Topical drug delivery in chronic rhinosinusitis patients before and after sinus surgery using pulsating aerosols.

OBJECTIVES: Chronic rhinosinusitis (CRS) is a common chronic disease of the upper airways and has considerable impact on quality of life. Topical delivery of drugs to the paranasal sinuses is challenging, therefore the rate of surgery is high. This study investigates the delivery efficiency of a pulsating aerosol in comparison to a nasal pump spray to the sinuses and the nose in healthy volunteers and in CRS patients before and after sinus surgery. METHODS: (99m)Tc-DTPA pulsating aerosols were applied in eleven CRSsNP patients without nasal polyps before and after sinus surgery. In addition, pulsating aerosols were studied in comparison to nasal pump sprays in eleven healthy volunteers. Total nasal and frontal, maxillary and sphenoidal sinus aerosol deposition and lung penetration were assessed by anterior and lateral planar gamma camera imaging. RESULTS: In healthy volunteers nasal pump sprays resulted in 100% nasal, non-significant sinus and lung deposition, while pulsating aerosols resulted 61.3+/-8.6% nasal deposition and 38.7% exit the other nostril. 9.7+/-2.0 % of the nasal dose penetrated into maxillary and sphenoidal sinuses. In CRS patients, total nasal deposition was 56.7+/-13.3% and 46.7+/-12.7% before and after sinus surgery, respectively (p<0.01). Accordingly, maxillary and sphenoidal sinus deposition was 4.8+/-2.2% and 8.2+/-3.8% of the nasal dose (p<0.01). Neither in healthy volunteers nor in CRS patients there was significant dose in the frontal sinuses. CONCLUSION: In contrast to nasal pump sprays, pulsating aerosols can deliver significant doses into posterior nasal spaces and paranasal sinuses, providing alternative therapy options before and after sinus surgery. Patients with chronic lung diseases based on clearance dysfunction may also benefit from pulsating aerosols, since these diseases also manifest in the upper airways.

Calibration of gamma camera systems for a multicentre European ¹²³I-FP-CIT SPECT normal database.

PURPOSE: A joint initiative of the European Association of Nuclear Medicine (EANM) Neuroimaging Committee and EANM Research Ltd. aimed to generate a European database of [(123)I]FP-CIT single photon emission computed tomography (SPECT) scans of healthy controls. This study describes the characterization and harmonization of the imaging equipment of the institutions involved. METHODS: (123)I SPECT images of a striatal phantom filled with striatal to background ratios between 10:1 and 1:1 were acquired on all the gamma cameras with absolute ratios measured from aliquots. The images were reconstructed by a core lab using ordered subset expectation maximization (OSEM) without corrections (NC), with attenuation correction only (AC) and additional scatter and septal penetration correction (ACSC) using the triple energy window method. A quantitative parameter, the simulated specific binding ratio (sSBR), was measured using the "Southampton" methodology that accounts for the partial volume effect and compared against the actual values obtained from the aliquots. Camera-specific recovery coefficients were derived from linear regression and the error of the measurements was evaluated using the coefficient of variation (COV). RESULTS: The relationship between measured and actual sSBRs was linear across all systems. Variability was observed between different manufacturers and, to a lesser extent, between cameras of the same type. The NC and AC measurements were found to underestimate systematically the actual sSBRs, while the ACSC measurements resulted in recovery coefficients close to 100% for all cameras (AC range 69-89%, ACSC range 87-116%). The COV improved from 46% (NC) to 32% (AC) and to 14% (ACSC) (p < 0.001). CONCLUSION: A satisfactory linear response was observed across all cameras. Quantitative measurements depend upon the characteristics of the SPECT systems and their calibration is a necessary prerequisite for data pooling. Together with accounting for partial volume, the correction for scatter and septal penetration is essential for accurate quantification.

Pulsating airflow and drug delivery to paranasal sinuses.

PURPOSE OF REVIEW: There is a high incidence of nasal disorders, including chronic rhinosinusitis (CRS), affecting about 14% of the total population. Topical treatment regimens show only limited efficacy of drug delivery to the posterior nose and paranasal sinuses. Nevertheless, the primary treatment option of CRS is a combination of topical or systemic steroids, antibiotics and functional endonasal sinus surgery (FESS). RECENT FINDINGS: Sinus ventilation and paranasal aerosol deposition can be achieved by using pulsating airflow. Studies using pulsating airflow in nasal casts and in healthy volunteers have shown that up to 8% of the nasally deposited drug can deposit within the sinuses, which could not be achieved using nasal pump sprays. In addition, compared with nasal pump sprays, retention kinetics of the radiolabel deposit in the nose was prolonged. SUMMARY: With this efficiency, topical aerosol therapies of sinus disorders can be achieved and, due to the prolonged retention, reduced application modes are possible. This offers new treatment options of sinus-nasal disorders prior or after FESS.

