Biology of primary breast cancer in older women beyond routine biomarkers.

PURPOSE: There are numerous biomarkers which may have potential predictive and prognostic significance in breast cancer. This is extremely important in older adults, who may opt for less aggressive therapy. This work outlines the literature on biological assessment outside of standard biomarkers (defined as ER, PgR, HER2, Ki67) in women ≥ 65 years with primary operable invasive breast cancer, to determine which additional biomarkers are relevant to outcome in older women. METHODS: Medline and Embase databases were searched. Studies were eligible if included ≥ 50 patients aged ≥ 65 years; stratified results by age; measured a biomarker outside of standard assay and reported patient data. RESULTS: A total of 12 studies were appraised involving 5000 patients, measuring 28 biomarkers. The studies were extremely varied in methodology and outcome but three themes emerged: 1. Differences in biomarker expression between younger and older women, indicating that breast cancer in older women is generally less aggressive compared to younger women; 2. Relationship of biomarker expression with survival, suggesting biomarkers which may exclusively predict response to primary treatment in older women; 3. Association of biomarker with chemotherapy, suggesting that older patients should not be declined chemotherapy based on age alone. CONCLUSION: There is evidence to support further investigation of B-cell lymphoma (BCL2), liver kinase (LK)B1, epidermal growth factor receptor (EGFR), cytoplasmic cyclin-E, mucin (MUC)1 and cytokeratins (CKs) as potential predictive or prognostic markers in older women with breast cancer undergoing surgery. Studies exploring these biomarkers in larger cohorts and in women undergoing non-operative therapies are required.

The impact of breast cancer surgery on functional status in older women - A systematic review of the literature.

Primary endocrine therapy as treatment of breast cancer is only recommended in older women with limited life expectancy. However, many older women opt for endocrine therapy due to concerns regarding frailty and potential decline in function after surgery. A decline in functional status after surgery is documented in some cancer types, such as colorectal, however, the full impact of breast cancer surgery is less understood. A systematic review was performed to examine the evidence for impact of breast cancer surgery on functional status in older women. PubMed and Embase databases were searched. Studies were eligible if performed within the last 10 years; included patients over the age of 65 years undergoing breast cancer surgery; included stratification of results by age; measured functional status pre-operatively and at least six months following surgery. A total of 11 studies including 12 030 women were appraised. Two studies represented level-II and nine level-IV evidence. Overall, physical activity level was negatively impacted by breast cancer surgery and this was compounded by the extent of surgery. Evidence for impact of breast cancer surgery on quality of life, fatigue and cognition, was conflicting. The possibility of decline in functional status after breast cancer surgery should be discussed in all older women considering surgery. A structured exercise program may improve the negative effects of surgery on physical activity. Further work is required in the areas of quality of life, fatigability and cognition.

Bridging the age gap in breast cancer: impact of omission of breast cancer surgery in older women with oestrogen receptor-positive early breast cancer on quality-of-life outcomes.

BACKGROUND: Primary endocrine therapy may be an alternative treatment for less fit women with oestrogen receptor (ER)-positive breast cancer. This study compared quality-of-life (QoL) outcomes in older women treated with surgery or primary endocrine therapy. METHODS: This was a multicentre, prospective, observational cohort study of surgery or primary endocrine therapy in women aged over 70 years with operable breast cancer. QoL was assessed using European Organisation for Research and Treatment of cancer QoL questionnaires QLQ-C30, -BR23, and -ELD14, and the EuroQol Five Dimensions 5L score at baseline, 6 weeks, and 6, 12, 18, and 24 months. Propensity score matching was used to adjust for baseline variation in health, fitness, and tumour stage. RESULTS: The study recruited 3416 women (median age 77 (range 69-102) years) from 56 breast units. Of these, 2979 (87.2 per cent) had ER-positive breast cancer; 2354 women had surgery and 500 received primary endocrine therapy (125 were excluded from analysis due to inadequate data or non-standard therapy). Median follow-up was 52 months. The primary endocrine therapy group was older and less fit. Baseline QoL differed between the groups; the mean(s.d.) QLQ-C30 global health status score was 66.2(21.1) in patients who received primary endocrine therapy versus 77.1(17.8) among those who had surgery plus endocrine therapy. In the unmatched analysis, changes in QoL between 6 weeks and baseline were noted in several domains, but by 24 months most scores had returned to baseline levels. In the matched analysis, major surgery (mastectomy or axillary clearance) had a more pronounced adverse impact than primary endocrine therapy in several domains. CONCLUSION: Adverse effects on QoL are seen in the first few months after surgery, but by 24 months these have largely resolved. Women considering surgery should be informed of these effects.

