Invasive breast cancer and breast cancer death after non-screen detected ductal carcinoma in situ from 1990 to 2018 in England: population based cohort study.

OBJECTIVES: To evaluate the long term risks of invasive breast cancer and death related to breast cancer after non-screen detected ductal carcinoma in situ. Risks for women in the general population and for women diagnosed with ductal carcinoma in situ via the screening programme were compared. DESIGN: Population based cohort study. SETTING: Data from the National Disease Registration Service. PARTICIPANTS: All 27 543 women in England who were diagnosed with ductal carcinoma in situ, outside the NHS breast screening programme, during 1990 to 2018. MAIN OUTCOME MEASURES: Incident invasive breast cancer and death caused by breast cancer. RESULTS: By 31 December 2018, 3651 women with non-screen detected ductal carcinoma in situ had developed invasive breast cancer, more than four times higher than expected from national cancer incidence rates (ratio of observed to expected rate was 4.21 (95% conference interval 4.07 to 4.35)). The ratio of observed to expected rate of developing invasive breast cancer remained increased throughout follow-up among women aged <45-70 years. The 25 year cumulative risks of invasive breast cancer by age at diagnosis of ductal carcinoma in situ were 27.3% for <45 years, 25.2% for 45-49 years, 21.7% for 50-59 years, and 20.8% for 60-70 years. 908 women died of breast cancer, almost four times higher than that expected from breast cancer death rates in the general population (ratio of observed to expected rate 3.83 (3.59 to 4.09)). The ratio of observed to expected rate of mortality attributed to breast cancer remained increased throughout follow-up. The 25 year cumulative risks of breast cancer death by age at ductal carcinoma in situ diagnosis were 7.6% for <45 years, 5.8% for 45-49 years, 5.9% for 50-59 years, and 6.2% for 60-70 years. Among women aged 50-64 years, and therefore eligible for breast screening by the NHS, the ratio of observed to expected rate of invasive breast cancer in women with non-screen detected compared with screen detected ductal carcinoma in situ was 1.26 (95% conference interval 1.17 to 1.35), while the ratio for mortality from breast cancer was 1.37 (1.17 to 1.60). Among 22 753 women with unilateral ductal carcinoma in situ undergoing surgery, those who had mastectomy rather than breast conserving surgery had a lower 25 year cumulative rate of ipsilateral invasive breast cancer (mastectomy 8.2% (95% conference interval 7.0% to 9.4%), breast conserving surgery with radiotherapy 19.8% (16.2% to 23.4%), and breast conserving surgery with no radiotherapy recorded 20.6% (18.7% to 22.4%)). However, reductions did not translate into a lower 25 year cumulative rate of deaths attributable to breast cancer (mastectomy 6.5% (4.9% to 10.9%), breast conserving surgery with radiotherapy 8.6% (5.9% to 15.5%), breast conserving surgery with no radiotherapy recorded 7.8% (6.3% to 11.5%)). CONCLUSIONS: For at least 25 years after their diagnosis, women with non-screen detected ductal carcinoma in situ had higher long term risks of invasive breast cancer and breast cancer death than women in the general population. Additionally, they had higher long term risks than women with screen detected ductal carcinoma in situ. Mastectomy was associated with lower risks of invasive breast cancer than breast conserving surgery, even when accompanied by radiotherapy. However, risks of breast cancer death appeared similar for mastectomy, breast conserving surgery with radiotherapy, and breast conserving surgery with no radiotherapy recorded.

Ki67 and breast cancer mortality in women with invasive breast cancer.

