Evaluation of a Transimpedance Matrix Algorithm to Detect Anomalous Cochlear Implant Electrode Position.

INTRODUCTION: Transimpedance measurements from cochlear implant electrodes have the potential to identify anomalous electrode array placement, such as tip fold-over (TFO) or fold-back, basal electrode kinking, or buckling. Analysing transimpedance may thus replace intraoperative or post-operative radiological imaging to detect any potential misplacements. A transimpedance algorithm was previously developed to detect deviations from a normal electrode position with the aim of intraoperatively detecting TFO. The algorithm had been calibrated on 35 forced, tip folded electrode arrays in six temporal bones to determine the threshold criterion required to achieve a sensitivity of 100%. Our primary objective here was to estimate the specificity of this TFO algorithm in patients, in a prospective study, for a series of electrode arrays shown to be normally inserted by post-operative imaging. METHODS: Intracochlear voltages were intraoperatively recorded for 157 ears, using Cochlear's Custom Sound™ EP 5 electrophysiological software (Cochlear Ltd., Sydney, NSW, Australia), for both Nucleus® CI512 and CI532 electrode arrays. The algorithm analysed the recorded 22 × 22 transimpedance matrix (TIM) and results were displayed as a heatmap intraoperatively, only visible to the technician in the operating theatre. After all clinical data were collected, the algorithm was evaluated on the bench. The algorithm measures the transimpedance gradients and corresponding phase angles (θ) throughout the TIM and calculates the gradient phase range. If this was greater than the predetermined threshold, the algorithm classified the electrode array insertion as having a TFO. RESULTS: Five ears had no intraoperative TIM and four anomalous matrices were identified from heatmaps and removed from the specificity analysis. Using the 148 remaining data sets (n = 103 CI532 and n = 45 CI512), the algorithm had an average specificity of 98.6% (95.80%-99.75%). CONCLUSION: The algorithm was found to be an effective screening tool for the identification of TFOs. Its specificity was within acceptable levels and resulted in a positive predictive value of 76%, with an estimated incidence of fold-over of 4% in perimodiolar arrays. This would mean 3 out of 4 cases flagged as a fold-over would be correctly identified by the algorithm, with the other being a false positive. The measurements were applied easily in theatre allowing it to be used as a routine clinical tool for confirming correct electrode placement.

In-vivo characterisation of an implanted microphone and totally implantable active middle ear implant.

OBJECTIVE: To objectively evaluate acoustic sensitivity of the implanted microphone, and maximum stable gain of a totally implantable active middle ear implant. DESIGN: Prospective, single centre evaluation. STUDY SAMPLE: Fourteen adult patients. RESULTS: Microphone sensitivity is approx. 10 dB lower than an externally worn conventional hearing aid, at frequencies up to 4000 Hz, and substantially lower at higher frequencies. The masking level due to microphone noise, which determines the softest test tones that can be detected, is estimated at <20 to <30 dB HL up to 1000 Hz, and <40 dB HL at higher frequencies. Maximum stable effective gain is the maximum amplification achievable without causing feedback whistling. In sensorineural hearing loss (SNHL) cases, it is 30-40 dB at frequencies up to 2000 Hz, allowing to compensate for even the maximum recommended hearing loss (60-70 dB HL). In both SNHL and mixed hearing loss (MHL) cases, maximum stable effective gain is lower (+20 to -30 dB) around 3000-6000 Hz. CONCLUSIONS: Microphone sensitivity is high enough to achieve aided thresholds of 20-40 dB HL. A strong correlation between actuator coupling efficiency and maximum stable effective gain implies that any effort to improve actuator efficiency should also increase the available gain.

Comparison of electrode impedance measures between a dexamethasone-eluting and standard Cochlear™ Contour Advance® electrode in adult cochlear implant recipients.

OBJECTIVE: To compare the difference in electrode impedance across discrete time points to 24 months post-activation for two groups of adult cochlear implant recipients, one using an investigational perimodiolar (Contour Advance®) array augmented with 40% concentration weight per weight (w/w) dexamethasone (the Drug Eluting Electrode, 'DEE' Group), and the other the commercially available Contour Advance ('Control' Group). DESIGN: Ten adult subjects were implanted with the DEE and fourteen with the Control. Electrode impedances were measured intra-operatively, one-week post-surgery, at initial activation (approximately two-weeks post-surgery), and at approximately one, three, six, 12 and 24 months post-activation. Two different impedance measurements were obtained: 1) in MP1+2 mode using Custom Sound programming software; and 2) 4-point impedance measures utilising BP+2 stimulation mode with recording on non-stimulating electrodes. Data were analysed with respect to both impedance averaged across all electrodes, and impedance for electrodes grouped into basal, middle and apical sections. RESULTS: Group mean MP1+2 impedance for the DEE was significantly lower than for the Control at all post-operative time points examined, and for each of the basal, middle and apical cochlear regions. Group mean 4-point impedance was significantly lower for the DEE than the Control in the basal region at six, 12 and 24 months post-activation and in the middle region at 12- and 24-months post-activation. The pattern of change in MP1+2 impedance differed significantly in the early post-operative period prior to device activation. A significant 4.8 kOhm reduction in impedance between surgery and one-week was observed for the DEE group but not for the Control. A 2.0 kOhm increase between the one and two week post-operative time points was observed for the Control but not for the DEE group. CONCLUSION: While rates of adoption of different surgical approaches differed between the groups and this may have had a confounding effect, the results suggest that passive elution of dexamethasone from the investigational device was associated with a change in the intracochlear environment following surgical implantation of the electrode array, as evidenced by the lower electrode impedance measures.

