SUVmax of (62)Cu-ATSM and (18)F-FDG was compared by Spearman's rank correlation test. RESULTS: Two of the 17 patients that were enrolled in our study were excluded from the final analysis. Of the 15 remaining patients, 9 patients were free of disease and 6 patients had residual/recurrent tumors. The SUVmax differed significantly (p < 0.05) between patients with or without residual/recurrent tumor on (62)Cu-ATSM PET/CT. Six of the 10 patients with tumors SUVmax >5.00 had residual/recurrent tumor, whereas all of the 5 patients with tumors SUVmax <5.00 were free of disease. There was no significant difference in FDG uptake between patients with and without residual/recurrent tumor. CONCLUSIONS: The results of this pilot study suggested that (62)Cu-ATSM uptake may be a predictive indicator of tumor response to chemoradiotherapy in patients with locally advanced head and neck cancer.

Kinetic and theoretical comprehension of diverse rate laws and reactivity gaps in Coriolus hirsutus laccase-catalyzed oxidation of acido and cyclometalated Ru(II) complexes.

The reactivity of the acido Ru(II) complexes cis-[RuCl(2)(LL)(2)], [RuCO(3)(LL)(2)], cis-[RuCO(3)-(bquin)(2)] (LL = 2,2'-bipyridine (bpy) and 1,10-phenanthroline (phen); bquin = 2,2'-biquinoline) and cyclometalated Ru(II) derivatives of 2-phenylpyridine and 4-(2-tolyl)pyridine [Ru(o-C(6)H(4)-2-py)(phen)(2)]PF(6) (1), [Ru(o-C(6)H(3)-p-R-2-py)(bpy)(MeCN)(2)]PF(6) (2), and [Ru(o-C(6)H(3)-p-R-2-py)(phen)(MeCN)(2)]PF(6) (3) (R = H (a), Me (b)) toward laccase from Coriolus hirsutus has been investigated by conventional UV-vis spectroscopy at pH 3-7 and 25 degrees C. The acido and cyclometalated complexes are readily oxidized into the corresponding Ru(III) species, but the two types of complexes differ substantially in reactivity and obey different rate laws. The acido complexes are oxidized more slowly and the second-order kinetics, first-order in laccase and Ru(II), holds with the rate constants around 5 x 10(4) M(-1) s(-1) at pH 4.5 and 25 degrees C. The cyclometalated complexes 1-3 react much faster and the hyperbolic Michaelis-Menten kinetics holds. However, it is not due to formation of an enzyme-substrate complex but rather because of the ping-pong mechanism of catalysis, viz. E(ox) + Ru(II) --> E(red) + Ru(III) (k(1)); E(red) + 1/4O(2) --> E(ox) (k(2)), with the rate constants k(1) in the range (2-9) x 10(7) M(-1) s(-1) under the same conditions. The huge values of k(1) move the enzymatic oxidation toward a kinetic regime when the dioxygen half-reaction becomes the rate-limiting step. Cyclometalated compounds 1-3 can therefore be used for routine estimation of k(2), that is, the rate constant for reoxidation for laccases by dioxygen. The mechanism proposed was confirmed by the direct stopped-flow measurements of the k(2) rate constant (8.1 x 10(5) M(-1) s(-1) at 26 degrees C) and supported by the theoretical modeling of interaction between the bpy analogue of 1 and Coriolus hirsutes laccase using Monte Carlo simulations.

Assessment of migration of HIV-1-loaded dendritic cells labeled with 111In-oxine used as a therapeutic vaccine in HIV-1-infected patients.

Monocyte-derived dendritic cells (DCs) loaded with heat-inactivated HIV are used in therapeutic immunizations. It is not known whether they migrate in vivo to lymph nodes. We used an (111)In-oxine-labeled DC (ILDC) method to visualize the migration of DCs. The activity, time and incubation medium were investigated to obtain the highest cellular viability and radiolabeling yield. A trypan-blue exclusion test was used to determine the cellular viability. In five patients, 2 x 10(6) ILDCs were injected subcutaneously in the arm. An initial dynamic study was performed during the first 5 min after injection. This was followed by static acquisitions at several time points, using a high-resolution (general electric) gamma-camera and quantifying the activity at regions of interest drawn on the injection point. The sensitivity of the gamma-camera was evaluated. The highest number of viable DCs (>83%) and the best radiolabeling yield (>70%) were obtained with 1.11 MBq (111)In-oxine, after 10 min of incubation at 37 degrees C in sodium chloride solution 0.9%. We did not observe migration of ILDCs to local lymph nodes in any patient. However, focal uptake at the place of injection continued during the study period. We observed a higher than expected loss of activity from the injection point (median A(t)/A(0) = 0.60 at day 2), which correlated with an increase in total cytotoxic T lymphocytes (CD8(+) and granzyme B(+) cells) in the lypmphoid tissue observed after immunization (R(2) = 0.92, p = 0.03). If more than 20,000 ILDCs had migrated, they could have been detected. In future trials, a higher number of DCs or alternative methods should be used to assess the migration of DCs to lymph nodes.

