Cancer risk management strategies and perceptions of unaffected women 5 years after predictive genetic testing for BRCA1/2 mutations

In a French national cohort of unaffected females carriers/non-carriers of a BRCA1/2 mutation, long-term preventive strategies and breast/ovarian cancer risk perceptions were followed up to 5 years after test result disclosure, using self-administered questionnaires. Response rate was 74%. Carriers (N=101) were younger (average age±SD=37±10) than non-carriers (N=145; 42±12). There were four management strategies that comprised 88% of the decisions made by the unaffected carriers: 50% opted for breast surveillance alone, based on either magnetic resonance imaging (MRI) and other imaging (31%) or mammography alone (19%); 38% opted for either risk reducing salpingo-oophorectomy (RRSO) and breast surveillance, based on MRI and other imaging (28%) or mammography alone (10%). The other three strategies were: risk reducing mastectomy (RRM) and RRSO (5%), RRM alone (2%) and neither RRM/RRSO nor surveillance (6%). The results obtained for various age groups are presented here. Non-carriers often opted for screening despite their low cancer risk. Result disclosure increased carriers' short-term high breast/ovarian cancer risk perceptions (P⩽0.02) and decreased non-carriers' short- and long-term perceptions (P<0.001). During follow-up, high breast cancer risk perceptions increased with time among those who had no RRM and decreased in the opposite case; high ovarian cancer risk perceptions increased further with time among those who had no RRSO and decreased in the opposite case; RRSO did not affect breast cancer risk perceptions. Informed decision-making involves letting women know whether opting for RRSO and breast MRI surveillance is as effective in terms of survival as RRM and RRSO

How Much, How Fast?: A Review and Science Plan for Research on the Instability of Antarctica’s Thwaites Glacier in the 21st century

Constraining how much and how fast the West Antarctic Ice Sheet (WAIS) will change in the coming decades has recently been identified as the highest priority in Antarctic research (National Academies, 2015). Here we review recent research on WAIS and outline further scientific objectives for the area now identified as the most likely to undergo near-term significant change: Thwaites Glacier and the adjacent Amundsen Sea. Multiple lines of evidence point to an ongoing rapid loss of ice in this region in response to changing atmospheric and oceanic conditions. Models of the ice sheet's dynamic behavior indicate a potential for greatly accelerated ice loss as ocean-driven melting at the Thwaites Glacier grounding zone and nearby areas leads to thinning, faster flow, and retreat. A complete retreat of the Thwaites Glacier basin would raise global sea level by more than three meters by entraining ice from adjacent catchments. This scenario could occur over the next few centuries, and faster ice loss could occur through processes omitted from most ice flow models such as hydrofracture and ice cliff failure, which have been observed in recent rapid ice retreats elsewhere. Increased basal melt at the grounding zone and increased potential for hydrofracture due to enhanced surface melt could initiate a more rapid collapse of Thwaites Glacier within the next few decades

The Influence of Number and Timing of Pregnancies on Breast Cancer Risk for Women With BRCA1 or BRCA2 Mutations

International audienceBACKGROUND:Full-term pregnancy (FTP) is associated with a reduced breast cancer (BC) risk over time, but women are at increased BC risk in the immediate years following an FTP. No large prospective studies, however, have examined whether the number and timing of pregnancies are associated with BC risk for BRCA1 and BRCA2 mutation carriers.METHODS:Using weighted and time-varying Cox proportional hazards models, we investigated whether reproductive events are associated with BC risk for mutation carriers using a retrospective cohort (5707 BRCA1 and 3525 BRCA2 mutation carriers) and a prospective cohort (2276 BRCA1 and 1610 BRCA2 mutation carriers), separately for each cohort and the combined prospective and retrospective cohort.RESULTS:For BRCA1 mutation carriers, there was no overall association with parity compared with nulliparity (combined hazard ratio [HRc] = 0.99, 95% confidence interval [CI] = 0.83 to 1.18). Relative to being uniparous, an increased number of FTPs was associated with decreased BC risk (HRc = 0.79, 95% CI = 0.69 to 0.91; HRc = 0.70, 95% CI = 0.59 to 0.82; HRc = 0.50, 95% CI = 0.40 to 0.63, for 2, 3, and ≥4 FTPs, respectively, P trend < .0001) and increasing duration of breastfeeding was associated with decreased BC risk (combined cohort P trend = .0003). Relative to being nulliparous, uniparous BRCA1 mutation carriers were at increased BC risk in the prospective analysis (prospective hazard ration [HRp] = 1.69, 95% CI = 1.09 to 2.62). For BRCA2 mutation carriers, being parous was associated with a 30% increase in BC risk (HRc = 1.33, 95% CI = 1.05 to 1.69), and there was no apparent decrease in risk associated with multiparity except for having at least 4 FTPs vs. 1 FTP (HRc = 0.72, 95% CI = 0.54 to 0.98).CONCLUSIONS:These findings suggest differential associations with parity between BRCA1 and BRCA2 mutation carriers with higher risk for uniparous BRCA1 carriers and parous BRCA2 carriers