Transcriptomic analysis of human primary breast cancer identifies fatty acid oxidation as a target for metformin.

BACKGROUND: Epidemiological studies suggest that metformin may reduce the incidence of cancer in patients with diabetes and multiple late phase clinical trials assessing the potential of repurposing this drug are underway. Transcriptomic profiling of tumour samples is an excellent tool to understand drug bioactivity, identify candidate biomarkers and assess for mechanisms of resistance to therapy. METHODS: Thirty-six patients with untreated primary breast cancer were recruited to a window study and transcriptomic profiling of tumour samples carried out before and after metformin treatment. RESULTS: Multiple genes that regulate fatty acid oxidation were upregulated at the transcriptomic level and there was a differential change in expression between two previously identified cohorts of patients with distinct metabolic responses. Increase in expression of a mitochondrial fatty oxidation gene composite signature correlated with change in a proliferation gene signature. In vitro assays showed that, in contrast to previous studies in models of normal cells, metformin reduces fatty acid oxidation with a subsequent accumulation of intracellular triglyceride, independent of AMPK activation. CONCLUSIONS: We propose that metformin at clinical doses targets fatty acid oxidation in cancer cells with implications for patient selection and drug combinations. CLINICAL TRIAL REGISTRATION: NCT01266486.

Integrated Pharmacodynamic Analysis Identifies Two Metabolic Adaption Pathways to Metformin in Breast Cancer.

Late-phase clinical trials investigating metformin as a cancer therapy are underway. However, there remains controversy as to the mode of action of metformin in tumors at clinical doses. We conducted a clinical study integrating measurement of markers of systemic metabolism, dynamic FDG-PET-CT, transcriptomics, and metabolomics at paired time points to profile the bioactivity of metformin in primary breast cancer. We show metformin reduces the levels of mitochondrial metabolites, activates multiple mitochondrial metabolic pathways, and increases 18-FDG flux in tumors. Two tumor groups are identified with distinct metabolic responses, an OXPHOS transcriptional response (OTR) group for which there is an increase in OXPHOS gene transcription and an FDG response group with increased 18-FDG uptake. Increase in proliferation, as measured by a validated proliferation signature, suggested that patients in the OTR group were resistant to metformin treatment. We conclude that mitochondrial response to metformin in primary breast cancer may define anti-tumor effect.

Fitting recommendations and clinical benefit associated with use of the NAL-NL2 hearing-aid prescription in Nucleus cochlear implant recipients.

OBJECTIVE: For a group of cochlear implant recipients, who use hearing aids in the contralateral ear, the benefit of NAL-NL2 relative to a recipients' own prescription was assessed. Whether there was a preferred frequency response and/or gain deviation from NAL-NL2 was then investigated. DESIGN: Speech recognition and self-reported ratings of benefit were examined for the recipients' own prescription compared to the NAL-NL2 prescription, in the bimodal and hearing-aid alone conditions. Paired-comparison of hearing-aid frequency response was conducted with default NAL-NL2 and two variants, a low frequency boost or cut. Using a loudness balancing procedure, the hearing-aid gain required to achieve equal loudness between the devices was measured. STUDY SAMPLE: Sixteen adults with post-lingual hearing loss. RESULTS: A 22% increase in group median word score in quiet with use of NAL-NL2 in the hearing-aid alone condition. In the bimodal condition there was no improvement with NAL-NL2. Default NAL-NL2 frequency response was preferred by 67% of participants. For 56% of participants, the preferred gain to achieve loudness balance across bimodal devices was within 5-dB of prescribed values. CONCLUSIONS: The NAL-NL2 prescription provides a high level of clinical performance, and an acceptable frequency response and gain for most participants.

Slip imaging: reducing ambiguity in breast lesion assessment.

