Feasibility of Intraoperative Breast MRI and the Role of Prone Versus Supine Positioning in Surgical Planning for Breast-Conserving Surgery.

We assessed the feasibility of supine intraoperative MRI (iMRI) during breast-conserving surgery (BCS), enrolling 15 patients in our phase I trial between 2012 and 2014. Patients received diagnostic prone MRI, BCS, pre-excisional supine iMRI, and postexcisional supine iMRI. Feasibility was assessed based on safety, sterility, duration, and image-quality. Twelve patients completed the study; mean duration = 114 minutes; all images were adequate; no complications, safety, or sterility issues were encountered. Substantial tumor-associated changes occurred (mean displacement = 67.7 mm, prone-supine metric, n = 7). We have demonstrated iMRI feasibility for BCS and have identified potential limitations of prone breast MRI that may impact surgical planning.

Intraoperative Supine Breast MR Imaging to Quantify Tumor Deformation and Detection of Residual Breast Cancer: Preliminary Results.

Purpose To use intraoperative supine magnetic resonance (MR) imaging to quantify breast tumor deformation and displacement secondary to the change in patient positioning from imaging (prone) to surgery (supine) and to evaluate residual tumor immediately after breast-conserving surgery (BCS). Materials and Methods Fifteen women gave informed written consent to participate in this prospective HIPAA-compliant, institutional review board-approved study between April 2012 and November 2014. Twelve patients underwent lumpectomy and postsurgical intraoperative supine MR imaging. Six of 12 patients underwent both pre- and postsurgical supine MR imaging. Geometric, structural, and heterogeneity metrics of the cancer and distances of the tumor from the nipple, chest wall, and skin were computed. Mean and standard deviations of the changes in volume, surface area, compactness, spherical disproportion, sphericity, and distances from key landmarks were computed from tumor models. Imaging duration was recorded. Results The mean differences in tumor deformation metrics between prone and supine imaging were as follows: volume, 23.8% (range, -30% to 103.95%); surface area, 6.5% (range, -13.24% to 63%); compactness, 16.2% (range, -23% to 47.3%); sphericity, 6.8% (range, -9.10% to 20.78%); and decrease in spherical disproportion, -11.3% (range, -60.81% to 76.95%). All tumors were closer to the chest wall on supine images than on prone images. No evidence of residual tumor was seen on MR images obtained after the procedures. Mean duration of pre- and postoperative supine MR imaging was 25 minutes (range, 18.4-31.6 minutes) and 19 minutes (range, 15.1-22.9 minutes), respectively. Conclusion Intraoperative supine breast MR imaging, when performed in conjunction with standard prone breast MR imaging, enables quantification of breast tumor deformation and displacement secondary to changes in patient positioning from standard imaging (prone) to surgery (supine) and may help clinicians evaluate for residual tumor immediately after BCS. © RSNA, 2016 Online supplemental material is available for this article.

High-resolution renal perfusion mapping using contrast-enhanced ultrasonography in ischemia-reperfusion injury monitors changes in renal microperfusion.

Alterations in renal microperfusion play an important role in the development of acute kidney injury with long-term consequences. Here we used contrast-enhanced ultrasonography as a novel method for depicting intrarenal distribution of blood flow. After infusion of microbubble contrast agent, bubbles were collapsed in the kidney and postbubble destruction refilling was measured in various regions of the kidney. Local perfusion was monitored in vivo at 15, 30, 45, 60 minutes and 24 hours after 28 minutes of bilateral ischemia in 12 mice. High-resolution, pixel-by-pixel analysis was performed on each imaging clip using customized software, yielding parametric perfusion maps of the kidney, representing relative blood volume in each pixel. These perfusion maps revealed that outer medullary perfusion decreased disproportionately to the reduction in the cortical and inner medullary perfusion after ischemia. Outer medullary perfusion was significantly decreased by 69% at 60 minutes postischemia and remained significantly less (40%) than preischemic levels at 24 hours postischemia. Thus, contrast-enhanced ultrasonography with high-resolution parametric perfusion maps can monitor changes in renal microvascular perfusion in space and time in mice. This novel technique can be translated to clinical use in man.

