Josephine Harter

A large-scale study of the ultrawideband microwave dielectric properties of normal, benign and malignant breast tissues obtained from cancer surgeries

The development of microwave breast cancer detection and treatment techniques has been driven by reports of substantial contrast in the dielectric properties of malignant and normal breast tissues. However, definitive knowledge of the dielectric properties of normal and diseased breast tissues at microwave frequencies has been limited by gaps and discrepancies across previously published studies. To address these issues, we conducted a large-scale study to experimentally determine the ultrawideband microwave dielectric properties of a variety of normal, malignant and benign breast tissues, measured from 0.5 to 20 GHz using a precision open-ended coaxial probe. Previously, we reported the dielectric properties of normal breast tissue samples obtained from reduction surgeries. Here, we report the dielectric properties of normal (adipose, glandular and fibroconnective), malignant (invasive and non-invasive ductal and lobular carcinomas) and benign (fibroadenomas and cysts) breast tissue samples obtained from cancer surgeries. We fit a one-pole Cole-Cole model to the complex permittivity data set of each characterized sample. Our analyses show that the contrast in the microwave-frequency dielectric properties between malignant and normal adipose-dominated tissues in the breast is considerable, as large as 10:1, while the contrast in the microwave-frequency dielectric properties between malignant and normal glandular/fibroconnective tissues in the breast is no more than about 10%.

A large-scale study of the ultrawideband microwave dielectric properties of normal breast tissue obtained from reduction surgeries.

The efficacy of emerging microwave breast cancer detection and treatment techniques will depend, in part, on the dielectric properties of normal breast tissue. However, knowledge of these properties at microwave frequencies has been limited due to gaps and discrepancies in previously reported small-scale studies. To address these issues, we experimentally characterized the wideband microwave-frequency dielectric properties of a large number of normal breast tissue samples obtained from breast reduction surgeries at the University of Wisconsin and University of Calgary hospitals. The dielectric spectroscopy measurements were conducted from 0.5 to 20 GHz using a precision open-ended coaxial probe. The tissue composition within the probes sensing region was quantified in terms of percentages of adipose, fibroconnective and glandular tissues. We fit a one-pole Cole-Cole model to the complex permittivity data set obtained for each sample and determined median Cole-Cole parameters for three groups of normal breast tissues, categorized by adipose tissue content (0-30%, 31-84% and 85-100%). Our analysis of the dielectric properties data for 354 tissue samples reveals that there is a large variation in the dielectric properties of normal breast tissue due to substantial tissue heterogeneity. We observed no statistically significant difference between the within-patient and between-patient variability in the dielectric properties.

Frozen Section Analysis for Intraoperative Margin Assessment During Breast-Conserving Surgery Results in Low Rates of Re-excision and Local Recurrence

BackgroundNegative surgical margins minimize the risk of local recurrence after breast-conserving surgery. Intraoperative frozen section analysis (FSA) is one method for margin evaluation. We retrospectively analyzed records of patients who received breast-conserving therapy with intraoperative FSA of the lumpectomy cavity to assess re-excision rates and local control.MethodsRecords were retrospectively reviewed for individuals who underwent breast-conserving surgery for ductal carcinoma in situ (DCIS) or invasive carcinoma between 1993 and 2003. Inclusion criteria were a minimum of 2 years follow-up and intact tumor at the time of operation. The major outcome measure was local recurrence. The Kaplan-Meier test was used to evaluate local recurrence rates between groups.Results290 subjects with an average age of 57.2 years (range 27–89) underwent 292 lumpectomies with FSA. 11.3% had DCIS, 73.3% had infiltrating ductal, 5.8% had infiltrating lobular, and 9.6% exhibited other forms of invasive carcinoma. 70 subjects underwent additional resection at the time of breast surgery, 16 underwent subsequent re-excision, and 17 underwent subsequent mastectomy. At a median follow-up of 53.4 months (range 5.8–137.8), there were six local recurrences (2.74%) in patients who had breast-conserving procedures and two local recurrences in patients who underwent mastectomy. There were no statistically significant associations among local recurrence rate, tumor size, nodal status, or overall stage. Local recurrences were higher in patients with DCIS compared with invasive carcinoma, and tumors >2cm.ConclusionsIntraoperative FSA allows resection of suspicious or positive margins at the time of lumpectomy and results in low rates of local recurrence and re-excision. The low local recurrence rate reported here is comparable to those reported with other margin assessment techniques.

