Noninvasive Functional Imaging Modality Research Articles

Functional magnetic particle imaging (fMPI) of cerebrovascular changes in the rat brain during hypercapnia

Objective. Non-invasive functional brain imaging modalities are limited in number, each with its own complex trade-offs between sensitivity, spatial and temporal resolution, and the directness with which the measured signals reflect neuronal activation. Magnetic particle imaging (MPI) directly maps the cerebral blood volume (CBV), and its high sensitivity derives from the nonlinear magnetization of the superparamagnetic iron oxide nanoparticle (SPION) tracer confined to the blood pool. Our work evaluates functional MPI (fMPI) as a new hemodynamic functional imaging modality by mapping the CBV response in a rodent model where CBV is modulated by hypercapnic breathing manipulation. Approach. The rodent fMPI time-series data were acquired with a mechanically rotating field-free line MPI scanner capable of 5 s temporal resolution and 3 mm spatial resolution. The rat’s CBV was modulated for 30 min with alternating 5 min hyper-/hypocapnic states, and processed using conventional fMRI tools. We compare our results to fMRI responses undergoing similar hypercapnia protocols found in the literature, and reinforce this comparison in a study of one rat with 9.4T BOLD fMRI using the identical protocol. Main results. The initial image in the time-series showed mean resting brain voxel SNR values, averaged across rats, of 99.9 following the first 10 mg kg−1 SPION injection and 134 following the second. The time-series fit a conventional General Linear Model with a 15%–40% CBV change and a peak pixel CNR between 12 and 29, 2–6× higher than found in fMRI. Significance. This work introduces a functional modality with high sensitivity, although currently limited spatial and temporal resolution. With future clinical-scale development, a large increase in sensitivity could supplement other modalities and help transition functional brain imaging from a neuroscience tool focusing on population averages to a clinically relevant modality capable of detecting differences in individual patients.

The Impact of Left Ventricle Ejection Fraction Reduction and Transient Ischemic Dilation in Patients With Normal Single-Photon Emission Computed Tomography (SPECT) Myocardial Perfusion Imaging.

Coronary artery disease (CAD) is a leading cause of death in developed countries. Non-invasive functional imaging modalities are currently recommended as initial diagnostic tests in patients with an intermediate-high pretest probability of CAD. Single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) creates images of regional myocardial tracer uptake, reflecting relative myocardial blood flow. However, there are other non-perfusion predictors of CAD, such as transient ischemic dilatation (TID) and reduced post-stress left ventricle ejection fraction (LVEF). Available data regarding these parameters is controversial. The aim of our study was to evaluate the incidence of significant CAD in patients with non-perfusion high-risk markers of ischemia despite a normal SPECT-MPI. Single-center, observational, retrospective, and longitudinal study. Inclusion criteria were age ≥18 years, normal SPECT-MPI, and availability of gated study for LVEF and volume analysis. Exclusion criteria were any known cardiomyopathy or congenital heart disease and known CAD. Non-perfusion high-risk markers: LVEF reduction ≥5% on post-stress images; TID (defined as a stress/rest left ventricle volume ratio ≥ 1.15), including end-systolic, end-diastolic, and mean volumes. The primary endpoint was the identification of significant CAD (stenosis >70% on an epicardial coronary artery or >50% on the left main artery) on invasive coronary angiography. A total of 197 patients met the inclusion criteria. Mean age was 64 ± 12.6 years and 59.4% (n = 117) of patients were male.Overall, 26% of patients had LVEF reduction ≥5% on stress study; 24.9% had a stress/rest end-systolic volume ratio ≥ 1.15; 7.1% had a stress/rest mean volume ratio ≥ 1.15; 7.1% had a stress/rest end-diastolic volume ratio ≥ 1.15. Time-to-primary endpoint was significantly lower in patients with LVEF reduction ≥5% on stress study (67.99 (95% CI 60.49-75.49) vs. 77.56 months (95% CI 75.14-79.99); p = 0.003) and in patients with stress/rest end-systolic volume ratio ≥ 1.15 (68.39 (95% CI 60.69-76.10) vs. 77.31 months (95% ICCI 74.68-79.76); p = 0.013). In patients with normal perfusion on SPECT-MPI, the incidence of significant CAD was significantly higher in those with LVEF reduction ≥ 5% on stress study and in those with a stress/rest end-systolic volume ratio ≥ 1.15, during a follow-up period of five years.

