Deep Learning How to Fit an Intravoxel Incoherent Motion Model to Diffusion-Weighted MRI

Purpose: This prospective clinical study assesses the feasibility of training a deep neural network (DNN) for intravoxel incoherent motion (IVIM) model fitting to diffusion-weighted magnetic resonance imaging (DW-MRI) data and evaluates its performance. Methods: In May 2011, ten male volunteers (age range: 29 to 53 years, mean: 37 years) underwent DW-MRI of the upper abdomen on 1.5T and 3.0T magnetic resonance scanners. Regions of interest in the left and right liver lobe, pancreas, spleen, renal cortex, and renal medulla were delineated independently by two readers. DNNs were trained for IVIM model fitting using these data; results were compared to least-squares and Bayesian approaches to IVIM fitting. Intraclass Correlation Coefficients (ICC) were used to assess consistency of measurements between readers. Intersubject variability was evaluated using Coefficients of Variation (CV). The fitting error was calculated based on simulated data and the average fitting time of each method was recorded. Results: DNNs were trained successfully for IVIM parameter estimation. This approach was associated with high consistency between the two readers (ICCs between 50 and 97%), low intersubject variability of estimated parameter values (CVs between 9.2 and 28.4), and the lowest error when compared with least-squares and Bayesian approaches. Fitting by DNNs was several orders of magnitude quicker than the other methods but the networks may need to be re-trained for different acquisition protocols or imaged anatomical regions. Conclusion: DNNs are recommended for accurate and robust IVIM model fitting to DW-MRI data. Suitable software is available at (1)

Development of micro-computed tomography for human fetal post-mortem imaging

Perinatal autopsy is an essential way of assessing the cause of fetal loss during pregnancy. However, parents are reluctant to consent to an invasive autopsy. Modern imaging techniques can offer a non-invasive solution, but most current clinical techniques are unable to offer adequate image resolution for early gestation miscarriages, typically below 20weeks gestation or 300g body weight. This thesis describes evaluating micro-CT imaging for this purpose, culminating in developing a pragmatic clinical protocol. Within this thesis, five aspects are evaluated: 1. Scan preparation. The optimal concentration and immersion time for I2KI was established, with a formula to predict the immersion time required for full iodination. 2. Imaging parameters. Optimal micro-CT imaging parameters were investigated, comparing the signal-to-noise (SNR) and relative contrast-to-noise ratio (rCNR) across different settings. 3. Patient factors. The effect of demographics/external factors on image quality was evaluated. Maceration was identified as having the greatest detriment to image quality, yet high image quality was attained in the majority of scans. Fetal weight and number of projections were also noted to be positive predictors. 4. Image SNR / rCNR. Assessments were tested across whole fetus organ volumes with imaging parameters defined as 110kV, 200µA, 250ms, 2frames-per-projection, enabling a single anatomical area to be optimally imaged within a clinically relevant timeframe, <30minutes. 5. Parental experience. A pilot study consisting of parents who have experienced a miscarriage was also undertaken. Response to the technique was overwhelmingly positive, with key potential benefits being increased choice and uptake of autopsy investigations with multiple mental health benefits. Finally, the future direction of this work within the clinical setting is presented. The clinical impact of the research is to be able to offer parents a more acceptable non-invasive imaging investigation following miscarriage

Metabolic rate of major organs and tissues in young adult South Asian women

BACKGROUND/OBJECTIVES: Major organ-specific and tissue-specific metabolic rate (Ki) values were initially estimated using in vivo methods, and values reported by Elia (Energy metabolism: tissue determinants and cellular corollaries, Raven Press, New York, 1992) were subsequently supported by statistical analysis. However, the majority of work to date on this topic has addressed individuals of European descent, whereas population variability in resting energy metabolism has been reported. We aimed to estimate Ki values in South Asian females. // SUBJECTS/METHODS: This cross-sectional study recruited 70 healthy young women of South Asian ancestry. Brain and organs were measured using magnetic resonance imaging, skeletal muscle mass by dual-energy X-ray absorptiometry, fat mass by the 4-component model, and whole-body resting energy expenditure by indirect calorimetry. Organ and tissue Ki values were estimated indirectly using regression analysis through the origin. Preliminary analysis suggested overestimation of heart mass, hence the modeling was repeated with a literature-based 22.5% heart mass reduction. // RESULTS: The pattern of derived Ki values across organs and tissues matched that previously estimated in vivo, but the values were systematically lower. However, adjusting for the overestimation of heart mass markedly improved the agreement. // CONCLUSIONS: Our results support variability in Ki values among organs and tissues, where some are more metabolically “expensive” than others. Initial findings suggesting lower organ/tissue Ki values in South Asian women were likely influenced by heart mass estimation bias. The question of potential ethnic variability in organ-specific and tissue-specific energy metabolism requires further investigation

