Determination of mammographic breast density using a deep convolutional neural network

OBJECTIVE: High breast density is a risk factor for breast cancer. The aim of this study was to develop a deep convolutional neural network (dCNN) for the automatic classification of breast density based on the mammographic appearance of the tissue according to the American College of Radiology Breast Imaging Reporting and Data System (ACR BI-RADS) Atlas. METHODS: In this study, 20,578 mammography single views from 5221 different patients (58.3 ± 11.5 years) were downloaded from the picture archiving and communications system of our institution and automatically sorted according to the ACR density (a-d) provided by the corresponding radiological reports. A dCNN with 11 convolutional layers and 3 fully connected layers was trained and validated on an augmented dataset. The model was finally tested on two different datasets against: i) the radiological reports and ii) the consensus decision of two human readers. None of the test datasets was part of the dataset used for the training and validation of the algorithm. RESULTS: The optimal number of epochs was 91 for medio-lateral oblique (MLO) projections and 94 for cranio-caudal projections (CC), respectively. Accuracy for MLO projections obtained on the validation dataset was 90.9% (CC: 90.1%). Tested on the first test dataset of mammographies (850 MLO and 880 CC), the algorithm showed an accordance with the corresponding radiological reports of 71.7% for MLO and of 71.0% for CC. The agreement with the radiological reports improved in the differentiation between dense and fatty breast for both projections (MLO = 88.6% and CC = 89.9%). In the second test dataset of 200 mammographies, a good accordance was found between the consensus decision of the two readers on both, the MLO-model (92.2%) and the right craniocaudal-model (87.4%). In the differentiation between fatty (ACR A/B) and dense breasts (ACR C/D), the agreement reached 99% for the MLO and 96% for the CC projections, respectively. CONCLUSIONS: The dCNN allows for accurate classification of breast density based on the ACR BI-RADS system. The proposed technique may allow accurate, standardized, and observer independent breast density evaluation of mammographies. ADVANCES IN KNOWLEDGE: Standardized classification of mammographies by a dCNN could lead to a reduction of falsely classified breast densities, thereby allowing for a more accurate breast cancer risk assessment for the individual patient and a more reliable decision, whether additional ultrasound is recommended

Isolation of infectious, non-fibrillar and oligomeric prions from a genetic prion disease

Prions are transmissible agents causing lethal neurodegenerative diseases that are composed of aggregates of misfolded cellular prion protein (PrPSc). Despite non-fibrillar oligomers having been proposed as the most infectious prion particles, prions purified from diseased brains usually consist of large and fibrillar PrPSc aggregates, whose protease-resistant core (PrPres) encompasses the whole C-terminus of PrP. In contrast, PrPSc from Gerstmann-Sträussler-Scheinker disease associated with alanine to valine substitution at position 117 (GSS-A117V) is characterized by a small protease-resistant core, which is devoid of the C-terminus. We thus aimed to investigate the role of this unusual PrPSc in terms of infectivity, strain characteristics, and structural features. We found, by titration in bank voles, that the infectivity of GSS-A117V is extremely high (109.3 ID50 U/g) and is resistant to treatment with proteinase K (109.0 ID50 U/g). We then purified the proteinase K-resistant GSS-A117V prions and determined the amount of infectivity and PrPres in the different fractions, alongside the morphological characteristics of purified PrPres aggregates by electron microscopy. Purified pellet fractions from GSS-A117V contained the expected N- and C-terminally cleaved 7 kDa PrPres, although the yield of PrPres was low. We found that this low yield depended on the low density/small size of GSS-A117V PrPres, as it was mainly retained in the last supernatant fraction. All fractions were highly infectious, thus confirming the infectious nature of the 7 kDa PrPres, with infectivity levels that directly correlated with the PrPres amount detected. Finally, electron microscopy analysis of these fractions showed no presence of amyloid fibrils, but only very small and indistinct, non-fibrillar PrPresparticles were detected and confirmed to contain PrP via immunogold labelling. Our study demonstrates that purified aggregates of 7 kDa PrPres, spanning residues ∼90–150, are highly infectious oligomers that encode the biochemical and biological strain features of the original sample. Overall, the autocatalytic behaviour of the prion oligomers reveals their role in the propagation of neurodegeneration in patients with Gerstmann-Sträussler-Scheinker disease and implies that the C-terminus of PrPSc is dispensable for infectivity and strain features for this prion strain, uncovering the central PrP domain as the minimal molecular component able to encode infectious prions. These findings are consistent with the hypothesis that non-fibrillar prion particles are highly efficient propagators of disease and provide new molecular and morphological constraints on the structure of infectious prions