Detailed magnetoelectric analysis of a nerve impulse propagation along the brachial plexus

ObjectiveTo visualize impulse conduction along the brachial plexus through simultaneous electromagnetic measurements. MethodsNeuromagnetic fields following median nerve stimulation were recorded above the clavicle with a superconducting quantum interference device biomagnetometer system in 7 healthy volunteers. Compound nerve action potentials (CNAPs) were obtained from 12 locations. Pseudocolor maps of equivalent currents reconstructed from magnetic fields and isopotential contour maps were superimposed onto X-ray images. Surface potentials and current waveforms at virtual electrodes along the brachial plexus were compared. ResultsIn magnetic field analysis, the leading axonal current followed by a trailing backward current traveled rostrally along the brachial plexus. The spatial extent of the longitudinal intra-axonal currents corresponded to the extent of the positive–negative-positive potential field reflecting transmembrane volume currents. The peaks and troughs of the intra-axonal biphasic current waveforms coincided with the zero-crossings of triphasic CNAP waveforms. The amplitudes of CNAPs and current moments were linearly correlated. ConclusionsReconstructed neural activity in magnetic field analysis visualizes not only intra-axonal currents, but also transmembrane volume currents, which are in good agreement with the surface potential field. SignificanceMagnetoneurography is a novel non-invasive functional imaging modality for the brachial plexus whose performance can surpass that of electric potential measurement.

Three-compartment-breast (3CB) prior-guided diffuse optical tomography based on dual-energy digital breast tomosynthesis (DBT).

Diffuse optical tomography (DOT) is a non-invasive functional imaging modality that uses near-infrared (NIR) light to measure the oxygenation state and the concentration of hemoglobin. By complementarily using DOT with other anatomical imaging modalities, physicians can diagnose more accurately through additional functional image information. In breast imaging, diagnosis of dense breasts is often challenging because the bulky fibrous tissues may hinder the correct tumor characterization. In this work, we proposed a three-compartment-breast (3CB) decomposition-based prior-guided optical tomography for enhancing DOT image quality. We conjectured that the 3CB prior would lead to improvement of the spatial resolution and also of the contrast of the reconstructed tumor image, particularly for the dense breasts. We conducted a Monte-Carlo simulation to acquire dual-energy X-ray projections of a realistic 3D numerical breast phantom and performed digital breast tomosynthesis (DBT) for setting up a 3CB model. The 3CB prior was then used as a structural guide in DOT image reconstruction. The proposed method resulted in the higher spatial resolution of the recovered tumor even when the tumor is surrounded by the fibroglandular tissues compared with the typical two-composition-prior method or the standard Tikhonov regularization method.

Multidimensional Diffusion Magnetic Resonance Imaging for Characterization of Tissue Microstructure in Breast Cancer Patients: A Prospective Pilot Study.

Simple SummaryIn this prospective pilot study, we investigated the potential of clinical multidimensional diffusion magnetic resonance imaging (MDD MRI) for the microstructural characterization of breast cancers and normal fibroglandular breast tissue. The method relies on advanced gradient waveforms to encode the signal with information about cell densities, shapes, and orientations, and to quantify tissue composition as a probability distribution of diffusion tensors in a space with dimensions analogous to those on a cellular level. Sixteen patients with breast cancer underwent MDD MRI within a clinically feasible scan time of approximately 4 min, providing voxel-resolved distributions and parameter maps with microstructural information that is not accessible with conventional methods.Diffusion-weighted imaging is a non-invasive functional imaging modality for breast tumor characterization through apparent diffusion coefficients. Yet, it has so far been unable to intuitively inform on tissue microstructure. In this IRB-approved prospective study, we applied novel multidimensional diffusion (MDD) encoding across 16 patients with suspected breast cancer to evaluate its potential for tissue characterization in the clinical setting. Data acquired via custom MDD sequences was processed using an algorithm estimating non-parametric diffusion tensor distributions. The statistical descriptors of these distributions allow us to quantify tissue composition in terms of metrics informing on cell densities, shapes, and orientations. Additionally, signal fractions from specific cell types, such as elongated cells (bin1), isotropic cells (bin2), and free water (bin3), were teased apart. Histogram analysis in cancers and healthy breast tissue showed that cancers exhibited lower mean values of “size” (1.43 ± 0.54 × 10−3 mm2/s) and higher mean values of “shape” (0.47 ± 0.15) corresponding to bin1, while FGT (fibroglandular breast tissue) presented higher mean values of “size” (2.33 ± 0.22 × 10−3 mm2/s) and lower mean values of “shape” (0.27 ± 0.11) corresponding to bin3 (p < 0.001). Invasive carcinomas showed significant differences in mean signal fractions from bin1 (0.64 ± 0.13 vs. 0.4 ± 0.25) and bin3 (0.18 ± 0.08 vs. 0.42 ± 0.21) compared to ductal carcinomas in situ (DCIS) and invasive carcinomas with associated DCIS (p = 0.03). MDD enabled qualitative and quantitative evaluation of the composition of breast cancers and healthy glands.

