Image processing can cause some malignant soft-tissue lesions to be missed in digital mammography images.

AIM: To investigate the effect of image processing on cancer detection in mammography. METHODS AND MATERIALS: An observer study was performed using 349 digital mammography images of women with normal breasts, calcification clusters, or soft-tissue lesions including 191 subtle cancers. Images underwent two types of processing: FlavourA (standard) and FlavourB (added enhancement). Six observers located features in the breast they suspected to be cancerous (4,188 observations). Data were analysed using jackknife alternative free-response receiver operating characteristic (JAFROC) analysis. Characteristics of the cancers detected with each image processing type were investigated. RESULTS: For calcifications, the JAFROC figure of merit (FOM) was equal to 0.86 for both types of image processing. For soft-tissue lesions, the JAFROC FOM were better for FlavourA (0.81) than FlavourB (0.78); this difference was significant (p=0.001). Using FlavourA a greater number of cancers of all grades and sizes were detected than with FlavourB. FlavourA improved soft-tissue lesion detection in denser breasts (p=0.04 when volumetric density was over 7.5%) CONCLUSIONS: The detection of malignant soft-tissue lesions (which were primarily invasive) was significantly better with FlavourA than FlavourB image processing. This is despite FlavourB having a higher contrast appearance often preferred by radiologists. It is important that clinical choice of image processing is based on objective measures.

A Pilot Study on the Development of Remote Quality Control of Digital Mammography Systems in the NHS Breast Screening Programme.

In the UK, physicists and radiographers perform routine quality control (QC) of digital mammography equipment at daily, weekly and monthly intervals. The tests performed and tolerances are specified by standard protocols. The manual nature of many of the tests introduces variability due to the positioning of regions of interest (ROIs) and can be time consuming. The tools on workstations provided by manufacturers limit the range of analysis that radiographers can perform and do not allow for a standard set of tools and analysis because they are specific to a given manufacturer. Automated software provides a means of reducing the variability in the analysis and also provides the possibility of additional, more complex analysis than is currently performed on the daily, weekly and monthly checks by radiographers. To this end, a set of tools has been developed to analyse the routine images taken by radiographers. As well as automatically reproducing the usual measurements by radiographers more complex analysis is provided. A QC image collection system has been developed which automatically routes QC data from a clinical site to a centralised server for analysis. A Web-based interface has been created that allows the users to view the performance of the mammographic equipment. The pilot system obtained over 3000 QC images from seven X-ray units at a single screening centre over 2 years. The results show that these tools and methods of analysis can highlight changes in a detector over time that may otherwise go unnoticed with the conventional analysis.

Inter-limb musculoskeletal differences in competitive ten-pin bowlers: a preliminary analysis.

OBJECTIVES: To compare musculoskeletal characteristics of the loaded and non-loaded forearm and upper leg of competitive ten-pin bowlers. METHODS: 10 competitive bowlers (30.6∓6.8 yrs) had their areal bone mineral density (aBMD) and body composition measured with Dual Energy X-ray Absorptiometry (DXA). Volumetric bone mineral density (vBMD) and bone characteristics were assessed at 4% and 66% of the limb length of each radius and 50% of the limb length of each femur using a pQCT. Bone and muscle characteristics of the loaded and non-loaded limbs were compared and analyzed using paired t-tests. RESULTS: The loaded arm of competitive bowlers had significantly (p<0.05) greater bone free lean body mass (BFLBM) (5%) and ultra distal radius site (UD radius) aBMD (6.3%) compared to the non-loaded side. Cortical and trabecular vBMD was significantly (p<0.05) greater (1.3%, 4.8%) at the radius 66% and 4% sites in the loaded forearm, respectively. aBMD of the femoral neck, trochanter, and total hip were significantly greater (12.2-15.6%) in the slide leg. Total (5.2%) and cortical (9.2%) bone areas, total (8.2%) and cortical (8.7%) bone mineral content (BMC), and cortical wall thickness (9%) were significantly greater at the 50% femur site in the slide leg compared to the contralateral side. CONCLUSION: The femoral shaft of bowlers adapts by increasing bone area and cortical thickness without a change in vBMD, while the loaded radius adapts by increasing vBMD.

Further factors for the estimation of mean glandular dose using the United Kingdom, European and IAEA breast dosimetry protocols.