Investigating the Relationship between Parental Education, Asthma and Rhinitis in Children Using Path Analysis

Parental socioeconomic position (SEP) is a known determinant of a child's health. We aimed to investigate whether a low parental education, as proxy of SEP, has a direct effect on physician-diagnosed asthma, current asthma and current allergic rhinitis in children, or whether associations are mediated by exposure to other personal or environmental risk factors. This study was a secondary data analysis of two cross-sectional studies conducted in Italy in 2006. Data from 2687 adolescents (10-14 years) were analyzed by a path analysis model using generalized structural equation modelling. Significant direct effects were found between parental education and family characteristics (number of children (coefficient = 0.6229, p < 0.001) and crowding index (1.1263, p < 0.001)) as well as with exposure to passive smoke: during pregnancy (maternal: 0.4697, p < 0.001; paternal: 0.4854, p < 0.001), during the first two years of children's life (0.5897, p < 0.001) and currently (0.6998, p < 0.001). An indirect effect of parental education was found on physician-diagnosed asthma in children mediated by maternal smoking during pregnancy (0.2350, p < 0.05) and on current allergic rhinitis mediated by early environmental tobacco smoke (0.2002; p < 0.05). These results suggest the importance of promotion of ad-hoc health policies for promoting smoking cessation, especially during pregnancy

Male breast cancer: Clinical features and multimodal treatment in a retrospective survey analysis at Italian centers

AIMS AND BACKGROUND: We report a collection of data about early breast cancer in male patients from 13 Italian institutions. METHODS AND STUDY DESIGN: We obtained data from patient charts and performed statistical analysis. The primary end points were overall survival and disease-free survival. RESULTS: A total of 205 men with invasive breast cancer was identified, with a median age of 66 years. Pathological characteristics were heterogeneous for T stage, N stage and HER2 status. Histological subtype was predominantly ductal infiltrating carcinoma. Most of them were hormone receptor positive. Mastectomy was the most common strategy. Postsurgical treatment was not standardized. Patients with large tumors were more likely to be treated with chemotherapy. Disease recurrence was associated with an ER+ and PR+ status. CONCLUSIONS: We identified a correlation between relapse and hormone receptor expression, as is the case in female breast cance

The Pattern of Progression to First-Line Treatment with Dabrafenib and Trametinib in Patients with Unresectable or Metastatic, BRAF-Mutated, Cutaneous Melanoma: Results of the Observational T-WIN Study

In patients with B-RAF-mutated cutaneous melanoma, targeted therapies are the treatment of choice to achieve a rapid response. In this multicentric, prospective, observational study, patients with B-RAF-mutated cutaneous melanoma who were treated with dabrafenib and trametinib were categorized in two cohorts (cohort A: limited disease (n = 104) and cohort B: bulky disease (n = 97)) according to lactate dehydrogenase levels. The primary endpoint was the progression pattern; the secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety data. From baseline to time of progression, there was a progression from nodal to other sites of disease in cohort A and from skin and nodal to other sites in cohort B. In both the cohorts, the number of involved organs and metastases at each location decreased. The median OS was 32.4 months (95% CI: 20.1 months (not estimable)) for cohort A, and 10.5 months (95% CI: 8.3–14.4 months) for cohort B; median PFS was 12.4 months (95% CI: 10.9–17.0 months) for cohort A, and 8.1 months (95% CI: 6.3–9.4 months) for cohort B. No new safety signals were reported. This study describes the patterns of first-line treatment progression with dabrafenib and trametinib in Italian clinical practice. The effectiveness and safety data were consistent with previous trials and extended to a real-world heterogeneous population