Whole-Head Magnetoencephalogram and Its Application in Developmental Communication Disorders Research: A Review

The human brain undergoes tremendous changes during the first decade of life. The susceptibility of the immature central nervous system to factors such as adverse environments and genetic factors is attributed to its plasticity. Neurodevelopmental disorders (NDDs) occur once the immature brain veers off the typical developmental trajectory. However, little is known about the neurophysiological traits of atypically developing children because it is challenging for them to remain still during recording. Magnetoencephalography (MEG) is a noninvasive neuroimaging technique with high-spatiotemporal resolution. An ultralow magnetic field produced by neural electrical activity can be detected using a highly sensitive whole-head magnetometer array. Current cryogenic SQUID-MEG combined with individual MRI has shown great potential in reflecting neural activity under resting states and during tasks. MEG instrumentation for children is expected to be an effective tool for investigating brain dynamics, which provides neuropsychological evidence for atypical development in communication ability. In this paper, the advantages of pediatric MEG in neurodevelopmental disorder studies are discussed first and compared with those of several noninvasive functional imaging modalities. Existing commercial pediatric MEG systems are summarized based on their respective characteristics and parameters. State-of-the-art newly emerging sensing techniques based on spin-exchange relaxation-free (SERF) along with their application in detecting infants' brain responses are introduced. Recent discoveries on MEG biomarkers in children with NDDs are then summarized concerning disorders that have comorbidities in communication, such as specific language impairment (SLI), autism spectrum disorders (ASD), dyslexia and stuttering. Progress on multimodality research and total-field wearable SERF magnetometers offers insight into the neuropsychological substrates of communication disorders.

Influence of current injection scheme on electrical impedance tomography for monitoring of the respiratory function of obese subjects

Electrical impedance tomography (EIT) has been proposed as a noninvasive radiation-free functional imaging modality for bedside monitoring of lung ventilation. Due to the intrinsic low sensitivity of measured boundary voltages with respect to internal conductivity changes, EIT image reconstructions are more challenging for the regions that are located deeper from the attached surface electrodes. Considering the worldwide prevalence of obesity, it is highly desirable for an EIT system to produce high-quality images from obese as well as lean subjects. In EIT, the internal current density distribution and the sensitivity of a boundary voltage to a change of internal conductivity vary with respect to the current injection scheme. We quantified the range of measured boundary voltages subject to a chosen current injection scheme and investigated the influence of various obesity levels on the number of distinguishable boundary voltages given a fixed amount of system noise. We found that the 0-skip current injection scheme, where neighboring electrode pairs are used for current injections, could be most favorable to improve spatial resolution but produces the smallest number of distinguishable boundary voltages. To obtain an enough number of distinguishable boundary voltages from an obese subject, the gap between current injection electrodes should be increased depending on the circumference of a chosen imaging plane. We suggested a guideline for current injection schemes in EIT to produce images with better quality from obese as well as lean subjects.

Relative contribution of individual versus combined functional imaging studies in predicting seizure freedom in pediatric epilepsy surgery: an area under the curve analysis.

