Surgical management of ductal carcinoma in situ of the breast: A large retrospective study from a single institution

Background: Management of breast ductal carcinoma in situ (DCIS) has various approaches with distinct institutional specific practice. Here, we review DCIS management in a single institution with emphasise on re-operation rates and outcome. Methods: DCIS cases diagnosed at the Nottingham Breast Institute between 1987 and 2017 were identified (n=1,249). Clinicopathological data was collected. Cases were histologically reviewed, and different factors associated with primary operation selection, re-excision, presence of residual tumour in the re-excision specimens, use of radiotherapy and ipsilateral recurrences were analysed. Results: 34% of DCIS patients were initially treated by mastectomy and were more frequently symptomatic, of high nuclear tumour grade, size >40mm, and associated with comedo necrosis and Paget’s disease of the nipple. Further surgery was due to involved or narrow surgical margins. Residual tumour tissue was detected in 53% of the re-excision specimens. Re-excision rates of patients treated with breast conserving surgery (BCS) were reduced from approximately 70% to 23% and the final mastectomy rates decreased from 60% to 20%. Changes in surgical practice with acceptance of smaller excision margins and more frequent use of local radiotherapy have led to a significant decrease not only in the re-excision rate but also in the final mastectomy rate together with non-significant reduction in 5- and 10-year local recurrence rates. Conclusion: Although BCS is increasingly the preferred primary surgical option for DCIS management, a proportion of low-risk DCIS patients continue to undergo re-excision surgery or completion mastectomy. Despite acceptance of smaller margins, recurrence rate is decreasing

How does aging influence object-location and name-location binding during a visual short-term memory task?

Objective: Age-related impairments in human visual short-term memory (VSTM) may reflect a reduced ability to retain bound object representations, viz., object form, name, spatial, and temporal location (so called ‘memory sources’). Our objective is to examine how healthy aging affects VSTM in a battery of memory recognition tasks in which sequentially presented objects, locations, and names (as auditory stimuli) were learned, with one component cued at test. Methods: Thirty-six young healthy adults (18-30 years) and 36 normally aging older adults (>60 years with no underlying health and vision issues) completed five VSTM tasks: 1. Object recognition for two or four objects; 2. Spatial location recognition for two or four objects; 3. Bound object-location recognition for two or four objects; 4. Object recognition with location priming for two or four objects; 5. Bound name (auditory)-location (cross-modal) recognition for four objects. Results: Significantly lower performance for older adults was found in spatial location recognition [task 2, p=0.03, 2 (memory loads) × 2 (age groups) ANOVA], bound object-location recognition [task 3, p˂0.001, 2 (memory loads) × 2 (age groups) ANOVA], object recognition with location priming [task 4, p=0.02, 2 (memory loads) × 2 (age groups) ANOVA], and bound name-location recognition [task 5, p=0.001, independent samples t-test] tasks. A significant age group-task interaction was found (p =0.02) Conclusion: Performance for all tests except test 1 was impaired in older adults. Lower performance for older adults was most significant in VSTM tasks requiring object-location (visual only) or name-location (auditory and visual) binding. The findings are compatible with the ‘memory source’ model, demonstrating that age-related binding performance is influenced by spatial coding and location priming deficits

DNA damage response markers are differentially expressed in BRCA-mutated breast cancers

Cells have stringent DNA repair pathways that are specific for each different set of DNA lesions which is accomplished through the integration of complex array of proteins. However, BRCA-mutated breast cancer (BC) has defective DNA repair mechanisms. This study aims to investigate differential expression of a large panel of DNA repair markers to characterise DNA repair mechanisms in BRCA-associated tumours compared to sporadic tumours in an attempt to characterise these tumours in routine practice. Immunohistochemistry and tissue microarray technology were applied to a cohort of clinically annotated series of sporadic (n = 1849), BRCA1-mutated (n = 48), and BRCA2-mutated (n = 27) BC. The following DNA damage response (DDR) markers are used; BRCA1, BRCA2, RAD51, Ku70/Ku80, BARD, PARP1 (cleaved), PARP1 (non-cleaved), and P53 in addition to basal cytokeratins, ER, PR, and HER2. A significant proportion of BRCA1 tumours were positive for PARP1 (non-cleaved), and negative for BARD1 and RAD51 compared with sporadic BC. BRCA2 tumours were significantly positive for PARP1 (non-cleaved) compared with sporadic tumours. RAD51 was significantly higher in BRCA1 compared with BRCA2 tumours (p = 0.005). When BRCA1/2 BCs were compared to triple-negative (TN) sporadic tumours of the studied DDR proteins, BARD1 (p < 0.001), PARP1 (non-cleaved) (p < 0.001), and P53 (p = 0.002) remained significantly different in BRCA1/2 tumours compared with TN BC. DNA repair markers showed differential expression in BRCA-mutated tumours, with a substantial degree of disruption of DNA repair pathways in sporadic BC especially TN BC. DNA double-strand break (DSB) repair is assisted by PARP1 expression in BRCA-mutated tumours, whereas the loss of DSB repair via RAD51 is predominant in BRCA1 rather than BRCA2 BC