Clinical potential of pulsating aerosol for sinus drug delivery.

There is a high incidence of nasal disorders including chronic rhinosinusitis (CRS), affecting ∼ 14% of the total population. However, a topical treatment regimen shows only modest efficacy, and drug delivery to the posterior nose, osteomeatal area, and paranasal sinuses is still a challenge. Therefore, the primary treatment option of CRS is functional endonasal sinus surgery (FESS). Most nasally administered aerosolized drugs are efficiently filtered by the nasal valve and do not reach the sinuses, the site of chronic inflammation. Sinus ventilation, nasal and paranasal aerosol deposition can be achieved by using a pulsating airflow, offering new topical treatment options for nasal disorders. Inhalation studies in nasal casts and in healthy volunteers have shown up to 8% of the nasally deposited drug within the sinuses, which could not be achieved using nasal pump sprays. In addition, compared with nasal pump sprays, retention kinetics of the radiolabel deposit in the nose was prolonged by about a factor of five. With this efficiency, topical aerosol therapies of sinus disorders can be achieved and, owing to the prolonged retention, reduced application modes are possible. This offers new treatment options of sinus-nasal disorders in comparison with or after FESS.

Thymosin beta4 is an essential paracrine factor of embryonic endothelial progenitor cell-mediated cardioprotection.

BACKGROUND: Prolonged myocardial ischemia results in cardiomyocyte loss despite successful revascularization. We have reported that retrograde application of embryonic endothelial progenitor cells (eEPCs) provides rapid paracrine protection against ischemia-reperfusion injury. Here, we investigated the role of thymosin beta4 (Tbeta4) as a mediator of eEPC-mediated cardioprotection. METHODS AND RESULTS: In vitro, neonatal rat cardiomyocytes were subjected to hypoxia-reoxygenation in the absence or presence of eEPCs with or without Tbeta4 short hairpin RNA (shRNA) transfection. In vivo, pigs (n=9 per group) underwent percutaneous left anterior descending artery occlusion for 60 minutes on day 1. After 55 minutes of ischemia, control eEPCs (5x10(6) cells) or cells transfected with Tbeta4 shRNA when indicated or 15 mg Tbeta4 alone were retroinfused into the anterior interventricular vein. Segmental endocardial shortening in the infarct zone at 150-bpm atrial pacing, infarct size (triphenyl tetrazolium chloride viability and methylene blue exclusion), and inflammatory cell influx (myeloperoxidase activity) were determined 24 hours later. Survival of neonatal rat cardiomyocytes increased from 32+/-4% to 90+/-2% after eEPC application, an effect sensitive to shRNA transfection compared with Tbeta4 (45+/-7%). In vivo, infarct size decreased with eEPC application (38+/-4% versus 54+/-4% of area at risk; P<0.01), an effect abolished by Tbeta4 shRNA (62+/-3%). Segmental subendocardial shortening improved after eEPC treatment (22+/-3% versus -3+/-4% of control area) unless Tbeta4 shRNA was transfected (-6+/-4%). Retroinfusion of Tbeta4 mimicked eEPC application (infarct size, 37+/-3%; segmental endocardial shortening, 34+/-7%). Myeloperoxidase activity (3323+/-388 U/mg in controls) was decreased by eEPCs (1996+/-546 U/mg) or Tbeta4 alone (1455+/-197 U/mg) but not Tbeta4 shRNA-treated eEPCs (5449+/-829 U/mg). CONCLUSIONS: Our findings show that short-term cardioprotection derived by regional application of eEPCs can be attributed, at least in part, to Tbeta4.

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.

Selective internal radiation therapy with SIR-Spheres in patients with nonresectable liver tumors.