Bridging the age gap in breast cancer: cluster randomized trial of two decision support interventions for older women with operable breast cancer on quality of life, survival, decision quality, and treatment choices.

BACKGROUND: Rates of surgery and adjuvant therapy for breast cancer vary widely between breast units. This may contribute to differences in survival. This cluster RCT evaluated the impact of decision support interventions (DESIs) for older women with breast cancer, to ascertain whether DESIs influenced quality of life, survival, decision quality, and treatment choice. METHODS: A multicentre cluster RCT compared the use of two DESIs against usual care in treatment decision-making in older women (aged at least ≥70 years) with breast cancer. Each DESI comprised an online algorithm, booklet, and brief decision aid to inform choices between surgery plus adjuvant endocrine therapy versus primary endocrine therapy, and adjuvant chemotherapy versus no chemotherapy. The primary outcome was quality of life. Secondary outcomes included decision quality measures, survival, and treatment choice. RESULTS: A total of 46 breast units were randomized (21 intervention, 25 usual care), recruiting 1339 women (670 intervention, 669 usual care). There was no significant difference in global quality of life at 6 months after the baseline assessment on intention-to-treat analysis (difference -0.20, 95 per cent confidence interval (C.I.) -2.69 to 2.29; P = 0.900). In women offered a choice of primary endocrine therapy versus surgery plus endocrine therapy, knowledge about treatments was greater in the intervention arm (94 versus 74 per cent; P = 0.003). Treatment choice was altered, with a primary endocrine therapy rate among women with oestrogen receptor-positive disease of 21.0 per cent in the intervention versus 15.4 per cent in usual-care sites (difference 5.5 (95 per cent C.I. 1.1 to 10.0) per cent; P = 0.029). The chemotherapy rate was 10.3 per cent at intervention versus 14.8 per cent at usual-care sites (difference -4.5 (C.I. -8.0 to 0) per cent; P = 0.013). Survival was similar in both arms. CONCLUSION: The use of DESIs in older women increases knowledge of breast cancer treatment options, facilitates shared decision-making, and alters treatment selection. Trial registration numbers: EudraCT 2015-004220-61 (https://eudract.ema.europa.eu/), ISRCTN46099296 (http://www.controlled-trials.com).

Patterns of biomarker expression in patients treated with primary endocrine therapy - a unique insight using core needle biopsy tissue microarray.

PURPOSE: Prediction of response to primary endocrine therapy (PET) in older women is based on measurement of oestrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor (HER)-2. This study uses a unique method for construction of core needle biopsy (CNB) tissue microarray (TMA), to correlate expression of a panel of 17 biomarkers with clinical outcome, in patients receiving PET. METHODS: Over 37 years (1973-2010), 1758 older (≥ 70 years) women with operable primary breast cancer were managed in a single institution. Of these, 693 had sufficient good-quality CNB to construct TMA, of which 334 had ER-positive tumours treated by PET with a minimum of 6-month follow-up. A panel of biomarkers was measured by immunohistochemistry (ER, PgR, HER2, Ki-67, p53, CK5/6, CK 7/8, EGFR, BCL-2, MUC1, VEGF, LKB1, BRCA1, HER3, HER4, PTEN and AIB1). Expression of each biomarker was dichotomised into 'low' or 'high' based on breast cancer-specific survival (BCSS). RESULTS: From the panel of biomarkers, multivariate analysis showed: High ER (p = 0.003) and PgR (p = 0.002) were associated with clinical benefit of PET at 6 months, as opposed to progressive disease. High ER (p = 0.0023), PgR (p < 0.001) and BCL-2 (p = 0.043) and low LKB1 (p = 0.022) were associated with longer time to progression. High PgR (p < 0.001) and low MUC1 (p = 0.021) were associated with better BCSS. Expression of other biomarkers did not show any significant correlation. CONCLUSIONS: In addition to ER and PgR; MUC1, BCL-2 and LKB1 are important in determining the outcome of PET in this cohort.