BACKGROUND: The percentage of cells staining positive for Ki67 is sometimes used for decision-making in patients with early invasive breast cancer (IBC). However, there is uncertainty regarding the most appropriate Ki67 cut points and the influence of interlaboratory measurement variability. We examined the relationship between breast cancer mortality and Ki67 both before and after accounting for interlaboratory variability and 8 patient and tumor characteristics. METHODS: A multicenter cohort study of women with early IBC diagnosed during 2009-2016 in more than 20 NHS hospitals in England and followed until December 31, 2020. RESULTS: Ki67 was strongly prognostic of breast cancer mortality in 8212 women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative early IBC (Ptrend < .001). This relationship remained strong after adjustment for patient and tumor characteristics (Ptrend < .001). Standardization for interlaboratory variability did little to alter these results. For women with Ki67 scores of 0%-5%, 6%-10%, 11%-19%, and 20%-29% the corresponding 8-year adjusted cumulative breast cancer mortality risks were 3.3% (95% confidence interval [CI] = 2.8% to 4.0%), 3.7% (95% CI = 3.0% to 4.4%), 3.4% (95% CI = 2.8% to 4.1%), and 3.4% (95% CI = 2.8% to 4.1%), whereas for women with Ki67 scores of 30%-39% and 40%-100%, these risks were higher, at 5.1% (95% CI = 4.3% to 6.2%) and 7.7% (95% CI = 6.6% to 9.1) (Ptrend < .001). Similar results were obtained when the adjusted analysis was repeated with omission of pathological information about tumor size and nodal involvement, which would not be available preoperatively for patients being considered for neoadjuvant therapy. CONCLUSION: Our findings confirm the prognostic value of Ki67 scores of 30% or more in women with ER-positive, HER2-negative early IBC, irrespective of interlaboratory variability. These results also suggest that Ki67 may be useful to aid decision-making in the neoadjuvant setting.

Deep EHR Spotlight: a Framework and Mechanism to Highlight Events in Electronic Health Records for Explainable Predictions.

The wide adoption of Electronic Health Records (EHR) has resulted in large amounts of clinical data becoming available, which promises to support service delivery and advance clinical and informatics research. Deep learning techniques have demonstrated performance in predictive analytic tasks using EHRs yet they typically lack model result transparency or explainability functionalities and require cumbersome pre-processing tasks. Moreover, EHRs contain heterogeneous and multi-modal data points such as text, numbers and time series which further hinder visualisation and interpretability. This paper proposes a deep learning framework to: 1) encode patient pathways from EHRs into images, 2) highlight important events within pathway images, and 3) enable more complex predictions with additional intelligibility. The proposed method relies on a deep attention mechanism for visualisation of the predictions and allows predicting multiple sequential outcomes.

Invasive breast cancer and breast cancer mortality after ductal carcinoma in situ in women attending for breast screening in England, 1988-2014: population based observational cohort study.

OBJECTIVE: To evaluate the long term risks of invasive breast cancer and death from breast cancer after ductal carcinoma in situ (DCIS) diagnosed through breast screening. DESIGN: Population based observational cohort study. SETTING: Data from the NHS Breast Screening Programme and the National Cancer Registration and Analysis Service. PARTICIPANTS: All 35 024 women in England diagnosed as having DCIS by the NHS Breast Screening Programme from its start in 1988 until March 2014. MAIN OUTCOME MEASURES: Incident invasive breast cancer and death from breast cancer. RESULTS: By December 2014, 13 606 women had been followed for up to five years, 10 998 for five to nine years, 6861 for 10-14 years, 2620 for 15-19 years, and 939 for at least 20 years. Among these women, 2076 developed invasive breast cancer, corresponding to an incidence rate of 8.82 (95% confidence interval 8.45 to 9.21) per 1000 women per year and more than double that expected from national cancer incidence rates (ratio of observed rate to expected rate 2.52, 95% confidence interval 2.41 to 2.63). The increase started in the second year after diagnosis of DCIS and continued until the end of follow-up. In the same group of women, 310 died from breast cancer, corresponding to a death rate of 1.26 (1.13 to 1.41) per 1000 women per year and 70% higher than that expected from national breast cancer mortality rates (observed:expected ratio 1.70, 1.52 to 1.90). During the first five years after diagnosis of DCIS, the breast cancer death rate was similar to that expected from national mortality rates (observed:expected ratio 0.87, 0.69 to 1.10), but it then increased, with values of 1.98 (1.65 to 2.37), 2.99 (2.41 to 3.70), and 2.77 (2.01 to 3.80) in years five to nine, 10-14, and 15 or more after DCIS diagnosis. Among 29 044 women with unilateral DCIS undergoing surgery, those who had more intensive treatment (mastectomy, radiotherapy for women who had breast conserving surgery, and endocrine treatment in oestrogen receptor positive disease) and those with larger final surgical margins had lower rates of invasive breast cancer. CONCLUSIONS: To date, women with DCIS detected by screening have, on average, experienced higher long term risks of invasive breast cancer and death from breast cancer than women in the general population during a period of at least two decades after their diagnosis. More intensive treatment and larger final surgical margins were associated with lower risks of invasive breast cancer.