Intraoperative real-time MRI-guided stereotactic biopsy followed by laser thermal ablation for progressive brain metastases after radiosurgery.

Stereotactic radiosurgery is one of the treatment options for brain metastases. However, there are patients who will progress after radiosurgery. One of the potential treatments for this subset of patients is laser ablation. Image-guided stereotactic biopsy is important to determine the histopathological nature of the lesion. However, this is usually based on preoperative, static images, which may affect the target accuracy during the actual procedure as a result of brain shift. We therefore performed real-time intraoperative MRI-guided stereotactic aspiration and biopsies on two patients with symptomatic, progressive lesions after radiosurgery followed immediately by laser ablation. The patients tolerated the procedure well with no new neurologic deficits. Intraoperative MRI-guided stereotactic biopsy followed by laser ablation is safe and accurate, providing real-time updates and feedback during the procedure.

Potential of minimally invasive procedures in the treatment of uterine fibroids: a focus on magnetic resonance-guided focused ultrasound therapy.

Minimally invasive treatment options are an important part of the uterine fibroid-treatment arsenal, especially among younger patients and in those who plan future pregnancies. This article provides an overview of the currently available minimally invasive therapy options, with a special emphasis on a completely noninvasive option: magnetic resonance-guided focused ultrasound (MRgFUS). In this review, we describe the background of MRgFUS, the patient-selection criteria for MRgFUS, and how the procedure is performed. We summarize the published clinical trial results, and review the literature on pregnancy post-MRgFUS and on the cost-effectiveness of MRgFUS.

Multimodal imaging for improved diagnosis and treatment of cancers.

The authors review methods for image-guided diagnosis and therapy that increase precision in the detection, characterization, and localization of many forms of cancer to achieve optimal target definition and complete resection or ablation. A new model of translational, clinical, image-guided therapy research is presented, and the Advanced Multimodality Image-Guided Operating (AMIGO) suite is described. AMIGO was conceived and designed to allow for the full integration of imaging in cancer diagnosis and treatment. Examples are drawn from over 500 procedures performed on brain, neck, spine, thorax (breast, lung), and pelvis (prostate and gynecologic) areas and are used to describe how they address some of the many challenges of treating brain, prostate, and lung tumors. Cancer 2015;121:817-827. © 2014 American Cancer Society.

Science to practice: opening the blood-brain barrier with focused ultrasound-a potential treatment for Alzheimer disease?

Burgess et al ( 1 ) present intriguing results of repetitive transient opening of the blood-brain barrier (BBB) in a transgenic mouse model of advanced Alzheimer disease (AD). The results underscore the potential of using magnetic resonance (MR) imaging-guided focused ultrasound and microbubble ultrasonography (US) contrast agents for the disruption of the BBB as a potential long-term therapy to reduce amyloid plaque burden and improve cognitive performance. This daring conclusion that is based on an experimental animal model should now be confirmed in humans. Considering that the technology is commercially available and given the immense clinical need, clinical trials in this AD treatment should be initiated as soon as possible.

Application of desorption electrospray ionization mass spectrometry imaging in breast cancer margin analysis.

Distinguishing tumor from normal glandular breast tissue is an important step in breast-conserving surgery. Because this distinction can be challenging in the operative setting, up to 40% of patients require an additional operation when traditional approaches are used. Here, we present a proof-of-concept study to determine the feasibility of using desorption electrospray ionization mass spectrometry imaging (DESI-MSI) for identifying and differentiating tumor from normal breast tissue. We show that tumor margins can be identified using the spatial distributions and varying intensities of different lipids. Several fatty acids, including oleic acid, were more abundant in the cancerous tissue than in normal tissues. The cancer margins delineated by the molecular images from DESI-MSI were consistent with those margins obtained from histological staining. Our findings prove the feasibility of classifying cancerous and normal breast tissues using ambient ionization MSI. The results suggest that an MS-based method could be developed for the rapid intraoperative detection of residual cancer tissue during breast-conserving surgery.

Intraoperative mass spectrometry mapping of an onco-metabolite to guide brain tumor surgery.