The goal of this study was to evaluate the predictive value and relative contribution of noninvasive presurgical functional imaging modalities based on the authors' institutional experience in pursuing seizure-free surgical outcomes in children with medically refractory epilepsy. This was a retrospective, single-institution, observational cohort study of pediatric patients who underwent evaluation and surgical treatment for medically refractory partial epilepsy between December 2003 and June 2016. During this interval, 108 children with medically refractory partial epilepsy underwent evaluation for localization and resective epilepsy surgery. Different noninvasive functional imaging modalities, including ictal SPECT, FDG-PET, and magnetoencephalography-magnetic source imaging, were utilized to augment a standardized paradigm (electroencephalography/semiology, MRI, and neuropsychology findings) for localization. Outcomes were evaluated at a minimum of 2 years (mean 7.5 years) utilizing area under the receiver operating characteristic curve analysis. Localizing modalities and other clinical covariates were examined in relation to long-term surgical outcomes. There was variation in the contribution of each test, and no single presurgical workup modality could singularly and reliably predict a seizure-free outcome. However, concordance of presurgical modalities yielded a high predictive value. No difference in long-term outcomes between inconclusive (normal or diffusely abnormal) and abnormal focal MRI results were found. Long-term survival analyses revealed a statistically significant association between seizure freedom and patients with focal ictal EEG, early surgical intervention, and no history of generalized convulsions. Comprehensive preoperative evaluation utilizing multiple noninvasive functional imaging modalities is not redundant and can improve pediatric epilepsy surgical outcomes.

Dynamic Activation Patterns of the Motor Brain Revealed by Diffuse Optical Tomography.

Diffuse optical tomography (DOT), a subset of functional near-infrared spectroscopy (fNIRS), is a noninvasive functional imaging modality for studying the human brain in normal and diseased conditions. It measures changes in concentrations of oxygenated hemoglobin (HbO) and deoxygenated hemoglobin (Hb) in the blood vasculature of the brain. In contrast to functional magnetic resonance imaging (fMRI), the gold standard in human brain imaging, DOT offers the advantage of higher temporal resolution, portability, lower cost, multiple contrasts and usability for persons who cannot otherwise utilize MRI-based imaging modalities, including bedridden patients and infants, etc. The goal of the present study was to evaluate performance of a DOT method in studying dynamic patterns of brain activations involving motor control. CW-fNIRS data were acquired in four sessions from a healthy male participant when he performed a motor task in a block-design experiment. Results from experimental data showed pronounced activity in the primary motor cortex (M1), contralateral to the clenching hand. It was further observed that the M1 activity was consistent over four sessions. Furthermore, temporal dynamics of motor activity at each session further revealed well-sequenced activation patterns among M1, premotor cortex (PMC), and supplementary motor area (SMA). Timed ipsilateral motor activity suppression was also observed several seconds after the onset of contralateral M1 activity. More importantly, these temporal dynamics were similarly observed in all four sessions. These preliminary results suggest that the DOT method has the sensitivity, reliability, and spatio-temporal resolutions to study activities originated from the motor cortices. A full-scope evaluation and validation in more participants on the motor system can establish it as a promising neuroimaging tool to study, such as, infants at the risk of cerebral palsy or elders with Parkinson's due to its portability and usability in clinical environments.

Non-invasive functional assessment of coronary stenosis by cardiac computed tomography

The increased number of patients with coronary artery disease (CAD) is of great clinical relevance and involves a large burden of the healthcare system. The management of these patients is focused on relieving symptoms and improving clinical outcomes. Therefore, the ideal test would provide the correct diagnosis and actionable information. To this aim, several non-invasive functional imaging modalities are usually used as gatekeeper to invasive coronary angiography, but their diagnostic performance remains low with limited accuracy when compared to obstructive CAD at the time of invasive coronary angiography or invasive fractional flow reserve (FFR) assessment. For these reasons, an urgent need for non-invasive techniques that evaluate both the functional and morphological severity of CAD is growing. Coronary computed tomography angiography (CCTA) has emerged as a unique non-invasive technique providing coronary artery anatomic imaging. More recently, the evaluation of FFR with CCTA (FFRCT) has demonstrated high diagnostic performance compared to invasive FFR. Moreover, this tool has been proven to be more cost-effective than standard diagnostic pathways in large prospective multicenter trials, and to have a prognostic role. Additionally, stress myocardial computed tomography perfusion (stress CTP) represents a novel tool for the diagnosis of ischemia with high diagnostic accuracy. With advances in technical development, both static and dynamic computed tomography myocardial perfusion protocols offer functional assessment with an acceptable increase in radiation exposure. Compared to other imaging techniques, both FFRCT and stress CTP allow the combination of the anatomical evaluation of coronary arteries and the functional relevance of coronary artery lesions, having the potential to revolutionize the diagnostic paradigm of suspected CAD. FFRCT and stress CTP should be integrated in diagnostic pathways of patients with stable CAD and will likely result in a decrease of invasive diagnostic procedures and costs.