Relationship of long-term air pollution exposure with asthma and rhinitis in Italy: an innovative multipollutant approach

Background: air pollution is a complex mixture; novel multipollutant approaches could help understanding the health effects of multiple concomitant exposures to air pollutants. Aim: to assess the relationship of long-term air pollution exposure with the prevalence of respiratory/allergic symptoms and diseases in an Italian multicenter study using single and multipollutant approaches. Methods: 14420 adults living in 6 Italian cities (Ancona, Pavia, Pisa, Sassari, Turin, Verona) were investigated in 2005-2011 within 11 different study cohorts. Questionnaire information about risk factors and health outcomes was collected. Machine learning derived mean annual concentrations of PM10, PM2.5, NO2 and mean summer concentrations of O3 (μg/m3) at residential level (1-km resolution) were used for the period 2013-2015. The associations between the four pollutants and respiratory/allergic symptoms/diseases were assessed using two approaches: a) logistic regression models (single-pollutant models), b) principal component logistic regression models (multipollutant models). All the models were adjusted for age, sex, education level, smoking habits, season of interview, climatic index and included a random intercept for cohorts. Results: the three-year average (± standard deviation) pollutants concentrations at residential level were: 20.3 ± 6.8 μg/m3 for PM2.5, 29.2 ± 7.0 μg/m3 for PM10, 28.0 ± 11.2 μg/m3 for NO2, and 70.9 ± 4.3 μg/m3 for summer O3. Through the multipollutant models the following associations emerged: PM10 and PM2.5 were related to 14-25% increased odds of rhinitis, 23-34% of asthma and 30-33% of night awakening; NO2 was related to 6-9% increased odds of rhinitis, 7-8% of asthma and 12% of night awakening; O3 was associated with 37% increased odds of asthma attacks. Overall, the Odds Ratios estimated through the multipollutant models were attenuated when compared to those of the single-pollutant models. Conclusions: this study enabled to obtain new information about the health effects of air pollution on respiratory/allergic outcomes in adults, applying innovative methods for exposure assessment and multipollutant analyses

Outcomes in patients with BRAFV600-mutated melanoma and brain metastases at baseline treated with dabrafenib plus trametinib

Background: Brain metastases (BM) and lactate dehydrogenase (LDH) levels above the upper limit of normal (ULN) are associated with poor prognosis in patients with melanoma. Although treatment with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib have demonstrated long-term clinical benefit in patients with melanoma, data on their efficacy in patients with BM are limited. Methods: DESCRIBE Italy is an observational, retrospective, real-world study evaluating dabrafenib plus trametinib in 499 patients with BRAF(V600)-mutant stage III unresectable or stage IV melanoma from various sites across Italy. Here, we analyzed the clinical outcomes for the subgroup of patients receiving first-line treatment and presenting with BM at diagnosis and assessed the impact of predictive factors such as LDH levels and the presence of other metastases on median progression-free survival (mPFS). Results: Overall, 325 evaluable patients were on first-line therapy and are the focus of this analysis; of these, 76 patients (23.4%) had BM at baseline. mPFS was lower for patients with BM at baseline compared with overall patients (8.7 months vs 9.3 months, respectively). Patients with BM at diagnosis and LDH >ULN had a considerably shorter mPFS compared with patients with LDH & LE;ULN (5.3 months vs 9.9 months, respectively). mPFS was noticeably longer for patients with cerebral metastases only compared with patients with cerebral and other metastases (15.0 months vs 8.7 months, respectively). Conclusions: Dabrafenib plus trametinib showed effectiveness in a real-world population of patients with advanced BRAF(V600)-mutated melanoma and BM at baseline, supporting its use in this population with poor outcomes

Efficacy of trastuzumab in unselected patients with HER2-positive metastatic breast cancer: A retrospective analysis

