Sequencing of chemotherapy and radiotherapy for early breast cancer (Review)

Background: After surgery for localised breast cancer, radiotherapy (RT) improves both local control and breast cancer-specific survival. In patients at risk of harbouring micro-metastatic disease, adjuvant chemotherapy (CT) improves 15-year survival. However, the best sequence of administering these two types of adjuvant therapy for early-stage breast cancer is unclear. Objectives: To determine the effects of different sequencing of adjuvant CT and RT for women with early breast cancer. Search methods: An updated search was carried out in the Cochrane Breast Cancer Group's Specialised Register (20 May 2011), MEDLINE (14 December 2011), EMBASE (20 May 2011) and World Health Organization (WHO) International Clinical Trials Registry Platform (20 May 2011). Details of the search strategy and methods of coding for the Specialised Register are described in the Group's module in The Cochrane Library. We extracted studies that had been coded as 'early', 'chemotherapy' and 'radiotherapy'. Selection criteria: We included randomised controlled trials evaluating different sequencing of CT and RT. Data collection and analysis: We assessed the eligibility and quality of the identified studies and extracted data from the published reports of the included trials. We derived odds ratios (OR) and hazard ratios (HR) from the available numerical data. Toxicity data were extracted, where reported. We used a fixed-effect model for meta-analysis and conducted analyses on the basis of the method of sequencing of the two treatments. Main results: Three trials reporting two different sequencing comparisons were identified. There were no significant differences between the various methods of sequencing adjuvant therapy for local recurrence-free survival, overall survival, relapse-free survival and metastasis-free survival based on 1166 randomised women in three trials. Concurrent chemoradiation increased anaemia (OR 1.54; 95% confidence interval (CI) 1.10 to 2.15), telangiectasia (OR 3.85; 95% CI 1.37 to 10.87) and pigmentation (OR 15.96; 95% CI 2.06 to 123.68). Treated women did not report worse cosmesis with concurrent chemoradiation but physician-reported assessments did (OR 1.14; 95% CI 0.42 to 3.07). Other measures of toxicity did not differ between the two types of sequencing. On the basis of one trial (244 women), RT before CT was associated with an increased risk of neutropenic sepsis (OR 2.96; 95% CI 1.26 to 6.98) compared with CT before RT, but other measures of toxicity did not differ. Authors' conclusions: The data included in this review, from three well-conducted randomised trials, suggest that different methods of sequencing CT and RT do not appear to have a major effect on recurrence or survival for women with breast cancer if RT is commenced within seven months after surgery

Across-arc geochemical variations in the Southern Volcanic Zone, Chile (34.5- 38.0°S): Constraints on Mantle Wedge and Input Compositions

Crustal assimilation (e.g. Hildreth and Moorbath, 1988) and/or subduction erosion (e.g. Stern, 1991; Kay et al., 2005) are believed to control the geochemical variations along the northern portion of the Chilean Southern Volcanic Zone. In order to evaluate these hypotheses, we present a comprehensive geochemical data set (major and trace elements and O-Sr-Nd-Hf-Pb isotopes) from Holocene primarily olivine-bearing volcanic rocks across the arc between 34.5-38.0°S, including volcanic front centers from Tinguiririca to Callaqui, the rear arc centers of Infernillo Volcanic Field, Laguna del Maule and Copahue, and extending 300 km into the backarc. We also present an equivalent data set for Chile Trench sediments outboard of this profile. The volcanic arc (including volcanic front and rear arc) samples primarily range from basalt to andesite/trachyandesite, whereas the backarc rocks are low-silica alkali basalts and trachybasalts. All samples show some characteristic subduction zone trace element enrichments and depletions, but the backarc samples show the least. Backarc basalts have higher Ce/Pb, Nb/U, Nb/Zr, and Ta/Hf, and lower Ba/Nb and Ba/La, consistent with less of a slab-derived component in the backarc and, consequently, lower degrees of mantle melting. The mantle-like δ18O in olivine and plagioclase phenocrysts (volcanic arc = 4.9-5.6 and backarc = 5.0-5.4 per mil) and lack of correlation between δ18O and indices of differentiation and other isotope ratios, argue against significant crustal assimilation. Volcanic arc and backarc samples almost completely overlap in Sr and Nd isotopic composition. High precision (double-spike) Pb isotope ratios are tightly correlated, precluding significant assimilation of older sialic crust but indicating mixing between a South Atlantic Mid Ocean-Ridge Basalt (MORB) source and a slab component derived from subducted sediments and altered oceanic crust. Hf-Nd isotope ratios define separate linear arrays for the volcanic arc and backarc, neither of which trend toward subducting sediment, possibly reflecting a primarily asthenospheric mantle array for the volcanic arc and involvement of enriched Proterozoic lithospheric mantle in the backarc. We propose a quantitative mixing model between a mixed-source, slab-derived melt and a heterogeneous mantle beneath the volcanic arc. The model is consistent with local geodynamic parameters, assuming water-saturated conditions within the slab