For many intraoperative decisions surgeons depend on frozen section pathology, a technique developed over 150 y ago. Technical innovations that permit rapid molecular characterization of tissue samples at the time of surgery are needed. Here, using desorption electrospray ionization (DESI) MS, we rapidly detect the tumor metabolite 2-hydroxyglutarate (2-HG) from tissue sections of surgically resected gliomas, under ambient conditions and without complex or time-consuming preparation. With DESI MS, we identify isocitrate dehydrogenase 1-mutant tumors with both high sensitivity and specificity within minutes, immediately providing critical diagnostic, prognostic, and predictive information. Imaging tissue sections with DESI MS shows that the 2-HG signal overlaps with areas of tumor and that 2-HG levels correlate with tumor content, thereby indicating tumor margins. Mapping the 2-HG signal onto 3D MRI reconstructions of tumors allows the integration of molecular and radiologic information for enhanced clinical decision making. We also validate the methodology and its deployment in the operating room: We have installed a mass spectrometer in our Advanced Multimodality Image Guided Operating (AMIGO) suite and demonstrate the molecular analysis of surgical tissue during brain surgery. This work indicates that metabolite-imaging MS could transform many aspects of surgical care.

Magnetic resonance-guided focused ultrasound: a new technology for clinical neurosciences.

Transcranial MRI-guided focused ultrasound (TcMRgFUS) is an old idea but a new technology that may change the entire clinical field of the neurosciences. TcMRgFUS has no cumulative effect, and it is applicable for repeatable treatments, controlled by real-time dosimetry, and capable of immediate tissue destruction. Most importantly, it has extremely accurate targeting and constant monitoring. It is potentially more precise than proton beam therapy and definitely more cost effective. Neuro-oncology may be the most promising area of future TcMRgFUS applications.

Automatic segmentation of invasive breast carcinomas from dynamic contrast-enhanced MRI using time series analysis.

PURPOSE: To accurately segment invasive ductal carcinomas (IDCs) from dynamic contrast-enhanced MRI (DCE-MRI) using time series analysis based on linear dynamic system (LDS) modeling. MATERIALS AND METHODS: Quantitative segmentation methods based on black-box modeling and pharmacokinetic modeling are highly dependent on imaging pulse sequence, timing of bolus injection, arterial input function, imaging noise, and fitting algorithms. We modeled the underlying dynamics of the tumor by an LDS and used the system parameters to segment the carcinoma on the DCE-MRI. Twenty-four patients with biopsy-proven IDCs were analyzed. The lesions segmented by the algorithm were compared with an expert radiologist's segmentation and the output of a commercial software, CADstream. The results are quantified in terms of the accuracy and sensitivity of detecting the lesion and the amount of overlap, measured in terms of the Dice similarity coefficient (DSC). RESULTS: The segmentation algorithm detected the tumor with 90% accuracy and 100% sensitivity when compared with the radiologist's segmentation and 82.1% accuracy and 100% sensitivity when compared with the CADstream output. The overlap of the algorithm output with the radiologist's segmentation and CADstream output, computed in terms of the DSC was 0.77 and 0.72, respectively. The algorithm also shows robust stability to imaging noise. Simulated imaging noise with zero mean and standard deviation equal to 25% of the base signal intensity was added to the DCE-MRI series. The amount of overlap between the tumor maps generated by the LDS-based algorithm from the noisy and original DCE-MRI was DSC = 0.95. CONCLUSION: The time-series analysis based segmentation algorithm provides high accuracy and sensitivity in delineating the regions of enhanced perfusion corresponding to tumor from DCE-MRI.

Mass spectrometry imaging as a tool for surgical decision-making.

