Within-patient comparison between [68Ga]Ga-tilmanocept PET/CT lymphoscintigraphy and [99mTc]Tc-tilmanocept lymphoscintigraphy for sentinel lymph node detection in oral cancer: a pilot study.

PURPOSE: To compare sentinel lymph node (SLN) identification using [68Ga]Ga-tilmanocept PET/CT lymphoscintigraphy to [99mTc]Tc-tilmanocept lymphoscintigraphy (including SPECT/CT) in early-stage oral cancer. Furthermore, to assess whether reliable intraoperative SLN localization can be performed with a conventional portable gamma-probe using [99mTc]Tc-tilmanocept without the interference of [68Ga]Ga-tilmanocept in these patients. METHODS: This prospective within-patient comparison pilot study evaluated SLN identification by [68Ga]Ga-tilmanocept PET/CT lymphoscintigraphy compared to conventional lymphoscintigraphy using [99mTc]Tc-tilmanocept (~ 74 MBq) in 10 early-stage oral cancer patients scheduled for SLN biopsy. After conventional [99mTc]Tc-tilmanocept lymphoscintigraphy, patients underwent peritumoral administration of [68Ga]Ga-tilmanocept (~ 10 MBq) followed by PET/CT acquisition initiated 15 min after injection. Intraoperative SLN localization was performed under conventional portable gamma-probe guidance the next day; the location of harvested SLNs was correlated to both lymphoscintigraphic images in each patient. RESULTS: A total of 24 SLNs were identified by [99mTc]Tc-tilmanocept lymphoscintigraphy, all except one were also identified by [68Ga]Ga-tilmanocept PET/CT lymphoscintigraphy. [68Ga]Ga-tilmanocept PET/CT lymphoscintigraphy identified 4 additional SLNs near the injection site, of which two harbored metastases. Lymphatic vessels transporting [68Ga]Ga-tilmanocept were identified by PET/CT lymphoscintigraphy in 80% of patients, while draining lymphatic vessels were visualized by [99mTc]Tc-tilmanocept lymphoscintigraphy in 20% of patients. Of the 33 SLNs identified by [68Ga]Ga-tilmanocept PET/CT lymphoscintigraphy, 30 (91%) were intraoperatively localized under conventional gamma-probe guidance. CONCLUSION: [68Ga]Ga-tilmanocept PET/CT lymphoscintigraphy provided more accurate identification of SLNs and improved visualization of lymphatic vessels compared to [99mTc]Tc-tilmanocept lymphoscintigraphy. When combined with peritumoral administration of [99mTc]Tc-tilmanocept, SLNs detected by [68Ga]Ga-tilmanocept PET/CT lymphoscintigraphy can be reliably localized during surgery under conventional gamma-probe guidance.

CXCR4 expression in glioblastoma tissue and the potential for PET imaging and treatment with [68Ga]Ga-Pentixafor /[177Lu]Lu-Pentixather.

PURPOSE: CXCR4 (over)expression is found in multiple human cancer types, while expression is low or absent in healthy tissue. In glioblastoma it is associated with a poor prognosis and more extensive infiltrative phenotype. CXCR4 can be targeted by the diagnostic PET agent [68Ga]Ga-Pentixafor and its therapeutic counterpart [177Lu]Lu-Pentixather. We aimed to investigate the expression of CXCR4 in glioblastoma tissue to further examine the potential of these PET agents. METHODS: CXCR4 mRNA expression was examined using the R2 genomics platform. Glioblastoma tissue cores were stained for CXCR4. CXCR4 staining in tumor cells was scored. Stained tissue components (cytoplasm and/or nuclei of the tumor cells and blood vessels) were documented. Clinical characteristics and information on IDH and MGMT promoter methylation status were collected. Seven pilot patients with recurrent glioblastoma underwent [68Ga]Ga-Pentixafor PET; residual resected tissue was stained for CXCR4. RESULTS: Two large mRNA datasets (N = 284; N = 540) were assesed. Of the 191 glioblastomas, 426 cores were analyzed using immunohistochemistry. Seventy-eight cores (23 tumors) were CXCR4 negative, while 18 cores (5 tumors) had both strong and extensive staining. The remaining 330 cores (163 tumors) showed a large inter- and intra-tumor variation for CXCR4 expression; also seen in the resected tissue of the seven pilot patients-not directly translatable to [68Ga]Ga-Pentixafor PET results. Both mRNA and immunohistochemical analysis showed CXCR4 negative normal brain tissue and no significant correlation between CXCR4 expression and IDH or MGMT status or survival. CONCLUSION: Using immunohistochemistry, high CXCR4 expression was found in a subset of glioblastomas as well as a large inter- and intra-tumor variation. Caution should be exercised in directly translating ex vivo CXCR4 expression to PET agent uptake. However, when high CXCR4 expression can be identified with [68Ga]Ga-Pentixafor, these patients might be good candidates for targeted radionuclide therapy with [177Lu]Lu-Pentixather in the future.