In Vivo Detection of Extrapancreatic Insulin Gene Expression in Diabetic Mice by Bioluminescence Imaging

Extrapancreatic tissues such as liver may serve as potential sources of tissue for generating insulin-producing cells. The dynamics of insulin gene promoter activity in extrapancreatic tissues may be monitored in vivo by bioluminescence-imaging (BLI) of transgenic mice Tg(RIP-luc) expressing the firefly luciferase (luc) under a rat-insulin gene promoter (RIP).The Tg(RIP-luc) mice were made diabetic by a single injection of the pancreatic beta-cell toxin streptozotocin. Control mice were treated with saline. Mice were subject to serum glucose measurement and bioluminescence imaging daily. On day eight of the treatment, mice were sacrificed and tissues harvested for quantitative luciferase activity measurement, luciferase protein cellular localization, and insulin gene expression analysis.Streptozotocin-induced diabetic Tg(RIP-luc) mice demonstrated a dramatic decline in the BLI signal intensity in the pancreas and a concomitant progressive increase in the signal intensity in the liver. An average of 5.7 fold increase in the liver signal intensity was detected in the mice that were exposed to hyperglycemia for 8 days. Ex vivo quantitative assays demonstrated a 34-fold induction of the enzyme activity in the liver of streptozotocin-treated mice compared to that of the buffer-treated controls. Luciferase-positive cells with oval-cell-like morphology were detected by immunohistochemistry in the liver samples of diabetic mice, but not in that of non-treated control transgenic mice. Gene expression analyses of liver RNA confirmed an elevated expression of insulin genes in the liver tissue exposed to hyperglycemia.BLI is a sensitive method for monitoring insulin gene expression in extrapancreatic tissues in vivo. The BLI system may be used for in vivo screening of biological events or pharmacologic activators that have the potential of stimulating the generation of extrapancreatic insulin-producing cells

Mapping the Human Vasculature by In Vivo Phage Display

In vivo phage display screenings by intravenous injection of a random phage-displayed peptide library allow for the selection of peptides that localize to specific vascular beds. At the University of Texas MD Anderson Cancer Center, we have had the opportunity to perform phage display screenings in cancer patients in order to select for cancer specific targets directly in humans. These targets serve to define biochemical diversity of endothelial cell surfaces and can be validated and explored towards the design of vascular-targeted pharmacology. In the most recent patient screen, samples were recovered from hepatocellular carcinoma (HCC) as well as 26 additional tissues. High-throughput sequencing and multidimensional bioinformatics analysis of recovered peptides led to the identification of extensive panels of motifs that are predicted to distinctly localize to tissue-specific vascular beds. Utilizing peptide affinity purification and phage based binding assays, we have shown that the HCC targeting peptide (SGVGAASL) identified from this patient screen, selectively binds to HCC in vitro as well as in vivo facilitated by a receptor mediated interaction with the giantin protein. FACS and protein fractionational experiments showed that the giantin polypeptide, normally considered an intracellular protein, is uniquely expressed on the surface of HCC cell lines as well as activated endothelial cells. shRNA mediated depletion of giantin expression lead to a loss of proliferation and adhesion in cancer cells. Finally, an extensive study of giantin expression in patient HCC tissue uncovered a unique expression pattern on the surface of tumor-associated vasculature. Collectively, these data support a functional role for giantin on the surface of HCC tumor endothelium that could potentially be exploited for delivery of imaging and therapeutic agents. Ultimately, this work serves as the foundation of a high-throughput integrative platform for discovery and validation of tissue-specific motifs towards a comprehensive understanding of the vascular landscape in humans

Total-liver-volume perfusion CT using 3-D image fusion to improve detection and characterization of liver metastases