Reliability of preoperative breast biopsies showing ductal carcinoma in situ and implications for non-operative treatment: a cohort study.

PURPOSE: The future of non-operative management of DCIS relies on distinguishing lesions requiring treatment from those needing only active surveillance. More accurate preoperative staging and grading of DCIS would be helpful. We identified determinants of upstaging preoperative breast biopsies showing ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC), or of upgrading them to higher-grade DCIS, following examination of the surgically excised specimen. METHODS: We studied all women with DCIS at preoperative biopsy in a large specialist cancer centre during 2000-2014. Information from clinical records, mammography, and pathology specimens from both preoperative biopsy and excised specimen were abstracted. Women suspected of having IBC during biopsy were excluded. RESULTS: Among 606 preoperative biopsies showing DCIS, 15.0% (95% confidence interval 12.3-18.1) were upstaged to IBC and a further 14.6% (11.3-18.4) upgraded to higher-grade DCIS. The risk of upstaging increased with presence of a palpable lump (21.1% vs 13.0%, pdifference = 0.04), while the risk of upgrading increased with presence of necrosis on biopsy (33.0% vs 9.5%, pdifference < 0.001) and with use of 14G core-needle rather than 9G vacuum-assisted biopsy (22.8% vs 7.0%, pdifference < 0.001). Larger mammographic size increased the risk of both upgrading (pheterogeneity = 0.01) and upstaging (pheterogeneity = 0.004). CONCLUSIONS: The risk of upstaging of DCIS in preoperative biopsies is lower than previously estimated and justifies conducting randomized clinical trials testing the safety of active surveillance for lower grade DCIS. Selection of women with low grade DCIS for such trials, or for active surveillance, may be improved by consideration of the additional factors identified in this study.

Role of tamoxifen in idiopathic gynecomastia: A 10-year prospective cohort study.

BACKGROUND: Idiopathic gynecomastia is a benign breast disorder characterized by overdevelopment of male breast tissue. It can cause discomfort and concern, resulting in patients seeking diagnosis and treatment. We aimed to evaluate the efficacy of tamoxifen therapy in resolving this condition. METHODS: We undertook a prospective cohort study of all male patients who presented to our breast clinic, were diagnosed with primary gynecomastia, and were treated with a trial of tamoxifen 10 mg daily therapy, over a 10-year period from October 2004 to October 2015. All patients underwent routine investigations to exclude secondary causes of gynecomastia. The end point of interest was the complete resolution of gynecomastia. RESULTS: We included 81 patients in this study. The mean age was 42.8 years (SD 19.5 years). Of these, 28.4% were bilateral gynecomastia and 71.6% were unilateral. The majority (87.7%) of cases presented with accompanying mastalgia. Following treatment, 90.1% (n = 73) had a complete response of their gynecomastia with tamoxifen therapy. Only eight patients did not have a complete resolution following tamoxifen therapy, of which two underwent subsequent surgical resection of their symptomatic gynecomastia. CONCLUSION: Our study is the largest to date examining the role of tamoxifen in idiopathic gynecomastia, and our results show approximately nine in every 10 men treated with tamoxifen therapy had successful resolution of their symptoms. We support its use for idiopathic gynecomastia in eligible men following the careful discussion of its risks and benefits.

Closure methods of the appendix stump for complications during laparoscopic appendectomy.

