Mammographic breast density: comparison of methods for quantitative evaluation.

PURPOSE: To evaluate the results from two software tools for measurement of mammographic breast density and compare them with observer-based scores in a large cohort of women. MATERIALS AND METHODS: Following written informed consent, a data set of 36 281 mammograms from 8867 women were collected from six United Kingdom centers in an ethically approved trial. Breast density was assessed by one of 26 readers on a visual analog scale and with two automated density tools. Mean differences were calculated as the mean of all the individual percentage differences between each measurement for each case (woman). Agreement in total breast volume, fibroglandular volume, and percentage density was assessed with the Bland-Altman method. Association with observer's scores was calculated by using the Pearson correlation coefficient (r). RESULTS: Correlation between the Quantra and Volpara outputs for total breast volume was r = 0.97 (P < .001), with a mean difference of 43.5 cm(3) for all cases representing 5.0% of the mean total breast volume. Correlation of the two measures was lower for fibroglandular volume (r = 0.86, P < .001). The mean difference was 30.3 cm(3) for all cases representing 21.2% of the mean fibroglandular tissue volume result. Quantra gave the larger value and the difference tended to increase with volume. For the two measures of percentage volume density, the mean difference was 1.61 percentage points (r = 0.78, P < .001). Comparison of observer's scores with the area-based density given by Quantra yielded a low correlation (r = 0.55, P < .001). Correlations of observer's scores with the volumetric density results gave r values of 0.60 (P < .001) and 0.63 (P < .001) for Quantra and Volpara, respectively. CONCLUSION: Automated techniques for measuring breast density show good correlation, but these are poorly correlated with observer's scores. However automated techniques do give different results that should be considered when informing patient personalized imaging. (©) RSNA, 2015 Clinical trial registration no. ISRCTN 73467396.Supported by the National Institute for Health Research’s Health Technology Assessment Programme.This is the final version of the article. It first appeared at http://pubs.rsna.org/doi/full/10.1148/radiol.1414150

Promoting Early Presentation intervention sustains increased breast cancer awareness in older women for three years: A randomized controlled trial

Objective In a randomized controlled trial, the Promoting Early Presentation intervention increased older women’s breast cancer awareness after two years. We investigated whether this increase was sustained at three years, and the effect on breast screening self-referral. Methods We randomly allocated 867 women attending their final invited breast screening appointment to the Promoting Early Presentation intervention or usual care. We examined breast cancer awareness after three years and breast screening self-referrals after four years. Results Women in the Promoting Early Presentation intervention arm had higher breast cancer awareness at three years than the usual care arm (odds ratio: 10.4; 95% confidence interval: 3.1 to 34.8). There were no differences in proportions self-referring for breast screening between arms, but statistical power was limited. Conclusion The Promoting Early Presentation intervention has a sustained effect on breast cancer awareness in older women. The effect on self-referral for breast screening is unclear

Accuracy of Digital Breast Tomosynthesis for Depicting Breast Cancer Subgroups in a UK Retrospective Reading Study (TOMMY Trial)

Purpose To compare the diagnostic performance of two-dimensional (2D) mammography, 2D mammography plus digital breast tomosynthesis (DBT), and synthetic 2D mammography plus DBT in depicting malignant radiographic features. Materials and Methods In this multicenter, multireader, retrospective reading study (the TOMMY trial), after written informed consent was obtained, 8869 women (age range, 29–85 years; mean, 56 years) were recruited from July 2011 to March 2013 in an ethically approved study. From these women, a reading dataset of 7060 cases was randomly allocated for independent blinded review of (a) 2D mammography images, (b) 2D mammography plus DBT images, and (c) synthetic 2D mammography plus DBT images. Reviewers had no access to results of previous examinations. Overall sensitivities and specificities were calculated for younger women and those with dense breasts. Results Overall sensitivity was 87% for 2D mammography, 89% for 2D mammography plus DBT, and 88% for synthetic 2D mammography plus DBT. The addition of DBT was associated with a 34% increase in the odds of depicting cancer (odds ratio [OR] = 1.34, P = .06); however, this level did not achieve significance. For patients aged 50–59 years old, sensitivity was significantly higher (P = .01) for 2D mammography plus DBT than it was for 2D mammography. For those with breast density of 50% or more, sensitivity was 86% for 2D mammography compared with 93% for 2D mammography plus DBT (P = .03). Specificity was 57% for 2D mammography, 70% for 2D mammography plus DBT, and 72% for synthetic 2D mammography plusmDBT. Specificity was significantly higher than 2D mammography (P < .001in both cases) and was observed for all subgroups (P < .001 for all cases). Conclusion The addition of DBT increased the sensitivity of 2D mammography in patients with dense breasts and the specificity of 2D mammography for all subgroups. The use of synthetic 2D DBT demonstrated performance similar to that of standard 2D mammography with DBT. DBT is of potential benefit to screening programs, particularly in younger women with dense breasts. © RSNA, 2015The TOMMY Trial (a comparison of digital breast tomosynthesis with mammography in the UK Breast Screening Programme) was supported by the NIHR Health Technology Assessment Programme.This is the final published version of the article. It was originally published in Radiology (Gilbert et al., Radiology, 2015, doi:10.1148/radiol.2015142566). The final version is available at http://dx.doi.org/10.1148/radiol.201514256

Accuracy of Digital Breast Tomosynthesis for Depicting Breast Cancer Subgroups in a UK Retrospective Reading Study (TOMMY Trial).

