Alex Hartov

Quantitative fluorescence in intracranial tumor: implications for ALA-induced PpIX as an intraoperative biomarker.

OBJECT Accurate discrimination between tumor and normal tissue is crucial for optimal tumor resection. Qualitative fluorescence of protoporphyrin IX (PpIX), synthesized endogenously following δ-aminolevulinic acid (ALA) administration, has been used for this purpose in high-grade glioma (HGG). The authors show that diagnostically significant but visually imperceptible concentrations of PpIX can be quantitatively measured in vivo and used to discriminate normal from neoplastic brain tissue across a range of tumor histologies. METHODS The authors studied 14 patients with diagnoses of low-grade glioma (LGG), HGG, meningioma, and metastasis under an institutional review board-approved protocol for fluorescence-guided resection. The primary aim of the study was to compare the diagnostic capabilities of a highly sensitive, spectrally resolved quantitative fluorescence approach to conventional fluorescence imaging for detection of neoplastic tissue in vivo. RESULTS A significant difference in the quantitative measurements of PpIX concentration occurred in all tumor groups compared with normal brain tissue. Receiver operating characteristic (ROC) curve analysis of PpIX concentration as a diagnostic variable for detection of neoplastic tissue yielded a classification efficiency of 87% (AUC = 0.95, specificity = 92%, sensitivity = 84%) compared with 66% (AUC = 0.73, specificity = 100%, sensitivity = 47%) for conventional fluorescence imaging (p < 0.0001). More than 81% (57 of 70) of the quantitative fluorescence measurements that were below the threshold of the surgeons visual perception were classified correctly in an analysis of all tumors. CONCLUSIONS These findings are clinically profound because they demonstrate that ALA-induced PpIX is a targeting biomarker for a variety of intracranial tumors beyond HGGs. This study is the first to measure quantitative ALA-induced PpIX concentrations in vivo, and the results have broad implications for guidance during resection of intracranial tumors.

Electrical impedance spectroscopy of the breast: clinical imaging results in 26 subjects

Electrical impedance spectroscopy (EIS) is a potential, noninvasive technique to image women for breast cancer. Studies have shown characteristic frequency dispersions in the electrical conductivity and permittivity of malignant versus normal tissue. Using a multifrequency EIS system, we imaged the breasts of 26 women. All patients had mammograms ranked using the American College of Radiology (ACR) BIRADS system. Of the 51 individual breasts imaged, 38 were ACR 1 negative, six had ACR 4-5 suspicious lesions, and seven had ACR 2 benign findings such as fibroadenomas or calcifications. A radially translatable circular array of 16 Ag/AgCl electrodes was placed around the breast while the patient lay prone. We applied trigonometric voltage patterns at ten frequencies between 10 and 950 kHz. Anatomically coronal images were reconstructed from this data using nonlinear partial differential equation methods. Typically, ACR 1-rated breasts were interrogated in a single central plane whereas ACR 2-5-rated breasts were imaged in multiple planes covering the region of suspicion. In general, a characteristic homogeneous image emerged for mammographically normal cases while focal inhomogeneities were observed in images from women with malignancies. Using a specific visual criterion, EIS images identified 83% of the ACR 4-5 lesions while 67% were detected using a numerical criterion. Overall, multifrequency electrical impedance imaging appears promising for detecting breast malignancies, but improvements must be made before the method reaches its full potential.

Modeling of retraction and resection for intraoperative updating of images.

OBJECTIVEIntraoperative tissue deformation that occurs during the course of neurosurgical procedures may compromise patient-to-image registration, which is essential for image guidance. A new approach to account for brain shift, using computational methods driven by sparsely available operating room (OR) data, has been augmented with techniques for modeling tissue retraction and resection. METHODSModeling strategies to arbitrarily place and move an intracranial retractor and to excise designated tissue volumes have been implemented within a computationally tractable framework. To illustrate these developments, a surgical case example, which uses OR data and the preoperative neuroanatomic image volume of the patient to generate a highly resolved, heterogeneous, finite-element model, is presented. Surgical procedures involving the retraction of tissue and the resection of a left frontoparietal tumor were simulated computationally, and the simulations were used to update the preoperative image volume to represent the dynamic OR environment. RESULTSRetraction and resection techniques are demonstrated to accurately reflect intraoperative events, thus providing an approach for near-real-time image-updating in the OR. Information regarding subsurface deformation and, in particular, changing tumor margins is presented. Some of the current limitations of the model, with respect to specific tissue mechanical responses, are highlighted. CONCLUSIONThe results presented demonstrate that complex surgical events such as tissue retraction and resection can be incorporated intraoperatively into the model-updating process for brain shift compensation in high-resolution preoperative images.

