Rimma Axelsson

An open-label, multicenter, phase 2a study to assess the feasibility of imaging metastases in late-stage cancer patients with the αvβ3-selective angiogenesis imaging agent 99mTc-NC100692

Background: The αvβ3 integrin is one of the angiogenesis-related membrane proteins highly expressed on the neovasculature of breast cancer and lung carcinomas. Labeling of the αvβ3 integrin with 99mTc-NC100692 provides a potential tool for imaging angiogenesis and hence the presence of malignant lesions. Purpose: To determine the feasibility of detecting metastatic lesions in liver, lung, bone, and brain with scintigraphy using the αvβ3-avid imaging agent 99mTc-NC100692 in patients with breast or lung cancer, and to assess its safety profile. Material and Methods: Twenty-five patients—15 with lung cancer and 10 with breast cancer—were recruited at 10 centers. Metastases were newly diagnosed by computed tomography, magnetic resonance imaging, or bone scintigraphy, i.e., the reference standard. Patients underwent whole-body scans of approximately 10–15 min duration beginning at 45 min post-injection and a SPECT acquisition of approximately 30 min beginning at 75 min after injection of up to 1100 MBq 99mTc-NC100692. In case of liver metastases, dynamic acquisitions of 15 min were performed starting immediately post-injection. Safety measurements were performed up to 2.5 hours after injection and included hematology, serum biochemistry, coagulation, urine analysis, vital signs, oximetry, 12-lead ECG assessments, and a physical examination. Results: In patients with breast cancer, 99mTc-NC100692 scintigraphy detected 1 of 7 liver, 4 of 5 lung, 8 of 17 bone, and 1 of 1 brain metastases. The corresponding numbers for lung cancer patients were 0 of 2, 17 of 18, 2 of 2, and 7 of 9. There was overall stability through the follow-up period for all investigated safety parameters. Conclusion: Scintigraphy with 99mTc-NC100692 is feasible for detection of lung and brain metastases from breast and lung cancer, while the detection of liver and bone lesions is poor. The use of 99mTc-NC100692 is safe and well tolerated.

Multimodality imaging using SPECT/CT and MRI and ligand functionalized 99mTc-labeled magnetic microbubbles

BackgroundIn the present study, we used multimodal imaging to investigate biodistribution in rats after intravenous administration of a new 99mTc-labeled delivery system consisting of polymer-shelled microbubbles (MBs) functionalized with diethylenetriaminepentaacetic acid (DTPA), thiolated poly(methacrylic acid) (PMAA), chitosan, 1,4,7-triacyclononane-1,4,7-triacetic acid (NOTA), NOTA-super paramagnetic iron oxide nanoparticles (SPION), or DTPA-SPION.MethodsExaminations utilizing planar dynamic scintigraphy and hybrid imaging were performed using a commercially available single-photon emission computed tomography (SPECT)/computed tomography (CT) system. For SPION containing MBs, the biodistribution pattern of 99mTc-labeled NOTA-SPION and DTPA-SPION MBs was investigated and co-registered using fusion SPECT/CT and magnetic resonance imaging (MRI). Moreover, to evaluate the biodistribution, organs were removed and radioactivity was measured and calculated as percentage of injected dose.ResultsSPECT/CT and MRI showed that the distribution of 99mTc-labeled ligand-functionalized MBs varied with the type of ligand as well as with the presence of SPION. The highest uptake was observed in the lungs 1 h post injection of 99mTc-labeled DTPA and chitosan MBs, while a similar distribution to the lungs and the liver was seen after the administration of PMAA MBs. The highest counts of 99mTc-labeled NOTA-SPION and DTPA-SPION MBs were observed in the lungs, liver, and kidneys 1 h post injection. The highest counts were observed in the liver, spleen, and kidneys as confirmed by MRI 24 h post injection. Furthermore, the results obtained from organ measurements were in good agreement with those obtained from SPECT/CT.ConclusionsIn conclusion, microbubbles functionalized by different ligands can be labeled with radiotracers and utilized for SPECT/CT imaging, while the incorporation of SPION in MB shells enables imaging using MR. Our investigation revealed that biodistribution may be modified using different ligands. Furthermore, using a single contrast agent with fusion SPECT/CT/MR multimodal imaging enables visualization of functional and anatomical information in one image, thus improving the diagnostic benefit for patients.

Lack of accuracy for the proposed 'Dubois criteria' in Alzheimer's disease: a validation study from the Swedish brain power initiative.