The United Kingdom, European and IAEA protocols for breast dosimetry in mammography make use of s-factors which allow for the use of different target/filter combinations. To supplement the existing protocols, a Monte Carlo computer program has been used to calculate s-factors for mammography using a tungsten target with silver filters of thicknesses 50-75 microm and for the same target filtered with 0.5 mm aluminium. The dosimetry protocols use slabs of polymethyl methacrylate (PMMA) of specified thicknesses to simulate the exposure of typical breasts. The equivalent thickness of PMMA has been calculated using a simplified approach for a wider range of x-ray spectra and for breast thicknesses of 2-11 cm. The results show that for the tungsten/silver target/filter combination, a single s-factor of 1.042 can be used with the protocols, but when the tungsten target is filtered with 0.5 mm of aluminium, it is necessary to select from a tabulation of s-factors against breast thickness. The equivalent thicknesses of PMMA for a given breast thickness show some dependence on beam quality and the values obtained differ from those presently used in the dosimetry protocols by an amount which depends upon breast thickness and half value layer (HVL). For the extreme case of an 11 cm breast and an HVL of 0.62 mm Al, the use of the protocol thickness would give rise to an error of 10%, but for breast thicknesses of 6 cm or less, the error is typically 2-3%.

Can the channelized Hotelling observer including aspects of the human visual system predict human observer performance in mammography?

PURPOSE: In mammography, images are processed prior to display. Model observers (MO) are candidates to objectively evaluate processed images if they can predict human observer performance for detail detection. The aim of this study was to investigate if the channelized Hotelling observer (CHO) can be configured to predict human observer performance in mammography like images. METHODS: The performance correlation between human observers and CHO has been evaluated using different channel-sets and by including aspects of the human visual system (HVS). The correlation was investigated for the detection of disk-shaped details in simulated white noise (WN) and clustered lumpy backgrounds (CLB) images, representing respectively quantum noise limited and mammography like images. The images were scored by the MO and five human observers in 2-alternative forced choice experiments. RESULTS: For WN images the most useful formulation of the CHO to predict human observer performance was obtained using three difference of Gaussian channels without adding HVS aspects (RLR2=0.62). For CLB images the most useful formulation was the partial least square channel-set without adding HVS aspects (RLR2=0.71). The correlation was affected by detail size and background. CONCLUSIONS: This study has shown that the CHO can predict human observer performance. Due to object size and background dependency it is important that the range of object sizes and allowed variability in background are specified and validated carefully before the CHO can be implemented for objective image quality assessment.

Quantitative profile of estrogen receptor variants/isoforms in Taiwanese women with breast cancer.

AIM: To quantify ER variants/isoforms for women with breast cancer in Taiwan, an area with remarkably low breast cancer rates, but with an early onset and poor prognosis. METHODS: Real-time PCR technology was exploited to quantify mRNAs of ERalpha, ERalphaE3Delta, ERalphaE5Delta, ERalphaE7Delta and ERbeta, in 49 breast cancer and paired adjacent normal tissues. Clinical parameters were assembled and tested for assocation with the ER expression. RESULTS: Comparison of cancer and matched normal samples showed significantly decreased ERbeta (p < 0.001) in cancer tissues, and constant amounts of ERalpha and their variants. The results revealed significantly lower ERalphaE7Delta/ERalpha (p = 0.030) and ERbeta/ERalpha (p = 0.035) ratios in patients with lymph node (LN) metastasis than in those without LN metastasis. CONCLUSION: Our data suggests that ERalphaE7Delta and ERbeta may regulate ERalpha in normal human breast tissue.

MEDXVIEWER: PROVIDING A WEB-ENABLED WORKSTATION ENVIRONMENT FOR COLLABORATIVE AND REMOTE MEDICAL IMAGING VIEWING, PERCEPTION STUDIES AND READER TRAINING.

MedXViewer (Medical eXtensible Viewer) has been developed to address the need for workstation-independent, picture archiving and communication system (PACS)-less viewing and interaction with anonymised medical images. The aim of this paper is to describe the design and features of MedXViewer as well as to introduce the new features available in the latest release (version 1.2). MedXViewer currently supports digital mammography and tomosynthesis. The flexible software design used to develop MedXViewer allows it to be easily extended to support other imaging modalities. Regions of interest can be drawn by a user, and any associated information about a mark, an image or a study can be added. The questions and settings can be easily configured depending on the need of the research allowing both ROC and FROC studies to be performed. Complex tree-like questions can be asked where a given answer presents the user to new questions. The hanging protocol can be specified for each study. Panning, windowing, zooming and moving through slices are all available while modality-specific features can be easily enabled, e.g. quadrant zooming in digital mammography and tomosynthesis studies. MedXViewer can integrate with a web-based image database OPTIMAM Medical Image Database allowing results and images to be stored centrally. The software can, alternatively, run without a network connection where the images and results can be encrypted and stored locally on a machine or external drive. MedXViewer has been used for running remote paper-less observer studies and is capable of providing a training infrastructure and coordinating remote collaborative viewing sessions.

