Bircan Erbas

The natural history of ductal carcinoma in situ of the breast : a review

BackgroundDuctal carcinoma in situ represents about 20% of all tumours diagnosed within mammographic screening programs. The natural history of DCIS is poorly understood, as it cannot be observed directly. Estimates of the proportion of DCIS that progress to invasive cancer, as well as factors that may influence progression, are important for clinical management. Here we review various sources of evidence regarding the natural history of DCIS.MethodsWe identified relevant publications of studies on: follow-up studies of DCIS initially misdiagnosed as benign, studies of recurrence of DCIS as invasive cancer, autopsy studies, studies of risk factors for DCIS, animal studies and studies that used mathematical models to study growth of DCIS and invasive cancer. Data sources included the MEDLINE data base, searches of articles cited in key reviews and editorials.ResultsThe most direct evidence regarding the progression of DCIS to invasive cancer comes from studies where DCIS was initially misdiagnosed as benign and treated by biopsy alone. These studies suggest that between 14–53% of DCIS may progress to invasive cancer over a period of 10 or more years. The reported prevalence of undiagnosed DCIS in autopsy studies, of approximately 9%, has been used to suggest a larger reservoir of DCIS may exist in the population. All types of study designs reviewed had limitations that may bias the estimate of progression in either direction.ConclusionThe available evidence suggests not all DCIS will progress to invasive cancer in the medium term but precise estimates of progression are not possible given the limitations of the data. Mathematical modelling of various scenarios of progression and studies of genetic factors involved in progression may shed further light on the natural history of DCIS.

Twin study of genetic and environmental influences on adult body size, shape, and composition

OBJECTIVE: To investigate the genetic and environmental influences on adult body size, shape, and composition in women and men, and to assess the impact of age.MATERIALS AND METHODS: In this cross-sectional study of 325 female and 299 male like-sex healthy twin pairs, on average 38 y old (18–67 y), we determined zygosity by DNA similarity, and performed anthropometry and bioelectrical impedance analysis of body composition. The contribution to the total phenotypic variance of genetic, common environment, and individual environment was estimated in multivariate analysis using the FISHER program. Further, these variance components were analysed as linear functions of age.RESULTS: In both women and men genetic contributions were significant for all phenotypes. Heritability for body mass index was 0.58 and 0.63; for body fat%, 0.59 and 0.63; for total skinfolds, 0.61 and 0.65; for extremity skinfolds 0.65 and 0.62; for truncal skinfolds, 0.50 and 0.69; for suprailiac skinfolds, 0.49 and 0.48; for waist circumference, 0.48 and 0.61; for hip, 0.52 and 0.58; for lean body mass/height2, 0.61 and 0.56; and for height, 0.81 and 0.69, respectively. There was no strong evidence of common environmental effects under the assumptions of no nonadditive effect. The pattern of age trends was inconsistent. However, when significant there was a decrease in heritability with advancing age.DISCUSSION: These findings suggest that adult body size, shape, and composition are highly heritable in both women and men, although a decreasing tendency is seen with advancing age.

Mechanisms of Bone Loss Following Allogeneic and Autologous Hemopoietic Stem Cell Transplantation