Exploring Women Healthcare Leaders' Perceptions on Barriers to Leadership in Greek Context.

Background: Gender inequalities have been identified as important derailment factors for health workforce and health system sustainability. Literature holds responsible a list of gendered barriers faced by female health workforce. However, there is a gap in the evidence based research on women leaders' own perceptions of barriers to leading positions advancement. This study aims to explore leadership barriers perceived by women healthcare leaders within country's context; research focused on Greece due to country's poor performance on gender equality index and current economic turbulence. Study supplements survey data and provides orientation for further gender sensitive research in health workforce development through country's specificity lens to better inform education and policy makers. Methods: The best-worst object case survey method was used, applying an online questionnaire designed in Qualtrics. The online questionnaire was sent to 30 purposively invited participants. Respondents were asked to tick the most and the least important barriers to women's leadership in provided choice scenarios. Descriptive data analysis was used to understand and interpret the results. Results: Women leaders perceived stereotypes, work/life balance, lack of equal career advancement, lack of confidence, gender gap and gender bias to be the barriers with the greatest relative importance in constraining opportunities for pursuing leading positions in Greek healthcare setting. Twenty more barriers were identified and ranked lower in relative importance. The results are considered exploratory and not to obtain population based outcomes. Conclusion: This exploratory study reports the perceived barriers of women leaders in pursuing leading positions within Greek healthcare context. The findings point mainly to organizational and socio-cultural related barriers potentially aggravated by country's unfortunate current economic turbulence. Further extensive research is required to establish grounded conclusions and better inform education and policy makers in developing gender sensitive strategies to sustainable health workforce development.

Mechanisms and mitigating factors for venous thromboembolism in chronic kidney disease: the REGARDS study.

Essentials Chronic kidney disease (CKD) is associated with procoagulant and inflammatory biomarkers. We studied the association of CKD and venous thromboembolism (VTE) in a case-cohort study. Factor VIII, D-dimer and C-reactive protein appeared to explain the association of CKD and VTE. Statin use was protective against VTE in those with and without CKD. SUMMARY: Background Chronic kidney disease (CKD) is associated with venous thromboembolism (VTE) risk via unknown mechanisms. Whether factors associated with reduced VTE risk in the general population might also be associated with reduced VTE risk in CKD patients is unknown. Objectives To determine whether thrombosis biomarkers attenuate VTE risk, and whether factors associated with reduced VTE risk are similarly effective in CKD patients. Methods Baseline biomarkers were measured in a cohort (294 VTE cases; 939 non-cases) from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a nationwide prospective cohort study of 30 239 persons aged ≥45 years with 4.3 years of follow-up. The hazard ratio (HR) of VTE per 10 mL min-1 1.73 m-2 decrease in estimated glomerular filtration rate (eGFR), and the percentage attenuation of this HR by each biomarker, were calculated. Associations of protective factors (physical activity, lower body mass index [BMI], and aspirin, warfarin and statin use) with VTE were estimated in those with and without CKD. Results The HR for VTE with lower eGFR was 1.13 (95% confidence interval [CI] 1.02-1.25), and VTE risk was attenuated by 23% (95% CI 5-100) by D-dimer, by 100% (95% CI 50-100) by factor VIII, and by 15% (95% CI 2-84) by C-reactive protein. Normal BMI was associated with lower VTE risk in those without CKD (HR 0.47, 95% CI 0.32-0.70), but not in those with CKD (HR 1.07, 95% CI 0.51-2.22). Statin use, physical activity and warfarin use were associated with lower VTE risk in both groups. Conclusions Procoagulant and inflammatory biomarkers mediated the association of eGFR with VTE. Higher physical activity, statin use and warfarin use mitigated VTE risk in those with CKD and those without CKD, but normal BMI did not mitigate VTE risk in CKD patients.

Effect of a financial incentive on the acceptance of a smoking cessation programme with service charge: a cluster-controlled trial.