Blood and urine analyses after radioembolization of liver malignancies with [166Ho]Ho-acetylacetonate-poly(l-lactic acid) microspheres.

BACKGROUND: [166Ho]Ho-acetylacetonate-poly(L-lactic acid) microspheres were used in radioembolization of liver malignancies by intra-arterial administration. The primary aim of this study was to assess the stability and biodistribution of these microspheres. MATERIALS AND METHODS: Peripheral blood and urine samples were obtained from two clinical studies. Patient and in vitro experiment samples were analyzed using inductively coupled plasma mass spectrometry (ICP-MS), gamma-ray spectroscopy, light microscopy, Coulter particle counting, and high performance liquid chromatography (HPLC). RESULTS: The median percentage holmium compared to the total amount injected into the hepatic artery was 0.19% (range 0.08-2.8%) and 0.32% (range 0.03-1.8%) in the 1 h blood plasma and 24 h urine, respectively. Both the blood plasma and urine were correlated with the neutron irradiation exposure required for [166Ho]Ho-AcAc-PLLA microsphere production (ρ = 0.616, p = 0.002). After a temporary interruption of the phase 2 clinical study, the resuspension medium was replaced to precipitate [166Ho]Ho3+ pre-administration using phosphate. The in vitro near-maximum neutron irradiation experiments showed significant [166Ho]Ho-AcAc-PLLA microsphere damage. CONCLUSION: The amount of holmium in the peripheral blood and urine samples after [166Ho]Ho-AcAc-PLLA microsphere intrahepatic infusion was low. A further decrease was observed after reformulation of the resuspension solution but minimization of production damage is necessary.

Treatment of fetal tachycardia with sotalol: transplacental pharmacokinetics and pharmacodynamics.

OBJECTIVES: The aim of this study was to investigate the pharmacokinetics and pharmacodynamics of sotalol in the treatment of fetal tachycardia. BACKGROUND: Maternally administered, intrauterine therapy of fetal tachycardia is dependent on the transplacental passage of the antiarrhythmic agent. METHODS: In a prospective study of patients treated for fetal tachycardia with sotalol, concentrations of sotalol were determined in maternal and umbilical blood and in amniotic fluid, and the relationship between these concentrations and the occurrence of conversion to sinus rhythm was investigated. RESULTS: Eighteen fetal patients were studied, nine with atrial flutter and nine with supraventricular tachycardia. Fourteen were treated with sotalol; 13 converted to sinus rhythm, of whom 2 relapsed. There was one intrauterine death. Four patients were treated with sotalol and digoxin, of whom two were treated successfully. Mean birth weight was 3,266 g. The daily maternal sotalol dose was linearly related to the maternal plasma concentration. The mean fetal/maternal sotalol plasma concentration was 1.1 (range 0.67 to 2.87, SD 0.63), and the mean amniotic fluid/fetal blood ratio of sotalol was 3.2 (range 1.28 to 5.8, SD 1.4). The effectiveness of sotalol therapy could not be extrapolated from maternal blood levels. CONCLUSIONS: Sotalol is a potent antiarrhythmic agent in the treatment of fetal tachycardia. The placental transfer is excellent. Sotalol accumulates in amniotic fluid but not in the fetus itself. Therefore it seems that renal excretion in the fetus is efficient and greater than the oral absorption by fetal swallowing. The maternal blood level is not a reliable predictor of the chances of success of therapy. Sotalol is not associated with fetal growth restriction.

