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The importance of hormone receptor status in assigning treatment and the potential use of human epidermal growth factor receptor 2 (HER2)-targeted therapy have made it beneficial for laboratories to improve detection techniques. Because interlaboratory variability in immunohistochemistry (IHC) tests may also affect studies of breast cancer subtypes in different countries, we undertook a Web-based quality improvement training and a comparative study of accuracy of immunohistochemical tests of breast cancer biomarkers between a well-established laboratory in the United States (University of Chicago) and a field laboratory in Ibadan, Nigeria. Two hundred and thirty-two breast tumor blocks were evaluated for estrogen receptors (ERs), progesterone receptors (PRs), and HER2 status at both laboratories using tissue microarray technique. Initially, concordance analysis revealed κ scores of 0.42 (moderate agreement) for ER, 0.41 (moderate agreement) for PR, and 0.39 (fair agreement) for HER2 between the 2 laboratories. Antigen retrieval techniques and scoring methods were identified as important reasons for discrepancy. Web-based conferences using Web conferencing tools such as Skype and WebEx were then held periodically to discuss IHC staining protocols and standard scoring systems and to resolve discrepant cases. After quality assurance and training, the agreement improved to 0.64 (substantial agreement) for ER, 0.60 (moderate agreement) for PR, and 0.75 (substantial agreement) for HER2. We found Web-based conferences and digital microscopy useful and cost-effective tools for quality assurance of IHC, consultation, and collaboration between distant laboratories. Quality improvement exercises in testing of tumor biomarkers will reduce misclassification in epidemiologic studies of breast cancer subtypes and provide much needed capacity building in resource-poor countries.

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BACKGROUND: Irreversible electroporation (IRE) is a novel ablation tool that uses brief high-voltage pulses to treat cancer. The efficacy of the therapy depends upon the distribution of the electric field, which in turn depends upon the configuration of electrodes used. METHODS: We sought to optimize the electrode configuration in terms of the distance between electrodes, the depth of electrode insertion, and the number of electrodes. We employed a 3D Finite Element Model and systematically varied the distance between the electrodes and the depth of electrode insertion, monitoring the lowest voltage sufficient to ablate the tumor, V(IRE). We also measured the amount of normal (non-cancerous) tissue ablated. Measurements were performed for two electrodes, three electrodes, and four electrodes. The optimal electrode configuration was determined to be the one with the lowest V(IRE), as that minimized damage to normal tissue. RESULTS: The optimal electrode configuration to ablate a 2.5 cm spheroidal tumor used two electrodes with a distance of 2 cm between the electrodes and a depth of insertion of 1 cm below the halfway point in the spherical tumor, as measured from the bottom of the electrode. This produced a V(IRE) of 3700 V. We found that it was generally best to have a small distance between the electrodes and for the center of the electrodes to be inserted at a depth equal to or deeper than the center of the tumor. We also found the distance between electrodes was far more important in influencing the outcome measures when compared with the depth of electrode insertion. CONCLUSIONS: Overall, the distribution of electric field is highly dependent upon the electrode configuration, but the optimal configuration can be determined using numerical modeling. Our findings can help guide the clinical application of IRE as well as the selection of the best optimization algorithm to use in finding the optimal electrode configuration.

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Irreversible electroporation (IRE) uses high-voltage pulses applied to tissue, which cause dielectric breakdown of cell membranes resulting in cell death. IRE is a promising technique for ablation of nonresectable tumors because it can be configured to spare critical structures such as blood vessels. A consequence of pulse application is an increase in tissue electrical conductivity due to current pathways being opened in cell membranes. We propose a novel IRE method introducing electrode switching and pulse sequencing in which tissue conductivity is first increased using preparatory pulses in order to form high-conductivity zones, which then helps provide higher electric field intensity within the targeted tissue as subsequent pulses are applied, and hence, enhances the efficiency and selectivity of the IRE treatment. We demonstrate the potential of this method using computational models on simple geometries.