Fraction size in radiation treatment for breast conservation in early breast cancer

Backgroun

On the Limits of Liberalism in Participatory Environmental Governance: Conflict and Conservation in Ukraine\u27s Danube Delta

Participatory management techniques are widely promoted in environmental and protected area governance as a means of preventing and mitigating conflict. The World Bank project that created Ukraine’s Danube Biosphere Reserve included such ‘community participation’ components. The Reserve, however, has been involved in conflicts and scandals in which rumour, denunciation and prayer have played a prominent part. The cases described in this article demonstrate that the way conflict is escalated and mitigated differs according to foundational assumptions about what ‘the political’ is and what counts as ‘politics’. The contrasting forms of politics at work in the Danube Delta help to explain why a 2005 World Bank assessment report could only see failure in the Reserve’s implementation of participatory management, and why liberal participatory management approaches may founder when introduced in settings where relationships are based on non-liberal political ontologies. The author argues that environmental management needs to be rethought in ways that take ontological differences seriously rather than assuming the universality of liberal assumptions about the individual, the political and politics

Fraction size in radiation therapy for breast conservation in early breast cancer (Review)

Background: Shortening the duration of radiation therapy would benefit women with early breast cancer treated with breast conserving surgery. It may also improve access to radiation therapy by improving efficiency in radiation oncology departments globally. This can only happen if the shorter treatment is as effective and safe as conventional radiation therapy. This is an update of a Cochrane Review first published in 2008 and updated in 2009. Objectives: To assess the effect of altered radiation fraction size for women with early breast cancer who have had breast conserving surgery. Search methods: We searched the Cochrane Breast Cancer Specialised Register (23 May 2015), CENTRAL (The Cochrane Library 2015, Issue 4), MEDLINE (Jan 1996 to May 2015), EMBASE (Jan 1980 to May 2015), the WHO International Clinical Trials Registry Platform (ICTRP) search portal (June 2010 to May 2015) and ClinicalTrials.gov (16 April 2015), reference lists of articles and relevant conference proceedings. No language or publication constraints were applied. Selection criteria: Randomised controlled trials of altered fraction size versus conventional fractionation for radiation therapy in women with early breast cancer who had undergone breast conserving surgery. Data collection and analysis: Two authors performed data extraction independently, with disagreements resolved by discussion. We sought missing data from trial authors. Main results: We studied 8228 women in nine studies. Eight out of nine studies were at low or unclear risk of bias. Altered fraction size (delivering radiation therapy in larger amounts each day but over fewer days than with conventional fractionation) did not have a clinically meaningful effect on: local recurrence-free survival (Hazard Ratio (HR) 0.94, 95% CI 0.77 to 1.15, 7095 women, four studies, high-quality evidence), cosmetic outcome (Risk ratio (RR) 0.90, 95% CI 0.81 to 1.01, 2103 women, four studies, high-quality evidence) or overall survival (HR 0.91, 95% CI 0.80 to 1.03, 5685 women, three studies, high-quality evidence). Acute radiation skin toxicity (RR 0.32, 95% CI 0.22 to 0.45, 357 women, two studies) was reduced with altered fraction size. Late radiation subcutaneous toxicity did not differ with altered fraction size (RR 0.93, 95% CI 0.83 to 1.05, 5130 women, four studies, high-quality evidence). Breast cancer-specific survival (HR 0.91, 95% CI 0.78 to 1.06, 5685 women, three studies, high quality evidence) and relapse-free survival (HR 0.93, 95% CI 0.82 to 1.05, 5685 women, three studies, moderate-quality evidence) did not differ with altered fraction size. We found no data for mastectomy rate. Altered fraction size was associated with less patient-reported (P < 0.001) and physician-reported (P = 0.009) fatigue at six months (287 women, one study). We found no difference in the issue of altered fractionation for patient-reported outcomes of: physical well-being (P = 0.46), functional well-being (P = 0.38), emotional well-being (P = 0.58), social well-being (P = 0.32), breast cancer concerns (P = 0.94; 287 women, one study). We found no data with respect to costs. Authors' conclusions: We found that using altered fraction size regimens (greater than 2 Gy per fraction) does not have a clinically meaningful effect on local recurrence, is associated with decreased acute toxicity and does not seem to affect breast appearance, late toxicity or patient-reported quality-of-life measures for selected women treated with breast conserving therapy. These are mostly women with node negative tumours smaller than 3 cm and negative pathological margins