PURPOSE: To compare the diagnostic performance of two-dimensional (2D) mammography, 2D mammography plus digital breast tomosynthesis (DBT), and synthetic 2D mammography plus DBT in depicting malignant radiographic features. MATERIALS AND METHODS: In this multicenter, multireader, retrospective reading study (the TOMMY trial), after written informed consent was obtained, 8869 women (age range, 29-85 years; mean, 56 years) were recruited from July 2011 to March 2013 in an ethically approved study. From these women, a reading dataset of 7060 cases was randomly allocated for independent blinded review of (a) 2D mammography images, (b) 2D mammography plus DBT images, and (c) synthetic 2D mammography plus DBT images. Reviewers had no access to results of previous examinations. Overall sensitivities and specificities were calculated for younger women and those with dense breasts. RESULTS: Overall sensitivity was 87% for 2D mammography, 89% for 2D mammography plus DBT, and 88% for synthetic 2D mammography plus DBT. The addition of DBT was associated with a 34% increase in the odds of depicting cancer (odds ratio [OR] = 1.34, P = .06); however, this level did not achieve significance. For patients aged 50-59 years old, sensitivity was significantly higher (P = .01) for 2D mammography plus DBT than it was for 2D mammography. For those with breast density of 50% or more, sensitivity was 86% for 2D mammography compared with 93% for 2D mammography plus DBT (P = .03). Specificity was 57% for 2D mammography, 70% for 2D mammography plus DBT, and 72% for synthetic 2D mammography plusmDBT. Specificity was significantly higher than 2D mammography (P < .001in both cases) and was observed for all subgroups (P < .001 for all cases). CONCLUSION: The addition of DBT increased the sensitivity of 2D mammography in patients with dense breasts and the specificity of 2D mammography for all subgroups. The use of synthetic 2D DBT demonstrated performance similar to that of standard 2D mammography with DBT. DBT is of potential benefit to screening programs, particularly in younger women with dense breasts. (©) RSNA, 2015.The TOMMY Trial (a comparison of digital breast tomosynthesis with mammography in the UK Breast Screening Programme) was supported by the NIHR Health Technology Assessment Programme.This is the final published version of the article. It was originally published in Radiology (Gilbert et al., Radiology, 2015, doi:10.1148/radiol.2015142566). The final version is available at http://dx.doi.org/10.1148/radiol.201514256

Promoting early presentation of breast cancer in older women: Implementing an evidence-based intervention in routine clinical practice

Background: Women over 70 with breast cancer have poorer one-year survival and present at a more advanced stage than younger women. Promoting early symptomatic presentation in older women may reduce stage cost effectively and is unlikely to lead to overdiagnosis. After examining efficacy in a randomised controlled trial, we piloted a brief health professional-delivered intervention to equip women to present promptly with breast symptoms, as an integral part of the final invited mammogram at age ~70, in the English National Health Service Breast Screening Programme. Methods: We trained mammographers, who then offered the intervention to older women in four breast screening services. We examined breast cancer awareness at baseline and one month in women receiving the intervention, and also in a service where the intervention was not offered. Results. We trained 27 mammographers to deliver the intervention confidently to a high standard. Breast cancer awareness increased 7-fold at one month in women receiving the intervention compared with 2-fold in the comparison service (odds ratio 15.2, 95% confidence interval 10.0 to 23.2). Conclusions: The PEP Intervention can be implemented in routine clinical practice with a potency similar to that achieved in a randomised controlled trial. It has the potential to reduce delay in diagnosis for breast cancer in older women

Mammographic density and breast cancer risk in breast screening assessment cases and women with a family history of breast cancer.

