Kristin Jensen

STRIKING DECREASE IN THE TOTAL PRECURSOR B-CELL COMPARTMENT DURING EARLY CHILDHOOD AS EVIDENCED BY FLOW CYTOMETRY AND GENE EXPRESSION CHANGES

The number of circulating B-cells in peripheral blood plateaus between 2 and 24 months of age, and thereafter declines gradually. How this reflects the kinetics of the precursor B-cell pool in the bone marrow is of clinical interest, but has not been studied thoroughly in humans. The authors analyzed bone marrow (n = 37) from healthy children and adults (flow cytometry) searching for age-related changes in the total precursor B-cell compartment. In an age-matched cohort (n = 25) they examined age-related global gene expression changes (Affymetrix) in unsorted bone marrow with special reference to the recombination activating gene 1, RAG1. Subsequently, they searched the entire gene set for transcripts correlating to the RAG1 profile to discover other known and possibly new precursor B-cell related transcripts. Both methods disclosed a marked, transient increase of total precursor B-cells at 6–20 months, followed by a rapid decrease confined to the first 2 years. The decline thereafter was considerably slower, but continued until adulthood. The relative composition of total precursor B-cells, however, did not change significantly with age. The authors identified 54 genes that were highly correlated to the RAG1 profile (r ≥ .9, p < 1 × 10−8). Of these 54 genes, 15 were characteristically B-lineage associated like CD19, CD79, VPREB, EBF1, and PAX5; the remaining 39 previously not described as distinctively B-lineage related. The marked, transient increase in precursor B-cells and RAG1 transcriptional activity is not reflected by a similar peak in B-cells in peripheral blood, whereas the sustained plateau concurs in time.

Increased ID2 Levels in Adult Precursor B Cells as Compared with Children Is Associated with Impaired Ig Locus Contraction and Decreased Bone Marrow Output

Precursor B cell production from bone marrow in mice and humans declines with age. Because the mechanisms behind are still unknown, we studied five precursor B cell subsets (ProB, PreBI, PreBII large, PreBII small, immature B) and their differentiation-stage characteristic gene expression profiles in healthy individual toddlers and middle-aged adults. Notably, the composition of the precursor B cell compartment did not change with age. The expression levels of several transcripts encoding V(D)J recombination factors were decreased in adults as compared with children: RAG1 expression was significantly reduced in ProB cells, and DNA-PKcs, Ku80, and XRCC4 were decreased in PreBI cells. In contrast, TdT was 3-fold upregulated in immature B cells of adults. Still, N-nucleotides, P-nucleotides, and deletions were similar for IGH and IGK junctions between children and adults. PreBII large cells in adults, but not in children, showed highly upregulated expression of the differentiation inhibitor, inhibitor of DNA binding 2 (ID2), in absence of changes in expression of the ID2-binding partner E2A. Further, we identified impaired Ig locus contraction in adult precursor B cells as a likely mechanism by which ID2-mediated blocking of E2A function results in reduced bone marrow B cell output in adults. The reduced B cell production was not compensated by increased proliferation in adult immature B cells, despite increased Ki67 expression. These findings demonstrate distinct regulatory mechanisms in B cell differentiation between adults and children with a central role for transcriptional regulation of ID2.

Radiation exposure in patients treated with endovascular aneurysm repair: what is the risk of cancer, and can we justify treating younger patients?

Background Endovascular aneurysm repair (EVAR) is becoming the mainstay treatment of abdominal aortic aneurisms (AAA). The postoperative follow-up regime includes a lifelong series of CT angiograms (CTAs) at different intervals in addition to EVAR, which will confer significant cumulative radiation exposure over time. Purpose To examine the impact of age and follow-up regime over time on cumulative radiation exposure and attributable cancer risk after EVAR. Material and Methods We calculated a mean effective dose (ED) for the EVAR procedure, CTA, and plain abdominal X-rays (PAX). Cumulative ED was calculated for standard, complex, and simplified surveillance over 5, 10, and 15 years for different age groups. Results For EVAR, the mean ED was 34 mSv (range, 12–75 mSv) per procedure. For PAX, the ED was 1.1 mSv (range, 0.3–4.4 mSv), and for CTA it was 8.0 mSv (range, 2–20 mSv). For a 55-year-old man, an attributable cancer risk (ACR) in standard surveillance at 5 and 15 years of follow-up was 0.35% and 0.65%, respectively. The corresponding values were 0.22% and 0.37% for a 75-year-old man. When using a simplified follow-up, the ACRs for a 55-year-old at 5 and 15 years were 0.30% and 0.37%, respectively. These values were 0.18% and 0.21% for a 75-year-old man. A complex follow-up with half-yearly CTA over similar age and time span doubled the ACR. Conclusion Treating younger patients with EVAR poses a low ACR of 0.65% (15-year standard surveillance) compared to a lifetime cancer risk of 44%. A simplified surveillance should be used if treating younger patients, which will halve the ACR over 15 years.