Noninvasive Anatomical and Functional Imaging of Orthotopic Glioblastoma Development and Therapy using Multispectral Optoacoustic Tomography

PURPOSE: Here we demonstrate the potential of multispectral optoacoustic tomography (MSOT), a new non-invasive structural and functional imaging modality, to track the growth and changes in blood oxygen saturation (sO2) in orthotopic glioblastoma (GBMs) and the surrounding brain tissues upon administration of a vascular disruptive agent (VDA). METHODS: Nude mice injected with U87MG tumor cells were longitudinally monitored for the development of orthotopic GBMs up to 15 days and observed for changes in sO2 upon administration of combretastatin A4 phosphate (CA4P, 30 mg/kg), an FDA approved VDA for treating solid tumors. We employed a newly-developed non-negative constrained approach for combined MSOT image reconstruction and unmixing in order to quantitatively map sO2 in whole mouse brains. RESULTS: Upon longitudinal monitoring, tumors could be detected in mouse brains using single-wavelength data as early as 6 days post tumor cell inoculation. Fifteen days post-inoculation, tumors had higher sO2 of 63 ± 11% (n = 5, P < .05) against 48 ± 7% in the corresponding contralateral brain, indicating their hyperoxic status. In a different set of animals, 42 days post-inoculation, tumors had lower sO2 of 42 ± 5% against 49 ± 4% (n = 3, P < .05) in the contralateral side, indicating their hypoxic status. Upon CA4P administration, sO2 in 15 days post-inoculation tumors dropped from 61 ± 9% to 36 ± 1% (n = 4, P < .01) within one hour, then reverted to pre CA4P treatment values (63 ± 6%) and remained constant until the last observation time point of 6 hours. CONCLUSION: With the help of advanced post processing algorithms, MSOT was capable of monitoring the tumor growth and assessing hemodynamic changes upon administration of VDAs in orthotopic GBMs.

Appropriate use of noninvasive ischemia testing to guide revascularization decision making following acute ST elevation myocardial infarction in Latin American countries: Results from an Expert Panel Meeting of the International Atomic Energy Agency

Across Latin American and Caribbean countries (LAC), cardiovascular disease and especially ischemic heart disease is currently the main cause of death both in men and in women. For most LAC, public and community health efforts aim to define care strategies which are both clinically and cost effective and promote primary and secondary prevention, resulting in improved patient outcomes. The optimal approach to deal with acute events such as ST-elevation myocardial infarction (STEMI) is a matter of controversy; however, there is an expanding role for assessing residual ischemic burden in STEMI patients following primary percutaneous coronary intervention (PPCI). Although randomized clinical trials have established the value of staged fractional flow reserve (FFR)-guided revascularization, the use of noninvasive functional imaging modalities may play a similar role at a much lower cost. For LAC, available stress imaging techniques could be applied to define residual ischemia in the non-infarct related artery and to target revascularization in a staged procedure after PPCI. The use of nuclear cardiac imaging, supported by its relatively wide availability, moderate cost, and robust quantitative capabilities, may serve to guide effective care and to reduce subsequent cardiac events in patients with coronary artery disease. This noninvasive approach may avert potential safety issues with repeat and lengthy invasive procedures, and serve as a baseline for subsequent follow-up stress testing following the index STEMI event. This consensus document was devised from an Expert Panel Meeting of the International Atomic Energy Agency (IAEA), highlighting available evidence with a focus on the utility of stress myocardial perfusion imaging in post-STEMI patients. The document could serve as guidance to the prudent and appropriate use of nuclear imaging for targeting therapeutic management and avoiding unnecessary invasive procedures within LAC, where resources could be scarce.

Abstract OT2-02-03: Pilot study of zirconium-89 bevacizumab positron emission tomography for imaging angiogenesis in patients with inflammatory breast carcinoma receiving preoperative chemotherapy