Can the non-pre-whitening model observer, including aspects of the human visual system, predict human observer performance in mammography?

PURPOSE: In mammography, images are processed prior to display. Current methodologies based on physical image quality measurements are however not designed for the evaluation of processed images. Model observers (MO) might be suitable for this evaluation. The aim of this study was to investigate whether the non-pre-whitening (NPW) MO can be used to predict human observer performance in mammography-like images by including different aspects of the human visual system (HVS). METHODS: The correlation between human and NPW MO performance has been investigated for the detection of disk shaped objects in simulated white noise (WN) and clustered lumpy backgrounds (CLB), representing quantum noise limited and mammography-like images respectively. The images were scored by the MO and five human observers in a 2-alternative forced choice experiment. RESULTS: For WN images it was found that the log likelihood ratio (RLR2), which expresses the goodness of fit, was highest (0.44) for the NPW MO without addition of HVS aspects. For CLB the RLR2 improved from 0.46 to 0.65 with addition of HVS aspects. The correlation was affected by object size and background. CONCLUSIONS: This study shows that by including aspects of the HVS, the performance of the NPW MO can be improved to better predict human observer performance. This demonstrates that the NPW MO has potential for image quality assessment. However, due to the dependencies found in the correlation, the NPW MO can only be used for image quality assessment for a limited range of object sizes and background variability.

Site-specific associations of muscle thickness with bone mineral density in middle-aged and older men and women.

It is unknown whether age-related site-specific muscle loss is associated with areal bone mineral density (aBMD) in older adults. To examine the relationships between aBMD and whole-body muscle thickness distribution, 97 healthy adults (46 women and 51 men) aged 50-78 years volunteered. Total and appendicular lean soft tissue mass, aBMD of the lumbar spine (LS-aBMD) and femoral neck (FN-aBMD) were determined using dual-energy X-ray absorptiometry. Muscle thickness (MT) was measured by ultrasound at nine sites of the body (forearm, upper arm, trunk, upper leg, and lower leg). Relationships of each co-variate with aBMD were tested partialling out the effect of age. aBMD was not correlated with either MT of the trunk or anterior lower leg in either sex. In men, significant and relatively strong correlations were observed between anterior and posterior upper arms, posterior lower leg, and anterior upper leg MT and LS-aBMD or FN-aBMD. In women, significant correlations were observed between anterior and posterior upper legs, posterior lower leg, and anterior upper arm MT and FN-aBMD. LS-aBMD was only correlated with forearm and posterior upper leg MT in women. In conclusion, the site-specific association of MT and aBMD differs between sexes and may be associated with the participants' daily physical activity profile.

SIMULATING LOCAL DENSE AREAS USING PMMA TO ASSESS AUTOMATIC EXPOSURE CONTROL IN DIGITAL MAMMOGRAPHY.

Current digital mammography (DM) X-ray systems are equipped with advanced automatic exposure control (AEC) systems, which determine the exposure factors depending on breast composition. In the supplement of the European guidelines for quality assurance in breast cancer screening and diagnosis, a phantom-based test is included to evaluate the AEC response to local dense areas in terms of signal-to-noise ratio (SNR). This study evaluates the proposed test in terms of SNR and dose for four DM systems. The glandular fraction represented by the local dense area was assessed by analytic calculations. It was found that the proposed test simulates adipose to fully glandular breast compositions in attenuation. The doses associated with the phantoms were found to match well with the patient dose distribution. In conclusion, after some small adaptations, the test is valuable for the assessment of the AEC performance in terms of both SNR and dose.

Tissue distribution and cDNA cloning of a human fatty acid transport protein (hsFATP4).

Fatty acid uptake is partly controlled by the FATP gene family, of which at least five members are known in mice. Using the mmFATP1 cDNA as hybridization probe, a 1.6 kb partial cDNA clone was isolated from a human heart cDNA library. With 5' and 3' RACE procedures, the complete cDNA was isolated. Sequence comparisons with its mouse homologues identified this clone as hsFATP4.

Radiation doses received in the UK Breast Screening Programme in 2001 and 2002.