Photoelectrocatalytic oxidation of remazol turquoise blue and toxicological assessment of its oxidation products.

The ability of photoelectrocatalytic oxidation to degrade the commercially important copper-phtalocyanine dye, remazol turquoise blue 15 (RTB) was investigated. The best experimental condition was optimized, evaluating the performance of Ti/TiO2 thin-film electrodes prepared by sol-gel method in the decolourization of 32 mg L(-1) RTB dye in 0.5 mol L(-1) Na2SO4 pH 8 and applied potential of +1.5 V versus SCE under UV irradiation. Spectrophotometric measurements, high performance liquid chromatography, dissolved organic carbon (TOC) evaluation and stripping analysis of yielding solution obtained after 3 h of photoelectrolysis leads to 100% of absorbance removal from wavelength of 250-800 nm, 79.6% of TOC reduction and the releasing of up to 54.6% dye-bound copper (0.85 mg L(-1)) into the solution. Both, original and oxidized dye solution did not presented mutagenic activity with the strains TA98 and TA100 of Salmonella in the presence and absence of S9 mix at the tested doses. Nevertheless, the yielding photoelectrocatalytic oxidized solution showed an increase in the acute toxicity for Vibrio fischeri bacteria, explained by copper liberation during treatment.

The assessment of the viability of the endospores of Rhinosporidium seeberi with MTT (3-[4, 5-dimethyl-2-thiazolyl]-2, 5-diphenyl-2H-tetrazolium bromide).

This report describes tests with Evan's Blue and MTT (3-[4, 5-dimethyl-2-thiazolyl]-2, 5-diphenyl-2H-tetrazolium bromide) for the assessment of the viability of rhinosporidial endospores. MTT stained a proportion of the spherical bodies that we regard as the Electron Dense Bodies (EDBs), and the cytoplasm of freshly prepared endospores or ones that were stored at 4 degrees. Slow-freezing at -20 degrees C, exposure to 10% formalin, or 0.1% sodium azide of the endospores abolished MTT-staining in both sites. Evan's Blue stained the EDBs and cytoplasm of fresh endospores or those stored at 4 degrees, and of sodium azide-treated or frozen (-20 degrees)-thawed endospores. TMRE (tetramethyl-rhodamine ethyl ester) specifically labelled the spherical bodies, supporting the conclusion that these spherical bodies have a mitochondrial-like structure. TMRE-staining was however retained in endospores after their treatment with formalin, sodium azide and slow-freezing while MTT-staining was abolished in all these treated endospores. These results indicate that EvB and TMRE were capable of revealing the morphological integrity of endospores but failed to identify the metabolic inactivation of the endospores after treatment with formalin, sodium azide or slow-freezing. Only MTT was capable of identifying metabolically active endospores and hence their viability and could prove to be of value in standardizing models of infection.

Assessment of bioaccumulation and neurotoxicity in rats with portacaval anastomosis and exposed to manganese phosphate: a pilot study.

The use of the additive methylcyclopentadienyl manganese tricarbonyl in unleaded gasoline has resulted in increased attention to the potential toxic effects of manganese (Mn). Hypothetically, people with chronic liver disease may be more sensitive to the adverse neurotoxic effects of Mn. In this work, bioaccumulation of Mn, as well as histopathology and neurobehavioral damage, in end-to-side portacaval anastomosis (PCA) rats exposed to Mn phosphate via inhalation was investigated. During the week before the PCA operation, 4 wk after the PCA operation, and at the end of exposure, the rats were subjected to a locomotor evaluation (day-night activities) using a computerized autotrack system. Then a group of 6 PCA rats (EXP) was exposed to 3050 microg m(-3) (Mn phosphate) for 8 h/day, 5 days/wk for 4 consecutive weeks and compared to a control group (CON), 7 PCA rats exposed to 0.03 microg m(-3). After exposure, the rats were euthanized and Mn content in tissues and organs was determined by neutron activation analysis. The manganese concentrations in blood (0.05 microg/g vs. 0.02 microg/g), lung (1.32 microg/g vs. 0.24 microg/g), cerebellum (0.85 microg/g vs. 0.64 microg/g), frontal cortex (0.87 microg/g vs. 0.61 microg/g), and globus pallidus (3.56 microg/g vs. 1.33 microg/g) were significantly higher in the exposed group compared to the control group (p <.05). No difference was observed in liver, kidney, testes, and caudate putamen between the two groups. Neuronal cell loss was assessed by neuronal cell counts. The loss of cells in globus pallidus and caudate putamen as well as in frontal cortex was significantly higher (p <.05) for the EXP group. Assessment of the locomotor activities did not reveal any significant difference. This study constitutes a first step toward our understanding of the potential adverse effects of Mn in sensitive populations.