Abstract Background: Inflammatory breast cancer (IBC) continues to have a poor prognosis despite standard tri-modality treatment with chemotherapy, mastectomy and radiation. Current methods of assessing primary tumor response (i.e., clinical exam and breast magnetic resonance imaging [MRI]) are limited for distinguishing residual tumor from responsive disease because of persistent morphologic changes in the breast. Therefore, the inability to accurately assess tumor response during treatment often results in the continuation of ineffective systemic chemotherapy until definitive pathologic evaluation at mastectomy. IBC has a highly angiogenic phenotype which is believed to play a role in this tumor's aggressiveness. The novel radiotracer Zirconium-89 (89Zr)-bevacizumab was developed for imaging tumor angiogenesis with PET. We hypothesize that, as an imaging biomarker of angiogenesis, 89Zr-bevacizumab-PET/CT is a more specific noninvasive functional imaging modality for detecting the presence of tumor angiogenesis compared to current diagnostic methods and will serve as a predictor of response to therapy in patients (pts) with IBC. Methods: Pts with newly diagnosed HER2neg IBC who will receive preoperative chemotherapy are eligible for this pilot study. 89Zr-bevacizumab-PET/CT, breast MRI and FDG-PET/CT are performed before, after 2 cycles, and at the completion of preoperative therapy. Biopsies of primary IBC tumors are obtained prior to and after 2 cycles of preoperative therapy. At the completion of preoperative therapy, pts proceed to mastectomy or biopsy if ineligible to proceed to mastectomy based on current standards for assessing primary tumor response, i.e., clinical exam, breast MRI and lack of systemic progression. At the time of mastectomy, standard evaluation of the surgical specimen will determine pathologic response of IBC to preoperative chemotherapy. A research sample will be collected if residual cancer is present at the time of mastectomy for histologic evaluation of tumor angiogenesis. Objectives/Correlatives: The primary objective is to determine feasibility of 89Zr-bevacizumab-PET/CT imaging in pts with IBC. The primary endpoint is assessment of radiolabeling of chelated bevacizumab and number of successfully acquired 89Zr-bevacizumab-PET/CT scans. Correlative studies will be performed on IBC tissue to assess extent of angiogenesis including microvessel density, vessel diameter, vascular pericyte coverage and tumor VEGF levels. Secondary objectives are: 1) To determine if 89Zr-bevacizumab accumulation in primary IBC tumors correlates with the extent of angiogenesis determined by correlative analysis on IBC tissue; 2) To assess the predictive value of 89Zr-bevacizumab-PET/CT after 2 cycles and at the end of preoperative therapy for determining pathologic response at mastectomy as given by residual cancer burden. Statistics: This is an accrual, not statistical based, feasibility justification. Planned sample size is 10 in order to make a preliminary statement about feasibility and ability for 89Zr-bevacizumab-PET/CT to serve as a surrogate in vivo biomarker of tumor angiogenesis and response to preoperative chemotherapy. Clinical Trial Information: NCT01894451. Citation Format: Jacene HA, Overmoyer B, Schlosnagle EJ, Abbott A, Yeh E, Paolino J, Goel S, Culhane A, Bellon JR, Nakhlis F, Hirshfield-Bartek J, Van den Abbeele A. Pilot study of zirconium-89 bevacizumab positron emission tomography for imaging angiogenesis in patients with inflammatory breast carcinoma receiving preoperative chemotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-02-03.

Abstract P3-01-02: Clinical, anatomical and histological characteristics of breast lesions visualized by photoacoustic mammography; first clinical study in CK project

