Reducing inequalities by supporting individuals to make informed decisions about accepting their breast screening invitations.

OBJECTIVES: Individuals from deprived areas are less likely to attend breast screening. Inequalities in the coverage of breast screening are associated with poorer cancer outcomes. Individuals who have a positive first experience are more likely to attend subsequent mammograms. This work evaluates the provision of an additional telephone call to individuals who have never attended breast screening, to establish whether this increases attendance. SETTING AND METHODS: 1423 patients from four general practitioner practices within socially deprived areas of National Health Service Tayside (UK) comprised the study population. In addition to their standard appointment letter, individuals were to receive a call at least 24 h prior to their appointment. The call identified barriers to screening, and offered a supportive, problem-solving approach to overcoming these barriers. Data collected included: age, Scottish Index of Multiple Deprivation, first-time invite or previous non-attender, if contactable, duration of call, number of days prior to appointment, and confirmation appointment letter was received. The primary outcome was attendance at the screening. RESULTS: Contact by phone was made with 678 (47.6%) of the study population. Of those, 483 (71.2%) attended their appointment, 122 (18%) cancelled and 73 (10.8%) did not attend (DNA), versus 344 (46.2%) attending, 34 (4.6%) cancelling and 367 (49.3%) not attending among those who were not able to be contacted. Those who received a call were more likely to attend their appointment and less likely to DNA compared to individuals not receiving the call. CONCLUSION: The intervention is simple and low cost; results indicate that the additional call may increase attendance and reduce DNA appointments at breast screening.

Breast cancer stromal clotting activation (Tissue Factor and thrombin): A pre-invasive phenomena that is prognostic in invasion.

BACKGROUND: Tumor stroma, of which fibroblasts are the most abundant cell, resembles a non-healing wound, where a procoagulant environment creates a permissive milieu for cancer growth. We aimed to determine if tumor expression of coagulation factors (procoagulant phenotype), and systemic hypercoagulability, occur at the preinvasive (ductal carcinoma in situ; DCIS) stage and correlate with breast cancer subtype, disease-free survival (DFS), and overall survival (OS). METHODS: In a prospective cohort of early breast cancer (DCIS, n = 76; invasive, n = 248) tumor, normal breast and plasma were examined. Fibroblast and epithelial expression of Tissue Factor (TF), thrombin, PAR1, PAR2, and plasma thrombin-antithrombin (TAT) and D-dimer were correlated with clinicopathological data, and 5-year survival. RESULTS: Fibroblast expression of TF, thrombin, and PAR1 was increased in DCIS and invasive cancer compared to normal breast fibroblasts (P ≤ .003, all). Fibroblast TF, thrombin, PAR1, and PAR2 was increased in cancers with high Ki67, high grade, ER- (vs ER+), and HER2+ (vs HER2-) (all P < .05). On univariate analysis, fibroblast TF expression was inversely associated with DFS (P = .04) and OS (P = .02). D-dimer was higher in node positive (507 (CI: 411-625) ng/mL, n = 68) vs negative patients (428 (CI: 387-472) ng/mL, n = 171, P = .004) and inversely associated with OS (P = .047). On multivariate analysis, plasma TAT was associated with reduced OS (HR 3.26, CI 1.16-3.1, P = .02), with a high plasma TAT (≥3.2 ng/mL) associated with > 3-fold mortality risk compared to low TAT. CONCLUSION: This demonstrates procoagulant phenotypic changes occur in fibroblasts at the preinvasive stage. Fibroblast procoagulant phenotype is associated with aggressive breast cancer subtypes and reduced survival. Coagulation may be a therapeutic target in breast cancer.

mTOR-dependent abnormalities in autophagy characterize human malformations of cortical development: evidence from focal cortical dysplasia and tuberous sclerosis.

Focal cortical dysplasia (FCD) is a localized malformation of cortical development and is the commonest cause of severe childhood epilepsy in surgical practice. Children with FCD are severely disabled by their epilepsy, presenting with frequent seizures early in life. The commonest form of FCD in children is characterized by the presence of an abnormal population of cells, known as balloon cells. Similar pathological changes are seen in the cortical malformations that characterize patients with tuberous sclerosis complex (TSC). However, the cellular and molecular mechanisms that underlie the malformations of FCD and TSC are not well understood. We provide evidence for a defect in autophagy in FCD and TSC. We have found that balloon cells contain vacuoles that include components of the autophagy pathway. Specifically, we show that balloon cells contain prominent lysosomes by electron microscopy, immunohistochemistry for LAMP1 and LAMP2, LysoTracker labelling and enzyme histochemistry for acid phosphatase. Furthermore, we found that balloon cells contain components of the ATG pathway and that there is cytoplasmic accumulation of the regulator of autophagy, DOR. Most importantly we found that there is abnormal accumulation of the autophagy cargo protein, p62. We show that this defect in autophagy can be, in part, reversed in vitro by inhibition of the mammalian target of rapamycin (mTOR) suggesting that abnormal activation of mTOR may contribute directly to a defect in autophagy in FCD and TSC.