The purpose of this study was to evaluate the feasibility of a totalliver- volume perfusion CT (CTP) technique for the detection and characterization of livermetastases. Twenty patients underwent helical CT of the total liver volume before and 11 times after intravenous contrast-material injection. To decrease distortion artifacts, all phases were co-registered using 3-D image fusion before creating blood-flow maps. Lesion-based sensitivity and specificity for liver metastases of first the conventional four phases (unenhanced, arterial, portal venous, and equilibrium) and later all 12 phases including blood-flow maps were determined as compared to intraoperative ultrasound and surgical exploration. Arterial and portal venous perfusion was calculated for normalappearing and metastatic liver tissue. Total-liver-volume perfusion values were comparable to studies using single-level CTP. Compared to fourphase CT, total -liver-volume CTP increased sensitivity to 89.2 from 78.4% (P=0.046) and specificity to 82.6 from 78.3% (P=0.074). Total - liver-volume CTP is a noninvasive, quantitative, and feasible technique. Preliminary results suggest an improved detection of liver metastases for CTP compared to four-phase CT

偏光分解顕微鏡を用いたアルコール性肝線維症の線維化の量的・質的評価系の開発

Liver fibrosis is assessed mainly by conventional staining or second harmonic generation (SHG) microscopy, which can only provide collagen content in fibrotic area. We propose to use polarization-resolved SHG (PR-SHG) microscopy to quantify liver fibrosis in terms of collagen fiber orientation and crystallization. Liver samples obtained from autopsy cases with fibrosis stage of F0–F4 were evaluated with an SHG microscope, and 12 consecutive PR-SHG images were acquired while changing the polarization azimuth angle of the irradiated laser from 0° to 165° in 15° increments using polarizer. The fiber orientation angle (φ) and degree (ρ) of collagen were estimated from the images. The SHG-positive area increased as the fibrosis stage progressed, which was well consistent with Sirius Red staining. The value of φ was random regardless of fibrosis stage. The mean value of ρ (ρ-mean), which represents collagen fiber crystallinity, varied more as fibrosis progressed to stage F3, and converged to a significantly higher value in F4 than in other stages. Spatial dispersion of ρ (ρ-entropy) also showed increased variation in the stage F3 and decreased variation in the stage F4. It was shown that PR-SHG could provide new information on the properties of collagen fibers in human liver fibrosis

Development of the minimally invasive paediatric & perinatal autopsy

Introduction Perinatal autopsy contributes useful clinical information to patient management in approximately 40% of cases but remains poorly accepted due to parental concerns regarding disfigurement. Post-mortem imaging is an alternative, but 1.5 T MRI lacks resolution below 18 gestational weeks. Additionally, the Royal College of Pathologists autopsy guidelines recommend extensive tissue sampling as part of the investigation of fetal loss, which imaging alone cannot provide. Possible mitigating strategies include micro-CT for phenotyping small fetuses and laparoscopic techniques to obtain tissue samples. Interrogation of the evidence base for tissue sampling in different clinical scenarios is necessary to develop evidence-based practice and recommendations. Methods Minimally Invasive Autopsy with Laparoscopy (MinImAL) was performed in 103 cases. Micro-CT was optimised in extracted organs and the diagnostic accuracy evaluated in 20 fetuses. The Great Ormond Street Autopsy Database was retrospectively interrogated to investigate the yield of internal examination and visceral histology to the cause of death in 5,311 cases. Results MinImAL examination is reliable (97.8% successfully completed, 91/93) with good tissue sampling success rates (100% in lung, kidney, heart). Micro-CT offers an accurate method of scanning small fetuses (97.5% agreement with autopsy, 95% CI, 96.6-98.4) with fewer non-diagnostic indices than standard autopsy in < 14 weeks gestation (22/440 vs 48/348 respectively; p<0.001). Histology of macroscopically normal viscera is valuable in the investigation of infant and childhood deaths. However, it provides almost no useful information relevant to cause of death or main diagnosis (<1%) in fetal cases. Conclusions MinImAL examination offers a reliable method of internal examination and tissue sampling, which may be acceptable when standard autopsy is declined. Micro-CT provides an accurate, non-invasive method for phenotyping early gestation fetal anatomy. Histological sampling of macroscopically normal visceral organs is valuable when investigating infant or child deaths but of limited value in fetal loss and hence should not be routinely performed