Size does matter: High volume breast surgeons accept smaller excision margins for wide local excision – A national survey of the surgical management of wide local excision margins in UK breast cancer patients

IntroductionOptimal margins for wide local excision (WLE) have not been clearly established. Larger margins lead to lower recurrence rates but at the expense of cosmetic appearance. NICE guidelines recommend a 2 mm margin for ductal carcinoma in-situ (DCIS), whilst the British Association of Surgical Oncology (BASO) recommend units develop local guidelines. There are presently no specific guidelines for invasive cancer. We surveyed members of the Association of Breast Surgeons (ABS) in order to establish current practice nationally. We hypothesised that larger units may accept narrower excision margins to the benefit of better cosmesis.Materials and methodsA postal questionnaire was sent to all ABS members in October 2010. This consisted of questions about the current practice of the surgeon and their unit. 481 questionnaires were posted in total, all questionnaires returned by April 2011 were analysed.ResultsQuestionnaire response rate was 60% (281). Surgeons operating on over 50 cancers per year accepted smaller margins than those operating on less than 50 (p < 0.02). Acceptable adequate anterior and radial margins ranged from 0 to 10 mm for DCIS and 0 to 5 mm for invasive cancer. A variety of approaches to re-excising anterior margins were reported.ConclusionsThis survey suggests that substantial variations exist in current practice with regard to the approach to WLE. Operator workload appears to influence what is deemed to be an acceptable margin. There is a need for standardised national and international guidelines.     

Interactions between peroxisome proliferator-activated receptor-gamma 2 gene polymorphisms and size at birth on blood pressure and the use of antihypertensive medication

OBJECTIVE: The combination of small birth size and the Pro12Pro variant of the peroxisome proliferator-activated receptor-gamma 2 (PPAR-gamma 2) gene has been shown to be associated with insulin resistance, which is linked to hypertension. We examined whether the association between small body size at birth and adult blood pressure is modulated by PPAR-gamma 2 gene polymorphism, and whether the use of any class of antihypertensive medication is related to birth size. DESIGN AND METHODS: A total of 500 subjects from an original epidemiological cohort of 7086 men and women aged 65-75 years attended a clinical study. Two hundred and eight of them (73 men and 135 women) were taking antihypertensive medication and are included in this study. The Pro12Ala polymorphism of the PPAR-gamma 2 gene was determined using the polymerase chain reaction single-strand conformation polymorphism method. RESULTS AND CONCLUSIONS: Hypertensive subjects with low birth weight or short length at birth and the Pro12Pro variant had raised systolic blood pressure. We suggest that insulin resistance enhances the regulatory responses of the renin-angiotensin system, leading to raised blood pressure levels. Those hypertensive subjects who had small birth size and the Pro12Pro variant tended to use angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers (ACEI/ARB). This could be because insulin resistance interacts with the renin-angiotensin system in ways that make ACEI/ARB an effective therapy. Alternative explanations include more severe and treatment resistant hypertension, leading to application of ACEI/ARB, or co-morbid conditions, such as myocardial infarction and type 2 diabetes, known to be linked to low birth weight.     

Effect of particle size on hydroxyapatite crystal-induced tumor necrosis factor alpha secretion by macrophages

Macrophages may promote a vicious cycle of inflammation and calcification in the vessel wall by ingesting neointimal calcific deposits (predominantly hydroxyapatite) and secreting tumor necrosis factor (TNF)alpha, itself a vascular calcifying agent. Here we have investigated whether particle size affects the proinflammatory potential of hydroxyapatite crystals in vitro and whether the nuclear factor (NF)-kappaB pathway plays a role in the macrophage TNFalpha response. The particle size and nano-topography of nine different crystal preparations was analyzed by X-ray diffraction, Raman spectroscopy, scanning electron microscopy and gas sorbtion analysis. Macrophage TNFalpha secretion was inversely related to hydroxyapatite particle size (P=0.011, Spearman rank correlation test) and surface pore size (P=0.014). A necessary role for the NF-kappaB pathway was demonstrated by time-dependent I kappaB alpha degradation and sensitivity to inhibitors of I kappaB alpha degradation. To test whether smaller particles were intrinsically more bioactive, their mitogenic activity on fibroblast proliferation was examined. This showed close correlation between TNFalpha secretion and crystal-induced fibroblast proliferation (P=0.007). In conclusion, the ability of hydroxyapatite crystals to stimulate macrophage TNFalpha secretion depends on NF-kappaB activation and is inversely related to particle and pore size, with crystals of 1-2 microm diameter and pore size of 10-50 A the most bioactive. Microscopic calcific deposits in early stages of atherosclerosis may therefore pose a greater inflammatory risk to the plaque than macroscopically or radiologically visible deposits in more advanced lesions.     

