Nasreddin Abolmaali

Infarct remodeling after intracoronary progenitor cell treatment in patients with acute myocardial infarction (TOPCARE-AMI): mechanistic insights from serial contrast-enhanced magnetic resonance imaging.

Background—Experimental and initial clinical studies suggest that transplantation of circulating blood– (CPC) or bone marrow–derived (BMC) progenitor cells may beneficially affect postinfarction remodeling processes after acute myocardial infarction (AMI). To relate functional characteristics of the infused cells to quantitative measures of outcome at 4-month follow-up, we performed serial contrast-enhanced MRI and assessed the migratory capacity of the transplanted progenitor cells immediately before intracoronary infusion. Methods and Results—In 28 patients with reperfused AMI receiving either BMCs or CPCs into the infarct artery 4.7±1.7 days after AMI, serial contrast-enhanced MRI performed initially and after 4 months revealed a significant increase in global ejection fraction (from 44±10% to 49±10%; P =0.003), a decrease in end-systolic volume (from 69±26 to 60±28 mL; P =0.003), and unchanged end-diastolic volumes (122±34 versus 117±37 mL; P =NS). Infarct size, measured as late enhancement (LE) volume, decreased significantly, from 46±32 to 37±28 mL (P <0.05). There was a significant correlation between the reduction in LE volume and global ejection fraction improvement. The migratory capacity of transplanted cells as assessed ex vivo toward a gradient of vascular endothelial growth factor for CPCs and stromal cell derived factor-1 for BMCs was closely correlated with the reduction of LE volume. By multivariate analysis, migratory capacity remained the most important independent predictor of infarct remodeling. Conclusions—Analysis of serial contrast-enhanced MRI suggests that intracoronary infusion of adult progenitor cells in patients with AMI beneficially affects postinfarction remodeling processes. The migratory capacity of the infused cells is a major determinant of infarct remodeling, disclosing a causal effect of progenitor cell therapy on regeneration enhancement.

Cathepsin L is required for endothelial progenitor cell-induced neovascularization

Infusion of endothelial progenitor cells (EPC), but not of mature endothelial cells, promotes neovascularization after ischemia. We performed gene expression profiling of EPC and endothelial cells to identify genes that might be important for the neovascularization capacity of EPC. Notably, the protease cathepsin L (CathL) was highly expressed in EPC as opposed to endothelial cells and was essential for matrix degradation and invasion by EPC in vitro. CathL-deficient mice showed impaired functional recovery following hind limb ischemia, supporting the concept of a crucial role for CathL in postnatal neovascularization. Infused CathL-deficient progenitor cells neither homed to sites of ischemia nor augmented neovascularization. Forced expression of CathL in mature endothelial cells considerably enhanced their invasive activity and sufficed to confer their capacity for neovascularization in vivo. We concluded that CathL has a critical role in the integration of circulating EPC into ischemic tissue and is required for EPC-mediated neovascularization.

Exploratory prospective trial of hypoxia-specific PET imaging during radiochemotherapy in patients with locally advanced head-and-neck cancer

PURPOSE To explore in a prospective trial the prognostic value of hypoxia imaging before and during radiochemotherapy in patients with locally advanced head and neck cancer. PATIENTS AND METHODS Twenty-five patients with stage III/IV head and neck cancer were investigated with [(18)F]-fluoromisonidazole (FMISO) PET/CT at four time points during radiochemotherapy (baseline, 8-10 Gy, 18-20 Gy,50-60 Gy). FMISO PET/CT image parameters were extracted including maximum-tumour-to-background (TBR(max)) and thresholded volume at different TBR ratios. CT volume and baseline FDG-PET/CT image parameters were also included. Parameters at all time points were investigated for their prognostic value with the local-progression-free-survival endpoint (LPFS). Significance was evaluated with multivariate Cox (including clinical parameters) and Log-rank tests. RESULTS FMISO-image parameters were found to have a strong association with the LPFS endpoint, and were strongest at the week 1 and 2 time points (p = 0.023-0.048 and 0.042-0.061 respectively on multivariate Cox). Parameters measured at baseline were only significant on univariate analysis. None of the clinical parameters, and also FDG- or CT-delineated volumes, were significantly associated with LPFS. CONCLUSION This prospective, exploratory study demonstrated that FMISO-PET/CT imaging during the initial phase of treatment carries strong prognostic value. FMISO-PET/CT imaging at 1 or 2 weeks during treatment could be promising way to select patients that would benefit from hypoxia modification or dose-escalated treatment. A validation study is on-going.