BACKGROUND: Laparoscopic appendectomy is amongst the most common general surgical procedures performed in the developed world. Arguably, the most critical part of this procedure is effective closure of the appendix stump to prevent catastrophic intra-abdominal complications from a faecal leak into the abdominal cavity. A variety of methods to close the appendix stump are used worldwide; these can be broadly divided into traditional ligatures (such as intracorporeal or extracorporeal ligatures or Roeder loops) and mechanical devices (such as stapling devices, clips, or electrothermal devices). However, the optimal method remains unclear. OBJECTIVES: To compare all surgical techniques now used for appendix stump closure during laparoscopic appendectomy. SEARCH METHODS: In June 2017, we searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 6) in the Cochrane Library, MEDLINE Ovid (1946 to 14 June 2017), Embase Ovid (1974 to 14 June 2017), Science Citation Index - Expanded (14 June 2017), China Biological Medicine Database (CBM), the World Health Organization International Trials Registry Platform search portal, ClinicalTrials.gov, Current Controlled Trials, the Chinese Clinical Trials Register, and the EU Clinical Trials Register (all in June 2017). We searched the reference lists of relevant publications as well as meeting abstracts and Conference Proceedings Citation Index to look for additional relevant clinical trials. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) that compared mechanical appendix stump closure (stapler, clips, or electrothermal devices) versus ligation (Endoloop, Roeder loop, or intracorporeal knot techniques) for uncomplicated appendicitis. DATA COLLECTION AND ANALYSIS: Two review authors identified trials for inclusion, collected data, and assessed risk of bias independently. We performed the meta-analysis using Review Manager 5. We calculated the odds ratio (OR) for dichotomous outcomes and the mean difference (MD) for continuous outcomes, with 95% confidence intervals (CIs). MAIN RESULTS: We included eight randomised studies encompassing 850 participants. Five studies compared titanium clips versus ligature, two studies compared an endoscopic stapler device versus ligature, and one study compared an endoscopic stapler device, titanium clips, and ligature. In our analyses of primary outcomes, we found no differences in total complications (OR 0.97, 95% CI 0.27 to 3.50, 8 RCTs, very low-quality evidence), intraoperative complications (OR 0.93, 95% CI 0.34 to 2.55, 8 RCTs, very low-quality evidence), or postoperative complications (OR 0.80, 95% CI 0.21 to 3.13, 8 RCTs, very low-quality evidence) between ligature and all types of mechanical devices. However, our analyses of secondary outcomes revealed that use of mechanical devices saved approximately nine minutes of total operating time when compared with use of a ligature (mean difference (MD) -9.04 minutes, 95% CI -12.97 to -5.11 minutes, 8 RCTs, very low-quality evidence). However, this finding did not translate into a clinically or statistically significant reduction in inpatient hospital stay (MD 0.02 days, 95% CI -0.12 to 0.17 days, 8 RCTs, very low-quality evidence). Available information was insufficient for reliable comparison of total hospital costs and postoperative pain/quality of life between the two approaches. Overall, evidence across all analyses was of very low quality, with substantial potential for confounding factors. Given the limitations of all studies in terms of bias and the low quality of available evidence, a clear conclusion regarding superiority of any one particular type of mechanical device over another is not possible. AUTHORS' CONCLUSIONS: Evidence is insufficient at present to advocate omission of conventional ligature-based appendix stump closure in favour of any single type of mechanical device over another in uncomplicated appendicitis.

Making progress in early breast cancer: Taking time or accepting risk?

Outcomes for patients diagnosed with early breast cancer in developed countries have improved substantially over recent decades. Adjuvant therapies have contributed to this improvement and their benefits have been confirmed in large randomised controlled trials (RCTs) and meta-analyses. Lower event rates, whilst welcome, have created problems for RCTs, that need to be larger and often take longer to provide a reliable result. In an effort to maintain the rate of progress and to obviate the complexity, cost and time required to conduct large RCTs, there has been an increased tendency to rely on observational data to determine a treatment effect and also to accelerate progress by the use of a surrogate marker (pathological complete remission after neoadjuvant chemotherapy). We highlight the pitfalls in these approaches and suggest some simplifications in the conduct of RCTs.

Rheumatic Mitral Valve Disease Is Associated With Worse Outcomes in Stroke: A Thailand National Database Study.