A Broadband High-Frequency Electrical Impedance Tomography System for Breast Imaging

Bio-electric impedance signatures arise primarily from differences in cellular morphologies within an organ and can be used to differentiate benign and malignant pathologies, specifically in the breast. Electrical impedance tomography (EIT) is an imaging modality that determines the impedance distribution within tissue and has been used in prior work to map the electrical properties of breast at signal frequencies ranging from a few kHz to 1 MHz. It has been suggested that by extending the frequency range, additional information of clinical significance may be obtained. We have, therefore, developed a new EIT system for breast imaging which covers the frequency range from 10 kHz to 10 MHz. The instrument developed here is a distributed processor tomograph with 64 channels, capable of generating and measuring voltages and currents. Electrical benchmarking has shown the system to have a SNR greater than 94 dB up to 2 MHz, 90 dB up to 7 MHz, and 65 dB at 10 MHz. In addition, the system measures impedances to an accuracy of 99.7% and has channel-to-channel variations of less than 0.05%. Phantom imaging has demonstrated the ability to image across the entire frequency range in both single-and multiplane configurations. Further, 96 women have participated safely in breast exams with the system and the associated conductivity spectra obtained from 3-D image reconstructions range from 0.0237 S/m at 10 kHz to 0.2174 S/m at 10 MHz. These findings are consistent with impedance values reported in the literature.

The correlation of in vivo and ex vivo tissue dielectric properties to validate electromagnetic breast imaging: initial clinical experience

Electromagnetic (EM) breast imaging provides low-cost, safe and potentially a more specific modality for cancer detection than conventional imaging systems. A primary difficulty in validating these EM imaging modalities is that the true dielectric property values of the particular breast being imaged are not readily available on an individual subject basis. Here, we describe our initial experience in seeking to correlate tomographic EM imaging studies with discrete point spectroscopy measurements of the dielectric properties of breast tissue. The protocol we have developed involves measurement of in vivo tissue properties during partial and full mastectomy procedures in the operating room (OR) followed by ex vivo tissue property recordings in the same locations in the excised tissue specimens in the pathology laboratory immediately after resection. We have successfully applied all of the elements of this validation protocol in a series of six women with cancer diagnoses. Conductivity and permittivity gauged from ex vivo samples over the frequency range 100 Hz-8.5 GHz are found to be similar to those reported in the literature. A decrease in both conductivity and permittivity is observed when these properties are gauged from ex vivo samples instead of in vivo. We present these results in addition to a case study demonstrating how discrete point spectroscopy measurements of the tissue can be correlated and used to validate EM imaging studies.

Electrical Impedance Spectroscopy of the Human Prostate

Tissue electrical impedance is a function of its architecture and has been used to differentiate normal and cancer tissues in a variety of organs including breast, cervix, skin, and bladder. This paper investigates the possibility of differentiating normal and malignant prostate tissue using bioimpedance spectra. A probe was designed to measure impedance spectra over the range of 10 kHz to 1 MHz. The probe was fully characterized using discrete loads and saline solutions of different concentrations. Impedance spectra of five ex vivo prostates were measured in the operating room immediately following radical prostatectomy. Wilcoxon signed-rank tests were used to compare the normal and malignant findings. The impedance probe had a signal-to-noise ratio (SNR) > 84 dB across the entire spectrum and measured a tissue volume of approximately 46 mm3. At 10 kHz, prostate conductivity (sigma) ranged from 0.232 S/m to 0.310 S/m for tumor and from 0.238 S/m to 0.901 S/m for normal tissue. At 1 MHz the ranges were 0.301 S/m to 0.488 S/m for tumor and 0.337 S/m to 1.149 S/m for normal. Prostate permittivity (epsivr) ranged from 6.64 times104 to 1.25 times105 for tumor and from 9.08 times104 to 4.49 times105 for normal tissues at 10 kHz. And, at 1 MHz the er ranges were 9.23 times102 to 1.88 times103 for tumor and 1.16 times103 to 2.18 times103 for normal tissue. Both sigma and epsivr of tumor tissue were found to be significantly lower than that of normal tissue (P < 0.0001). Conductivity and permittivity are both higher in normal prostate tissues than they are in malignant tissue making them suitable parameters for tissue differentiation. This is in agreement with trends observed in other tissues reported in much of the literature. Expanded studies are needed to further validate this finding and to explore the biological mechanism responsible for generating the results.