A differential role for the posterior cerebellum in the adaptive control of convergence eye movements

Introduction The vergence oculomotor system possesses two robust adaptive mechanisms; a fast “dynamic” and a slow “tonic” system that are both vital for single, clear and comfortable binocular vision. The neural substrates underlying these vergence adaptive mechanisms in humans is unclear. Methods We investigated the role of the posterior cerebellum in convergence adaptation using inhibitory continuous theta-burst repetitive transcranial magnetic stimulation (cTBS) within a double-blind, sham controlled design while eye movements were recorded at 250hz via infrared oculography. Results In a preliminary experiment we validated our stimulation protocols by reproducing results from previous work on saccadic adaptation during the classic double-step adaptive shortening paradigm. Following this, across a series of three separate experiments we observed a clear dissociation in the effect of cTBS on convergence adaptation. Dynamic adaptation was substantially reduced while tonic adaptation was unaffected. Baseline dynamic fusional vergence response were also unaffected by stimulation. Conclusions These results indicate a differential role for the posterior cerebellum in the adaptive control of convergence eye movements and provide initial evidence that repetitive transcranial magnetic stimulation is a viable tool to investigate the neurophysiology of vergence control. The results are discussed in the context of the current models of implicit motor adaptation of vergence and their application to clinical populations and technology design in virtual and augmented head mounted display architectures. Significance statement The cerebellum plays a critical role in the adaptive control of motor systems. Vergence eye movements shift our gaze in depth allowing us to see in 3D and exhibit two distinct adaptive mechanisms that are engaged under a range of conditions including reading, wearing head-mounted displays and using a new spectacle prescription. It is unclear what role the cerebellum plays in these adaptive mechanisms. To answer this, we temporarily disrupted the function of the posterior cerebellum using non-invasive brain stimulation and report impairment of only one adaptive mechanism, providing evidence for neural compartmentalization. The results have implications for vergence control models and applications to comfort and experience studies in head-mounted displays and the rehabilitation of clinical populations exhibiting vergence dysfunctions.National Science and Engineering Research Council of Canada || Canadian Foundation of Innovators || American Academy of Optometry Foundation || Canadian Institutes for Health Research

Biological and clinical significance of PARP1 protein expression in breast cancer

Poly(ADP-ribose) polymerase-1 (PARP1) is a key facilitator of DNA repair. PARP inhibitors have gained recent attention as promising therapeutic agents for the treatment of solid tumours including breast cancer (BC). However, the biological and clinical significance of PARP1 expression in BC and its role in DNA-damage response (DDR) remain to be defined. We investigated the expression of PARP1 expression, cleaved (PARP1c) and non-cleaved (PAR1nc) forms, in a large and well-characterised cohort of clinically annotated stage I–III operable BCs (n = 1,269) and 43 BRCA1-mutated BCs using immunohistochemistry. PARP1 expression was correlated to clinicopathological variables, outcome and expression of other key DNA repair proteins (BRCA1, RAD51, Ku70/80, PIASγ and CHK1). Expression of PARP1 was exclusively nuclear. 49 and 85 % of sporadic BC showed expression PARP1nc and PARP1c, respectively. In BRCA1-mutated tumours, PARP1nc/PARP1c was highly expressed (95 and 79 %, respectively). PARP1nc expression was positively associated with premenopausal younger age patients, larger size and higher tumour grade. PARP1 was positively associated with DDR-proteins; RAD51, BRCA1, CHK1 and PIASγ (p < 0.001). Negative association was found between PARP1nc and Ki67. PARP1c was associated with ER (p < 0.001). Different associations between PARP1 and DDR-proteins were observed when stratified based on ER/BRCA1 status. PARP1 was not an independent predictor of outcome in sporadic or BRCA1-mutated BC. Our results demonstrate a potential biological role for PARP1c and PARP1nc in DNA repair in BC based on the significant association with other key DNA damage repair proteins. These associations were not restricted to ER-negative or triple-negative subgroup

Heaviness, health and happiness: a cross-sectional study of 163 066 UK Biobank participants