The mean glandular doses (MGD) to samples of women attending for mammographic screening are measured routinely at screening centres in the UK Breast Screening Programme (NHSBSP). This paper reviews a large representative sample of dose measurements collected during screening in the NHSBSP in 2001 and 2002 for 53 218 films, using 290 X-ray sets, for 16 505 women. The average MGD was 2.23 mGy per oblique film and 1.96 mGy per craniocaudal film; similar to those found previously in the NHSBSP for the years 1997 and 1998. Increasing use of sophisticated units with automatic beam quality selection has reduced the radiation dose received by large breasts, with only 2% of oblique mammograms having doses in excess of 5 mGy. The increasing use of large format film has also reduced the doses to this sub-group. However the total dose per woman has increased due to the introduction of two view screening at every visit. The MGD to the standard breast was found to vary from 0.76 mGy to 2.29 mGy, with 97% of units below the recommended upper limit of 2 mGy, illustrating the benefit of strict quality control. A reduction in dose of 3% was observed between the age bands 50-54 years and 60-64 years. This study has confirmed that the proposed national diagnostic reference level (NDRL) of 3.5 mGy for 55 mm thick breasts is an appropriate value to identify systems giving unusually high doses, with just 3.5% of systems exceeding this level. In most cases these higher doses were explained by the design of one particular make of X-ray set and its mode of operation. Average doses for oblique views of average sized breasts were fairly well correlated with the dose to the standard breast, and typically 42% higher. This highlights the need for a revised definition of the standard breast used in the UK to better reflect the exposure factors and doses received in clinical practice.

Dose assessment in contrast enhanced digital mammography using simple phantoms simulating standard model breasts.

Slabs of polymethyl methacrylate (PMMA) or a combination of PMMA and polyethylene (PE) slabs are used to simulate standard model breasts for the evaluation of the average glandular dose (AGD) in digital mammography (DM) and digital breast tomosynthesis (DBT). These phantoms are optimized for the energy spectra used in DM and DBT, which normally have a lower average energy than used in contrast enhanced digital mammography (CEDM). In this study we have investigated whether these phantoms can be used for the evaluation of AGD with the high energy x-ray spectra used in CEDM. For this purpose the calculated values of the incident air kerma for dosimetry phantoms and standard model breasts were compared in a zero degree projection with the use of an anti scatter grid. It was found that the difference in incident air kerma compared to standard model breasts ranges between -10% to +4% for PMMA slabs and between 6% and 15% for PMMA-PE slabs. The estimated systematic error in the measured AGD for both sets of phantoms were considered to be sufficiently small for the evaluation of AGD in quality control procedures for CEDM. However, the systematic error can be substantial if AGD values from different phantoms are compared.

Average glandular dose in digital mammography and digital breast tomosynthesis: comparison of phantom and patient data.

For the evaluation of the average glandular dose (AGD) in digital mammography (DM) and digital breast tomosynthesis (DBT) phantoms simulating standard model breasts are used. These phantoms consist of slabs of polymethyl methacrylate (PMMA) or a combination of PMMA and polyethylene (PE). In the last decades the automatic exposure control (AEC) increased in complexity and became more sensitive to (local) differences in breast composition. The question is how well the AGD estimated using these simple dosimetry phantoms agrees with the average patient AGD. In this study the AGDs for both dosimetry phantoms and for patients have been evaluated for 5 different x-ray systems in DM and DBT modes. It was found that the ratios between patient and phantom AGD did not differ considerably using both dosimetry phantoms. These ratios averaged over all breast thicknesses were 1.14 and 1.15 for the PMMA and PMMA-PE dosimetry phantoms respectively in DM mode and 1.00 and 1.02 in the DBT mode. These ratios were deemed to be sufficiently close to unity to be suitable for dosimetry evaluation in quality control procedures. However care should be taken when comparing systems for DM and DBT since depending on the AEC operation, ratios for particular breast thicknesses may differ substantially (0.83-1.96). Although the predictions of both phantoms are similar we advise the use of PMMA + PE slabs for both DM and DBT to harmonize dosimetry protocols and avoid any potential issues with the use of spacers with the PMMA phantoms.

Preparation of a novel streptokinase mutant with improved stability.

The novel mutant streptokinase, SK-K59E, can activate human plasminogen as efficiently as the purified commercially available streptokinase. Several peptide bonds including Lys59-Ser60 in native streptokinase were hydrolyzed in reaction with plasmin and peptides of small molecular masses were generated. The plasminogen activator activity of native streptokinase in reaction with human plasmin declined to 25% of the original activity in a 120-min incubation. On the other hand, the NH2-terminal peptide of SK-K59E remained intact in reaction with plasmin and the activator activity of streptokinase decreased to 75% of the original activity in 120 min. The major degraded peptide fragments of native streptokinase in reaction with plasmin had molecular masses of 36 and 30 kDa. However, two major peptide fragments of 42 and 34 kDa were observed in the reaction of SK-K59E with human plasmin. The 42 kDa peptide fragment, which contained NH2-terminal of streptokinase, could activate human plasminogen as efficiently as the native streptokinase. SK-K59E can induce greater degree of caseinolysis and fibrinolysis than the native streptokinase. In conclusion, the results demonstrate that the prevention of cleavage at Lys59 of streptokinase prolongs the half-life of streptokinase in complex with plasmin and that the NH2-terminal of streptokinase (Ile1-Lys59) plays an important role in maintaining its stability.