Abstract Background: Photoacoustic mammography (PAM) is an optical imaging technique potentially capable of imaging breast vasculature as well as measuring hemoglobin oxygen saturation(SO2) in focal breast lesions. We presented the initial observation on first 20 cases using the first generation PAM (PAM-01) prototype made by Canon Inc.(Tokyo, Japan) (spatial resolution:2mm) in SABCS 2013. Here we report the clinico-pathological characteristics of all cases recruited in the first clinical study in CK project (Kyoto University/Canon joint research project) between Aug 2010 and March 2012. Methods: 57 patients were recruited in IRB approved study at Kyoto University Hospital, Japan. Forty-two breast harboring lesions and when possible contralateral breasts were evaluated by PAM-01. Axial maximum intensity projection (MIP)s were obtained and signals from consecutive MIPs confirmed to be associated with the tumor location in MRI by an expert breast radiologist were considered to be the region of interest (ROI).The same depth was used for ROI in the normal breast as control. Histological sections from the widest area of the lesions were evaluated post-excisional by immunohistochemistry using anti-CD31 as endothelial marker and anti-carbonic anhydrase IX (CA IX) as hypoxia marker. Histological slides were scanned and divided into 1680 squares (0.84x0.84 mm2)(Hamamatsu Inc. Japan) for image analysis. Total vascular perimeter (TVP)-in mm- was calculated for all the histological section by using Image Pro-Plus 7.0 software (Media Cybernetics, USA). Tumor area was measured in mm2. TVP index was calculated as TVP/area. Results: Photoacoustic signal was detected in 30 lesions out of 42 at the depth of 26.8 ± 12.8 mm from which 80% were located superior to nipple. CA IX positive cases in comparison with CA IX negative cases significantly showed higher TVP index (p-value =0.028 Mann-Whitney Test ) suggesting more angiogenic profile of hypoxic tumors. However, lesions without any detectable signal were reported to have only a bigger mass size histologically (26.6 vs. 14.8 mm, p-value 0.28, Mann-Whitney Test) regardless of their TVP index or CA IX expression level. Moreover,SO2 was calculated 70.9% for signals located inside tumors and 85.5% for signals associated with subcutaneous vessels in the same breast (p-value &amp;lt;0.0001 Wilcoxon Test) compatible with the SO2 data from normal counterpart at tumor depth in the other breast (81.9%) (p-value 0.0001 Wilcoxon Test). Tumors bigger than 2 cm also tended to have lower SO2 (65.6%) compared with tumors smaller than 2 cm (70.1%) in accordance with higher TVP index in bigger tumors (p-value &amp;lt;0.001 Student T-test). Conclusion: This is the largest clinical study of PAM till today and the correlation between histological profile of hypoxia and tumor microvasculature with PAM signal visibility as well as tissue SO2 seems promising. However, the improvement of techniques and resolution is necessary to develop a more clinically applicable non-invasive functional breast imaging modality for analyzing breast tumor vasculature and hypoxia. Some of these improvements have taken place for the second generation PAM (PAM-02) which is now under a clinical evaluation study. Citation Format: Elham Fakhrejahani, Masae Torii, Yasufumi Asao, Iku Yamaga, Toshiyuki Kitai, Masako Kataoka, Shotaro Kanao, Masahiro Takada, Tsuyoshi Shiina, Masakazu Toi. Clinical, anatomical and histological characteristics of breast lesions visualized by photoacoustic mammography; first clinical study in CK project [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-01-02.

Functional relevance of coronary artery disease by cardiac magnetic resonance and cardiac computed tomography: myocardial perfusion and fractional flow reserve.

Coronary artery disease (CAD) is one of the leading causes of morbidity and mortality and it is responsible for an increasing resource burden. The identification of patients at high risk for adverse events is crucial to select those who will receive the greatest benefit from revascularization. To this aim, several non-invasive functional imaging modalities are usually used as gatekeeper to invasive coronary angiography, but the diagnostic yield of elective invasive coronary angiography remains unfortunately low. Stress myocardial perfusion imaging by cardiac magnetic resonance (stress-CMR) has emerged as an accurate technique for diagnosis and prognostic stratification of the patients with known or suspected CAD thanks to high spatial and temporal resolution, absence of ionizing radiation, and the multiparametric value including the assessment of cardiac anatomy, function, and viability. On the other side, cardiac computed tomography (CCT) has emerged as unique technique providing coronary arteries anatomy and more recently, due to the introduction of stress-CCT and noninvasive fractional flow reserve (FFR-CT), functional relevance of CAD in a single shot scan. The current review evaluates the technical aspects and clinical experience of stress-CMR and CCT in the evaluation of functional relevance of CAD discussing the strength and weakness of each approach.

The Electrophysiological Cardiac Ventricular Substrate in Patients After Myocardial Infarction: Noninvasive Characterization With Electrocardiographic Imaging

The aim of this study was to noninvasively image the electrophysiological (EP) substrate of human ventricles after myocardial infarction and define its characteristics. Ventricular infarct border zone is characterized by abnormal cellular electrophysiology and altered structural architecture and is a key contributor to arrhythmogenesis. The ability to noninvasively image its electrical characteristics could contribute to understanding of mechanisms and to risk-stratification for ventricular arrhythmia. Electrocardiographic imaging, a noninvasive functional EP imaging modality, was performed during sinus rhythm (SR) in 24 subjects with infarct-related myocardial scar. The abnormal EP substrate on the epicardial aspect of the scar was identified, and its location, size, and morphology were compared with the anatomic scar imaged by other noninvasive modalities. Electrocardiographic imaging constructs epicardial electrograms that have characteristics of reduced amplitude (low voltage) and fractionation. Electrocardiographic imaging colocalizes the epicardial electrical scar to the anatomic scar with a high degree of accuracy (sensitivity 89%, specificity 85%). In nearly all subjects, SR activation patterns were affected by the presence of myocardial scar. Late potentials could be identified and were almost always within ventricular scar. Electrocardiographic imaging accurately identifies areas of anatomic scar and complements standard anatomic imaging by providing scar-related EP characteristics of low voltages, altered SR activation, electrogram fragmentation, and presence of late potentials.