BACKGROUND AND PURPOSE: Rheumatic valvular heart disease is associated with the increased risk of cerebrovascular events, although there are limited data on the prognosis of patients with rheumatic mitral valve disease (RMVD) after stroke. METHODS: We examined the association between RMVD and both serious and common cardiovascular and noncardiovascular (respiratory and infective) complications in a cohort of hospitalized stroke patients based in Thailand. Factors associated with in-hospital mortality were also explored. Data were obtained from a National Insurance Database. All hospitalized strokes between October 1, 2004, and January 31, 2013, were included in the current study. Characteristics and outcomes were compared for RMVD and non-RMVD patients. Logistic regression, propensity score matching, and multivariate models were used to assess study outcomes. RESULTS: In total, 594 681 patients (mean [SD] age=64 [14.5] years) with a diagnosis of stroke (ischemic=306 154; hemorrhagic=195 392; undetermined=93 135) were included in this study, of whom 5461 had RMVD. Results from primary analyses showed that after ischemic stroke, and controlling for potential confounding covariates, RMVD was associated (P<0.001) with increased odds for cardiac arrest (odds ratio [95% confidence interval]=2.13 [1.68-2.70]), shock (2.13 [1.64-2.77]), arrhythmias (1.70 [1.21-2.39]), respiratory failure (2.09 [1.87-2.33]), pneumonia (2.00 [1.81-2.20]), and sepsis (1.39 [1.19-1.63]). In hemorrhagic stroke patients, RMVD was associated with increased odds (fully adjusted model) for respiratory failure (1.26 [1.01-1.57]), and in patients with undetermined stroke, RMVD was associated with increased odds (fully adjusted analyses) for shock (3.00 [1.46-6.14]), respiratory failure (2.70 [1.91-3.79]), and pneumonia (2.42 [1.88-3.11]). CONCLUSIONS: RMVD is associated with the development of cardiac arrest, shock, arrhythmias, respiratory failure, pneumonia, and sepsis after acute stroke.

A Nationwide Cross-Sectional Survey of UK Breast Surgeons' Views on the Management of Ductal Carcinoma In Situ.

Background. There is wide variation in the management of Ductal Carcinoma In Situ (DCIS) nationwide. We aimed to investigate whether the attitudes of surgeons towards different aspects of DCIS treatment varied by seniority of surgeon or by geographical region within the UK. Materials and Methods. A nationwide online survey targeted at UK breast surgeons was undertaken. The anonymous survey contained questions regarding demographics of respondents and specific questions regarding DCIS management that were identified as areas of uncertainty during a systematic search of the literature. Results. Responses from 80 surgeons were obtained. Approximately 57% were male and the majority were consultant or specialist registrar. Approximately 63% of participants were based in district general hospitals with all training deaneries represented. Surgeons' views on the prognosis and management of DCIS varied geographically across the UK and terminology for DCIS varied with surgeon seniority. Surgeons' views particularly differed from national guidance on indications for SLNB, tamoxifen, and follow-up practice. Conclusion. Our survey reaffirms that, irrespective of national guidelines and attempts at uniformity, there continues to be a wide variety of views amongst breast surgeons regarding the ideal management of DCIS. However, by quantifying this variation, it may be possible to take it into account when examining long-term trends in nationwide treatment data.

Management of pruritus in chronic liver disease.

Background. There continues to be uncertainty on the ideal treatment of pruritus in chronic liver disease. The aim of this study was to gather the latest information on the evidence-based management of pruritus in chronic liver disease. Methodology. A literature search for pruritus in chronic liver disease was conducted using Pubmed and Embase database systems using the MeSH terms "pruritus," "chronic liver disease," "cholestatic liver disease," and "treatment." Results. The current understanding of the pathophysiology of pruritus is described in addition to detailing research into contemporary treatment options of the condition. These medical treatments range from bile salts, rifampicin, and opioid receptor antagonists to antihistamines. Conclusion. The burden of pruritus in liver disease patients persists and, although it is a common symptom, it can be difficult to manage. In recent years there has been greater study into the etiology and treatment of the condition. Nonetheless, pruritus remains poorly understood and many patients continue to suffer, reiterating the need for further research to improve our understanding of the etiology and treatment for the condition.