The Effect of Calcium Channel Blockers on Moderate or Severe Albuminuria in Diabetic,Hypertensive Patients

ObjectivesInhibitors of the renin-angiotensin system are recommended for the management of albuminuria in patients with hypertension and diabetes mellitus, but there is little consensus about alternative therapies. Calcium channel blockers are recommended for the management of hypertension, but the data are controversial regarding their role in patients with albuminuria. This review was designed to assess the efficacy of calcium channel blockers compared with inhibitors of the renin-angiotensin system in decreasing albuminuria in diabetic, hypertensive patients with nephropathy.MethodsWe searched MEDLINE, Embase, CENTRAL, and ClinicalTrials.gov for records that compared calcium channel blockers to inhibitors of the renin-angiotensin system and reported pre- and postintervention albuminuria measurements. Two reviewers independently screened abstracts for randomized, controlled trials in adults. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to select 29 trials from 855 records. We synthesized the data through a random-effects model.ResultsWe analyzed data from 2113 trial participants with hypertension and diabetes mellitus who had the equivalent of ≥30 mg/day of urinary albumin excretion. Inhibitors of the renin-angiotensin system were more effective than calcium channel blockers in decreasing albuminuria (standardized difference in means ?0.442; confidence interval, ?0.660 to ?0.225; P < .001). This finding was independent of the blood pressure response to treatment. There was no difference between the 2 drug classes regarding markers of renal function.ConclusionsInhibitors of the renin-angiotensin system are superior to calcium channel blockers for the reduction of albuminuria in nephropathy due to hypertension and diabetes mellitus. The net clinical benefit, however, is small.     

Differential modulation of L-type Ca2+ current by SR Ca2+ release at the T-tubules and surface membrane of rat ventricular myocytes

We have characterized modulation of ICa by Ca2+ at the t-tubules (ie, in control cells) and surface sarcolemma (ie, in detubulated cells) of cardiac ventricular myocytes, using the whole-cell patch clamp technique to record ICa. ICa inactivation was significantly slower in detubulated cells than in control cells (27.1+/-7.8 ms, n=22, versus 16.4+/-7.9 ms, n=22; P<0.05). In atrial myocytes, which lack t-tubules, ICa inactivation was not changed by the treatment used to produce detubulation. In the presence of ryanodine or BAPTA, or when Ba2+ was used as the charge carrier, the rate of inactivation was not significantly different in control and detubulated cells. Frequency-dependent facilitation occurred in control cells but not in detubulated cells, and was abolished by ryanodine. These results suggest that Ca2+ released from the SR has a greater effect on ICa in the t-tubules than at the surface sarcolemma. This does not appear to be due to differences in local Ca2+ release from the SR, because the gain of Ca2+ release was not significantly different in control and detubulated cells. These data suggest that the t-tubules are a key site for the regulation of transsarcolemmal Ca2+ flux by Ca2+ release from the SR; this could play a role in altered Ca2+ homeostasis in pathological conditions. The full text of this article is available online at http://circres.ahajournals.org.     

Food Insecurity and Cost-Related Medication Underuse Among Nonelderly Adults in a Nationally Representative Sample