Olfactory bulb volumes in patients with idiopathic Parkinson's disease : a pilot study

Summary.Olfactory loss is among early signs of idiopathic Parkinson’s disease (IPD). The present pilot study aimed to investigate whether this loss would be reflected in a decreased volume of the olfactory bulb (OB) established through magnetic resonance imaging. Eleven consecutive IPD patients were compared to 9 healthy, age-matched controls. Results indicated that there is little or no difference between IPD patients and healthy controls in terms of OB volume. Based upon the relation between loss of olfactory input to the olfactory bulb and consecutive decrease in volume, these data support the idea that olfactory loss in IPD is not a primary consequence of damage to the olfactory epithelium but rather results from central-nervous changes.

Increasing olfactory bulb volume due to treatment of chronic rhinosinusitis—a longitudinal study

Differentiation of progenitor cells into neurons in the olfactory bulb depends on olfactory stimulation that can lead to an increase in olfactory bulb volume. In this study, we investigated whether the human olfactory bulb volume increases with increasing olfactory function due to treatment of chronic rhinosinusitis. Nineteen patients with chronic rhinosinusitis were investigated before and after treatment. For comparison, additional measurements were performed in 18 healthy volunteers. Volumetric measurements of the olfactory bulb were based on planimetric manual contouring of magnetic resonance scans. Olfactory function was evaluated separately for each nostril using tests for odour threshold, odour discrimination and odour identification. Measurements were performed on two occasions, 3 months apart. In healthy controls, the olfactory bulb volume did not change significantly between the two measurements. In contrast, the olfactory bulb volume in patients increased significantly from the initial 64.5 +/- 3.2 to 70.0 +/- 3.5 mm(3) on the left side (P = 0.02) and from 60.9 +/- 3.5 to 72.4 +/- 2.8 mm(3) on the right side (P < 0.001). The increase in olfactory bulb volume correlated significantly with an increase in odour thresholds (r = 0.60, P = 0.006, left side; r = 0.49, P = 0.03, right side), but not with changes in odour discrimination or odour identification. Results of this study support the idea that stimulation of olfactory receptor neurons impacts on the cell death in the olfactory bulb, not only in rodents but also in humans. To our knowledge, this is the first longitudinal study that describes an enlargement of the human olfactory bulb due to improvement of peripheral olfactory function.

Additional PET/CT in week 5-6 of radiotherapy for patients with stage III non-small cell lung cancer as a means of dose escalation planning?

BACKGROUND AND PURPOSE Loco-regional failure after radiotherapy with total doses of 60-70 Gy for non-small cell lung cancer (NSCLC) remains a major clinical problem. Escalation of radiation dose is often limited because of exceeding normal tissue constraints. The present study was designed to test the hypothesis that a reduction in disease volume during radiotherapy detected by FDG PET/CT would facilitate radiation dose escalation, whilst remaining within normal tissue constraints. MATERIALS AND METHODS Ten patients with localised inoperable NSCLC were prospectively enrolled. Each received standard 3D-conformally planned radiotherapy to a dose of 66 Gy in 33 fractions over 6.5 weeks. FDG PET/CT imaging in the treatment position was performed prior to treatment and repeated following 50 or 60 Gy. CT and PET-delineated gross tumour volumes were generated and a composite created. A margin of 15mm was added in all planes to form the planning target volume (PTV). Treatment planning was performed to compare two dose escalation strategies: 78 Gy delivered to the initial PTV with treatment in two phases (shrinking field), i.e., 66 Gy to the initial PTV with a 12 Gy-boost to the PTV after 50/60 Gy. As an alternative planning approach the maximal dose without exceeding normal tissue constraints was evaluated for each patient (individualized dose prescription). RESULTS There was a median PTV reduction after 50/60 Gy of 20%. Delivering 78 Gy to the initial PTV could have been achieved in 4/10 patients. Of the remaining 6, delivering 78 Gy to the initial PTV would have exceeded normal tissue constraints and no benefit was seen when delivered in two phases. The results from the individualized dose prescription indicated a higher median maximal dose when treatment would be given in two phases compared to one phase resulting in a modest increase of calculated tumour control probability. CONCLUSIONS Our data suggest that despite tumour shrinkage determined by subsequent FDG PET/CT during treatment the tested adaptive targeting strategy would result only in a modest improvement in the context of dose escalation. Further studies on the optimal use of FDG PET/CT and other approaches for dose escalation in loco-regionally advanced NSCLC are warranted.