Decreased IL7Rα and TdT expression underlie the skewed immunoglobulin repertoire of human B-cell precursors from fetal origin

Newborns are unable to mount antibody responses towards certain antigens. This has been related to the restricted repertoire of immunoglobulin (Ig) genes of their B cells. The mechanisms underlying the restricted fetal Ig gene repertoire are currently unresolved. We here addressed this with detailed molecular and cellular analysis of human precursor-B cells from fetal liver, fetal bone marrow (BM), and pediatric BM. In the absence of selection processes, fetal B-cell progenitors more frequently used proximal V, D and J genes in complete IGH gene rearrangements, despite normal Ig locus contraction. Fewer N-nucleotides were added in IGH gene rearrangements in the context of low TdT and XRCC4 expression. Moreover, fetal progenitor-B cells expressed lower levels of IL7Rα than their pediatric counterparts. Analysis of progenitor-B cells from IL7Rα-deficient patients revealed that TdT expression and N-nucleotides additions in Dh-Jh junctions were dependent on functional IL7Rα. Thus, IL7Rα affects TdT expression, and decreased expression of this receptor underlies at least in part the skewed Ig repertoire formation in fetal B-cell precursors. These new insights provide a better understanding of the formation of adaptive immunity in the developing fetus.

Image Quality in Oncologic Chest Computerized Tomography With Iterative Reconstruction: A Phantom Study.

Objective The purpose of this study was to validate iterative reconstruction technique in oncologic chest computed tomography (CT). Methods An anthropomorphic thorax phantom with 4 simulated tumors was scanned on a 64-slice CT scanner with 2 different iterative reconstruction techniques: one model based (MBIR) and one hybrid (ASiR). Dose levels of 14.9, 11.1, 6.7, and 0.6 mGy were used, and all images were reconstructed with filtered back projection (FBP) and both iterative reconstruction algorithms. Hounsfield units (HU) and absolute noise were measured in the tumors, lung, heart, diaphragm, and muscle. Contrast-to-noise ratios (CNRs) and signal-to-noise ratios (SNRs) were calculated. Results Model-based iterative reconstruction (MBIR) increased CNRs of the tumors (21.1–192.2) and SNRs in the lung (−49.0–165.6) and heart (3.1–8.5) at all dose levels compared with FBP (CNR, 1.1–23.0; SNR, −7.5–31.6 and 0.2–1.1) and with adaptive statistical iterative reconstruction (CNR, 1.2–33.2; SNR, −7.3–37.7 and 0.2–1.5). At the lowest dose level (0.6 mGy), MBIR reduced the cupping artifact (HU range: 17.0 HU compared with 31.4–32.2). An HU shift in the negative direction was seen with MBIR. Conclusions Quantitative image quality parameters in oncologic chest CT are improved with MBIR compared with FBP and simpler iterative reconstruction algorithms. Artifacts at low doses are reduced. A shift in HU values was shown; thus, absolute HU values should be used with care.

A Liver Phantom Study: Ct Radiation Dose Reduction and Different Image Reconstruction Algorithms Affect Diagnostic Quality

Objective The aim of this study was to evaluate whether iterative reconstruction techniques for different dose levels and/or reduction of tube potential can increase liver lesion detectability. Methods An anthropomorphic liver phantom was scanned at different dose levels (CTDIvol 15 mGy, 7.5 mGy, 5 mGy, and 2.6 mGy) and tube potential levels (120 kV, 100 kV, and 80 kV). Images were reconstructed with the following algorithms: filtered back projection (FBP), adaptive statistical iterative reconstruction (ASiR) 40%, and a model-based iterative reconstruction (Veo). The presence or absence of lesions was assessed independently on a 4-point scale by 4 readers. The areas under the receiver operating characteristic curve were calculated. Results Veo improved detectability of hyperdense liver lesions compared with both FBP and ASiR 40% at most dose levels (15 mGy, 7.5 mGy, and 5 mGy with P < 0.05). Veo also improved detectability at reduced tube potential compared with FBP (120 kV, 100 kV, and 80 kV at 5 mGy with P < 0.05) and ASiR 40% (120 kV and 100 kV at 5 mGy with P < 0.05). For ASiR 40%, the area under the receiver operating characteristic curve was significantly larger compared with FBP only at dose levels 7.5 mGy and 2.6 mGy at 120 kV. In general, the reduction of tube potential reduced the lesion detectability. Conclusions This study shows that iterative reconstruction algorithms, in particular Veo, improve lesion detectability in a liver phantom. However, a too aggressive dose reduction may result in poorer image quality. Results considering different tube potentials diverged, thus careful consideration is necessary upon tube potential reduction.