Background/Aims: Our purpose was to investigate whether the new research criteria for Alzheimer’s disease proposed in 2007 by Dubois et al. are valid in a naturalistic memory clinic sample. Method: Retrospective diagnostic analyses were carried out to compare the traditional diagnostic criteria for dementia with the new criteria suggested by Dubois et al. No patient had gone through all procedures postulated as additional features in the proposed new Dubois criteria. Material: Two independent experienced geriatricians re-examined 150 complete patients’ records. The study physicians were blinded to any of the results of the core and additional features suggested by Dubois et al. to avoid circular diagnostic bias. Results:Among our 96 patients with a clinical diagnosis of subjective cognitive impairment and/or mild cognitive impairment, 2 of the patients with subjective cognitive impairment and 5 patients with mild cognitive impairment would classify as pre-dementia Alzheimer’s disease according to the Dubois criteria. In our 23 Alzheimer patients diagnosed clinically, only 12 of the cases fulfilled the criteria for Alzheimer’s disease suggested by Dubois et al. Interpretation: The proposed new criteria for Alzheimer’s disease are valid in 55% of our patients clinically diagnosed as having full-blown Alzheimer dementia. Additionally, 7.3% ‘true’ Alzheimer cases will be identified in a group of 96 clinically non-demented patients. Our results show that there is a large heterogeneity in a clinical naturalistic sample of patients with an Alzheimer phenotype. Conclusion: There is a need to further validate the currently existing biomarkers in large unselected samples and avoid the pitfall of workup bias and circular diagnostic processes. Additionally, valid age-specific cut-off values for the diagnostic markers in question have to be defined.

Comparison between visual assessment of MTA and hippocampal volumes in an elderly, non-demented population.

Background It is important to have a replicable easy method for monitoring atrophy progression in Alzheimers disease. Volumetric methods for calculating hippocampal volume are time-consuming and commonly used in research. Visual assessments of medial temporal lobe atrophy (vaMTA) is a rapid method for clinical use. This method has not been tested in a large non-demented population in comparison with volumetry mesurements. Since hippocampal volume decreases with time even in normal aging there is also a need to study the normal age differences of medial temporal lobe atrophy. Purpose To compare visual assessment of medial temporal lobe atrophy (vaMTA) with hippocampal volume in a healthy, non-demented elderly population. To describe normal ageing using vaMTA. Material and Methods Non-demented individuals aged 60, 66, 72, 78, 81, 84, and ≥87 years old were recruited from the Swedish National study on Ageing and Care in Kungsholmen (SNAC-K), Sweden. Standard magnetic resonance imaging (MRI) scans, vaMTA, and calculations of hippocampal volumes were performed in 544 subjects. Results Significant correlation (rs = −0.32, P < 0.001, sin; and rs = −0.26, P < 0.001, dx) was found between hippocampal volume measurements and vaMTA. In normal ageing, almost 95% of ≤66-year-olds had a medial temporal lobe atrophy (MTA) score ≤1, with possible scores ranging from 0 to 4. Subjects aged 72, 78, and 81 years scored ≤2, while the two oldest age groups had scores ≤3. Conclusion There was a highly significant correlation between volumetric measurements of the hippocampus and MTA scoring. In normal ageing, there is increasing MTA score. For non-demented elderly individuals ≤70 years, an MTA score of 0–1 may be considered normal, compared with MTA ≤2 for 70–80-years and MTA 3 for >80-year-old individuals.

Overtime reliability of medial temporal lobe atrophy rating in a clinical setting

Background Medial temporal lobe atrophy (MTA) is one of the first magnetic resonance imaging (MRI) signs in patients with Alzheimers disease (AD) and used as a measure of disease progression. Visual assessment of MTA is easy to perform but the reliability of MTA rating over time has not been studied. Purpose To investigate what happens to the MTA rating scores if two radiologists rate the same MRI scans six times over a period of 1 year. Material and Methods One hundred outpatients were included in this study. All patients underwent MRI with a protocol and sequences used for geriatric patients, according to local clinical standards. One neuroradiologist and one general radiologist independently of each other performed retrospective visual assessments of MTA six times, using the same scans, over a period of 1 year. Results Intra-rater kappa varied between κ 0.65 and 0.84 for the neuroradiologist and κ 0.38 and 0.74 for the general radiologist. Intra-rater weighted kappa (wκ) values showed almost perfect agreement for both investigators (wκ 0.83–0.94). Inter-rater reliability showed fair to moderate agreement, with the kappa value varying from κ 0.29 to 0.48 and weighted kappa values ranging from wκ 0.72 to 0.84. There was a statistically significant difference in rating between the two investigators. Conclusion Visual assessment of MTA repeated over time has a high grade of reproducibility when performed by an experienced investigator. The reproducibility drops when assessment is rarely performed. Inter-rater reliability is low when two investigators not working together are compared.

