Broad Epigenetic Signature of Maternal Care in the Brain of Adult Rats

BACKGROUND: Maternal care is associated with long-term effects on behavior and epigenetic programming of the NR3C1 (GLUCOCORTICOID RECEPTOR) gene in the hippocampus of both rats and humans. In the rat, these effects are reversed by cross-fostering, demonstrating that they are defined by epigenetic rather than genetic processes. However, epigenetic changes at a single gene promoter are unlikely to account for the range of outcomes and the persistent change in expression of hundreds of additional genes in adult rats in response to differences in maternal care. METHODOLOGY/PRINCIPAL FINDINGS: We examine here using high-density oligonucleotide array the state of DNA methylation, histone acetylation and gene expression in a 7 million base pair region of chromosome 18 containing the NR3C1 gene in the hippocampus of adult rats. Natural variations in maternal care are associated with coordinate epigenetic changes spanning over a hundred kilobase pairs. The adult offspring of high compared to low maternal care mothers show epigenetic changes in promoters, exons, and gene ends associated with higher transcriptional activity across many genes within the locus examined. Other genes in this region remain unchanged, indicating a clustered yet specific and patterned response. Interestingly, the chromosomal region containing the protocadherin-α, -β, and -γ (Pcdh) gene families implicated in synaptogenesis show the highest differential response to maternal care. CONCLUSIONS/SIGNIFICANCE: The results suggest for the first time that the epigenetic response to maternal care is coordinated in clusters across broad genomic areas. The data indicate that the epigenetic response to maternal care involves not only single candidate gene promoters but includes transcriptional and intragenic sequences, as well as those residing distantly from transcription start sites. These epigenetic and transcriptional profiles constitute the first tiling microarray data set exploring the relationship between epigenetic modifications and RNA expression in both protein coding and non-coding regions across a chromosomal locus in the mammalian brain

Additional Breast Cancer Detection at Digital Screening Mammography through Quality Assurance Sessions between Technologists and Radiologists

Background: Screening technologists may function as readers in breast cancer screening programs. In the Netherlands, they attend quality assurance sessions. The frequency and characteristics of additional breast cancers detected through these sessions have not been reported.Purpose: To determine the frequency and characteristics of cancers detected through quality assurance sessions.Materials and Methods: This secondary analysis of a prospective cohort included 466 647 screening mammograms obtained between January 1, 2009, and January 1, 2017. Mammograms were single read by certified screening technologists before being double read by two certified screening radiologists who were not blinded to the technologists' reading. The technologists and a coordinating screening radiologist regularly discussed mammograms that the technologists considered suspicious but that did not prompt recall at radiologist double reading. The coordinating radiologist decided whether secondary recall was indicated. During a 2-year follow-up, radiologic and pathologic outcome data for all recalled women were obtained. Characteristics of cancers detected at radiologist double reading and those detected through quality assurance sessions were compared by using chi(2) and Fisher exact tests.Results: A total of 14 142 women (mean age, 59 years +/- 7.8 [standard deviation]; range, 49-75 years) were recalled (recall rate, 3.0% [14 142 of 466 647]): 14 057 after radiologist double reading and 85 by the coordinating radiologists after quality assurance sessions. This resulted in 3156 screening-detected cancers (6.8 cancers detected per 1000 screenings), of which 26 (0.8% of screening-detected cancers [26 of 3156]) were detected after secondary recall through quality assurance sessions. The latter comprised eight ductal carcinomas in situ (88% intermediate or high grade [seven of eight]) and 18 invasive cancers (14 T1a-c and four T2+ cancers, 89% Nottingham grade I or II [16 of 18]). No significant differences in tumor characteristics were found (P values ranging from.22 to.95). Sensitivity of quality assurance sessions for additional cancer detection was 52% (26 of 50; 95% confidence interval: 38%, 66%).Conclusion: The role of quality assurance sessions in additional cancer detection is limited. Tumor characteristics did not differ significantly from those of cancers detected at radiologist double reading. (C) RSNA, 2020.</p

Causes and consequences of delayed diagnosis in breast cancer screening with a focus on mammographic features and tumour characteristics

PURPOSE: To study the prevalence, causes and consequences of delayed breast cancer diagnosis in the screening population. METHODS: This retrospective study was performed in women who underwent biennial screening mammography between January 1, 2009 and June 30, 2019. Patients were divided into 3 groups; screen-detectedbreast cancer (SDC) without a diagnostic delay, a primary diagnostic delay(i.e. missed cancer at previous screening round)and a delay in diagnostic work-up after recall. Women with a true interval cancer (IC; i.e. not visible on prior examinations) were excluded. Outcome parameters included mammographic and tumour characteristics, lymph node status and surgical treatment. RESULTS: In our sample of 4491 women with breast cancer (4292 SDC and 199 'missed' IC), respectively, a total of 1112 women experienced a diagnostic delay of = 4 months. Compared to women without a diagnostic delay (n = 2720), the 176 women with a delay in diagnostic work-up showed overall similar mammographic abnormalities (P = 0.052). These groups show similar distributions in invasive tumours, tumour stage and lymph node status (P = 0.25, P = 0.95 and P = 0.93, respectively). Women with a primary diagnostic delay (n = 936) showed less calcifications (P &lt; 0.001), and more masses with calcifications and architectural distortions on mammography (P = 0.01 and P = 0.04, respectively). Moreover, this group comprised larger tumours (P &lt; 0.001) and lymph node metastases (P &lt; 0.001), and more often underwent mastectomy (P &lt; 0.001). CONCLUSIONS: A primary diagnostic delay in breast cancer diagnosis results in less favourable tumour characteristics and relatively more mastectomies compared to no delay in breast cancer diagnosis and a delay in diagnostic work-up after recall