Sentinel lymph node biopsy before mastectomy and immediate breast reconstruction does not significantly delay surgery in early breast cancer.

BACKGROUND: Sentinel lymph node biopsy (SLNB) before mastectomy and immediate breast reconstruction (IBR) may help to avoid the negative cosmetic effects of radiotherapy on reconstructed breasts in lymph node-positive patients. Concerns have been raised regarding possible delays whilst awaiting the SLNB result prior to definitive surgery, which needs to be performed within 31 days of cancer diagnosis. The aim was to investigate whether initial SLNB delays mastectomy and IBR. METHODS: All patients who had IBR between January 2005 and 2007 were reviewed retrospectively. Before October 2005 axillary staging was performed simultaneously with mastectomy and IBR (Group I). After October 2005, SLNB was performed as an initial procedure and patients with positive SLNB were only offered a temporary tissue expander to be replaced by autogenous reconstruction after completing the cancer treatment (Group II). Date of diagnosis and waiting times were recorded and the two groups were compared. Different reasons for delays in treatment were studied. RESULTS: One hundred and thirty-nine IBR (123 patients) were included in the statistical analysis (67 IBR in Group I and 72 IBR in Group II). Seventy-one patients (57.7%) had no delay (mean waiting time of 23 days). Fifty-two patients (42.3%) had delay longer than 31 days (mean waiting time of 66 days). Group I patients had a mean waiting time (standard deviation) of 38.8 (38) days and Group II patients 42.7 (24) days (p = 0.51). CONCLUSIONS: In this group of patients, SLNB before mastectomy and IBR does not significantly delay definitive breast cancer surgery.

The clinical utility of Multiplate analyser measurement in platelet function testing following stroke and transient ischaemic attack.

BACKGROUND: Platelet responsiveness to aspirin in people with cerebrovascular disease is poorly understood. OBJECTIVES: To determine: (i) normal reference range, imprecision and reproducibility of the Multiplate instrument in healthy volunteers naive to aspirin; (ii) imprecision and reproducibility of the Multiplate instrument in acute stroke and transient ischaemic attack (TIA); (iii) the relationship between aspirin responsiveness and clinical outcome. MATERIALS AND METHODS: We evaluated platelet function response to three agonists [Adenosine Diphosphate (ADP), Arachidonic Acid (AA), Collagen (Col)] using the Mulitplate platelet function analyser in a two-phase pilot study. In phase 1, we recruited healthy volunteers to determine the normal reference range and imprecision of the Multiplate instrument. In phase 2, we assessed platelet function in acute stroke or TIA patients presenting to hospital. These patients were bled within 24 h of presentation and between 12 and 24 h after ≥75 mg dose of Aspirin. Patients were followed up to 1 yr to assess mortality and recurrent cardiovascular event. RESULTS: Overall, 29 healthy volunteers and 81 stroke/TIA patients were recruited. On assessing components of variance, Multiplate testing is reproducible and precise in volunteers and stroke/TIA patients. In stroke patients receiving aspirin, Bland-Altman plots show initial day 1 measurement provided a reliable measure of continuing response to aspirin at day 3. We defined one-third of patients as aspirin resistant [31.8% (95% CI: 22.1%-42.8%)] using cut off mean aggregation of ≥23.08% for AA and mean aggregation of ≥80.76% for ADP. CONCLUSION: The Multiplate device gives reproducible, precise results in volunteers and stroke/TIA patients.

Retinal phototransduction.

Vision is perhaps the most important of all our senses, and gives us an immense amount of information regarding the outside world. The initial format in which this information reaches the retina are photons; particles of energy radiation of a given wavelength emitted or reflected from our surroundings. The brain itself however, perceives information in electrical signals via action potentials and changes in electrochemical gradients. The processes involved in the transduction of photons into electrical potentials will be the focus of this article. This review article summarizes the recent advances in understanding these complex pathways and provides an overview of the main molecules involved in the neurobiology of vision.