Ultrasound elasticity imaging (elastography) is gaining popularity as an adjunct to B-mode ultrasound for breast cancer diagnosis. Cancerous masses are usually stiffer than normal tissue, hence, using elasticity imaging should lead to better differentiation between benign and malignant masses than using B-mode alone. Clinicians assess the mobility of masses on palpation; cancers usually being less mobile. We introduce a method to estimate mobility, called slip imaging and combine it with conventional B-mode and elasticity data. In the reported evaluation on 70 women recalled to a breast assessment clinic, images were scored by three breast radiologists independently. Diagnostic accuracy increased from 75.7% with B-mode alone, to 78.1% when including elasticity imaging, to 80.0% when further including slip imaging. Specificity increased (74.6%:75.4%:82.5% respectively), with an apparent trade-off in sensitivity (77.1%:81.3%:77.1%). We conclude that Slip imaging is potentially a useful adjunct to B-mode and elasticity imaging and should undergo further research and development.

A biologically inspired algorithm for microcalcification cluster detection.

The early detection of breast cancer greatly improves prognosis. One of the earliest signs of cancer is the formation of clusters of microcalcifications. We introduce a novel method for microcalcification detection based on a biologically inspired adaptive model of contrast detection. This model is used in conjunction with image filtering based on anisotropic diffusion and curvilinear structure removal using local energy and phase congruency. An important practical issue in automatic detection methods is the selection of parameters: we show that the parameter values for our algorithm can be estimated automatically from the image. This way, the method is made robust and essentially free of parameter tuning. We report results on mammograms from two databases and show that the detection performance can be improved by first including a normalisation scheme.

Hormone replacement therapy and false positive recall in the Million Women Study: patterns of use, hormonal constituents and consistency of effect.

INTRODUCTION: Current and recent users of hormone replacement therapy (HRT) have an increased risk of being recalled to assessment at mammography without breast cancer being diagnosed ('false positive recall'), but there is limited information on the effects of different patterns of HRT use on this. The aim of this study is to investigate in detail the relationship between patterns of use of HRT and false positive recall. METHODS: A total of 87,967 postmenopausal women aged 50 to 64 years attending routine breast cancer screening at 10 UK National Health Service Breast Screening Units from 1996 to 1998 joined the Million Women Study by completing a questionnaire before screening and were followed for their screening outcome. RESULTS: Overall, 399 (0.5%) participants were diagnosed with breast cancer and 2,629 (3.0%) had false positive recall. Compared to never users of HRT, the adjusted relative risk (95% CI) of false positive recall was: 1.62 (1.43-1.83), 1.80 (1.62-2.01) and 0.76 (0.52-1.10) in current users of oestrogen-only HRT, oestrogen-progestagen HRT and tibolone, respectively (p (heterogeneity) < 0.0001); 1.65 (1.43-1.91), 1.49 (1.22-1.81) and 2.11 (1.45-3.07) for current HRT used orally, transdermally or via an implant, respectively (p (heterogeneity) = 0.2); and 1.84 (1.67-2.04) and 1.75 (1.49-2.06) for sequential and continuous oestrogen-progestagen HRT, respectively (p (heterogeneity) = 0.6). The relative risk of false positive recall among current users appeared to increase with increasing time since menopause, but did not vary significantly according to any other factors examined, including duration of use, hormonal constituents, dose, whether single- or two-view screening was used, or the woman's personal characteristics. CONCLUSION: Current use of oestrogen-only and oestrogen-progestagen HRT, but not tibolone, increases the risk of false positive recall at screening.

Influence of personal characteristics of individual women on sensitivity and specificity of mammography in the Million Women Study: cohort study.

OBJECTIVES: To examine how lifestyle, hormonal, and other factors influence the sensitivity and specificity of mammography. METHODS: Women recruited into the Million Women Study completed a questionnaire about various personal factors before routine mammographic screening. A sample of 122,355 women aged 50-64 years were followed for outcome of screening and incident breast cancer in the next 12 months. Sensitivity and specificity were calculated by using standard definitions, with adjustment for potential confounding factors. RESULTS: Breast cancer was diagnosed in 726 (0.6%) women, 629 in screen positive and 97 in screen negative women; 3885 (3.2%) were screen positive but had no subsequent diagnosis of breast cancer. Overall sensitivity was 86.6% and specificity was 96.8%. Three factors had an adverse effect on both measures: use of hormone replacement therapy (sensitivity: 83.0% (95% confidence interval 77.4% to 87.6%), 84.7% (73.9% to 91.6%), and 92.1% (87.6% to 95.0%); specificity: 96.8% (96.6% to 97.0%), 97.8% (97.5% to 98.0%), and 98.1% (98.0% to 98.2%), respectively, for current, past, and never use); previous breast surgery v no previous breast surgery (sensitivity: 83.5% (75.7% to 89.1%) v 89.4% (86.5% to 91.8%); specificity: 96.2% (95.8% to 96.5%) v 97.4% (97.3% to 97.5%), respectively); and body mass index < 25 v > or = 25 (sensitivity: 85.7% (81.2% to 89.3%) v 91.0% (87.5% to 93.6%); specificity: 97.2% (97.0% to 97.3%) v 97.4% (97.3% to 97.6%), respectively). Neither sensitivity nor specificity varied significantly according to age, family history of breast cancer, parity, past oral contraceptive use, tubal ligation, physical activity, smoking, or alcohol consumption. CONCLUSIONS: The efficiency, and possibly the effectiveness, of mammographic screening is lower in users of hormone replacement therapy, in women with previous breast surgery, and in thin women compared with other women.