INTRODUCTION: Frontline health care professionals in Hong Kong may encounter high refusal rates for the Hospital Authority's Smoking Counselling and Cessation Programme (SCCP) when smokers know it is subject to a service charge. We compared SCCP booking and attendance rates among smokers with or without a financial incentive. METHODS: In this multicentre non-randomised cluster-controlled trial, adult smokers who attended one of six general out-patient clinics between November 2015 and April 2016 were invited to join an SCCP. Attendees in the three intervention-group centres but not the three control-group centres received a supermarket coupon to offset the service charge. RESULTS: A total of 173 smokers aged 18 years or older (92 in the intervention group and 81 in the control group) were recruited into the study. In the intervention group, 47 smokers (51%) agreed via a questionnaire that they would join the SCCP, compared with only 23 smokers in the control group (28%). The booking rates were 83% (n=39) in the intervention group and 83% (n=19) in the control group. Among those who had booked a place, 19 (49%) intervention-group participants and 11 (58%) control-group participants attended an SCCP session. Multivariable logistic regression revealed that offering a coupon was associated with agreeing to join an SCCP (odds ratio=4.963, 95% confidence interval=2.173-11.334; P<0.001) and booking an SCCP place (odds ratio=4.244, 95% confidence interval=1.838-9.799; P<0.001). CONCLUSION: Provision of a financial incentive was positively associated with agreement to join an SCCP and booking an SCCP place. Budget holders should consider providing the SCCP free of charge to increase smokers' access to the service.

Most important barriers and facilitators of HTA usage in decision-making in Europe.

BACKGROUND: To enhance usage of health technology assessment (HTA) in decision-making, it is important to prioritise important barriers and facilitators to the uptake of HTA. This study aims to quantify and compare the relative importance of barriers and facilitators regarding the use of HTA in several European countries. METHODS: A survey containing two best-worst scaling (BWS) object case studies (i.e. barriers and facilitators) were conducted among 136 policy makers and HTA researchers from the Netherlands, Germany, France, and United Kingdom. Hierarchical Bayes analysis generated the mean relative importance score (RIS) for each factor and subgroup analyses assessed differences between countries. RESULTS: Six barriers (RIS≥5) and five facilitators (RIS≥6) were deemed highly important. Eleven barriers and ten facilitators differed in their importance between countries. Policy characteristics, research & researcher characteristics, and organisation & resources were particularly important to facilitate uptake of HTA, such as an explicit framework for decision-making and research of sufficient quality. CONCLUSION: The most paramount barriers and facilitators to HTA usage were quantified. For all countries it is crucial to create an explicit framework for the decision-making context to include HTA evidence. Country differences in the quality of research emphasize the need for enhanced international collaboration in HTA.

Correction: Oestrogen receptor negative early operable primary breast cancer in older women-Biological characteristics and long-term clinical outcome.

[This corrects the article DOI: 10.1371/journal.pone.0188528.].

Oestrogen receptor negative early operable primary breast cancer in older women-Biological characteristics and long-term clinical outcome.

BACKGROUND: Older women are at the greatest risk of breast cancer development and a considerable number present with comorbidities. Although the majority of breast cancers in this age group express oestrogen receptor (ER), which makes endocrine therapy (primary or adjuvant) feasible, given the huge size of the elderly population, there remains a significant number of patients, in absolute term, whose tumours do not express ER and their management is challenging. METHODS: Of a consecutive series of 1,758 older (≥70 years) women with early operable primary breast cancer managed in a dedicated service from 1973-2010, 252(14.3%) had ER-negative (histochemical (H) score ≤50) tumours. Their clinical outcome was retrospectively reviewed and tumour samples collected from diagnostic core biopsies were analysed for progesterone receptor (PgR), HER2 and Ki67 using immunohistochemistry. RESULTS: The commonest primary treatment was surgery (N = 194, 77%) followed by primary endocrine therapy (14.3%), primary radiotherapy (5.6%) and supportive treatment only (3.1%). Among the patients undergoing surgery, most of them had grade 3 (78.1%) and node-negative disease (62.2%). Some of them (21.1%) received postoperative radiotherapy. At a median follow-up of 37.5 months, 117 patients had died, out of which 48.6% were due to breast cancer. For those who underwent surgery, the regional and local recurrence rates were 2% and 1.1% per annum respectively. For those who received primary endocrine therapy, 38% progressed at 6 months, however all patients who had primary radiotherapy achieved clinical benefit at 6 months. Regardless of treatment given, the 5-year breast cancer specific and overall survival rates were 70% and 50% respectively. Biological analysis based on good quality needle core biopsy specimensfrom181 patients showed that 26.8% (N = 49), 16.9% (N = 31) and 70.7% (N = 70)expressed positivity for PgR, HER2 and Ki67 respectively. No correlation between these biomarkers and breast cancer specific survival was demonstrated. CONCLUSION: Oestrogen receptor negative early operable primary breast cancer in older women is associated with poor prognostic features in terms of biology and clinical outcome. Surgery appears to produce the best outcome as a primary treatment, however for those where neither surgery nor chemotherapy is appropriate, primary radiotherapy can be beneficial.