Performance assessment of dynamic spiral scan modes with variable pitch for quantitative perfusion computed tomography.

Purpose:Perfusion computed tomography is increasingly being used in diagnostic radiology. Axial coverage of the traditional approach is limited to the width of the detector. Using continuous periodic table movement coverage can be increased beyond this limit. In this study, we compared tissue flow values determined from scans with a periodic spiral implementation with variable pitch with ones determined from standard dynamic scan modes. Methods:A flow phantom (preserved porcine kidney) was scanned with 2 settings of a periodic spiral (Adaptive 4D Spiral) with a range of 100 and 148 mm and a temporal sampling of 1.5 seconds. Additionally, the whole phantom was scanned with the standard dynamic mode (detector width 38.4 mm, temporal sampling 1.0 seconds) at various overlapping positions as a reference. Scan parameters (80 kV, 140 mAs, 40s scan time) were selected similar to a typical brain perfusion study. All scans were repeated 5 times. Tissue flow was calculated with a dedicated deconvolution algorithm. In a center slice and 3 additional slices at various off center positions flow values were recorded in a total of 126 regions of interest (ROI). Reproducibility was determined from the variation of the repeat scans. Agreement between periodic spirals and standard mode was determined by Bland Altman plots and correlation analysis. Results:The reproducibility of the tissue flow determination ranged from 2.7 to 4.4 mL/100 mL/min and was similar for all scan modes. The coefficient of variation ranged from 3.9% to 6.1%. Mean tissue flow in the 126 ROIs ranged from 35 to 121 mL/100 mL/min. There was excellent correlation between both periodic spiral ranges and the standard dynamic mode with a Pearson correlation coefficient of r = 0.97. The regression slope (intercept 0) for the 100 mm range was 1.01, for the 148 mm range it was 0.97. The absolute differences per ROI varied between 1.5 and 4.1 mL/100 mL/min, the relative differences between 1.9% and 6.5%. Differences did not depend on the slice location. Conclusions:Periodic spiral scan modes with variable pitch and a sampling rate of 1.5 seconds can be used for the quantitative determination of tissue flow. Their performance is equivalent to equidistant sampling with standard dynamic scan modes. The ranges of 100 and 148 mm investigated allow coverage of the whole brain or an entire organ for perfusion imaging.

Comment on "Developing DCE-CT to Quantify Intra-Tumor Heterogeneity in Breast Tumors With Differing Angiogenic Phenotype