Despite significant advances in image-guided therapy, surgeons are still too often left with uncertainty when deciding to remove tissue. This binary decision between removing and leaving tissue during surgery implies that the surgeon should be able to distinguish tumor from healthy tissue. In neurosurgery, current image-guidance approaches such as magnetic resonance imaging (MRI) combined with neuronavigation offer a map as to where the tumor should be, but the only definitive method to characterize the tissue at stake is histopathology. Although extremely valuable information is derived from this gold standard approach, it is limited to very few samples during surgery and is not practically used for the delineation of tumor margins. The development and implementation of faster, comprehensive, and complementary approaches for tissue characterization are required to support surgical decision-making--an incremental and iterative process with tumor removed in multiple and often minute biopsies. The development of atmospheric pressure ionization sources makes it possible to analyze tissue specimens with little to no sample preparation. Here, we highlight the value of desorption electrospray ionization as one of many available approaches for the analysis of surgical tissue. Twelve surgical samples resected from a patient during surgery were analyzed and diagnosed as glioblastoma tumor or necrotic tissue by standard histopathology, and mass spectrometry results were further correlated to histopathology for critical validation of the approach. The use of a robust statistical approach reiterated results from the qualitative detection of potential biomarkers of these tissue types. The correlation of the mass spectrometry and histopathology results to MRI brings significant insight into tumor presentation that could not only serve to guide tumor resection, but that is also worthy of more detailed studies on our understanding of tumor presentation on MRI.

Statistical Learning Algorithm for in situ and invasive breast carcinoma segmentation.

Dynamic Contrast Enhanced MRI (DCE-MRI) has proven to be a highly sensitive imaging modality in diagnosing breast cancers. However, analyzing the DCE-MRI is time-consuming and prone to errors due to the large volume of data. Mathematical models to quantify contrast perfusion, such as the black box methods and pharmacokinetic analysis, are inaccurate, sensitive to noise and depend on a large number of external factors such as imaging parameters, patient physiology, arterial input function, and fitting algorithms, leading to inaccurate diagnosis. In this paper, we have developed a novel Statistical Learning Algorithm for Tumor Segmentation (SLATS) based on Hidden Markov Models to auto-segment regions of angiogenesis, corresponding to tumor. The SLATS algorithm has been trained to identify voxels belonging to the tumor class using the time-intensity curve, first and second derivatives of the intensity curves ("velocity" and "acceleration" respectively) and a composite vector consisting of a concatenation of the intensity, velocity and acceleration vectors. The results of SLATS trained for the four vectors has been shown for 22 Invasive Ductal Carcinoma (IDC) and 19 Ductal Carcinoma In Situ (DCIS) cases. The SLATS trained for the velocity tuple shows the best performance in delineating the tumors when compared with the segmentation performed by an expert radiologist and the output of a commercially available software, CADstream.

Ambient mass spectrometry for the intraoperative molecular diagnosis of human brain tumors.

The main goal of brain tumor surgery is to maximize tumor resection while preserving brain function. However, existing imaging and surgical techniques do not offer the molecular information needed to delineate tumor boundaries. We have developed a system to rapidly analyze and classify brain tumors based on lipid information acquired by desorption electrospray ionization mass spectrometry (DESI-MS). In this study, a classifier was built to discriminate gliomas and meningiomas based on 36 glioma and 19 meningioma samples. The classifier was tested and results were validated for intraoperative use by analyzing and diagnosing tissue sections from 32 surgical specimens obtained from five research subjects who underwent brain tumor resection. The samples analyzed included oligodendroglioma, astrocytoma, and meningioma tumors of different histological grades and tumor cell concentrations. The molecular diagnosis derived from mass-spectrometry imaging corresponded to histopathology diagnosis with very few exceptions. Our work demonstrates that DESI-MS technology has the potential to identify the histology type of brain tumors. It provides information on glioma grade and, most importantly, may help define tumor margins by measuring the tumor cell concentration in a specimen. Results for stereotactically registered samples were correlated to preoperative MRI through neuronavigation, and visualized over segmented 3D MRI tumor volume reconstruction. Our findings demonstrate the potential of ambient mass spectrometry to guide brain tumor surgery by providing rapid diagnosis, and tumor margin assessment in near-real time.

Magnetic resonance-guided focused ultrasound surgery: Part 2: A review of current and future applications.