Limitations and improvements of the quantiplex branched-DNA assay in Hepatitis B virus-infected patients receiving lamivudine.

The branched DNA (bDNA) assay for hepatitis B virus (Chiron Corporation Emerville, USA) was investigated by application to HBV-infected patients in Taiwan, where the B and C genotypes of hepatitis B virus are most prevalent. The study group included sera with hepatitis B surface antigen (HBsAg) and e antigen (HBeAg); Group 1 (n=70) without treatment; Group 2 (n=28) lamivudine treatment less than 3 months; Group 3 (n=73) lamivudine treatment 3-12 months; Group 4 (n=45) HBeAg-negative sera after 1 year treatment with lamivudine; control group (n=36) HBsAg-negative sera. Comparison of identical-sample results showed a significantly higher coefficient of variation for low-level HBV DNA (<100 MEq/ml) than for high-level (> or =100 MEq/ml), indicating increasing assay inaccuracy uncertainty as the sample HBV DNA concentration decreased. It is thus concluded that low-titered sera should receive special careful pipetting and processing. It was also found that using the relative luminescence of the negative control plus two standard deviations (S.D.) as a new cutoff could promote sensitivity (97.1-->97.1%, 89.3-->100%, 76.7-->84.9%, and 17.8-->22.2% in Groups 1-4, respectively) and specificity (94.4-->97.2%). In summary, the bDNA HBV assay showed only moderate assay performance for samples with low HBV DNA levels. This problem can be improved partially by choosing a new cutoff value based on the relative luminescence of the negative controls in the kit.

Clinical comparison of high-dose interferon-alpha2b with or without ribavirin for treatment of interferon-relapsed chronic hepatitis C.

BACKGROUND: Interferon a with ribavirin combination therapy is effective but still unsatisfactory in the treatment of patients with interferon-relapsed chronic hepatitis C. AIMS: To compare, in a randomized, double blind, placebo-controlled study, high-dose interferon-alpha2b with or without ribavirin in the treatment for interferon-relapsers. PATIENTS: A total of 52 patients with interferon-relapsed chronic hepatitis C were randomly assigned to receive 24-week treatment with interferon-alpha2b (6 MU three times per week) combined with either ribavirin (1,000 to 1,200 mg per day) or a matched placebo and then followed for an additional 24 weeks. METHODS: Hepatitis C virus RNA was detected by reverse-transcription polymerase chain reaction. For determining viral concentration, the commercial bDNA Quantiplex hepatitis C virus-RNA 2.0 assay was used. Genotyping was performed by reverse hybridization assay RESULTS: At the end of treatment, no detectable hepatitis C virus RNA levels were observed in 92% (24/26) of patients on interferon alpha2b/ribavirin and 81% (21/26) of patients on interferon alpha2b/placebo. At the end of the follow-up, a higher sustained virological response rate was seen in patients treated with interferon alpha2b/ribavirin than those treated with interferon alpha2b/placebo (69% vs 23%, p < 0.001). Patients with either initially high levels of viral concentration or with genotype 1 responded poorly. Patients who received interferon-alpha2b/ribavirin treatment and in whom no hepatitis C virus RNA was detected at 4th week after treatment had 90% chance to achieve sustained virological response. CONCLUSIONS: High-dose interferon-alpha2b plus ribavirin treatment is highly effective in interferon-relapsed patients.

Additional factors for the estimation of mean glandular breast dose using the UK mammography dosimetry protocol.

The UK and European protocols for mammographic dosimetry use conversion factors that relate incident air kerma to the mean glandular dose (MGD) within the breast. The conversion factors currently used were obtained by computer simulation of a model breast with a composition of 50% adipose and 50% glandular tissues by weight (50% glandularity). Relative conversion factors have been calculated which allow the extension of the protocols to breasts of varying glandularity and for a wider range of mammographic x-ray spectra. The data have also been extended to breasts of a compressed thickness of 11 cm. To facilitate the calculation of MGD in patient surveys, typical breast glandularities are tabulated for women in the age ranges 40-49 and 50-64 years, and for breasts in the thickness range 2-11 cm. In addition, tables of equivalent thickness of polymethyl methacrylate have been provided to allow the simulation for dosimetric purposes of typical breasts of various thicknesses.