Quantitative Assessment of 99mTc-Depreotide Uptake in Patients with Non-Small-Cell Lung Cancer: Immunohistochemical Correlations

Background: Somatostatin receptor (SSTR) scintigraphy with 99mTc-depreotide is used for differential diagnosis of solitary pulmonary nodules. The method is based on SSTR expression in cancer tissue. Purpose: To estimate the expression of SSTRs in non-small-cell lung cancer (NSCLC) in vitro, and to determine the correlation between 99mTc-depreotide uptake in vivo and different tumor characteristics determined in vitro, such as tumor grade, and presence of SSTR2, MIB-1, and p53. Material and Methods: A total of 127 patients with lung lesions detected on computed tomography (CT) were investigated with SSTR scintigraphy after injection of 740 MBq 99mTc-depreotide. This study includes 19 patients with NSCLC with histologically proven diagnosis. The quantitative evaluation of 99mTc-depreotide was performed using region-of-interest analysis and includes tumor counts/cm3, background counts/cm3, and the ratio between tumor and background counts. Results: 99mTc-depreotide uptake was found in all NSCLC tumors, which expressed SSTR2 defined in vitro by immunochemical methods. SSTR2 expression was negatively correlated to the degree of the tumors differentiation (P<0.05). 99mTc-depreotide uptake in tumor cells did not correlate with tumor grade, or SSTR2, MIB-1, or p53 expression. Conclusion: There is an expression of SSTRs in NSCLC. The degree of tumor differentiation correlates negatively with SSTR2 measured in vitro and positively with MIB-1 expression in tumor tissue. No correlation was found between 99mTc-depreotide uptake and possible prognostic factors such as MIB-1 and p53 expression in tumor cells in NSCLC. Lastly, no correlation was found between 99mTc-depreotide uptake and tumor grade or SSTR2 expression.

Bolus Compared with Continuous Infusion of Microbubble Contrast Agent Using Real-Time Contrast Harmonic Imaging Ultrasound in Breast Tumors

Background: Contrast-enhanced ultrasound (CEUS) has gained interest because of its ability to gather vascular information in various organs. There is still a matter of debate concerning its value in breast lesions. The method of choice on how to administer the contrast agent varies depending on the organ to be studied. Infusion of microbubbles is used in echocardiography, while bolus administration is the preferred technique for abdominal organs. Purpose: To compare—in equal doses—bolus versus continuous infusion of microbubbles, using real-time contrast harmonic imaging in breast tumors. Material and Methods: A total of 29 female patients (mean age 54 years) with either clear malignant or benign findings in the breast or axilla were included. Contrast harmonic imaging (CHI US) was performed with a Philips iU22 using an L9-3 MHz linear probe, especially designed for this purpose. A low mechanical index (0.06–0.07) was used to avoid massive destruction of the microbubbles. A dose of 2.4 ml of Sono Vue was first infused intravenously over 1 min with an infusion pump. After 10 min, the same dose was injected as a bolus over 2 s, followed by a flush of 10 ml of saline solution. Contrast uptakes by the tumors were recorded 2 min from the moment of injection, with both methods for each patient. Results: Bolus administration of contrast agent provided a sharply demarcated enhancement and wash-out pattern for all lesions. The continuous infusion of the same contrast agent failed to show any wash-in/wash-out or time-to-peak/peak intensity phenomena in all cases. Conclusion: CEUS using real-time harmonic imaging in order to evaluate breast tumors should be performed with bolus administration of contrast agent in order to achieve better intensity/time curve outcomes.