BACKGROUND: Mammographic density has been shown to be a strong independent predictor of breast cancer and a causative factor in reducing the sensitivity of mammography. There remain questions as to the use of mammographic density information in the context of screening and risk management, and of the association with cancer in populations known to be at increased risk of breast cancer. AIM: To assess the association of breast density with presence of cancer by measuring mammographic density visually as a percentage, and with two automated volumetric methods, Quantra™ and VolparaDensity™. METHODS: The TOMosynthesis with digital MammographY (TOMMY) study of digital breast tomosynthesis in the Breast Screening Programme of the National Health Service (NHS) of the United Kingdom (UK) included 6020 breast screening assessment cases (of whom 1158 had breast cancer) and 1040 screened women with a family history of breast cancer (of whom two had breast cancer). We assessed the association of each measure with breast cancer risk in these populations at enhanced risk, using logistic regression adjusted for age and total breast volume as a surrogate for body mass index (BMI). RESULTS: All density measures showed a positive association with presence of cancer and all declined with age. The strongest effect was seen with Volpara absolute density, with a significant 3% (95% CI 1-5%) increase in risk per 10 cm3 of dense tissue. The effect of Volpara volumetric density on risk was stronger for large and grade 3 tumours. CONCLUSIONS: Automated absolute breast density is a predictor of breast cancer risk in populations at enhanced risk due to either positive mammographic findings or family history. In the screening context, density could be a trigger for more intensive imaging

Safety and Allele-Specific Immunogenicity of a Malaria Vaccine in Malian Adults: Results of a Phase I Randomized Trial

OBJECTIVES: The objectives were to evaluate the safety, reactogenicity, and allele-specific immunogenicity of the blood-stage malaria vaccine FMP1/AS02A in adults exposed to seasonal malaria and the impact of natural infection on vaccine-induced antibody levels. DESIGN: We conducted a randomized, double-blind, controlled phase I clinical trial. SETTING: Bandiagara, Mali, West Africa, is a rural town with intense seasonal transmission of Plasmodium falciparum malaria. PARTICIPANTS: Forty healthy, malaria-experienced Malian adults aged 18–55 y were enrolled. INTERVENTIONS: The FMP1/AS02A malaria vaccine is a 42-kDa recombinant protein based on the carboxy-terminal end of merozoite surface protein-1 (MSP-1(42)) from the 3D7 clone of P. falciparum, adjuvanted with AS02A. The control vaccine was a killed rabies virus vaccine (Imovax). Participants were randomized to receive either FMP1/AS02A or rabies vaccine at 0, 1, and 2 mo and were followed for 1 y. OUTCOME MEASURES: Solicited and unsolicited adverse events and allele-specific antibody responses to recombinant MSP-1(42) and its subunits derived from P. falciparum strains homologous and heterologous to the 3D7 vaccine strain were measured. RESULTS: Transient local pain and swelling were more common in the malaria vaccine group than in the control group (11/20 versus 3/20 and 10/20 versus 6/20, respectively). MSP-1(42) antibody levels rose during the malaria transmission season in the control group, but were significantly higher in malaria vaccine recipients after the second immunization and remained higher after the third immunization relative both to baseline and to the control group. Immunization with the malaria vaccine was followed by significant increases in antibodies recognizing three diverse MSP-1(42) alleles and their subunits. CONCLUSIONS: FMP1/AS02A was well tolerated and highly immunogenic in adults exposed to intense seasonal malaria transmission and elicited immune responses to genetically diverse parasite clones. Anti-MSP-1(42) antibody levels followed a seasonal pattern that was significantly augmented and prolonged by the malaria vaccine

Safety and Reactogenicity of an MSP-1 Malaria Vaccine Candidate: A Randomized Phase Ib Dose-Escalation Trial in Kenyan Children

OBJECTIVE: Our aim was to evaluate the safety, reactogenicity, and immunogenicity of an investigational malaria vaccine. DESIGN: This was an age-stratified phase Ib, double-blind, randomized, controlled, dose-escalation trial. Children were recruited into one of three cohorts (dosage groups) and randomized in 2:1 fashion to receive either the test product or a comparator. SETTING: The study was conducted in a rural population in Kombewa Division, western Kenya. PARTICIPANTS: Subjects were 135 children, aged 12–47 mo. INTERVENTIONS: Subjects received 10, 25, or 50 μg of falciparum malaria protein 1 (FMP1) formulated in 100, 250, and 500 μL, respectively, of AS02A, or they received a comparator (Imovax® rabies vaccine). OUTCOME MEASURES: We performed safety and reactogenicity parameters and assessment of adverse events during solicited (7 d) and unsolicited (30 d) periods after each vaccination. Serious adverse events were monitored for 6 mo after the last vaccination. RESULTS: Both vaccines were safe and well tolerated. FMP1/AS02A recipients experienced significantly more pain and injection-site swelling with a dose-effect relationship. Systemic reactogenicity was low at all dose levels. Hemoglobin levels remained stable and similar across arms. Baseline geometric mean titers were comparable in all groups. Anti-FMP1 antibody titers increased in a dose-dependent manner in subjects receiving FMP1/AS02A; no increase in anti-FMP1 titers occurred in subjects who received the comparator. By study end, subjects who received either 25 or 50 μg of FMP1 had similar antibody levels, which remained significantly higher than that of those who received the comparator or 10 μg of FMP1. A longitudinal mixed effects model showed a statistically significant effect of dosage level on immune response (F(3,1047) = 10.78, or F(3, 995) = 11.22, p < 0.001); however, the comparison of 25 μg and 50 μg recipients indicated no significant difference (F(1,1047) = 0.05; p = 0.82). CONCLUSIONS: The FMP1/AS02A vaccine was safe and immunogenic in malaria-exposed 12- to 47-mo-old children and the magnitude of immune response of the 25 and 50 μg doses was superior to that of the 10 μg dose