In vivo modeling of interstitial pressure in the brain under surgical load using finite elements

Current brain deformation models have predominantly reflected solid constitutive relationships generated from empirical ex vivo data and have largely overlooked interstitial hydrodynamic effects. In the context of a technique to update images intraoperatively for image-guided neuronavigation, we have developed and quantified the deformation characteristics of a three-dimensional porous media finite element model of brain deformation in vivo. Results have demonstrated at least 75-85 percent predictive capability, but have also indicated that interstitial hydrodynamics are important. In this paper we investigate interstitial pressure transient behavior in brain tissue when subjected to an acute surgical load consistent with neurosurgical events. Data are presented from three in vivo porcine experiments where subsurface tissue deformation and interhemispheric pressure gradients were measured under conditions of an applied mechanical deformation and then compared to calculations with our three-dimensional brain model. Results demonstrate that porous-media consolidation captures the hydraulic behavior of brain tissue subjected to comparable surgical loads and that the experimental protocol causes minimal trauma to porcine brain tissue. Working values for hydraulic conductivity of white and gray matter are also reported and an assessment of transient pressure gradient effects with respect to deformation is provided.

Design and implementation of a high frequency electrical impedance tomography system.

Electrical impedance tomography is an imaging modality being investigated for use in detection of breast cancer. Use of higher frequencies than have typically been employed may benefit the detection processes. In this current work we discuss the design and initial implementation of a system having a bandwidth of 10 MHz. Previous investigations into high frequency designs have proven more difficult than anticipated and shown that careful selection of systems architecture is critical to achieving broadband performance above 1 MHz. The design for this new system is based on a digital signal processor (DSP) which is used for control, signal generation and signal processing. Signal generation and detection, software design and preliminary system specifications are discussed.

Mutual-information-based image to patient re-registration using intraoperative ultrasound in image-guided neurosurgery

An image-based re-registration scheme has been developed and evaluated that uses fiducial registration as a starting point to maximize the normalized mutual information (nMI) between intraoperative ultrasound (iUS) and preoperative magnetic resonance images (pMR). We show that this scheme significantly (p<0.001) reduces tumor boundary misalignment between iUS pre-durotomy and pMR from an average of 2.5 mm to 1.0 mm in six resection surgeries. The corrected tumor alignment before dural opening provides a more accurate reference for assessing subsequent intraoperative tumor displacement, which is important for brain shift compensation as surgery progresses. In addition, we report the translational and rotational capture ranges necessary for successful convergence of the nMI registration technique (5.9 mm and 5.2 deg, respectively). The proposed scheme is automatic, sufficiently robust, and computationally efficient (<2 min), and holds promise for routine clinical use in the operating room during image-guided neurosurgical procedures.

Electrical properties of prostatic tissues: I. Single frequency admittivity properties.

PURPOSE Electrical properties of the prostate may provide sufficient contrast for distinguishing malignant and benign formations in the gland. We evaluated how well these electrical properties discriminate cancer from noncancer tissues in the prostate. MATERIALS AND METHODS Electrical admittivity (conductivity and permittivity) was recorded at 31 discrete frequencies of 0.1 to 100 kHz from each of 50 ex vivo human prostates. A specifically designed admittivity probe was used to gauge these electrical properties from sectioned prostate specimens. The specific tissue area probed was marked to provide precise colocalization between tissue histological assessment and recorded admittivity spectra. RESULTS Adenocarcinoma, benign prostatic hyperplasia, nonhyperplastic glandular tissue and stromal tissue were the primary tissue types probed. Mean cancer conductivity was significantly less than that of glandular and stromal tissues at all frequencies (p <0.05), while mean cancer permittivity was significantly greater than that of all benign tissues at 100 kHz (p <0.0001). ROC curves showed that permittivity at 100 kHz was optimal for discriminating cancer from all benign tissues. This parameter had 77% specificity at 70% sensitivity and an ROC AUC of 0.798. CONCLUSIONS The contrast in electrical admittivity properties of different prostate tissues shows promise for distinguishing cancer from benign tissues. Sensitivity and specificity exceed those reported for current prostate specific antigen screening practices at low prostate specific antigen, making this an attractive addition to the clinical armamentarium for identifying prostate cancer.