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We have deployed a recently completed spectroscopic electrical impedance tomography (EITS) imaging system in a small series of women (13 participants accrued to date) in order to investigate the feasibility of delivering EITS breast examinations on a routine basis. Hardware is driven with sinusoidally varying spatial patterns of applied voltage delivered to 16 electrodes over the 10 kHz to 1 MHz spectral range using a radially translating interface which couples the electrodes to the breast through direct contact. Imaging examinations have consisted of the acquisition of multi-channel measurements at ten frequencies on both breasts. Participants lie prone on an examination table with the breast to be imaged pendant in the electrode array that is located below the table. Examinations were comfortable and easy to deliver (about 10 minutes per breast including electrode-positioning time). Although localized near-surface electrode artefacts are evident in the acquired images, several findings have emerged. Permittivity images have generally been more informative than their conductivity counterparts, except in the case of fluid-filled cysts. Specifically, the mammographically normal breast appears to have characteristic absolute EITS permittivity and conductivity images that emerge across subjects. Structural features in the EITS images have correlated with limited clinical information available on participants with benign and malignant abnormality, cysts and scarring from previous lumpectomy and follow-up radiation therapy. Several cases from this preliminary experience are described.

Skin injury is a common side effect of breast- cancer radiation therapy. Although physicians often observe skin toxicity, quantifying its severity remains a challenge. We present a novel quantitative ultrasonic technique to evaluate skin changes associated with radiotherapy. An in vivo study with twelve breast- cancer patients was conducted. All patients received a standard course of post-surgery radiation therapy. Each patient received ultrasound scans to the irradiated breast and the untreated (contra-lateral) breast. Radio-frequency (RF) backscatter signals and B-mode images were acquired simultaneously. To quantify the severity of skin injury, two metrics were calculated from the RF signals: skin thickness and Pearson correlation coefficient of the subcutaneous layer. Comparing to the non-irradiated skin, the average thickness of the irradiated skin increased by 40% (p=0.005) and the average correlation coefficient of the irradiated hypodermis decreased by 35% (p=0.02). This study demonstrates the feasibility of using a non-invasive ultrasonic technique to detect and quantify radiation-induced skin changes.

Electrical impedance spectroscopic measurements over the range 1 kHz-1 MHz have been made in vivo in rat muscle exposed to single radiation doses of 50, 70, 90, and 150 Gy. Two electrode impedance measurements were recorded across the semitendonosis and semimembranosis muscle masses in the hind legs of rats prior to irradiation, within 48 hours post-irradiation, and monthly thereafter. Initial results show a dose response of the impedance spectra. Short term radiation effects, including edemic swelling, also appear to be detectable with this technique. Correlation between radiation induced tissue changes and impedance changes is established at a qualitative level. Eventually this technique will be used in combination with electrical impedance tomography to image the entire region of interest.

There is increasing evidence that alterations in the electrical property spectrum of tissues below 10 MHz is diagnostic for tissue pathology and/or pathophysiology. Yet, the complexity associated with constructing a high-fidelity multichannel, multifrequency data acquisition instrument has limited widespread development of spectroscopic electrical impedance imaging concepts. To contribute to the relatively sparse experience with multichannel spectroscopy systems this paper reports on the design, realization and evaluation of a prototype 32-channel instrument. The salient features of the system include a continuously selectable driving frequency up to 1 MHz, either voltage or current source modes of operation and simultaneous measurement of both voltage and current on each channel in either of these driving configurations. Comparisons of performance with recently reported fixed-frequency systems is favorable. Volts dc (VDC) signal-to-noise ratios of 75-80 dB are achieved and the noise floor for ac signals is near 100 dB below the signal strength of interest at 10 kHz and 60 dB down at 1 MHz. The added benefit of being able to record multispectral information on source and sense signal amplitudes and phases has also been realized. Phase-sensitive detection schemes and multiperiod undersampling techniques have been deployed to ensure measurement fidelity over the full bandwidth of system operation.