A significant proportion of patients will be long‐term survivors of bone marrow transplantation (BMT) and little is known about their risk of late bony complications. We therefore evaluated bone mineral density (BMD) prior to BMT, post‐transplantation changes in BMD, and mechanisms of bone loss in long‐term survivors. We performed two analyses. The first was a cross‐sectional study of 83 consecutive BMT patients (38 F, 45 M), examining the relationship between BMD and bone turnover, measured immediately prior to transplantation, and a number of disease and patient variables. The second was a prospective study of 39 patients (19F, 20 M) followed for a median of 30 months (range 5–64 months) following either allogeneic (allo, n = 29) or autologous (auto, n = 10) BMT to determine if bone loss was related to treatment of graft versus host disease (GVHD) with glucocorticoids and cyclosporine A, high bone turnover rates, or hypogonadism. Auto BMT recipients acted as a control group for effects of GVHD therapy on BMD. Prior to BMT, spinal and femoral neck (FN) BMDs were 8.6% and 14% lower in female auto BMT recipients than in female allo BMT recipients, respectively (p = 0.12 and p = 0.003). Urinary bone resorption markers were higher than in normal gender‐ and age‐matched control subjects. Patients treated previously with glucocorticoids also had 8% lower FN BMD. Glucocorticoid‐pretreated women with amenorrhoea had lower lumbar spine (LS) and FN BMDs than eumenorrheic women and women receiving HRT. Post‐allo BMT, patients lost 11.7% of FN BMD compared with a nonsignificant decrease of 1.1% post‐auto BMT (p < 0.001). Spinal BMD and total body bone mineral content (TBBMC) decreased by 3.9% and 3.5%, respectively, post‐allo, compared with an increase (1.5%, p = 0.03) or nonsignificant decrease (−3.7%, p = NS), respectively, post‐auto BMT. Post‐allo BMT bone loss correlated best with the cumulative prednisolone dose at the LS and FN, and with average daily prednisolone dose for TBBMC. At the spine, the rate of bone loss was 4%/10 g of prednisolone, while the rate of bone loss at the FN was greater (9%/10 g of prednisolone). Bone loss was also negatively related to the duration of cyclosporine therapy for GVHD and baseline deoxypyridinoline concentrations. Avascular necrosis of the femoral head occurred in four, and vertebral and rib fractures occurred in one of the allo BMT patients, but in no auto BMT patients. In conclusion, BMT recipients are at risk of osteoporosis secondary to bone loss associated with their underlying illness and/or chemotherapy, particularly in female autograft recipients, and in allograft recipients secondary to GVHD and its treatment.

The influence of childhood traffic-related air pollution exposure on asthma, allergy and sensitization: a systematic review and a meta-analysis of birth cohort studies

The impact of early childhood traffic‐related air pollution (TRAP) exposure on development of asthma and allergies remains unclear. Birth cohort studies are the best available study design to answer this question, but the evidence from such studies has not been synthesized to date. We conducted a systematic review and meta‐analyses of published birth cohort studies to understand the association between early childhood TRAP exposure, and subsequent asthma, allergies and sensitization. Increased longitudinal childhood exposure to PM2.5 and black carbon was associated with increasing risk of subsequent asthma in childhood (PM2.5: OR 1.14, 95%CI 1.00 to 1.30 per 2 μg/m3 and black carbon: OR 1.20, 95%CI 1.05 to 1.38 per 1 × 10−5 m−1). Also, early childhood exposure to TRAP was associated with development of asthma across childhood up to 12 years of age. The magnitude of these associations increased with age, and the pattern was prominent for PM2.5. Increasing exposure to PM2.5 was associated with sensitization to both aero‐ and food allergens. There was some evidence that TRAP was associated with eczema and hay fever. In summary, exposure to TRAP was related to asthma and allergic diseases. However, the substantial variability across studies warrants long‐term birth cohort studies with regular repeated follow‐ups to confirm these findings.