Axillary reverse mapping in N0 patients requiring sentinel lymph node biopsy - A systematic review of the literature and necessity of a randomised study.

OBJECTIVES: Axillary reverse mapping (ARM) is a technique to map and preserve arm lymphatics which may be damaged during surgery, resulting in lymphoedema. This work systematically reviews the incidence of lymphoedema following sentinel lymph node biopsy (SLNB) + ARM, compared to SLNB alone, for clinically node negative disease, as well as recurrence rate, other morbidity and the feasibility and difficulties of ARM. MATERIALS AND METHODS: The following databases were searched: PubMed, Embase, Cochrane Library. Abstracts submitted to recognised societies dedicated to research in oncology were included. Studies were eligible if performed within the last 10 years; ARM was used in any form; ARM performed during SLNB ± axillary lymph node dissection (ALND). Studies were analysed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: No studies were found meeting the initial inclusion criteria. Therefore, studies reporting use of SLNB + ARM (i.e. no comparison to SLNB) were reviewed. A second search was performed to identify studies reporting outcome following SLNB alone. Twelve studies reported data on patients undergoing SLNB + ARM and 23 studies on patients undergoing SLNB. Incidence of lymphoedema following SLNB + ARM was quoted between 0-4% and 0-63.4% following SLNB. Few studies commented on recurrence rate. Studies included were of mainly low level of evidence. CONCLUSION: Evidence is beginning to emerge for the use of ARM in order to reduce lymphoedema following axillary surgery. However, data regarding oncological safety of ARM is not clear and randomised controlled trials, with adequate follow-up, need to be performed to determine this.

What influences healthcare professionals' treatment preferences for older women with operable breast cancer? An application of the discrete choice experiment.

INTRODUCTION: Primary endocrine therapy (PET) is used variably in the UK as an alternative to surgery for older women with operable breast cancer. Guidelines state that only patients with "significant comorbidity" or "reduced life expectancy" should be treated this way and age should not be a factor. METHODS: A Discrete Choice Experiment (DCE) was used to determine the impact of key variables (patient age, comorbidity, cognition, functional status, cancer stage, cancer biology) on healthcare professionals' (HCP) treatment preferences for operable breast cancer among older women. Multinomial logistic regression was used to identify associations. RESULTS: 40% (258/641) of questionnaires were returned. Five variables (age, co-morbidity, cognition, functional status and cancer size) independently demonstrated a significant association with treatment preference (p < 0.05). Functional status was omitted from the multivariable model due to collinearity, with all other variables correlating with a preference for operative treatment over no preference (p < 0.05). Only co-morbidity, cognition and cancer size correlated with a preference for PET over no preference (p < 0.05). CONCLUSION: The majority of respondents selected treatment in accordance with current guidelines, however in some scenarios, opinion was divided, and age did appear to be an independent factor that HCPs considered when making a treatment decision in this population.

The assessment and management of older cancer patients: A SIOG surgical task force survey on surgeons' attitudes.

AIM: The Surgical Task Force at SIOG (International Society of Geriatric Oncology) designed this survey to explore the surgical oncologists' approach toward elderly cancer patients. METHODS: A web-based survey was sent to all members of ESSO (European Society of Surgical Oncology) and SSO (Society of Surgical Oncology). RESULTS: Two hundred and fifty-one surgeons responded (11% response rate) with a main interest on breast (62.1%), colorectal (43%) and hepatobiliary (27.4%) surgery. Almost all surgeons (>90%) offer surgery regardless the patient's age; only 48% consider mandatory a preoperative frailty assessment. The American Society of Anesthesiologists (ASA) score, nutritional and performance status are most frequently used as screening tools; only 6.4% surgeons use Comprehensive Geriatric Assessment (CGA) in daily practice and collaboration with geriatricians is low (36.3%). If proven to be effective, the majority of surgeons (71%) is prepared to pre-habilitate patients for up to 4 weeks before surgery. One in two surgeons would not offer an operation to patients with impaired cognitive status; conversely, one in three would proceed to surgery regardless of the patient's cognitive status, if functional capacity is conserved. Quality of life and functional recovery are regarded as the most important endpoints in onco-geriatric surgery. Large "real life" prospective observational studies and randomized controlled trials are demanded. CONCLUSION: Age is not perceived as a limitation to surgery. Screening for frailty is limited. A thorough CGA is seldom used and collaboration with geriatricians is rather uncommon. There is a need for clinical investigations focusing on pre-habilitation and other strategies to achieve better functional recovery.