The role of interventional venous sampling in localising neuroendocrine tumours

This review focuses on the role of interventional venous sampling in the diagnosis and localization of neuroendocrine tumours (NETs), and its role in relation to conventional and novel imaging techniques. Imaging of NETs has evolved together with advances in imaging technology. Imaging localization plays an important role in the subsequent management of these tumours. This article provides an overview of the application of venous sampling in the localization of NETs, presented with current evidence to support its continued role in the diagnostic work-up of pituitary, parathyroid, pancreatic, adrenal and ovarian endocrine disease. Interventional venous sampling continues to be a highly sensitive modality in the localization of NETs. Although significant advances in noninvasive anatomic and functional imaging modalities have reduced the reliance of this well established technique, the latest literature continues to support its important role in the diagnostic armament of these unique and rare tumours.

Development of radiotracers for oncology – the interface with pharmacology

There is an increasing role for positron emission tomography (PET) in oncology, particularly as a component of early phase clinical trials. As a non-invasive functional imaging modality, PET can be used to assess both pharmacokinetics and pharmacodynamics of novel therapeutics by utilizing radiolabelled compounds. These studies can provide crucial information early in the drug development process that may influence the further development of novel therapeutics. PET imaging probes can also be used as early biomarkers of clinical response and to predict clinical outcome prior to the administration of therapeutic agents. We discuss the role of PET imaging particularly as applied to phase 0 studies and discuss the regulations involved in the development and synthesis of novel radioligands. The review also discusses currently available tracers and their role in the assessment of pharmacokinetics and pharmacodynamics as applied to oncology.

Noninvasive Electrocardiographic Imaging (ECGI) of a univentricular heart with Wolff-Parkinson-White syndrome

Electrocardiographic imaging (ECGI) is a noninvasive functional imaging modality which reconstructs epicardial potentials, electrograms, and activation and recovery maps from body-surface ECG potentials. For this purpose, up to 256 ECGs are recorded by a 256-channel body surface potential mapping (BSPM) system and the heart-torso geometry is obtained using thoracic computed tomography (CT)1,2. This technique was developed and validated extensively in normal and abnormal canine hearts3–11. More recently, ECGI was validated in humans by comparison with direct intra-operative epicardial mapping in patients undergoing open-heart surgery12. To date, ECGI has been applied in adult human subjects for the following purposes: 1. To study cardiac electrophysiology of the normal adult human heart2. 2. To image electrophysiologic responses to pacing in heart failure patients undergoing cardiac resynchronization therapy13 (pacing sites were localized with an accuracy better than 10 mm)14. 3. To guide catheter ablation of focal ventricular and atrial tachycardias15,16. 4. To image typical atrial flutter prior to catheter ablation1 and atypical atrial flutter prior to a surgical Cox-Maze procedure17. Here we describe for the first time, a case where ECGI was applied to a pediatric patient with a congenital structural heart defect. The patient had a univentricular heart and Wolff-Parkinson-White syndrome, and ECGI was used to localize the accessory pathway and help guide catheter ablation. To date, there have been no reported cases of ECGI in the pediatric population.

Anisotropic diffusion regularization methods for diffuse optical tomography using edge prior information

Diffuse optical tomography (DOT) is a non-invasive functional imaging modality that aims to image the optical properties of biological organs. The forward problem of the light propagation of DOT can be modelled as a diffusion process and is expressed as a differential diffusion equation with boundary conditions. The solution of the DOT inverse problem can be formulated as a minimization of some functional that measures the discrepancy between the measured data and the data produced by representation of the modelled object. The minimization of this term alone would force the solution to be consistent with the data and the solver used for this purpose. But since in practice data are always accompanied with noise and with some jump discontinuities, these will unavoidably yield unsatisfactory solutions, so some regularization to restore the solution is required. In this paper we introduce an anisotropic regularization term using a priori structural information about the object. This term aims to reduce the noise associated with the data and to preserve the edges in the solution by a combined strategy using the a priori edge information and the diffusion flux analysis of the local structures at each iteration. To accelerate the iterative solver we use a particular method called the lagged diffusivity Newton–Krylov method. The whole proposed strategy, which makes use of a priori diffusion information has been developed and evaluated on simulated data.