Effect of antiepileptic medication on bone mineral measures

Objective: Long-term antiepileptic drug (AED) use has been associated with bone disease, but many previous studies have been limited by inadequate control subjects. We used a cotwin affected sib-pair model to investigate this issue. Methods: The authors studied 31 female twin (15 monozygous and 16 dizygous) and four sibling pairs (<3 years age difference) aged 21 to 75 years, in which one member had >12 months of AED treatment. Areal bone mineral density (ABMD, g/cm2) was measured at the lumbar spine (LS), total hip (TH), femoral neck (FN), and total forearm (FA). Three primary a priori defined subgroups were analyzed: a) use for >2 years, b) use of enzyme-inducing AEDs, or c) age older than 40 years. Results: For all pairs (n = 35), there were no significant within-pair differences in any ABMD measure. However, in Subgroup a (n = 27), there was a within-pair difference at the FA (0.513 vs 0.534, −3.9%, p = 0.016). In Subgroup b (n = 29), there was also a within-pair difference at the FA for AED user vs nonuser (0.508 vs 0.529, −3.8%, p = 0.010). In Subgroup c (n = 15), there were within-pair differences at the FA (0.492 vs 0.524, −6.1%, p = 0.017) and the LS (0.884 vs 0.980, −9.8%, p = 0.036). Conclusions: Patients using AEDs for >2 years, in particular those taking enzyme-inducing AEDs and those older than 40 years, have significantly lower bone mineral density at clinically relevant fracture risk sites.

Bone Mineral Density and Bone Turnover in Asthmatics Treated with Long-Term Inhaled or Oral Glucocorticoids†

Inhaled glucocorticoids are pivotal in maintenance therapy of chronic bronchial asthma; however, conflict exists over their effects on bone and mineral metabolism. We measured bone mineral density (BMD), bone turnover markers, and adrenal steroid hormones in 53 patients (34 female, 19 male) with chronic bronchial asthma who had taken either inhaled beclomethasone or budesonide in doses of ≥ 1500 μg/day for at least 12 months to determine pathogenetic mechanisms of bone loss. To account for the effect of prior oral glucocorticoid exposure we divided patients into two groups: one with (OG) and the other without (IG) a past history of maintenance (> 1 month) oral glucocorticoid therapy. Lumbar spine (LS) and proximal femur BMDs were ∼1 SD lower in men and women taking OG or high‐dose IG for chronic bronchial asthma, potentially equivalent to a doubling of the risk of fracture at these sites. Prior exposure to OG in women was also associated with lower LS and proximal femur BMDs, while men were more sensitive to the adverse effects of IG on LS and Wards triangle BMDs. Bone formation markers were decreased; however, bone resorption marker concentrations were normal. All patients had evidence of suppression of both endogenous glucocorticoid and adrenal androgen production. Both total duration of OG and biochemical bone turnover marker concentrations were negatively related to proximal femur and rib BMDs and total body bone mineral content, but not to LS BMD. These were stronger for bone resorption markers. Uncoupling of ongoing normal bone resorption from suppressed bone formation may therefore contribute to glucocorticoid‐associated bone loss in asthma. Adrenal androgen suppression may also increase the susceptibility of postmenopausal women in particular to bone loss with OG. Although the effects of high‐dose IG on BMD are associated with lower LS BMD in men, this observation should now be investigated further in prospective studies.

The effects of gonadectomy on bone size, mass, and volumetric density in growing rats are gender-, site-, and growth hormone-specific