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is a novel combination of technologies that is actively being realized as a noninvasive therapeutic tool for a myriad of conditions. These applications are reviewed with a focus on neurological use. A combined search of PubMed and MEDLINE was performed to identify the key events and current status of MRgFUS, with a focus on neurological applications. MRgFUS signifies a potentially ideal device for the treatment of neurological diseases. As it is nearly real time, it allows monitored provision of treatment location and energy deposition; is noninvasive, thereby limiting or eliminating disruption of normal tissue; provides focal delivery of therapeutic agents; enhances radiation delivery; and permits modulation of neural function. Multiple clinical applications are currently in clinical use and many more are under active preclinical investigation. The therapeutic potential of MRgFUS is expanding rapidly. Although clinically in its infancy, preclinical and early-phase I clinical trials in neurosurgery suggest a promising future for MRgFUS. Further investigation is necessary to define its true potential and impact.

The kinetics of blood brain barrier permeability and targeted doxorubicin delivery into brain induced by focused ultrasound.

Focused ultrasound (FUS) combined with a circulating microbubble agent is a promising strategy to non-invasively disrupt the blood-brain barrier (BBB) and could enable targeted delivery of therapeutics that normally do not leave the brain vasculature. This study investigated the kinetics of the BBB permeability using dynamic contrast-enhanced MRI (DCE-MRI) and the resulting payload of the chemotherapy agent, doxorubicin (DOX). We also investigated how the disruption and drug delivery were affected by a double sonication (DS) with two different time intervals (10 or 120 min). Two locations were sonicated transcranially in one hemisphere of the brain in 20 rats using a 690 kHz FUS transducer; the other hemisphere served as a control. For BBB disruption, 10 ms bursts were applied at 1 Hz for 60s and combined with IV injection of a microbubble ultrasound contrast agent (Definity; 10 µl/kg). DOX was injected immediately after the second location was sonicated. The transfer coefficient (K(trans)) for an MRI contrast agent (Gd-DTPA) was estimated serially at 4-5 time points ranging from 30 min to 7.5 hrs after sonication using DCE-MRI. After a single sonication (SS), the mean K(trans) was 0.0142 ± 0.006 min(-1) at 30 min and was two or more orders of magnitude higher than the non-sonicated targets. It decreased exponentially as a function of time with an estimated half-life of 2.22 hrs (95% confidence intervals (CI): 1.06-3.39 hrs). Adding a second sonication increased K(trans), and with a 120 min interval between sonications, prolonged the duration of the BBB disruption. Mean K(trans) estimates of 0.0205 (CI: 0.016-0.025) and 0.0216 (CI: 0.013-0.030) min(-1) were achieved after DS with 10 and 120 min delays, respectively. The half-life of the K(trans) decay that occurred as the barrier was restored was 1.8 hrs (CI: 1.20-2.41 hrs) for a 10 min interval between sonications and increased to 3.34 hrs (CI: 0.84-5.84 hrs) for a 120 min interval. DOX concentrations were significantly greater than in the non-sonicated brain for all experimental groups (p<0.0001), and 1.5-fold higher for DS with a 10 min interval between sonications. A linear correlation was found between the DOX concentration achieved and the K(trans) measured at 30 min after sonication (R: 0.7). These data suggest that one may be able to use Gd-DTPA as a surrogate tracer to estimate DOX delivery to the brain after FUS-induced BBB disruption. The results of this study provide information needed to take into account the dynamics BBB disruption over time after FUS.

Comparison of wideband steady-state free precession and T2-weighted fast spin echo in spine disorder assessment at 1.5 and 3 T.