The objective of this study is to evaluate the ability of dynamic contrast enhanced computed tomography (DCE-CT) to assess intratumor physiological heterogeneity in tumors with different angiogenic phenotypes. DCE-CT imaging was performed on athymic nude mice bearing xenograft wild type (MCF-7neo) and VEGF-transfected (MCF-7VEGF) tumors by using a clinical multislice CT, and compared to skeletal muscle. Parametrical maps of tumor physiology-perfusion (F), permeability-surface area (PS), fractional intravascular plasma (fp), and interstitial space ( fis)-were obtained by fitting the time-dependent contrast-enhanced curves to a two-compartmental kinetic model for each voxel (0.3 x 0.3 x 0.75 mm3). Mean physiological measurements were compared with positron emission tomography (PET) imaging, and the spatial distribution of tumor vasculature was compared with histology. No statistically significant difference was found in mean physiological values of F, PS, and fp in MCF-7neo and muscle, while fis of MCF-7neo was a factor of two higher (p<0.04). MCF-7neo tumors also showed a radial heterogeneity with significant higher physiological values in periphery than those in middle and core regions (p<0.01 for all physiological parameters). MCF-7VEGF tumors demonstrated significant increases in all physiological parameters compared with MCF-7neo tumors, and a distinct saccular heterogeneous pattern compared with MCF-7neo and muscle. Both PET imaging and histological results showed good correlation with the above results for this same mouse model. No statistically significant difference was found in the mean perfusion and intravascular volume measured by PET imaging and DCE-CT. Increases in cross-sectional area of blood vessels (p<0.002) were observed in MCF-7VEGF tumors than MCF-7neo, and their spatial distribution correlated well with the spatial distribution of fp obtained by DCE-CT. The results of this study demonstrated the feasibility of DCE-CT in quantification of spatial heterogeneity in tumor physiology in small animal models. Monitoring variations in the tumor environment using DCE-CT offers an in vivo tool for the evaluation and optimization of new therapeutic strategies.The objective of this study is to evaluate the ability of dynamic contrast enhanced computed tomography (DCE-CT) to assess intratumor physiological heterogeneity in tumors with different angiogenic phenotypes. DCE-CT imaging was performed on athymic nude mice bearing xenograft wild type (MCF-7neo) and VEGF-transfected (MCF-7VEGF) tumors by using a clinical multislice CT, and compared to skeletal muscle. Parametrical maps of tumor physiology-perfusion (F), permeability-surface area (PS), fractional intravascular plasma (fp), and interstitial space ( fis)-were obtained by fitting the time-dependent contrast-enhanced curves to a two-compartmental kinetic model for each voxel (0.3 x 0.3 x 0.75 mm3). Mean physiological measurements were compared with positron emission tomography (PET) imaging, and the spatial distribution of tumor vasculature was compared with histology. No statistically significant difference was found in mean physiological values of F, PS, and fp in MCF-7neo and muscle, while fis of MCF-7neo was a factor of two higher (p<0.04). MCF-7neo tumors also showed a radial heterogeneity with significant higher physiological values in periphery than those in middle and core regions (p<0.01 for all physiological parameters). MCF-7VEGF tumors demonstrated significant increases in all physiological parameters compared with MCF-7neo tumors, and a distinct saccular heterogeneous pattern compared with MCF-7neo and muscle. Both PET imaging and histological results showed good correlation with the above results for this same mouse model. No statistically significant difference was found in the mean perfusion and intravascular volume measured by PET imaging and DCE-CT. Increases in cross-sectional area of blood vessels (p<0.002) were observed in MCF-7VEGF tumors than MCF-7neo, and their spatial distribution correlated well with the spatial distribution of fp obtained by DCE-CT. The results of this study demonstrated the feasibility of DCE-CT in quantification of spatial heterogeneity in tumor physiology in small animal models. Monitoring variations in the tumor environment using DCE-CT offers an in vivo tool for the evaluation and optimization of new therapeutic strategies.

Serial FDG-PET on patients with head and neck cancer: Implications for radiation therapy

Purpose: To assess possible consequences for radiotherapy (RT) planning, e.g., reduction of treatment volume by a decreased tumour volume in Fluor-18-fluoro-deoxy-glucose-Positron emission tomography (FDG-PET) based on a close-meshed evaluation of FDG uptake in primary head and neck cancer (HNC) during RT. Materials and method: PET data were analysed using a source-to-background based algorithm. The following parameters were obtained: max. standardised uptake value (SUVmax), PET-based gross tumour volume (GTV-PET) and metabolic volume (MV). Results: While the median SUVmax decreased (initial: 15.2, 1st/2nd week: 10.2, 3rd/4th week: 6.5, 5th/6th week: 6.4), the median values of GTV-PET (9.3 cm3, 12.4 cm3, 14.0 cm3, 17.9 cm3) and MV (92.2 cm3, 61.7 cm3, 60.0 cm3, 71.3 cm3) seemed to increase during radiotherapy. The intra-individual development of SUVmax could be divided into two groups: group A having continuously decreasing values of SUVmax (n = 10 patients), and group B having a temporary increase of SUVmax (n = 13). Conclusions: Data suggest that a reduction of treatment volume is not possible by an adaptive re-planning based on FDG-PET, e.g., at 50 Gy. This may be caused by a consecutive therapy associated inflammation. This limitation is probably related to the use of a source-to-background based algorithm.

Pathology of the Olfactory Nerve

The olfactory system and especially the olfactory bulb (OB) as the first relay in the olfactory system represent highly plastic structures. For example, OB volume partly reflects the degree of afferent neural activity. Research indicates that smell deficits leading to a reduced sensory input result in structural changes at the level of the OB. Reduced OB volumes also may be considered characteristic of parosmia. Apart from discussing the clinical implications of these findings, the radiologic basics for assessment of olfactory-eloquent structures are addressed in detail.