Fusion of contrast-enhanced breast MR and mammographic imaging data.

Increasing use is being made of Gd-DTPA contrast-enhanced magnetic resonance imaging for breast cancer assessment since it provides 3D functional information via pharmacokinetic interaction between contrast agent and tumour vascularity, and because it is applicable to women of all ages as well as patients with post-operative scarring. Contrast-enhanced MRI (CE-MRI) is complementary to conventional X-ray mammography, since it is a relatively low-resolution functional counterpart of a comparatively high-resolution 2D structural representation. However, despite the additional information provided by MRI, mammography is still an extremely important diagnostic imaging modality, particularly for several common conditions such as ductal carcinoma in situ (DCIS) where it has been shown that there is a strong correlation between microcalcification clusters and malignancy. Pathological indicators such as calcifications and fine spiculations are not visible in CE-MRI and therefore there is clinical and diagnostic value in fusing the high-resolution structural information available from mammography with the functional data acquired from MRI imaging. This paper presents a novel data fusion technique whereby medial-lateral oblique (MLO) and cranial-caudal (CC) mammograms (2D data) are registered to 3D contrast-enhanced MRI volumes. We utilise a combination of pharmacokinetic modelling, projection geometry, wavelet-based landmark detection and thin-plate spline non-rigid 'warping' to transform the coordinates of regions of interest (ROIs) from the 2D mammograms to the spatial reference frame of the contrast-enhanced MRI volume. Of key importance is the use of a flexible wavelet-based feature extraction technique that enables feature correspondences to be robustly determined between the very different image characteristics of X-ray mammography and MRI. An evaluation of the fusion framework is demonstrated with a series of clinical cases and a total of 14 patient examples.

Nonrigid registration of 3-D free-hand ultrasound images of the breast.

Three-dimensional (3-D) ultrasound imaging of the breast enables better assessment of diseases than conventional two-dimensional (2-D) imaging. Free-hand techniques are often used for generating 3-D data from a sequence of 2-D slice images. However, the breast deforms substantially during scanning because it is composed primarily of soft tissue. This often causes tissue mis-registration in spatial compounding of multiple scan sweeps. To overcome this problem, in this paper, instead of introducing additional constraints on scanning conditions, we use image processing techniques. We present a fully automatic algorithm for 3-D nonlinear registration of free-hand ultrasound data. It uses a block matching scheme and local statistics to estimate local tissue deformation. A Bayesian regularization method is applied to the sample displacement field. The final deformation field is obtained by fitting a B-spline approximating mesh to the sample displacement field. Registration accuracy is evaluated using phantom data and similar registration errors are achieved with (0.19 mm) and without (0.16 mm) gaps in the data. Experimental results show that registration is crucial in spatial compounding of different sweeps. The execution time of the method on moderate hardware is sufficiently fast for fairly large research studies.

Comparison of various characteristics of women who do and do not attend for breast cancer screening.

BACKGROUND: Information regarding the characteristics and health of women who do and do not attend for breast cancer screening is limited and representative data are difficult to obtain. METHODS: Information on age, deprivation and prescriptions for various medications was obtained for all women at two UK general practices who were invited to breast cancer screening through the National Health Service Breast Screening Programme. The characteristics of women who attended and did not attend screening were compared. RESULTS: Of the 1064 women invited to screening from the two practices, 882 (83%) attended screening. Screening attenders were of a similar age to non-attenders but came from significantly less deprived areas (30% of attenders versus 50% of non-attenders came from the most deprived areas, P < 0.0001) and were more likely to have a current prescription for hormone replacement therapy (32% versus 19%, P < 0.0001). No significant differences in recent prescriptions of medication for hypertension, heart disease, hypercholesterolaemia, diabetes mellitus, asthma, thyroid disease or depression/anxiety were observed between attenders and non-attenders. CONCLUSION: Women who attend the National Health Service Breast Screening Programme come from less deprived areas and are more likely to have a current prescription for hormone replacement therapy than non-attenders, but do not differ in terms of age or recent prescriptions for various other medications.