Chronic Obstructive Pulmonary Disease and Lung Cancer: Underlying Pathophysiology and New Therapeutic Modalities

Chronic obstructive pulmonary disease (COPD) and lung cancer are major lung diseases affecting millions worldwide. Both diseases have links to cigarette smoking and exert a considerable societal burden. People suffering from COPD are at higher risk of developing lung cancer than those without, and are more susceptible to poor outcomes after diagnosis and treatment. Lung cancer and COPD are closely associated, possibly sharing common traits such as an underlying genetic predisposition, epithelial and endothelial cell plasticity, dysfunctional inflammatory mechanisms including the deposition of excessive extracellular matrix, angiogenesis, susceptibility to DNA damage and cellular mutagenesis. In fact, COPD could be the driving factor for lung cancer, providing a conducive environment that propagates its evolution. In the early stages of smoking, body defences provide a combative immune/oxidative response and DNA repair mechanisms are likely to subdue these changes to a certain extent; however, in patients with COPD with lung cancer the consequences could be devastating, potentially contributing to slower postoperative recovery after lung resection and increased resistance to radiotherapy and chemotherapy. Vital to the development of new-targeted therapies is an in-depth understanding of various molecular mechanisms that are associated with both pathologies. In this comprehensive review, we provide a detailed overview of possible underlying factors that link COPD and lung cancer, and current therapeutic advances from both human and preclinical animal models that can effectively mitigate this unholy relationship

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium.

INTRODUCTION: Height, body mass index (BMI), and weight gain are associated with breast cancer risk in the general population. It is unclear whether these associations also exist for carriers of pathogenic variants in the BRCA1 or BRCA2 genes. PATIENTS AND METHODS: An international pooled cohort of 8091 BRCA1/2 variant carriers was used for retrospective and prospective analyses separately for premenopausal and postmenopausal women. Cox regression was used to estimate breast cancer risk associations with height, BMI, and weight change. RESULTS: In the retrospective analysis, taller height was associated with risk of premenopausal breast cancer for BRCA2 variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04-1.38). Higher young-adult BMI was associated with lower premenopausal breast cancer risk for both BRCA1 (HR 0.75 per 5 kg/m2, 95% CI 0.66-0.84) and BRCA2 (HR 0.76, 95% CI 0.65-0.89) variant carriers in the retrospective analysis, with consistent, though not statistically significant, findings from the prospective analysis. In the prospective analysis, higher BMI and adult weight gain were associated with higher postmenopausal breast cancer risk for BRCA1 carriers (HR 1.20 per 5 kg/m2, 95% CI 1.02-1.42; and HR 1.10 per 5 kg weight gain, 95% CI 1.01-1.19, respectively). CONCLUSION: Anthropometric measures are associated with breast cancer risk for BRCA1 and BRCA2 variant carriers, with relative risk estimates that are generally consistent with those for women from the general population

Trends and connections across the Antarctic cryosphere

Satellite observations have transformed our understanding of the Antarctic cryosphere. The continent holds the vast majority of Earth’s fresh water, and blankets swathes of the Southern Hemisphere in ice. Reductions in the thickness and extent of floating ice shelves have disturbed inland ice, triggering retreat, acceleration and drawdown of marine-terminating glaciers. The waxing and waning of Antarctic sea ice is one of Earth’s greatest seasonal habitat changes, and although the maximum extent of the sea ice has increased modestly since the 1970s, inter-annual variability is high, and there is evidence of longer-term decline in its extent