Characteristics of screen-detected cancers following concordant or discordant recalls at blinded double reading in biennial digital screening mammography

ObjectivesTo analyse which mammographic and tumour characteristics led to concordant versus discordant recalls at blinded double reading to further optimise our breast cancer screening programme.MethodsWe included a consecutive series of 99,013 screening mammograms obtained between July 2013 and January 2015. All mammograms were double read in a blinded fashion. Discordant readings were routinely recalled without consensus or arbitration. During the 2-year follow-up, relevant data of the recalled women were collected. We compared mammographic characteristics, screening outcome and tumour characteristics between concordant and discordant recalls.ResultsThere were 2,543 concordant recalls (71.4%) and 997 discordant recalls (28.0%). The positive predictive value of a concordant recall was significantly higher (23.5% vs. 10.0%, p <0.001). The proportion of BI-RADS 0 was significantly higher in the discordant recall group (75.7% vs. 56.3%, p <0.001). Discordant recalls were more often an asymmetry or architectural distortion (21.8% vs. 13.2% and 9.3% vs. 6.5%, respectively, p <0.001). There were no differences in the distribution of DCIS and invasive cancers and tumour characteristics were comparable for the two groups, except for a more favourable tumour grade in the discordant recall group (54.7% vs. 39.9% grade I tumours, p = 0.022).ConclusionsScreen-detected cancers detected by a discordant reading show a more favourable tumour grade than cancers diagnosed after a concordant recall. The higher proportion of asymmetries and architectural distortions in this group provide a possible target for improving screening programmes by additional training of screening radiologists and the implementation of digital breast tomosynthesis.Key Points center dot With blinded double reading of screening mammograms, screen-detected cancers detected by a discordant reading show a more favourable tumour grade than cancers diagnosed after a concordant recall.center dot The proportions of asymmetries and architectural distortions are higher in case of a discordant reading.center dot Possible improvement strategies could target additional training of screening radiologists and the implementation of digital breast tomosynthesis in breast cancer screening programmes

Frequency and characteristics of contralateral breast abnormalities following recall at screening mammography

PurposeTo determine the frequency and characteristics of contralateral, non-recalled breast abnormalities following recall at screening mammography.MethodsWe included a series of 130,338 screening mammograms performed between 1 January 2014 and 1 January 2016. During the 1-year follow-up, clinical data were collected for all recalls. Screening outcome was determined for recalled women with or without evaluation of contralateral breast abnormalities.ResultsOf 3,995 recalls (recall rate 3.1%), 129 women (3.2%) underwent assessment of a contralateral, non-recalled breast abnormality. Most lesions were detected at clinical mammography and/or breast tomosynthesis (101 women, 78.3%). The biopsy rate was similar for recalled lesions and contralateral, non-recalled lesions, but the positive predictive value of biopsy was higher for recalled lesions (p = 0.01). A comparable proportion of the recalled lesions and contralateral, non-recalled lesions were malignant (p = 0.1). The proportion of ductal carcinoma in situ was similar for both groups, as well as invasive cancer characteristics and type of surgical treatment.ConclusionsAbout 3% of recalled women underwent evaluation of contralateral, non-recalled breast lesions. Evaluation of the contralateral breast after recall is important as we found that 15.5% of contralateral, non-recalled lesions were malignant. Contralateral cancers and screen-detected cancers show similar characteristics, stage and surgical treatment.Key Points center dot 3% of recalled women underwent evaluation of contralateral, non-recalled lesions center dot One out of seven contralateral, non-recalled lesions was malignant center dot A contralateral cancer was diagnosed in 0.5% of recalls center dot Screen-detected cancers and non-recalled, contralateral cancers showed similar histological characteristics center dot Tumour stage and surgical treatment were similar for both group

Impact of the second reader on screening outcome at blinded double reading of digital screening mammograms

BACKGROUND: To determine the impact of the second reader on screening outcome at blinded double reading of digital screening mammograms. METHODS: We included a consecutive series of 99,013 digital screening mammograms, obtained between July 2013 and January 2015 and double read in a blinded fashion. During 2-year follow-up, we collected radiology, surgery and pathology reports of recalled women. RESULTS: Single reading resulted in 2928 recalls and 616 screen-detected cancers (SDCs). The second reader recalled another 612 women, resulting in 82 additional SDCs. Addition of the second reader increased the recall rate (3.0% to 3.6%, p < 0.001), cancer detection rate (6.2-7.0 per 1000 screens, p < 0.001) and false positive recall rate (24.4-28.7 per 1000 screens, p < 0.001). Positive predictive value of recall (21.0% vs. 19.7%, p = 0.20) and of biopsy (52.1% vs. 50.9%, p = 0.56) were comparable for single reading and blinded double reading. Tumour characteristics were comparable for cancers detected by the first reader and cancers additionally detected by the second reader, except of a more favourable tumour grade in the latter group. CONCLUSIONS: At blinded double reading, the second reader significantly increases the cancer detection rate, at the expense of an increased recall rate and false positive recall rate