Relationship between HbA1c and cancer in people with or without diabetes: a systematic review.

AIM: To identify the relationship between HbA1c and cancers in people with or without diabetes. BACKGROUND: Cancer is a major public health problem, accounting for 8.2 million deaths worldwide in 2012. HbA1c level has been associated with the risk of developing certain cancers, although the existing evidence is conflicting. METHODS: EMBASE, MEDLINE, CINAHL and the Cochrane Library were searched. Eligible articles included randomized controlled trials, cohort studies, case-control studies, systematic reviews and meta-analyses. Participants of either sex, with or without Type 1 or 2 diabetes, were included. The studies were assessed using the Scottish Intercollegiate Guidelines Network (SIGN) criteria by two independent assessors. No meta-analysis was performed because of the heterogeneity of results. RESULTS: A total of 19 studies from 1006 met the inclusion criteria, of which 14 were cohort studies and five were nested case-control studies. Eight studies investigated outcomes for all cancer sites. Four of these studies reported that higher HbA1c levels were associated with higher incidence and/or mortality risk for all cancers. One study observed a U-shaped relationship between HbA1c and cancer incidence and mortality. Increasing HbA1c levels were associated with increasing risk of developing colorectal, pancreatic, respiratory and female genital tract cancers. No increased risk was observed for breast cancer, gastrointestinal or urological malignancies. CONCLUSION: HbA1c appears to be associated with cancer incidence and/or cancer mortality, but further studies are needed to fully understand the complex relationship between HbA1c and cancer.

Healthcare professionals' preferences for surgery or primary endocrine therapy to treat older women with operable breast cancer.

INTRODUCTION: Primary endocrine therapy (PET) is an alternative treatment to surgery for oestrogen receptor (ER) positive operable breast cancer in older women. However, there is variable use of PET in the UK, with up to 40% of patients aged over 70 receiving PET instead of surgery in some regions. Treatment options offered to patients rely heavily on healthcare professional (HCP) assessment and opinion on which treatments are appropriate. MATERIALS AND METHODS: This was a mixed methods study combining semi-structured interviews with HCPs working in high and low PET regions in the UK, followed by a postal questionnaire survey distributed via the Association of Breast Surgery (ABS). RESULTS: Thirty-four HCPs (20 breast surgeons; 13 nurse specialists; 1 geriatrician) were interviewed from 14 sites across the UK and 252/641 questionnaires returned (39%). There was an overriding view that PET is not suitable for patients under the age of 80 unless there are significant comorbidities. Opinion was split regarding the best way to treat patients with dementia. Patient preference was generally stated to be the most important factor when considering treatment, however only around a quarter 65/244 (26.6%) felt that all patients over the age of 70 should be offered PET as an alternative treatment option. CONCLUSIONS: Opinions differ on the best way to treat women over 70 with operable breast cancer, especially if they have co-existing dementia, as well as whether they should be offered PET as a treatment option. This may be a significant cause of treatment variation in the UK.

No evidence for a direct effect of von Willebrand factor's ABH blood group antigens on von Willebrand factor clearance.