Effect of cytochrome P450 2D6 genotype on maternal paroxetine plasma concentrations during pregnancy.

BACKGROUND AND OBJECTIVE: Increasing numbers of women in childbearing years are treated with antidepressants. Concerns regarding fetal exposure to medication has led to large studies on drug effects on birth outcome and on the risk of congenital anomalies. The risk of adverse effects due to paroxetine use during pregnancy has been associated with the extent of exposure. Nevertheless, few studies have covered dosing aspects in order to minimize fetal antidepressant exposure while limiting the risk of treatment failure. Essential pharmacokinetic data in pregnancy are lacking, even regarding paroxetine, one of the most commonly used antidepressants. We examined the changes of maternal paroxetine concentrations during pregnancy in relation to cytochrome P450 (CYP) 2D6 genotype. METHOD: An observational cohort study was conducted in 74 pregnant women aged from 25 to 45 years treated with paroxetine during pregnancy. Blood samples and information on dosing, weight, smoking and mood were provided at 16-20, 27-31 and 36-40 weeks of pregnancy. Samples were analysed for paroxetine plasma concentrations and CYP2D6 genotype. RESULTS: Women who were genotyped as extensive metabolizers (EMs) or ultra-rapid metabolizers (UMs) for CYP2D6 (EM n = 43; UM n = 1) showed steadily decreasing plasma paroxetine concentrations during the course of pregnancy, with a decrease of 0.3 microg/L (95% CI -0.58, -0.07) for each week of pregnancy. In contrast, plasma paroxetine concentrations of intermediate metabolizers (IMs [n = 25]) and poor metabolizers (PMs [n = 5]) increased during pregnancy, resulting in an increase of 0.82 microg/L (95% CI 0.42, 1.22) for each week of pregnancy. Weight gain, maternal age or smoking did not influence plasma drug concentrations. Decreasing plasma concentrations in EMs are in accordance with induced CYP2D6 activity during pregnancy. Accumulation of paroxetine in women with impaired CYP2D6 metabolism may be explained by competition with an endogenous substrate. In EMs/UMs the depressive symptoms increased significantly during the course of pregnancy, while in the IM/PM group these did not change. CONCLUSIONS: Differences in CYP2D6 genotype may have divergent effects on maternal plasma paroxetine concentrations during pregnancy, with therapeutic consequences. Accumulation of paroxetine in a considerable group of pregnant women will lead to unintended increased exposure of paroxetine to the unborn child. Knowledge about a patient's CYP2D6 genotype is indispensable when prescribing paroxetine in pregnancy [trialregister.nl Identifier ISRCTN25383361].

Population pharmacokinetics of allopurinol in full-term neonates with perinatal asphyxia.

In newborn infants, allopurinol is being tested as a free radical scavenger to prevent brain damage caused by reperfusion and oxygenation after perinatal hypoxia and ischemia (birth asphyxia). To develop rational dosing schemes for future studies, knowledge of the pharmacokinetics in this patient group is essential. In the present study, a population pharmacokinetic model was designed and validated for allopurinol in this specific patient group. One-compartment and 2-compartment models were fitted to plasma concentration time data of 24 newborns entered in 2 clinical trials using nonlinear mixed effects modeling. A bootstrap procedure was performed to check the robustness of the model. The data were best described using a 1-compartment model with linear elimination. Estimated pharmacokinetic parameters were volume of the central compartment (V, 0.79 L/kg) and total body clearance (CL, 0.078 L/h/kg), with 42% and 60% interindividual variability, respectively. The median values for these parameters of 1000 bootstrap replicates were very similar (95% confidence intervals were 0.67 to 0.96 and 0.054 to 0.10 for V and CL, respectively), indicating the robustness of the model. A population pharmacokinetic model has been designed and validated which adequately describes the data of 2 clinical studies in critically ill newborn infants. The model will be used to design dosing strategies for future evaluation of the benefits of allopurinol in these patients.