Differentiation between benign and malignant breast tumors using kinetic features of real-time harmonic contrast-enhanced ultrasound

Background Contrast-enhanced ultrasound (CEUS) has gained interest because of its ability to gather vascular information in diverse organs. There is still a subject of debate concerning its value in breast lesions, especially as a differential diagnostic tool. Purpose To investigate whether kinetic parameters of CEUS can differentiate between malignant and benign breast lesions. Material and Methods We evaluated 75 malignant and 21 benign lesions in the breast or axilla. Contrast harmonic imaging (CHI) US was performed after the injection of a bolus dose of 2.4 mL of Sono Vue® (Bracco, Milano, Italy). The following parameters were calculated for kinetic analysis: initial slope, time to peak enhancement, wash-out ratios W21 and W50 (relative decrease in signal intensity from the peak enhancement to 21 s and 50 s, respectively). Results A significant difference was found between the benign and malignant lesions in time-to-peak (P value <0.05) and wash-out ratios W21 (P value <0.001) and W50 (P value <0.001). The mean time-to-peak was 9.3 s for malignant and 14.6 s for benign lesions. The mean signal drop from peak to signal intensity measured at 50 s was 85% for malignant and 66% for benign lesions. There was no difference in absolute values of peak signal intensity and initial slope. The most significant difference between standardized benign and malignant wash-out curves was found at 21 s but statistical significance was reached in the range of 14–50 s. Conclusion Real-time CEUS can evolve into a new non-invasive option for differentiate malignant from benign breast lesions.

Treatment of Severe Chronic Graft-Versus-Host Disease with Decidual Stromal Cells and Tracing with 111Indium Radiolabeling

Decidual stromal cells (DSCs) isolated from fetal membranes of term placentas are easily expanded and are highly immunosuppressive in vitro. These cells express high levels of integrins that are of importance in homing to inflamed tissues. In this study, we investigated DSCs as a cellular therapy for chronic graft-versus-host disease (cGvHD), a severe complication after allogeneic hematopoietic stem cell transplantation. Subsequent to transplantation, three patients developed severe extensive cGvHD and were treated with DSCs (1-2.8 × 10(6) cells/kg). One-third of the DSCs administered to two patients were labeled with (111)Indium, and the in vivo distribution was tracked for 48 h. The (111)In-labeled DSCs were initially located in the lungs, followed by dissemination to the liver and spleen. The DSCs induced a partial response in two of the patients. Blood samples from the patients were extensively evaluated by flow cytometry, luminex, and enzyme-linked immunosorbent assay. The nonresponder had the highest proportion of T-cells with Th17 and Th2 phenotypes and the highest median plasma concentrations of IL-17 and IL-4. The same patient also had high frequencies of HLA-DR(+) T-cells and regulatory T-cells. To conclude, DSCs are safe to infuse with no adverse effects. We determined how stromal cells are distributed in vivo after infusion in a cGvHD setting. The methods established for analysis of blood samples will be useful in determining the effect of DSCs in a study comprising a larger patient material. This pilot study may provide a basis for further controlled investigations with DSCs in a clinical setting.

Voxel-Based Correlation between Coregistered Single-Photon Emission Computed Tomography and Dynamic Susceptibility Contrast Magnetic Resonance Imaging in Subjects with Suspected Alzheimer Disease

Background: Current diagnosis of Alzheimer disease is made by clinical, neuropsychologic, and neuroimaging assessments. Neuroimaging techniques such as magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT) could be valuable in the differential diagnosis of Alzheimer disease, as well as in assessing prognosis. Purpose: To compare SPECT and MRI in a cohort of patients examined for suspected dementia, including patients with no objective cognitive impairment (control group), mild cognitive impairment (MCI), and Alzheimer disease (AD). Material and Methods: 24 patients, eight with AD, 10 with MCI, and six controls, were investigated with SPECT using 99mTc-hexamethylpropyleneamine oxime (HMPAO, Ceretec; GE Healthcare Ltd., Little Chalsont UK) and dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) with a contrast-enhancing gadobutrol formula (Gadovist; Bayer Schering Pharma, Berlin, Germany). Voxel-based correlation between coregistered SPECT and DSC-MR images was calculated. Region-of-interest (ROI) analyses were then performed in 24 different brain areas using brain registration and analysis of SPECT studies (BRASS; Nuclear Diagnostics AB, Stockholm, Sweden) on both SPECT and DSC-MRI. Results: Voxel-based correlation between coregistered SPECT and DSC-MR showed a high correlation, with a mean correlation coefficient of 0.94. ROI analyses of 24 regions showed significant differences between the control group and AD patients in 10 regions using SPECT and five regions in DSC-MR. Conclusion: SPECT remains superior to DSC-MRI in differentiating normal from pathological perfusion, and DSC-MRI could not replace SPECT in the diagnosis of patients with Alzheimer disease.