Diagnosis of breast cancer using fluorescence and diffuse reflectance spectroscopy: a Monte-Carlo-model-based approach

We explore the use of Monte-Carlo-model-based approaches for the analysis of fluorescence and diffuse reflectance spectra measured ex vivo from breast tissues. These models are used to extract the absorption, scattering, and fluorescence properties of malignant and nonmalignant tissues and to diagnose breast cancer based on these intrinsic tissue properties. Absorption and scattering properties, including beta-carotene concentration, total hemoglobin concentration, hemoglobin saturation, and the mean reduced scattering coefficient are derived from diffuse reflectance spectra using a previously developed Monte Carlo model of diffuse reflectance. A Monte Carlo model of fluorescence described in an earlier manuscript was employed to retrieve the intrinsic fluorescence spectra. The intrinsic fluorescence spectra were decomposed into several contributing components, which we attribute to endogenous fluorophores that may present in breast tissues including collagen, NADH, and retinol/vitamin A. The model-based approaches removes any dependency on the instrument and probe geometry. The relative fluorescence contributions of individual fluorescing components, as well as beta-carotene concentration, hemoglobin saturation, and the mean reduced scattering coefficient display statistically significant differences between malignant and adipose breast tissues. The hemoglobin saturation and the reduced scattering coefficient display statistically significant differences between malignant and fibrous/benign breast tissues. A linear support vector machine classification using (1) fluorescence properties alone, (2) absorption and scattering properties alone, and (3) the combination of all tissue properties achieves comparable classification accuracies of 81 to 84% in sensitivity and 75 to 89% in specificity for discriminating malignant from nonmalignant breast tissues, suggesting each set of tissue properties are diagnostically useful for the discrimination of breast malignancy.

Ex vivo evaluation of anti-EpCAM immunocytokine huKS-IL2 in ovarian cancer.

Abstract: Despite encouraging responses to treatment, 70% to 80% of women with ovarian cancer will recur due to subclinical residual disease. One experimental agent that merits testing in this setting is the immunocytokine huKS-IL2. Immunocytokines are fusion proteins consisting of a humanized monoclonal antibody linked to IL-2 (or other cytokines). The humanized monoclonal antibody (mAb) huKS, which recognizes the epithelial cell adhesion molecule (EpCAM), has been used to construct the immunocytokine huKS-IL2. To determine the potential therapeutic use of huKS-IL2 in ovarian cancer, the authors evaluated the expression of EpCAM in these cancers and investigated the effects of huKS-IL2 on peritoneal white blood cells and peripheral blood mononuclear cells from women with ovarian cancer. EpCAM expression was determined by immunohistochemistry using both huKS-IL2 and the parent KS1/4 antibody. Ascites fluid was collected and the cellular fraction cultured with or without huKS-IL2 to evaluate the cellular content and potential anti-tumor effects of the peritoneal effector cells (PECs). Peritoneal cells were incubated with FITC-conjugated KS antibody to determine the relative amount of EpCAM-positive cells. Nonadherent cells were analyzed by flow cytometry for hematopoietic origin with CD45 mAb and for CD69 expression as an indication of immune cell activation. EpCAM-positive NIH:OVCAR-3 cells were radiolabeled as targets in a chromium release assay with either PECs or PBMCs as effector cells in the presence or absence of 0.25 mcg/mL huKS-IL2. Differences between treatments were determined by t test. Thirty-two of thirty-three (97%) ovarian cancers were found to express EpCAM via immunohistochemistry. Eleven cases were stained using both KS1/4 and huKS-IL2, and identical patterns of staining were seen. All ascites samples tested had EpCAM-positive cells by flow cytometry. The mean fluorescence intensity of CD69 expression on peritoneal WBCs was increased from 20.7 to 43.9 as a result of culturing with huKS-IL2, indicating effector cell activation. In chromium release assays, KS-IL2 facilitated cell lysis of NIH:OVCAR-3 by PBMCs from both healthy controls and patients with ovarian cancer. PECs from all cases tested showed significant cell lysis induced by huKS-IL2 compared with untreated control cultures. Based on these findings, huKS-IL2 warrants further investigation as a potential immunotherapy for patients with epithelial ovarian cancer, preferably in a minimal disease setting as seen after complete cytoreductive surgery, after a complete clinical response to primary therapy, or when elevated CA-125 levels predict recurrent disease prior to clinical relapse.