Synthesis of a diaryliodonium salt and its use in the direct arylation of andole: a two-step experiment for the organic teaching laboratory

In the past decade, C–H functionalization has been a very active topic of research in both academia and industry. When a H atom is replaced by an aryl (or heteroaryl) group, the transformation is termed “direct arylation”. This approach to the formation of key (hetero)aryl–(hetero)aryl bonds is complementary to traditional methods, such as the Suzuki–Miyaura and Stille reactions. Direct arylation/C–H functionalization is not represented in the majority of undergraduate chemistry laboratory curricula. An experiment is described here in which students carry out a multistep process, synthesizing a diaryliodonium salt and using it in the direct arylation of indole. Important organic and organometallic chemistry concepts are covered, including catalysis, traditional cross-coupling, C–H functionalization, multistep reaction processes, and regioselectivity. The experiment was successfully carried out by third- and fourth-year students in two universities over a two-year period (four times in total). Both high-yielding and low-yielding chemical steps were encountered, and a number of pedagogical approaches evolved

EXPRESS: Differential IL-1 signalling induced by BMPR2 deficiency drives pulmonary vascular remodelling

Background: Bone morphogenetic protein receptor type 2 (BMPR2) mutations are present in patients with heritable and idiopathic pulmonary arterial hypertension (PAH). Circulating levels of Interleukin-1 (IL-1) are raised in patients and animal models. Whether interplay between BMP and IL- 1 signalling can explain the local manifestation of PAH in the lung remains unclear. Methods: Cell culture, siRNA and mRNA microarray analysis of RNA isolated from human Pulmonary artery (PASMC) and Aortic (AoSMC) smooth muscle cells were used. R899X+/- BMPR2 transgenic mice fed western diet for six weeks were given daily injections of IL-1ß prior to assessment for PAH and tissue collection. Results: PASMC have reduced inflammatory activation in response to IL-1ß compared with AoSMCs, however PASMC with reduced BMPR2 demonstrated an exaggerated response. Mice treated with IL-1ß had higher white blood cell counts, and significantly raised serum protein levels of IL-6 and OPG plasma levels recapitulating in vitro data. Phenotypically, IL-1ß treated mice demonstrated increased pulmonary vascular remodelling. Conclusions: IL-1ß induces an exaggerated pulmonary artery specific transcriptomic inflammatory response when BMPR2 signalling is reduced