Phase 1/2a Study of the Malaria Vaccine Candidate Apical Membrane Antigen-1 (AMA-1) Administered in Adjuvant System AS01B or AS02A

Contains fulltext : 79496.pdf (publisher's version ) (Open Access)BACKGROUND: This Phase 1/2a study evaluated the safety, immunogenicity, and efficacy of an experimental malaria vaccine comprised of the recombinant Plasmodium falciparum protein apical membrane antigen-1 (AMA-1) representing the 3D7 allele formulated with either the AS01B or AS02A Adjuvant Systems. METHODOLOGY/PRINCIPAL FINDINGS: After a preliminary safety evaluation of low dose AMA-1/AS01B (10 microg/0.5 mL) in 5 adults, 30 malaria-naive adults were randomly allocated to receive full dose (50 microg/0.5 mL) of AMA-1/AS01B (n = 15) or AMA-1/AS02A (n = 15), followed by a malaria challenge. All vaccinations were administered intramuscularly on a 0-, 1-, 2-month schedule. All volunteers experienced transient injection site erythema, swelling and pain. Two weeks post-third vaccination, anti-AMA-1 Geometric Mean Antibody Concentrations (GMCs) with 95% Confidence Intervals (CIs) were high: low dose AMA-1/AS01B 196 microg/mL (103-371 microg/mL), full dose AMA-1/AS01B 279 microg/mL (210-369 microg/mL) and full dose AMA-1/AS02A 216 microg/mL (169-276 microg/mL) with no significant difference among the 3 groups. The three vaccine formulations elicited equivalent functional antibody responses, as measured by growth inhibition assay (GIA), against homologous but not against heterologous (FVO) parasites as well as demonstrable interferon-gamma (IFN-gamma) responses. To assess efficacy, volunteers were challenged with P. falciparum-infected mosquitoes, and all became parasitemic, with no significant difference in the prepatent period by either light microscopy or quantitative polymerase chain reaction (qPCR). However, a small but significant reduction of parasitemia in the AMA-1/AS02A group was seen with a statistical model employing qPCR measurements. SIGNIFICANCE: All three vaccine formulations were found to be safe and highly immunogenic. These immune responses did not translate into significant vaccine efficacy in malaria-naive adults employing a primary sporozoite challenge model, but encouragingly, estimation of parasite growth rates from qPCR data may suggest a partial biological effect of the vaccine. Further evaluation of the immunogenicity and efficacy of the AMA-1/AS02A formulation is ongoing in a malaria-experienced pediatric population in Mali. TRIAL REGISTRATION: www.clinicaltrials.gov NCT00385047

A descriptive model of patient readiness, motivators, and hepatitis C treatment uptake among Australian prisoners

Background: Hepatitis C virus infection (HCV) has a significant global health burden with an estimated 2%–3% of the world's population infected, and more than 350,000 dying annually from HCV-related conditions including liver failure and liver cancer. Prisons potentially offer a relatively stable environment in which to commence treatment as they usually provide good access to health care providers, and are organised around routine and structure. Uptake of treatment of HCV, however, remains low in the community and in prisons. In this study, we explored factors affecting treatment uptake inside prisons and hypothesised that prisoners have unique issues influencing HCV treatment uptake as a consequence of their incarceration which are not experienced in other populations. Method and Findings: We undertook a qualitative study exploring prisoners' accounts of why they refused, deferred, delayed or discontinued HCV treatment in prison. Between 2010 and 2013, 116 Australian inmates were interviewed from prisons in New South Wales, Queensland, and Western Australia. Prisoners experienced many factors similar to those which influence treatment uptake of those living with HCV infection in the community. Incarceration, however, provides different circumstances of how these factors are experienced which need to be better understood if the number of prisoners receiving treatment is to be increased. We developed a descriptive model of patient readiness and motivators for HCV treatment inside prisons and discussed how we can improve treatment uptake among prisoners.Conclusion: This study identified a broad and unique range of challenges to treatment of HCV in prison. Some of these are likely to be diminished by improving treatment options and improved models of health care delivery. Other barriers relate to inmate understanding of their illness and stigmatisation by other inmates and custodial staff and generally appear less amenable to change although there is potential for peer-based education to address lack of knowledge and stigma