Wideband steady-state free precession (WB-SSFP) is a modification of balanced steady-state free precession utilizing alternating repetition times to reduce susceptibility-induced balanced steady-state free precession limitations, allowing its use for high-resolution myelographic-contrast spinal imaging. Intertissue contrast and spatial resolution of complete-spine-coverage 3D WB-SSFP were compared with those of 2D T2-weighted fast spin echo, currently the standard for spine T2-imaging. Six normal subjects were imaged at 1.5 and 3 T. The signal-to-noise ratio efficiency (SNR per unit-time and unit-volume) of several tissues was measured, along with four intertissue contrast-to-noise ratios; nerve-ganglia:fat, intradural-nerves:cerebrospinal fluid, nerve-ganglia:muscle, and muscle:fat. Patients with degenerative and traumatic spine disorders were imaged at both MRI fields to demonstrate WB-SSFP clinical advantages and disadvantages. At 3 T, WB-SSFP provided spinal contrast-to-noise ratios 3.7-5.2 times that of fast spin echo. At 1.5 T, WB-SSFP contrast-to-noise ratio was 3-3.5 times that of fast spin echo, excluding a 1.7 ratio for intradural-nerves:cerebrospinal fluid. WB-SSFP signal-to-noise ratio efficiency was also higher. Three-dimensional WB-SSFP disadvantages relative to 2D fast spin echo are reduced edema hyperintensity, reduced muscle signal, and higher motion sensitivity. WB-SSFP's high resolution and contrast-to-noise ratio improved visualization of intradural nerve bundles, foraminal nerve roots, and extradural nerve bundles, improving detection of nerve compression in radiculopathy and spinal-stenosis. WB-SSFP's high resolution permitted reformatting into orthogonal planes, providing distinct advantages in gauging fine spine pathology.

Radiogenomic mapping of edema/cellular invasion MRI-phenotypes in glioblastoma multiforme.

BACKGROUND: Despite recent discoveries of new molecular targets and pathways, the search for an effective therapy for Glioblastoma Multiforme (GBM) continues. A newly emerged field, radiogenomics, links gene expression profiles with MRI phenotypes. MRI-FLAIR is a noninvasive diagnostic modality and was previously found to correlate with cellular invasion in GBM. Thus, our radiogenomic screen has the potential to reveal novel molecular determinants of invasion. Here, we present the first comprehensive radiogenomic analysis using quantitative MRI volumetrics and large-scale gene- and microRNA expression profiling in GBM. METHODS: Based on The Cancer Genome Atlas (TCGA), discovery and validation sets with gene, microRNA, and quantitative MR-imaging data were created. Top concordant genes and microRNAs correlated with high FLAIR volumes from both sets were further characterized by Kaplan Meier survival statistics, microRNA-gene correlation analyses, and GBM molecular subtype-specific distribution. RESULTS: The top upregulated gene in both the discovery (4 fold) and validation (11 fold) sets was PERIOSTIN (POSTN). The top downregulated microRNA in both sets was miR-219, which is predicted to bind to POSTN. Kaplan Meier analysis demonstrated that above median expression of POSTN resulted in significantly decreased survival and shorter time to disease progression (P<0.001). High POSTN and low miR-219 expression were significantly associated with the mesenchymal GBM subtype (P<0.0001). CONCLUSION: Here, we propose a novel diagnostic method to screen for molecular cancer subtypes and genomic correlates of cellular invasion. Our findings also have potential therapeutic significance since successful molecular inhibition of invasion will improve therapy and patient survival in GBM.

A wireless batteryless deep-seated implantable ultrasonic pulser-receiver powered by magnetic coupling.

This study tests a deep-seated implantable ultrasonic pulser-receiver, powered wirelessly by magnetic coupling. A 30-cm energy-transmitting coil was designed to wrap around the body, and was driven by a current of 1.2 A rms at a frequency of 5.7 MHz to generate a magnetic field. A 2-cm receiving coil was positioned at the center of the primary coil for receiving the magnetic energy and powering the implantable device. A capacitor-diode voltage multiplier in the implantable circuit was used to step-up the receiving coil voltage from 12.5 to 50 V to operate an ultrasonic pulser. FEA magnetic field simulations, bench-top, and ex vivo rabbit measurements showed that the magnetic energy absorption in body tissue is negligible and that the magnetic coupling is not sensitive to receiving coil placement. The receiving coil and the power conditioning circuits in the implantable device do not contain ferromagnetic material, so a magnetic-resonance-compatible device can be achieved. A 5-MHz ultrasound transducer was used to test the implantable circuit, operating in pulse-echo mode. The received echo was amplified, envelope-detected, frequency-modulated, and transmitted out of the rabbit body by a radio wave. The modulated echo envelope signal was received by an external receiver located about 10 cm away from the primary coil. The study concludes that operation of a batteryless and wireless deep-seated implantable ultrasonic pulser-receiver powered by coplanar magnetic coupling is feasible.