S100A8/A9 is a major component of the acute phase of inflammation, and appears to regulate cell proliferation, redox regulation and chemotaxis. We previously reported that S100A8/S100A9 are ...upregulated in the premetastatic lung. However, the detailed mechanisms by which S100A8 contributes to tumor progression have not been elucidated. In this study, we investigated the TLR4/MD-2 dependency by S100A8 on tumor progression. We found that S100A8 (2-89) peptide stimulated cell migration in a manner dependent on TLR4, MD-2 and MyD88. The S100A8 (2-89) peptide also activated p38 and NF-κB in TLR4-dependent manner. The peptide induced the upregulation of both IL-6 and Ccl2 in peritoneal macrophages obtained from wild-type mice, but not TLR4-deficient mice. We then investigated the responsible region of S100A8 for TLR4/MD-2 binding by a binding assay, and found that C-terminal region of S100A8 binds to TLR4/MD-2 complex. To further evaluate the TLR4 dependency on tumor microenvironment, Lewis lung carcinoma-bearing mice were treated with Eritoran, an antagonist of TLR4/MD-2 complex. We found that both tumor volume and pulmonary recruitment of myeloid-derived suppressor cells were reduced with the treatment of Eritoran for five consecutive days. Eritoran reduced the development of tumor vasculature, and increased tumor-infiltration of CD8(+) T-cells. Taken together, S100A8 appears to play a crucial role in the activation of the TLR4/MD-2 pathway and the promotion of a tumor growth-enhancing immune microenvironment.
As both the immune system and the blood-brain barrier (BBB) are likely to be developmentally immature in the perinatal period, neonatal gene transfer may be useful for the treatment of lysosomal ...storage disease (LSD) with neurological involvements such as metachromatic leukodystrophy (MLD). In this experiment, we examined the feasibility of single-strand adeno-associated viral serotype-9 (ssAAV9)-mediated systemic neonatal gene therapy of MLD mice. ssAAV9 vector expressing human arylsulfatase A (ASA) and green fluorescent protein (GFP) (ssAAV9/ASA) was injected into the jugular vein of newborn MLD mice. High levels of ASA expression were observed in the muscle and heart for at least 15 months. ASA was continuously secreted into plasma without development of antibodies against ASA. Global gene transfer into the brain and spinal cord (SC), across the BBB, and long-term ASA expression in the central nervous system were detected in treated mice. Significant inhibition of the accumulation of sulfatide (Sulf) in the brain and cervical SC was confirmed by Alcian blue staining and biochemical analysis of the Sulf content. In a behavior test, treated mice showed a greater ability to traverse narrow balance beams than untreated mice. These data clearly demonstrate that MLD mice model can be effectively treated through neonatal systemic injection of ssAAV9/ASA.
Abstract Objectives The purpose of this study was to evaluate lesion detectability of a dedicated breast positron-emission tomography (dbPET) scanner for breast cancers with an updated reconstruction ...mode, comparing it to whole-body positron-emission tomography/computed tomography (WB-PET/CT). Materials and methods A total of 179 histologically-proven breast cancer lesions in 150 females who underwent both WB-PET/CT and dbPET with18 F-fluorodeoxyglucose were retrospectively analyzed. The patient/breast/lesion-based sensitivities based on visual analysis were compared between dbPET and WB-PET/CT. For lesions visible on both PET images, SUVmax values of the tumors were measured, and tumor-to-background ratios (T/B ratios) of SUVmax were compared between the two scans. Subgroup analyses according to clinical tumor stage, histopathology and histological grade were also performed. Results Patient/breast/lesion-based sensitivities were 95%, 95%, and 92%, respectively, for dbPET, and 95%, 94%, and 88%, respectively, for WB-PET/CT. Mean ± standard deviation SUVmax values of FDG-avid tumors were 13.0 ± 9.7 on dbPET and 6.4 ± 4.8 on WB-PET. T/B ratios were also significantly higher in dbPET than in WB-PET/CT (8.1 ± 7.1 vs. 5.1 ± 4.5). In the subgroup analysis, no significant differences in sensitivities between dbPET and WB-PET/CT were found. However, T/B ratios of dbPET were significantly higher than those of WB-PET/CT in cT1c, cT2, cT3, invasive cancer, invasive carcinoma of no special type, mucinous carcinoma and Grades 1–3. Conclusion No significant differences in sensitivities were identified between dbPET using an updated reconstruction mode and WB-PET/CT; however, T/B ratios of dbPET were significantly higher than those of WB-PET/CT, indicating higher tumor conspicuity on dbPET.