MRI assessment of microvascular characteristics in experimental breast tumors using a new blood pool contrast agent (MS-325) with correlations to histopathology.

A new contrast medium, MS-325, was compared to albumin-(Gd-DTPA)(30) in 18 chemically induced rat breast tumors based on quantitative estimates of microvascular permeability (K(PS)) and fractional plasma volume (fPV) using a two-compartment bidirectional model. No significant correlation was found between MS-325-enhanced microvascular assays with either tumor grade or with microvascular counts (MVCs). In comparison, the correlation coefficient between K(PS) and histologic tumor grade using albumin-(Gd-DTPA)(30) (r =.58) was statistically significant (P <.01). Also, using albumin-(Gd-DTPA)(30), a significant correlation (r =.55, P <.05) was observed between the K(PS) and MVC, a biomarker of angiogenesis. Correlations between fPV and MVC were not statistically significant for either contrast medium. In conclusion, using MS-325, no significant correlations between the MR-estimated permeability values or plasma volumes were observed in experimental breast tumors with either the histologic tumor grade or MVC. This analysis confirms our previous determination that capillary permeability estimates, using a prototype large molecular contrast medium, albumin-(Gd-DTPA)(30), correlate significantly with both histologic tumor grade and MVC.

Environmental assessment of MMT fuel additive.

Methylcyclopentadienyl Manganese Tricarbonyl (MMT) has been shown to be an effective octane enhancer in gasoline. It is presently used in the U.S. in leaded gasoline and in Canada in both leaded and unleaded gasoline. Because MMT has a low vapor pressure and a short half-life in sunlight, it is unlikely that significant concentrations of MMT could occur in the environment as a result of its use as a gasoline additive. Greater than 99.9% of the manganese from MMT is converted into inorganic oxides of manganese during the combustion of MMT-containing gasoline. Authors of several health assessments on MMT concluded the increase in environmental levels of manganese oxides would be slight compared to the natural background levels of manganese and would present no health hazards. Studies showed that MMT usage had no effect on CO emissions, caused a slight decrease in NOx emissions, and a slight increase in HC emissions. MMT usage caused a decrease in NOx + HC emissions in one test and had no effect in another.

Assessment of the arterial input curve for [99mTc]-d,l-HM-PAO by rapid octanol extraction.

The in vitro conversion of the lipophilic molecule [99mTc]-d,l-hexamethylpropyleneamine oxime [( 99mTc]-d,l-HM-PAO) to a hydrophilic form was studied in saline, plasma, and blood at 37 degrees C by paper chromatography and by octanol extraction. The octanol:saline ratio was 79.9. From this value and the corresponding octanol: plasma and octanol:blood partitioning values, an estimate of the transport of the lipophilic compound by various components of blood was made: 20% is carried in hemoglobin, 53% by the plasma proteins and 27% by the water phases of the red blood cell and plasma. Octanol extraction provided a rapid method for measuring the radiochemical purity (RCP) of lipophilic [99mTc]-d,l-HM-PAO. In saline, the RCP declined with a half-life of more than 1 h. In human plasma and whole blood, the conversion of [99mTc]-d,l-HM-PAO was biexponential due to the differences in the conversion rates of the d and l isomeric forms. The initial half-life representing the conversion rate of the l form was 1.7 min in blood and 1.4 min in plasma, while the conversion half-life of the d form was 7.4 and 24.4 min, respectively. In vivo, the RCP of arterial blood sampled after an i.v. bolus injection showed an initial peak value of 75% (68-79%) during the initial, first passage of the bolus. It declined to approximately 35% (29-40%) after 1.5 min and reached very low levels (about 1%) at 6 to 10 min. Quantitative measurements of cerebral blood flow using [99mTc]-d,l-HM-PAO necessitates a rapid method for RCP determination in arterial blood such as the one described here.