Fine-needle aspiration optimizes surgical management in patients with thyroid cancer

BackgroundFine-needle aspiration (FNA) is accurate in diagnosing papillary, medullary, and anaplastic thyroid cancer, as well as lymphoma. Although many surgeons routinely perform FNA before surgery, some question whether FNA influences operative management. Therefore, to determine whether FNA affects surgical management in patients with thyroid cancer, we reviewed our experience.MethodsA total of 442 consecutive patients underwent thyroid surgery at 1 academic center. Of these, 411 had surgery for an index nodule in the absence of previous radiation or familial thyroid cancer. FNA, operative, and permanent histology findings were reviewed.ResultsThe average patient age was 46 years, and 79% were female. A total of 211 patients (51%) had a preoperative FNA, and 71 (17%) had a final diagnosis of cancer. The sensitivity and specificity of FNA for thyroid cancer were 89% and 92%, respectively. In the FNA group, 1 (2.4%) of 41 patients with papillary thyroid cancer required completion thyroidectomy. In contrast, in the no-FNA group, 4 (40%) of 10 patients with papillary thyroid cancer required a second operation. No patient in the FNA group received thyroid resection for lymphoma, whereas three (100%) of three patients with lymphoma in the no-FNA group were treated surgically. A total of 98% of the FNA group, compared with 54% of the no-FNA group, received optimal surgical treatment for thyroid cancer.ConclusionsFNA is a sensitive and specific test for the diagnosis of thyroid cancer, allowing definitive initial surgery and avoiding unnecessary procedures. Therefore, we recommend routine use of preoperative thyroid FNA, even in those patients in whom a resection is already planned.

Frequency-dependent complex modulus of the uterus: preliminary results

The frequency-dependent complex moduli of human uterine tissue have been characterized. Quantification of the modulus is required for developing uterine ultrasound elastography as a viable imaging modality for diagnosing and monitoring causes for abnormal uterine bleeding and enlargement, as well assessing the integrity of uterine and cervical tissue. The complex modulus was measured in samples from hysterectomies of 24 patients ranging in age from 31 to 79 years. Measurements were done under small compressions of either 1 or 2%, at low pre-compression values (either 1 or 2%), and over a frequency range of 0.1-100 Hz. Modulus values of cervical tissue monotonically increased from approximately 30-90 kPa over the frequency range. Normal uterine tissue possessed modulus values over the same range, while leiomyomas, or uterine fibroids, exhibited values ranging from approximately 60-220 kPa.

Fluorescence Spectroscopy: An Adjunct Diagnostic Tool to Image-Guided Core Needle Biopsy of the Breast

We explored the use of a fiber-optic probe for in vivo fluorescence spectroscopy of breast tissues during percutaneous image-guided breast biopsy. A total of 121 biopsy samples with accompanying histological diagnosis were obtained clinically and investigated in this study. The tissue spectra were analyzed using partial least-squares analysis and represented using a set of principal components (PCs) with dramatically reduced data dimension. For nonmalignant tissue samples, a set of PCs that account for the largest amount of variance in the spectra displayed correlation with the percent tissue composition. For all tissue samples, a set of PCs was identified using a Wilcoxon rank-sum test as showing statistically significant differences between: 1) malignant and fibrous/benign; 2) malignant and adipose; and 3) malignant and nonmalignant breast samples. These PCs were used to distinguish malignant from other nonmalignant tissue types using a binary classification scheme based on both linear and nonlinear support vector machine (SVM) and logistic regression (LR). For the sample set investigated in this study, the SVM classifier provided a cross-validated sensitivity and specificity of up to 81% and 87%, respectively, for discrimination between malignant and fibrous/benign samples, and up to 81% and 81%, respectively, for discriminating between malignant and adipose samples. Classification based on LR was used to generate receiver operator curves with an area under the curve (AUC) of 0.87 for discriminating malignant versus fibrous/benign tissues, and an AUC of 0.84 for discriminating malignant from adipose tissue samples. This study demonstrates the feasibility of performing fluorescence spectroscopy during clinical core needle breast biopsy, and the potential of this technique for identifying breast malignancy in vivo.

Model based and empirical spectral analysis for the diagnosis of breast cancer.

We explored the use of both empirical (Partial Least Squares, PLS) and Monte Carlo model based approaches for the analysis of fluorescence and diffuse reflectance spectra measured ex vivo from freshly excised breast tissues and for the diagnosis of breast cancer. Features extracted using both approaches, i.e. principal components (PCs) obtained from empirical analysis or tissue properties obtained from model based analysis, displayed statistically significant difference between malignant and non-malignant tissues, and can be used to discriminate breast malignancy with comparable sensitivity and specificity of up to 90%. The PC scores of a subset of PCs also displayed significant correlation with the tissue properties extracted from the model based analysis, suggesting both approaches likely probe the same sources of contrast in the tissue spectra that discriminate between malignant and non-malignant breast tissues but in different ways.

In Vitro Uterine Strain Imaging Preliminary Results

Uterine abnormalities, such as leiomyomas, endometrial polyps, and adenomyosis, are often clinically associated with irregular uterine bleeding. These abnormalities can have similar B‐mode characteristics but require different treatment. The objective of this study was to develop diagnostic techniques based on ultrasound strain imaging that would allow in vivo visualization and characterization of endometrial and myometrial uterine abnormalities, enabling physicians to improve diagnosis and treatment.