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Irreversible electroporation (IRE) is a novel therapy used to ablate tumors with high-field electric pulses applied in short durations. It is important to reduce the generation of heat in IRE to avoid the harmful effects of thermal damage. The objective of this simulation study was to examine the effects of saline irrigation in the reduction of heat upon electrodes used in IRE treatment of hepatocellular carcinoma. We used a two dimensional Finite Element Model of a tumor in a liver with electrodes placed at the center of the tumor. We simulated a typical electroporation protocol with varying thicknesses and conductivities of the saline layer, and we observed the maximum temperature and the distribution of the electric field and temperature in the tissue. Our results showed that the maximum temperature in the tissue decreases with the use of saline, but the surface area of the tumor that could potentially be thermally damaged may increase with the thickness and conductivity of the saline. With the use of saline, one can achieve upwards of a 17% reduction of the maximum temperature at the electrodes. Also, the distribution of temperature and the electric field becomes more homogenous between the electrodes as the conductivity of the saline layer increases for all thicknesses of saline. We conclude that irrigating electrodes with saline may be an effective measure to enhance the efficacy of irreversible electroporation by reducing the maximum temperature at the electrodes and also improving the extent and distribution of the electric field in the tissue. However, the properties of the saline should be adjusted so as to limit the increase of thermal damage propagated in the tissue.

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Macrophages, a key cell in the inflammatory cascade, have been associated with poor prognosis in cancers, including breast cancer. In this study, we investigated the relationship of a subset of macrophages-proliferating macrophages (promacs)-with clinico-pathologic characteristics of breast cancer, including tumor size, grade, stage, lymph node metastases, hormone receptor status, subtype, as well as early recurrence, and survival. This study included a discovery and validation set that was conducted at two institutions and laboratories (University of California, San Francisco and University of Chicago) using two independent cohorts of patients with breast cancer. Formalin-fixed, paraffin-embedded sections and/or tissue microarrays were double-stained with anti-CD68 (a macrophage marker) and anti-PCNA (a proliferation marker) antibodies. The presence of intratumoral promacs was significantly correlated with high grade, hormone receptor negative tumors, and a basal-like subtype. In contrast, there was no correlation between promacs and tumor size, stage, or the number of the involved lymph nodes. These findings were consistent between the two study cohorts. Finally, promac numbers were a significant predictor of recurrence and survival. In the pooled analysis, elevated promac levels were associated with a 77% increased risk of dying (P = 0.015). The presence of promacs in human breast cancer may serve as a prognostic indicator for poor outcomes and early recurrence and serve as a potential cellular target for novel therapeutic interventions.

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OBJECTIVE: Determine predictors of persistent postoperative detrusor overactivity and urge urinary incontinence after sling procedures for stress urinary incontinence STUDY DESIGN: Three hundred five women with mixed urinary incontinence underwent sling procedures for stress urinary incontinence. Risk factors for persistent detrusor overactivity and urge urinary incontinence were examined using logistic regression models. RESULTS: Women (31.5%) who had postoperative resolution of detrusor overactivity. Transobturator slings had the lowest rate of persistent detrusor overactivity (53%), followed by retropubic (SPARC = 66%; TVT = 64%) and bladder neck slings (86%). Predictors for persistent detrusor overactivity included age (odds ratio [OR], 1.38; P = .001), prior hysterectomy (OR, 1.95; P = .012), paravaginal repair (OR, 0.46; P = .015), nocturia (OR, 1.91; P = .013), maximum cystometric capacity (OR, 0.79; P < .001), detrusor overactivity volume (OR, 0.83; P = .006), urethral closure pressure (OR, 0.83; P < .001), and maximum urinary flow rate (OR, 0.77; P = .014). Persistent urge urinary incontinence was predicted by sling type (P < .001). CONCLUSION: When treating women with mixed urinary incontinence, age, nocturia, maximum cystometric capacity, and choice of sling procedure impact persistence of detrusor overactivity and urge urinary incontinence.

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