Electrical impedance spectroscopy (EIS) and high-frequency ultrasound (HFU) have been evaluated in various in vivo and in vitro models as potential methods to monitor biological changes induced by photodynamic therapy (PDT). EIS was assessed in tumor-bearing rat leg in vivo, in multicell tumor spheroids in vitro, and in normal rat liver tissue in vivo. HFU measurements, both imaging and backscatter frequency scanning, were tested in normal rat brain and skin treated in vivo. Marked changes in the EIS spectra were seen in all 3 models following PDT, depending on the photosensitizer and treatment parameters. With HFU, significant increases in echogenicity of the PDT-treated tissues were observed, with evidence of dose dependency and correlation with apoptotic cell death in vivo. While the results are encouraging for both modalities, a number of technical problems remain, particularly in the case of EIS, before these methods can be used reliably in mechanistic and clinical PDT applications.

Electrical impedance spectroscopy (EIS) has been evaluated as a non- or minimally-invasive technique to monitor the acute tissue response to photodynamic therapy (PDT). In this study the EIS spectra of normal muscle tissue in the rat hind leg were monitored immediately before and at time intervals up to 96 hours post-PDT treatment with different photosensitizers (Photofrin, ALA-induced PpIX, BenzoPorphyrin Derivative), at varying photosensitizer and light doses. EIS measurements were made using a pair of solid matrix Ag-AgCl electrodes placed parallel to one another on either side of the muscle mass and interfaced to a precision LCR impedance meter scanning the frequency range 1 - 1000 KHz. Independent histological grading of tissue injury was performed on tissue sections from treated and untreated legs at the 96 hour end point. Significant and PDT dose-dependent changes in the EIS spectra following treatment were observed, including increases in conductivity which correlated with the immediate post-PDT edematous response with Photofrin and ALA and which resolved or partially-resolved over the measurement time course. Photofrin treatments exhibited a clear drug dose response at 96 hours that was evident in both the EIS spectra and the histological sections. These changes included significant tissue necrosis as well as edema, inflammation and early fibroplasia. The BPD data were less clear, but potentially quite interesting. Most striking were below unity ratios of treated-to-untreated muscle spectra components at 24 hours which reversed to above unity by 96 hours in the through skin measurements. This phenomenon is indicative of a tissue response distinctly different than that observed with Photofrin or ALA. These data also suggest that EIS measured changes are sensitive enough to detect differences in PDT-initiated tissue damage that may be photosensitize-specific. While the data are derived from a small number of animals, the findings are quite encouraging in terms of the potential for EIS to track PDT-induced changes in tissue.

Electrical properties of tissues in the 10 KHz to 10 MHz range are known to be temperature sensitive making the monitoring and assessment of thermal insult delivered for therapeutic purposes possible through imaging schemes which spatially resolve these changes. We have been developing electrical impedance imaging technology from both the hardware data acquisition and software image reconstruction perspectives in order to realize the capability of spectroscopically examining the electrical property response of tissues undergoing hyperthermia therapy. Results from simulations, in vitro phantom experiments and in vivo studies including in human patients are presented. Specifically, a new prototype multi-frequency data acquisition system which is functional to 1 MHz in both voltage and current modes is described. In addition, recent advances in image reconstruction methods which include the enhancement techniques of total variation minimization, dual meshing and spatial filtering are discussed. It is also clear that the electrical impedance spectrum of tissue has the potential to monitor other types of treatment-induced injury. Preliminary in vivo electrical impedance measurements in a rat leg model suggest that the tissue damage from radiation therapy can be tracked with this technique. Both dose and time-dependent responses have been observed in the electrical impedance data when compared to measurements recorded in an untreated control. Correlations with histological examination have also been performed and indicate that electrical impedance spectroscopy may provide unique information regarding tissue functional status and cellular morphology. Representative results from these studies are reported.