Improved Liver Lesion Conspicuity With Iterative Reconstruction in Computed Tomography Imaging

Studies on iterative reconstruction techniques on computed tomographic (CT) scanners show reduced noise and changed image texture. The purpose of this study was to address the possibility of dose reduction and improved conspicuity of lesions in a liver phantom for different iterative reconstruction algorithms. An anthropomorphic upper abdomen phantom, specially designed for receiver operating characteristic analysis was scanned with 2 different CT models from the same vendor, GE CT750 HD and GE Lightspeed VCT. Images were obtained at 3 dose levels, 5, 10, and 15mGy, and reconstructed with filtered back projection (FBP), and 2 different iterative reconstruction algorithms; adaptive statistical iterative reconstruction and Veo. Overall, 5 interpreters evaluated the images and receiver operating characteristic analysis was performed. Standard deviation and the contrast to noise ratio were measured. Veo image reconstruction resulted in larger area under curves compared with those adaptive statistical iterative reconstruction and FBP image reconstruction for given dose levels. For the CT750 HD, iterative reconstruction at the 10mGy dose level resulted in larger or similar area under curves compared with FBP at the 15mGy dose level (0.88-0.95 vs 0.90). This was not shown for the Lightspeed VCT (0.83-0.85 vs 0.92). The results in this study indicate that the possibility for radiation dose reduction using iterative reconstruction techniques depends on both reconstruction technique and the CT scanner model used.

Quantitative Measurements Versus Receiver Operating Characteristics and Visual Grading Regression in CT Images Reconstructed with Iterative Reconstruction. A Phantom Study

RATIONALE AND OBJECTIVES This study aimed to evaluate the correlation of quantitative measurements with visual grading regression (VGR) and receiver operating characteristics (ROC) analysis in computed tomography (CT) images reconstructed with iterative reconstruction. MATERIALS AND METHODS CT scans on a liver phantom were performed on CT scanners from GE, Philips, and Toshiba at three dose levels. Images were reconstructed with filtered back projection (FBP) and hybrid iterative techniques (ASiR, iDose, and AIDR 3D of different strengths). Images were visually assessed by five readers using a four- and five-grade ordinal scale for liver low contrast lesions and for 10 image quality criteria. The results were analyzed with ROC and VGR. Standard deviation, signal-to-noise ratios, and contrast-to-noise ratios were measured in the images. RESULTS All data were compared to FBP. The results of the quantitative measurements were improved for all algorithms. ROC analysis showed improved lesion detection with ASiR and AIDR and decreased lesion detection with iDose. VGR found improved noise properties for all algorithms, increased sharpness with iDose and AIDR, and decreased artifacts from the spine with AIDR, whereas iDose increased the artifacts from the spine. The contrast in the spine decreased with ASiR and iDose. CONCLUSIONS Improved quantitative measurements in images reconstructed with iterative reconstruction compared to FBP are not equivalent to improved diagnostic image accuracy.

Choosing the Best Reconstruction Technique in Abdominal Computed Tomography: A Systematic Approach

Objective There is uncertainty regarding the effect of iterative reconstruction (IR) techniques and other reconstruction algorithms on image quality. The aim of this study was to optimize image quality in relation to radiation dose in computed tomography (CT) liver examinations by comparing images reconstructed with different abdominal filters with and without IR. Methods An anthropomorphic phantom was scanned on a Toshiba Aquilion ONE CT scanner. Images at 2 different dose levels were reconstructed with 12 different body reconstruction filters, all with both filtered back-projection and Adaptive Iterative Dose Reduction 3 dimensional. Receiver operating characteristic curves were constructed. The 2 reconstruction combinations with the highest scores from the phantom study were evaluated in a second comparison of clinical images. Six liver examinations were reconstructed with both filters and evaluated using visual grading analysis. Results Two combinations of reconstruction filters and IR were the only 2 options among the 8 best images at both dose levels (area under the curve, 0.96 and 0.94 for 15 mGy as well as 0.86 and 0.84 for 10 mGy). In the patient study, one of these filters in combination with IR scored slightly higher than the other in combination with IR (mean score, 2.60 and 2.57, respectively; P = 0.56). Iterative reconstruction did not significantly increase lesion detectability for any of the filters. Conclusions This study indicates that the preferred choice for reconstruction of CT liver examinations performed with the Toshiba Aquilion ONE should be the FC18 filter with IR, although the IR technique did not significantly improve lesion detectability and did not compensate for the dose reduction in this study.