Objectives
Dedicated breast PET (dbPET) systems have improved the detection of small breast cancers but have increased false-positive diagnoses due to an increased chance of noise detection. This ...study examined whether reproducibility assessment using paired images helped to improve noise discrimination and diagnostic performance in dbPET.
Methods
This study included 21 patients with newly diagnosed breast cancer who underwent
18
FFDG-dbPET and contrast-enhanced breast MRI. A 10-min dbPET data scan was acquired per breast, and two sets of reconstructed images were generated (named dbPET-1 and dbPET-2, respectively), each of which consisted of randomly allocated 5-min data from the 10-min data. Uptake spots higher than the background were indexed for the study with visual assessment. All indexed uptakes on dbPET-1 were evaluated using dbPET-2 for reproducibility. MRI findings based on the Breast Imaging-Reporting and Data System (BI-RADS) 2013 were used as the gold standard. Uptake spots that corresponded to BI-RADS 1 on MRI were considered noise, while those with BI-RADS 4b–6 were considered malignancies. The diagnostic performance of dbPET for malignancy was evaluated using four different criteria: any uptake on dbPET-1 regarded as positive (criterion A), a subjective visual assessment of dbPET-1 (criterion B), reproducibility assessment between dbPET-1 and dbPET-2 (criterion C), and a combination of B and C (criterion D).
Results
A total of 213 indexed uptake spots were identified on dbPET-1, including 152, 15, 6, 6, and 34 lesions classified as BI-RADS MRI categories 1, 2, 4b, 4c, and 5, respectively. Overall, 31.9% of the index uptake values were reproducible. All malignant lesions were reproducible, whereas 93.4% of noise was not reproducible. The sensitivities for malignancy for criteria A, B, C, and D were 100%, 91.3%, 100%, and 91.3%, respectively, with positive predictive values (PPVs) of 21.4%, 68.9%, 67.6%, and 82.4%, respectively.
Conclusions
Our results demonstrated that reproducibility assessment helped reduce false-positive findings caused by noise on dbPET without lowering the sensitivity for malignancy. While subjective visual assessment was also efficient in increasing PPV, it occasionally missed malignant uptake.
The aim of this work was to evaluate the performance characteristics of a newly developed dedicated breast PET scanner, according to National Electrical Manufacturers Association (NEMA) NU 4-2008 ...standards.
The dedicated breast PET scanner consists of 4 layers of a 32 × 32 lutetium oxyorthosilicate-based crystal array, a light guide, and a 64-channel position-sensitive photomultiplier tube. The size of a crystal element is 1.44 × 1.44 × 4.5 mm. The detector ring has a large solid angle with a 185-mm aperture and an axial coverage of 155.5 mm. The energy windows at depth of interaction for the first and second layers are 400-800 keV, and those at the third and fourth layers are 100-800 keV. A fixed timing window of 4.5 ns was used for all acquisitions. Spatial resolution, sensitivity, counting rate capabilities, and image quality were evaluated in accordance with NEMA NU 4-2008 standards. Human imaging was performed in addition to the evaluation.
Radial, tangential, and axial spatial resolution measured as minimal full width at half maximum approached 1.6, 1.7, and 2.0 mm, respectively, for filtered backprojection reconstruction and 0.8, 0.8, and 0.8 mm, respectively, for dynamic row-action maximum-likelihood algorithm reconstruction. The peak absolute sensitivity of the system was 11.2%. Scatter fraction at the same acquisition settings was 30.1% for the rat-sized phantom. Peak noise-equivalent counting rate and peak true rate for the ratlike phantom was 374 kcps at 25 MBq and 603 kcps at 31 MBq, respectively. In the image-quality phantom study, recovery coefficients and uniformity were 0.04-0.82 and 1.9%, respectively, for standard reconstruction mode and 0.09-0.97 and 4.5%, respectively, for enhanced-resolution mode. Human imaging provided high-contrast images with restricted background noise for standard reconstruction mode and high-resolution images for enhanced-resolution mode.