Purpose: To investigate a novel combination of two non‐invasive techniques, spectrophotometry and ultrasoundtissue characterization (UTC) imaging, to quantitatively evaluate breast tissue toxicity in radiation treatment.Method and Materials:Skin and soft tissue injury are the most common toxicities of breast cancerradiation therapy. There is currently no objective means of measuring breast tissue injury in the clinic. We investigated the combination of Spectrophotometry and UTC imaging to examine radiation toxicity. A spectrophotometer (Mexameter® MX) was used to measure the radiation damage to the skin surface and an ultrasound scanner (Ultrasonix® with 14‐MHz probe) was utilized to measure the soft tissue changes. Six imaging parameters were computed to quantitatively measure toxicity: melanin, erythema, skin thickness, UTC slope, intercept and midband value. Subjective clinical assessment of toxicity was done by a radiation oncologist. Statistical analysis was performed to correlate spectrophotometer and UTC findings with clinical assessments (RTOG clinical toxicity scale). To date, twelve breast cancer patients were enrolled. All patients received a standard course of radiation: the whole breast received 50–50.4 Gy followed by an electron boost of 10–16 Gy at the lumpectomy site. Each patient received a series of spectrophotometer and ultrasound scans prior to, during and post radiation treatment.Results: Twenty‐eight spectrophotometer and ultrasound scans were performed. The contra‐lateral (untreated) breast scans showed good accuracy and reproducibility. Our spectrophotometer and UTC evaluations were consistent with the clinical breast toxicity assessments. We observed significant patient variations. During six‐week radiation treatment, patient melanin increases were between 5 to 20%, erythema increases varied from 0% to 100%. Conclusion: The combination of spectrophotometer and UTC provides effective means of assessing radiation damage to the skin and the underlying breast tissue respectively. This tool becomes increasingly valuable as we evaluate new strategies for breast cancerradiation therapy, such as partial breast IMRT and MammoSite.

Purpose: There is much interest in using biological and functional imaging to provide guidance in IMRT dose painting. Yet, it is important to incorporate the performance characteristics of these modalities. In this study an example of UltrasoundTissue Typing (UTT) was utilized to investigate the implications of the imager's performance on the design of a population based prostate dose painting protocol. Method and Materials: The performance of an imaging modality can be evaluated via the receiver operating characteristic curve, which is a plot of the imaging modality's sensitivity versus false‐positive ratio (1‐specificity). As sensitivity increases, more tumors are detected, although specificity worsens, causing more false negatives. The UTT tumor map obtained with a specific sensitivity and specificity setup is fused with the patient's CTimage to guide IMRT planning. The optimal escalation dose to the tumor positive region identified by UTT, as well as the safe dose to the identified tumor negative background was obtained by maximizing uncomplicated control, which is a combination of tumor control probability (TCP), and weighted normal tissue complication probability (NTCP). Results: A practical dose escalation protocol requires a high specificity imager setup to reduce complications. For tumors at the high‐risk stage, with sensitivity at 0.6 and specificity at 0.9, optimal dose to the positive and negative regions are 88.2Gy and 83.6Gy respectively, which resulted in a 25% NTCP reduction compared to that the whole prostate is dose escalated to the same TCP. If the imager becomes more accurate, i.e., sensitivity improves to 0.9 when specificity remains at 0.9, the optimal plan would have a further 10% NTCP decrease with a 2% TCP increase. Conclusion: Performance characteristics of an imager as described by sensitivity and specificity has important implications in prostate dose painting, and should be considered in the future design of dose painting protocols.

Purpose: To systematically examine the impact of margin and imaging resolution on dose painting protocols with regards to target definition and patient eligibility. Method and Materials: The prostate PTV was formed by expanding the clinical target volume by 1‐cm. The intraprostatic tumor nodules (IPTNs) were digitized using data from Chen et al.(2000) corresponding to a >50% probability of occurrence. The IPTNs were then discretized on three different grids: 1mm2 (our treatment planning pixel size), 2mm2, and 6.6mm2; grid sizes reflect imaging modality resolution. 75.6Gy was prescribed to the PTV and the target dose for the IPTNs was 90Gy. Our standard rectal and bladder constraints were used with maximum dose of 91Gy to rectum and urethra. The margin on the tumor nodules was varied from 0.2 to 1.5cm. Results: The volumes for the IPTNs were 3.2, 4.9 and 10.2cc for the three grid sizes; CTV and PTV volumes for the whole gland were 44.2cc and 137.2cc. A typical distribution of IPTNs (4 foci), expanded with a 6mm symmetrical margin to 33cc was boosted to 90 cGy without exceeding critical organ constraints. Margins were 5mm and 5.5mm with grids applied. Once the absolute volume of the targets (IPTNs + margin) was accounted for, however, neither grid size nor margin size had an impact on the ability to escalate dose. The ratio of the boost region to the PTV volume was the determining factor. The limiting IPTNs+margin volume was 25% of the PTV volume. By relaxing the requirements to accept >90% coverage with 90Gy, acceptable plans could be achieved with IPTNs+margin volumes occupying ⩽ 36% of the PTV volume. Conclusion: A simple volume‐based screening method may be used to determine patient eligibility for inclusion in a clinical IPTN dose‐escalation study, irrespective of the cancer‐specific imaging system's resolution and required margins.