Objectives. We investigated whether nonelderly US adults (aged 18–64 years) in food-insecure households are more likely to report cost-related medication underuse than the food-secure, and whether the relationship between food insecurity and cost-related medication underuse differs by gender, chronic disease, and health insurance status.Methods. We analyzed data from the 2011 and 2012 National Health Interview Survey (n = 67 539). We examined the relationship between food insecurity and cost-related medication underuse with the χ² test and multivariate logistic regression with interaction terms.Results. Bivariate and multivariate analyses showed a dose–response relationship between food insecurity and cost-related medication underuse, with an increasing likelihood of cost-related medication underuse with increasing severity of food insecurity (P < .001). This association was conditional on health insurance status, but not substantially different by gender or chronic disease status. Being female, low-income, having no or partial health insurance, chronic conditions, functional limitations, or severe mental illness were positively associated with cost-related medication underuse.Conclusions. Using food insecurity as a risk factor to assess cost-related medication underuse could help increase identification of individuals who may need assistance purchasing medications and improve health for those in food-insecure households.Food insecurity refers to “limited or uncertain availability of nutritionally adequate and safe foods or limited or uncertain ability to acquire acceptable foods in socially acceptable ways.”1^(p6) Food insecurity is associated with poor health status and risk factors such as obesity, metabolic conditions, and chronic diseases, potentially attributable to intake of poor-quality diets, which increase the risk for obesity and cardiometabolic diseases.2–5 Studies of diabetic patients living in food-insecure households have shown poor outcomes such as poor glycemic control and increased physician use.6,7 Moreover, there is evidence that people living in food-insecure households are more likely to have poor mental health outcomes,8,9 use alcohol,10 and smoke cigarettes11—factors also associated with poor health status.Recent research suggests that people living in food-insecure households may adjust their behaviors in ways that are potentially detrimental to their health. Ivers and Cullen suggest that the vulnerability of food insecurity puts individuals at risk for engaging in coping strategies (e.g., withdrawal of children from school, theft, and risky sexual behaviors), particularly among women who tend to be children’s primary caregivers.12 One set of behaviors that has received relatively little attention as a potential coping mechanism for food insecurity until recently is reducing, skipping, delaying, or using lower-cost medications to compensate for lack of household resources to purchase food. These behaviors have been described as cost-related medication underuse.13,14Studies have demonstrated the relationship between cost-related medication underuse and poor health outcomes,15–19 but, to our knowledge, only 1 study has examined the relationship between food insecurity and cost-related medication underuse in the United States in a nationally representative sample.13 This study, which was restricted to individuals with chronic diseases, found that those living in food-insecure households were more likely to report cost-related medication underuse. Similar findings have been demonstrated from smaller studies in different parts of the country among people with diabetes, people with HIV/AIDS, and patients presenting at emergency departments.20–24We extend the literature on behaviors individuals living in food-insecure households may adopt to save money for food by examining the relationships between food insecurity and cost-related medication underuse in a nationally representative sample of nonelderly adults living in the United States. The objective of this analysis was to determine whether nonelderly adults (aged 18–64 years) living in food-insecure households in the United States are more likely to report cost-related medication underuse. We also examined whether the relationship between food insecurity and cost-related medication underuse differs by gender, chronic disease status, and health insurance status.     

Endorectal ultrasound and magnetic resonance imaging in rectal cancer staging

The majority of rectal cancers have local disease only at presentation, but despite meticulous surgery, a number of factors will influence outcome. Preoperative identification of adverse prognostic factors provides a rational basis for selecting preoperative therapy. Thin section MRI can influence preoperative therapeutic algorithms by T and N staging, demonstrating operability, and the potential risk of circumferential margin involvement. Endosonography may contribute to this, but has a greater role in determining intramural invasion for early tumors. The assessment of residual tumor after chemoradiotherapy remains difficult; PET scanning has been used in this situation [32], but has not been compared with MRI and is unlikely to show only residual cells with extensive fibrosis.     

Summary: peripheral pharmacology of cough

Hypersensitivity of the 'cough receptors' is one of the primary causes of uncontrollable and nonproductive cough. These receptors are therefore the logical targets in developing antitussive therapeutics. The articles in this section focus primarily on the types of lung afferents mediating the cough reflexes and the mechanisms involved in regulating the activity and sensitivity of these afferents. Several major issues have been discussed in these presentations, including the pharmacologic, physiologic and neurochemical characteristics of the cough receptors; the effect of phenotypic switch of the rapidly adapting receptors (RARs) during chronic airway infection; the interaction between RARs and C-fiber afferents both at the receptor level and in the centrally mediated reflex pathway; and the cellular mechanisms and ion channel species involved in the hypersensitivity of the cough receptors. A number of important questions have emerged from these investigations. Answers to these questions should further advance our understanding of the peripheral mechanisms of cough reflexes.