The dedicated breast PET scanner has excellent spatial resolution and high sensitivity. The performance of the dedicated breast PET scanner is considered to be reasonable enough to support its use in breast cancer imaging.
Purpose
To compare the diagnostic value of conventional, bilateral diffusion‐weighted imaging (DWI) and high‐resolution targeted DWI of known breast lesions.
Materials and Methods
Twenty‐one ...consecutive patients with known breast cancer or suspicious breast lesions were scanned with the conventional bilateral DWI technique, a high‐resolution, reduced field of view (rFOV) DWI technique, and dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) (3.0 T). We compared bilateral DWI and rFOV DWI quantitatively by measuring the lesions' apparent diffusion coefficient (ADC) values. For qualitative comparison, three dedicated breast radiologists scored image quality and performed lesion interpretation.
Results
In a phantom, ADC values were in good agreement with the reference values. Twenty‐one patients (30 lesions: 14 invasive carcinomas, 10 benign lesions of which 5 cysts, 3 high‐risk, and 3 in situ carcinomas) were included. Cysts and high‐risk lesions were excluded from the quantitative analysis. Quantitatively, both bilateral and rFOV DWI measured lower ADC values in invasive tumors than other lesions. In vivo, rFOV DWI gave lower ADC values than bilateral DWI (1.11 × 10‐3 mm2/s vs. 1.24 × 10‐3 mm2/s, P = 0.002). Regions of interest (ROIs) were comparable in size between the two techniques (2.90 vs. 2.13 cm2, P = 0.721). Qualitatively, all three radiologists scored sharpness of rFOV DWI images as significantly higher than bilateral DWI (P ≤ 0.002). Receiver operating characteristic (ROC) curve analysis showed a higher area under the curve (AUC) in BI‐RADS classification for rFOV DWI compared to bilateral DWI (0.71 to 0.93 vs. 0.61 to 0.76, respectively).
Conclusion
Tumor morphology can be assessed in more detail with high‐resolution DWI (rFOV) than with standard bilateral DWI by providing significantly sharper images. J. MAGN. RESON. IMAGING 2015. J. MAGN. RESON. IMAGING 2015;42:1656–1665.
Purpose
This study aimed to investigate the incidence of rim uptake (RU) or multifocal uptake (MU) by invasive breast cancers on a ring-type dedicated breast positron emission tomography (dbPET) ...scanner compared with whole-body PET (wbPET) scanner imaging and to correlate uptake patterns with pathological features and prognosis.
Methods
Between 2009 and 2011, 76 lesions in 74 patients with primary invasive breast cancers were included. Each patient underwent dbPET and wbPET scanning on the same day after administration of
18
F-fluorodeoxyglucose (FDG). The images were evaluated to identify specific uptake patterns (RU and MU). Their association with pathological characteristics and prognosis was analyzed.
Results
On dbPET, RU and MU patterns were observed in 18 lesions (24%) and 28 lesions (37%), respectively. On wbPET, RU and MU patterns were observed in six lesions (8%) and 17 lesions (22%), respectively. Lesions with RU on dbPET were of higher grade than lesions without RU (
P
= 0.024) and a higher Ki-67 index (mean; 31% vs. 18%,
P
= 0.015). They tended to be triple-negative (33% vs. 12%,
P
= 0.046) and less likely to be luminal A subtype (17% vs. 47%,
P
= 0.020). On wbPET, however, no significant differences in these markers were seen between RU and non-RU. The MU pattern did not correlate with pathological characteristics in either scanner. Lesions with RU or MU were not significantly associated with disease-free survival.
Conclusions
DbPET can identify detailed FDG distribution patterns of breast cancer better than wbPET. Breast cancer with RU on dbPET was associated with higher grade and triple-negative subtype.
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