AIMS AND BACKGROUND: The addition of trastuzumab to chemotherapy for HER2-positive metastatic breast cancer has significantly improved progression-free survival and overall survival, although most patients develop resistance or have a primarily resistant disease. The aim of the study was to describe the efficacy and safety of a first-line treatment in unselected metastatic HER2-positive breast cancer patients, treated according to clinical practice. METHODS: From 2000 to 2009, we conducted a retrospective multi-institutional analysis of 182 consecutive patients with HER2-positive metastatic breast cancer who underwent first-line treatment with trastuzumab. The primary end points were progression-free survival and overall survival; the secondary end points were survival after progression in patients treated with second-line chemotherapy with or without trastuzumab and safety. A total of 172 patients were analyzed. RESULTS: Median progression-free survival and overall survival were 1.2 (95% CI, 1.1-1.4) and 4.4 years (95% CI, 3.6-5.4), respectively. For 100 patients who received second-line chemotherapy, median survival after progression was significantly longer in those who also received trastuzumab: 2.8 (95% CI, 2.1-4.0) versus 1.2 years (95% CI, 0.6-1.9). CONCLUSIONS: Although based on retrospective data, the study confirms the role of trastuzumab as first-line treatment in metastatic breast cancer outside of a controlled trial. Moreover, information obtained on the use of trastuzumab beyond disease progression supports its use in this settin

Pregnancy-Related Complications in Patients With Fibromuscular Dysplasia: A Report From the European/International Fibromuscular Dysplasia Registry

Current literature suggests a higher risk of pregnancy-related complications in patients with renal fibromuscular dysplasia (FMD). The aim of our study was to assess the nature and prevalence of pregnancy-related complications in patients subsequently diagnosed with FMD. A call for participation was sent to centers contributing to the European/International FMD Registry. Patients with at least 1 pregnancy were included. Data on pregnancy were collected through medical files and FMD characteristics through the European/International FMD Registry. Data from 534 pregnancies were obtained in 237 patients. Despite the fact that, in 96% of cases, FMD was not diagnosed before pregnancy, 40% of women (n=93) experienced pregnancy-related complications, mostly gestational hypertension (25%) and preterm birth (20%), while preeclampsia was reported in only 7.5%. Only 1 patient experienced arterial dissection and another patient an aneurysm rupture. When compared with patients without pregnancy-related complications, patients with complicated pregnancies were younger at FMD diagnosis (43 versus 51 years old; P<0.001) and had a lower prevalence of cerebrovascular FMD (30% versus 52%; P=0.003) but underwent more often renal revascularization (63% versus 40%, P<0.001). In conclusion, the prevalence of pregnancy-related complications such as gestational hypertension and preterm birth was high in patients with FMD, probably related to the severity of renal FMD. However, the prevalence of preeclampsia and arterial complications was low/moderate. These findings emphasize the need to screen hypertensive women for FMD to ensure revascularization before pregnancy if indicated and appropriate follow-up during pregnancy, without discouraging patients with FMD from considering pregnancy.Current literature suggests a higher risk of pregnancy-related complications in patients with renal fibromuscular dysplasia (FMD). The aim of our study was to assess the nature and prevalence of pregnancy-related complications in patients subsequently diagnosed with FMD. A call for participation was sent to centers contributing to the European/International FMD Registry. Patients with at least 1 pregnancy were included. Data on pregnancy were collected through medical files and FMD characteristics through the European/International FMD Registry. Data from 534 pregnancies were obtained in 237 patients. Despite the fact that, in 96% of cases, FMD was not diagnosed before pregnancy, 40% of women (n=93) experienced pregnancy-related complications, mostly gestational hypertension (25%) and preterm birth (20%), while preeclampsia was reported in only 7.5%. Only 1 patient experienced arterial dissection and another patient an aneurysm rupture. When compared with patients without pregnancy-related complications, patients with complicated pregnancies were younger at FMD diagnosis (43 versus 51 years old; P<0.001) and had a lower prevalence of cerebrovascular FMD (30% versus 52%; P=0.003) but underwent more often renal revascularization (63% versus 40%, P<0.001). In conclusion, the prevalence of pregnancy-related complications such as gestational hypertension and preterm birth was high in patients with FMD, probably related to the severity of renal FMD. However, the prevalence of preeclampsia and arterial complications was low/moderate. These findings emphasize the need to screen hypertensive women for FMD to ensure revascularization before pregnancy if indicated and appropriate follow-up during pregnancy, without discouraging patients with FMD from considering pregnancy