&lt;b&gt;Background&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Obesity is known to increase the risk of many diseases and reduce overall quality of life. This study examines the relationship with self-reported health (SRH) and happiness.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods&lt;/b&gt; &lt;p&gt;&lt;/p&gt;We conducted a cross-sectional study of the 163 066 UK Biobank participants who completed the happiness rating. The association between adiposity and SRH and happiness was examined using logistic regression. SRH was defined as good (excellent, good), or poor (fair, poor). Self-reported happiness was defined as happy (extremely, very, moderately) or unhappy (moderately, very, extremely). &lt;p&gt;&lt;/p&gt; &lt;b&gt;Results&lt;/b&gt; &lt;p&gt;&lt;/p&gt;Poor health was reported by 44 457 (27.3%) participants. The adjusted ORs for poor health were 3.86, 2.92, 2.60 and 6.41 for the highest, compared with lowest, deciles of Body Mass Index, waist circumference, waist to hip ratio and body fat percent, respectively. The associations were stronger in men (p&lt;0.001). Overall, 7511 (4.6%) participants felt unhappy, and only class III obese participants were more likely to feel unhappy (adjusted OR 1.33, 95% CI 1.15 to 1.53, p&lt;0.001) but the associations differed by sex (p&lt;0.001). Among women, there was a significant association between unhappiness and all levels of obesity. By contrast, only class III obese men had significantly increased risk and overweight and class I obese men were less likely to be unhappy. &lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions&lt;/b&gt;&lt;p&gt;&lt;/p&gt;Obesity impacts adversely on happiness as well as health, but the association with unhappiness disappeared after adjustment for self-reported health, indicating this may be mediated by health. Compared with obese men, obese women are less likely to report poor health, but more likely to feel unhappy. &lt;p&gt;&lt;/p&gt

Bipolar at-risk criteria: an examination of which clinical features have optimal utility for identifying youth at risk of early transition from depression to bipolar disorders

Background: A clinical and research challenge is to identify which depressed youth are at risk of “early transition to bipolar disorders (ET-BD).” This 2-part study (1) examines the clinical utility of previously reported BD at-risk (BAR) criteria in differentiating ET-BD cases from unipolar depression (UP) controls; and (2) estimates the Number Needed to Screen (NNS) for research and general psychiatry settings. Methods: Fifty cases with reliably ascertained, ET-BD I  and II cases were matched for gender and birth year with 50 UP controls who did not develop BD over 2 years. We estimated the clinical utility for finding true cases and screening out non-cases for selected risk factors and their NNS. Using a convenience sample (N = 80), we estimated the NNS when adjustments were made to account for data missing from clinical case notes. Results: Sub-threshold mania, cyclothymia, family history of BD, atypical depression symptoms and probable antidepressant-emergent elation, occurred significantly more frequently in ET-BD youth. Each of these “BARDepression” criteria demonstrated clinical utility for screening out non-cases. Only cyclothymia demonstrated good utility for case finding in research settings; sub-threshold mania showed moderate utility. In the convenience sample, the NNS for each criterion ranged from ~4 to 7.  Conclusions: Cyclothymia showed the optimum profile for case finding, screening and NNS in research settings. However, its presence or absence was only reported in 50% of case notes. Future studies of ET-BD instruments should distinguish which criteria have clinical utility for case finding vs screening

Intra-operative spectroscopic assessment of surgical margins during breast conserving surgery

Background: In over 20% of breast conserving operations, postoperative pathological assessment of the excised tissue reveals positive margins, requiring additional surgery. Current techniques for intra-operative assessment of tumor margins are insufficient in accuracy or resolution to reliably detect small tumors. There is a distinct need for a fast technique to accurately identify tumors smaller than 1 mm2 in large tissue surfaces within 30 min. Methods: Multi-modal spectral histopathology (MSH), a multimodal imaging technique combining tissue auto-fluorescence and Raman spectroscopy was used to detect microscopic residual tumor at the surface of the excised breast tissue. New algorithms were developed to optimally utilize auto-fluorescence images to guide Raman measurements and achieve the required detection accuracy over large tissue surfaces (up to 4 × 6.5 cm2). Algorithms were trained on 91 breast tissue samples from 65 patients. Results: Independent tests on 121 samples from 107 patients - including 51 fresh, whole excision specimens - detected breast carcinoma on the tissue surface with 95% sensitivity and 82% specificity. One surface of each uncut excision specimen was measured in 12–24 min. The combination of high spatial-resolution auto-fluorescence with specific diagnosis by Raman spectroscopy allows reliable detection even for invasive carcinoma or ductal carcinoma in situ smaller than 1 mm2. Conclusions: This study provides evidence that this multimodal approach could provide an objective tool for intra-operative assessment of breast conserving surgery margins, reducing the risk for unnecessary second operations

Communication Biophysics

Contains reports on six research projects.National Institutes of Health (Grant 5 PO1 NS13126)National Institutes of Health (Grant 5 RO1 NS18682)National Institutes of Health (Grant 5 RO1 NS20322)National Institutes of Health (Grant 5 R01 NS20269)National Institutes of Health (Grant 5 T32NS 07047)Symbion, Inc.National Science Foundation (Grant BNS 83-19874)National Science Foundation (Grant BNS 83-19887)National Institutes of Health (Grant 6 RO1 NS 12846)National Institutes of Health (Grant 1 RO1 NS 21322