Peak volumetric bone mineral density (BMD) is determined by the growth in bone size relative to the mineral accrued within its periosteal envelope. Thus, reduced peak volumetric BMD may be the result of reduced mineral accrual relative to growth in bone size. Because sex steroids and growth hormone (GH) influence bone size and mass we asked: What are the effects of gonadectomy (Gx) on bone size, bone mineral content (BMC), areal and volumetric BMD in growing male and female rats? Does GH deficiency (GH−) reduce the amount of bone in the (smaller) bone, i.e., reduce volumetric BMD? Does GH– alter the effect of Gx on bone size and mineral accrual? Gx or sham surgery was performed at 6 weeks in GH− and GH replete (GH+) Fisher 344 male and female rats. Changes in bone size, volume, BMC, areal and volumetric BMD, measured using dual X‐ray absorptiometry (DPX‐L), were expressed as percentage of controls at 8 months (mean ± SEM). All results shown were significant (p < 0.05 level) unless otherwise stated. In GH+ and GH− males, respectively, Gx was associated with: lower femur volume (24%, 25%), BMC (43%, 45%), areal BMD (21%, 14%), and volumetric BMD (30%, 28%); lower spine (L1–L3) volume (26%, 28%), BMC (26%, 30%), and areal BMD (28%, 12%), but not volumetric BMD. Following Gx, GH+ females had increased femur volume (11%), no effect on BMC, decreased areal BMD (6%) and decreased volumetric BMD (17%); GH− females had no change in femur volume, but decreased femur BMC (24%), areal BMD (10%), and volumetric BMD (25%). In GH+ and GH− females, respectively, Gx was associated with a decrease in spine (L1–L3) BMC (12%, 15%), areal BMD (16%, 15%), and volumetric BMD (10%, 16%) with no change in volume. Deficits in non‐Gx GH− relative to non‐Gx GH+ (males, females, respectively) were: femur BMC (49%, 37%), areal BMD (23%, 8%), volume (19%, 19%) and volumetric BMD (37%, 22%); spine (L1–L3) BMC (46%, 42%), areal BMD (37%, 43%), volume (10%, 15%), and volumetric BMD (40%, 33%). Testosterone and GH are growth promoting in growing male rats, producing independent effects on bone size and mass; deficiency produced smaller appendicular bones with reduced volumetric BMD because deficits in mass were greater than deficits in size. At the spine, the reduction in size and accrual were proportional, resulting in a smaller bone with normal volumetric BMD. In growing female rats, estrogen was growth limiting at appendicular sites; deficiency resulted in a GH‐dependent increase in appendicular size, relatively reduced accrual, and so, reduced volumetric BMD in a bigger bone. At the spine, accrual was reduced while growth in size was normal, thus volumetric BMD was reduced in the normal sized bone. Understanding the pathogenesis of low volumetric BMD requires the study of the differing relative growth in size and mass of the axial and appendicular skeleton in the male and female and the regulators of the growth of these traits.

Do levels of airborne grass pollen influence asthma hospital admissions

Background The effects of environmental factors and ambient concentrations of grass pollen on allergic asthma are yet to be established.

The role of seasonal grass pollen on childhood asthma emergency department presentations.

Few studies have focused on the role of grass pollen on asthma emergency department (ED) presentations among children. None have examined whether a dose‐response effect exists between grass pollen levels and these asthma exacerbations.

Outdoor air pollution as a trigger for out-of-hospital cardiac arrests.

Background: Epidemiologic studies have reported associations between fine particulate air pollution and cardiovascular mortality or hospitalization for cardiac events. However the evidence regarding the association between air pollution and acute cardiac events, such as out-of-hospital cardiac arrest, is inconsistent. Methods: We investigated the association between particulate matter (PM) air pollution and out-of-hospital cardiac arrest using a case-crossover study of adults (age, 35+ years) in Melbourne, Australia. We included 8434 cases identified through the Victorian Cardiac Arrest Registry from 2003 through 2006. We excluded arrests with an obvious preceding noncardiac event such as trauma, poisoning, or drowning, leaving only those events that were presumed to have cardiac etiology. Air pollution concentrations obtained from a central monitoring site were used for day of the arrest and for lag 1, lag 2, and lag 3, including the average lag 0–1. Results: An interquartile range increase of 4.26 &mgr;g/m3 in PM2.5 over 2 days (lag 0–1) was associated with an increase in risk for an out-of-hospital cardiac arrest of 3.6% (95% confidence interval = 1.3% to 6.0%). PM10 and carbon monoxide also showed associations, but not as strong as for PM2.5. Longer lag periods did not show such strong relationships. There was no association of these cardiac events with ozone, sulfur dioxide, or nitrogen dioxide in any lag period. Individuals age 65–74 years old were most susceptible to PM2.5 exposure, while those 75 years and older had the lowest risk. Conclusion: These findings support an association between daily average PM2.5 concentrations and an increased risk of out-of-hospital cardiac arrests.