AIM: Transarterial embolization of branches of the hepatic artery with biocompatible 90Y-labeled microspheres (SIR-Spheres) is a local treatment modality for patients with liver tumors, which, most recently, has become available in Europe. The aim of this study was to evaluate the feasibility and efficacy of this selective internal radiation therapy (SIRT). METHODS: Twenty-three patients with nonresectable hepatic metastases or hepatocellular carcinoma nonresponding to polychemotherapy and/or other local treatment were treated with SIRT. SIR-Spheres (mean activity, 2270 MBq) were administered by gentle intra-arterial infusion in the hepatic artery. A follow-up was documented by fluorodeoxyglucose-positron emission tomography (FDG-PET), course of tumor markers, and computed tomography (CT). RESULTS: Common minor side-effects were abdominal pain, nausea, and fever. Mild pancreatitis and peptic ulceration were observed once each. Currently, all patients are still alive, with survival times ranging from 11 to 518 days from SIRT up to the present. Three-month follow-up investigations are available in 13 of 23 patients, which, so far, are showing a marked decrease of FDG uptake, a drop of tumor markers, and unchanged or slightly decreasing lesion size (CT) in 10 of 13 patients. Two patients showed stable findings, while another patient showed progressive disease. Long-term follow-up investigations are available in 2 of 23 patients, showing hepatic and extrahepatic progression 6 and 9 months after SIRT. CONCLUSIONS: Our initial experience confirms that SIRT is a promising local therapeutic approach in patients with nonresectable liver tumors which is feasible and has an acceptable toxicity profile. Prospective data on comparing this treatment alone or in combination with other modalities are needed to answer whether long-term survival in this unfavorable stage of disease can be markedly improved.

Radiation exposure of patients undergoing whole-body dual-modality 18F-FDG PET/CT examinations.

UNLABELLED: We investigated radiation exposure of patients undergoing whole-body 18F-FDG PET/CT examinations at 4 hospitals equipped with different tomographs. METHODS: Patient doses were estimated by using established dose coefficients for 18F-FDG and from thermoluminescent measurements performed on an anthropomorphic whole-body phantom. RESULTS: The most relevant difference between the protocols examined was the incorporation of CT as part of the combined PET/CT examination: Separate low-dose CT scans were acquired at 2 hospitals for attenuation correction of emission data in addition to a contrast-enhanced CT scan for diagnostic evaluation, whereas, at the other sites, contrast-enhanced CT scans were used for both purposes. Nevertheless, the effective dose per PET/CT examination was similar, about 25 mSv. CONCLUSION: The dosimetric concepts presented in this study provide a valuable tool for the optimization of whole-body 18F-FDG PET/CT protocols. Further reduction of patient exposure can be achieved by modifications to the existing hardware and software of PET/CT systems.

Selective pressure-regulated retroinfusion of fibroblast growth factor-2 into the coronary vein enhances regional myocardial blood flow and function in pigs with chronic myocardial ischemia.

OBJECTIVES: We sought to improve regional myocardial delivery and subsequent collateral perfusion induced by basic fibroblast growth factor-2 (FGF-2) using selective pressure-regulated retroinfusion of coronary veins for delivery. This hypothesis was tested in a newly developed pig model with percutaneous induction of chronic ischemia. BACKGROUND: Selective pressure-regulated retroinfusion of coronary veins is a catheter-based procedure that has been shown to provide effective regional delivery of drugs and gene vectors into ischemic myocardium. METHODS: A high-grade stenosis with subsequent progression to total occlusion within 28 days was induced by implanting a reduction stent graft into the left anterior descending artery (LAD). After seven days, a 30-min retroinfusion (anterior cardiac vein) was performed with (n = 7) or without (n = 7) 150 microg FGF-2 and compared with a 30-min antegrade infusion of 150 microg FGF-2 into the LAD (n = 7). Sonomicrometry to assess regional myocardial function at rest and during pacing, and microspheres to assess regional myocardial blood flow, were performed 28 days after implantation of the reduction stent. RESULTS: Retroinfusion of FGF-2 compared favorably with controls and with antegrade infusion of FGF-2 with regard to regional myocardial function at rest (18.5 +/- 4.1% vs. 5.7 +/- 2.9% vs. 7.9 +/- 1.8%, respectively, p < 0.05) and during pacing. Regional myocardial blood flow was also higher in the LAD territory after retroinfusion of FGF-2 (1.07 +/- 0.14 vs. 0.66 +/- 0.07 vs. 0.72 +/- 0.17 ml x min(-1) x g(-1), p < 0.05). CONCLUSIONS: Selective pressure-regulated retroinfusion increased tissue binding of FGF-2 and enhanced functionally relevant collateral perfusion compared with antegrade intracoronary delivery in pigs with chronic myocardial ischemia.