BACKGROUND: One of the major determinants of von Willebrand factor (VWF) plasma levels is ABO blood group status, and individuals with blood group O have ~ 25% lower plasma levels. The exact mechanism behind this relationship remains unknown, although effects on clearance have been postulated. OBJECTIVES: To determine whether clearance of VWF is directly dependent on the presence of ABH antigens on VWF. METHODS: Three type 3 von Willebrand disease (VWD) patients were infused with Haemate-P, and the relative loading of VWF with ABH antigens at different time points was measured. VWF-deficient mice were injected with purified plasma-derived human VWF obtained from donors with either blood group A, blood group B, or blood group O. RESULTS: In mice, we found no difference in clearance rate between plasma-derived blood group A, blood group B and blood group O VWF. Faster clearance of the blood group O VWF present in Haemate-P infused in type 3 VWD patients would have resulted in a relative increase in the loading of VWF with A and B antigens over time. However, we observed a two-fold decrease in the loading with A and B antigens in two out of three patients, and stable loading in the third patient. CONCLUSION: There is no direct effect of ABH antigens on VWF in VWF clearance. We demonstrate that, in a direct comparison within one individual, blood group O VWF is not cleared faster than blood group A or blood group B VWF. Clearance differences between blood group O and non-blood group O individuals may therefore be related to the blood group status of the individual rather than the ABH antigen loading on VWF itself.

A study of ductal versus non-ductal invasive breast carcinomas in older women: long-term clinical outcome and comparison with their younger counterparts.

Ductal carcinoma is the commonest histological type found in invasive breast carcinomas and may be associated with worse prognosis, when compared to non-ductal carcinoma. Older patients tend to display more favourable tumour biology than younger patients. This study aimed to investigate the significance of histological type and its relationship with clinical outcome in the older group. A total of 808 older (≥70 years) women with early operable primary breast cancer underwent surgery as their primary treatment, followed by optimal adjuvant therapies, in the Nottingham Breast Unit between 1973 and 2009. The histological types of the surgical specimens were reviewed and compared with those in a previously characterised younger (<70 years) series (N = 1,733), in terms of distribution and correlation with clinical outcome. Ductal type was associated with a significantly worse clinical outcome when compared to non-ductal type in the older group in terms of 10-year rates of metastasis-free survival (75 vs 79 %, p = 0.028) and overall survival (44 vs 52 %; p = 0.015). Similar worse clinical outcome was found with the ductal type in the younger group in terms of 10-year rates of metastasis-free survival (65 vs 79 %; p = 0.001) and overall survival (60 vs 78 %; p = 0.001). For all patients with ductal type carcinomas, the older series showed significantly better 10-year metastasis-free survival (75 vs 65 %, p < 0.001) and breast cancer-specific survival (75 vs 69 %, p = 0.025) when compared to the younger series. In both old and the young, ductal cancers were associated with poor survival outcome when compared to non-ductal cancers. When compared to their younger counterparts, older patients with ductal type carcinomas had better metastasis-free and breast cancer-specific survival rates (their lower overall survival was likely to be due to death from other causes), despite having a lower likelihood of receiving adjuvant systemic therapy.

Inherited metabolic diseases in the Southern Chinese population: spectrum of diseases and estimated incidence from recurrent mutations.

Inherited metabolic diseases (IMDs) are a large group of rare genetic diseases. The spectrum and incidences of IMDs differ among populations, which has been well characterised in Caucasians but much less so in Chinese. In a setting of a University Hospital Metabolic Clinic in Hong Kong, over 100 patients with IMDs have been seen during a period of 13 years (from 1997 to 2010). The data were used to define the spectrum of diseases in the Southern Chinese population. Comparison with other populations revealed a unique spectrum of common IMDs. Furthermore, the incidence of the common IMDs was estimated by using population carrier frequencies of known recurrent mutations. Locally common diseases (their estimated incidence) include (1) glutaric aciduria type 1 (∼1/60,000), (2) multiple carboxylase deficiency (∼1/60,000), (3) primary carnitine deficiency (∼1/60,000), (4) carnitine-acylcarnitine translocase deficiency (∼1/60,000), (5) glutaric aciduria type 2 (∼1/22,500), (6) citrin deficiency (∼1/17,000), (7) tetrahydrobiopterin-deficient hyperphenylalaninaemia due to 6-pyruvoyl-tetrahydropterin synthase deficiency (∼1/60,000), (8) glycogen storage disease type 1 (∼1/150,000). In addition, ornithine carbamoyltransferase deficiency and X-linked adrenoleukodystrophy are common X-linked diseases. Findings of the disease spectrum and treatment outcome are summarised here which may be useful for clinical practice. In addition, data will also be useful for policy makers in planning of newborn screening programs and resource allocation.