Deciphering variable mantle sources and hydrous inputs to arc magmas in Kamchatka

The chemistry of primitive arc rocks provides a window into compositional variability in the mantle wedge, as well as slab-derived inputs to subduction-related magmatism. However, in the long-term cycling of elements between Earth’s internal and external reservoirs, a key unknown is the importance of retaining mobile elements within the subduction system, through subduction-related metasomatism of the mantle. To address these questions, we have analysed olivine-hosted melt inclusions and corresponding bulk rocks from the Kamchatka arc. Suites of melt inclusions record evidence for entrapment along melt mixing arrays during assembly of diverse parental magma compositions. Systematic variations in parental magma B/Zr, Nb/Zr, Ce/B, and δ11 B are also apparent among the different eruptive centres studied. These element ratios constrain the nature of subduction-related metasomatism and provide evidence for ambient mantle heterogeneity and variable degrees of mantle melting. High Nb/Zr and low B/Zr in back-arc rocks indicate smaller degree melts, lower slab derived inputs, but relatively enriched mantle compositions. Similarly, small monogenetic eruptive centres located away from the main stratocones also tend to erupt magmas with relatively lower slab contribution and overall smaller melting degrees. Conversely, arc-front compositions reflect greater slab contributions and larger degree melts of a more depleted ambient mantle. Across-arc variations in δ11 B (ranging from ca. –6 ‰ in the rear-arc and Sredinny Ridge to +7 ‰ in the Central Kamchatka Depression) are generally consistent with variable addition of an isotopically heavy slab-derived component to a depleted MORB mantle composition. However, individual volcanic centres (e.g. Bakening volcano) show correlations between melt inclusion δ11 B and other geochemical indicators (e.g. Cl/K2O, Ce/B) that require mixing between isotopically distinct melt batches that have undergone different extents of crustal evolution and degassing processes. Our results show that while melt inclusion volatile inventories are largely overprinted during shallower melt storage and aggregation, incompatible trace element ratios and B isotope compositions more faithfully trace initial mantle compositions and subduction inputs. Furthermore, we suggest that the signals of compositional heterogeneity generated in the sub arc mantle by protracted metasomatism during earlier phases of subduction can be preserved during later magma assembly and storage in the crust

Tracing Volatiles, Halogens, and Chalcophile Metals during Melt Evolution at the Tolbachik Monogenetic Field, Kamchatka

Melt storage and supply beneath arc volcanoes may be distributed between a central stratovolcano and wider fields of monogenetic cones, indicating complex shallow plumbing systems. However, the impact of such spatially variable magma storage conditions on volatile degassing and trace element geochemistry is unclear. This study explores magma generation and storage processes beneath the Tolbachik volcanic field, Kamchatka, Russia, in order to investigate the evolution of the magmatic volatile phase and, specifically, the strong enrichment of chalcophile metals (in particular, Cu) in this system. We present new geochemical data for a large suite of olivine- and clinopyroxene-hosted melt inclusions (and host phenocrysts) from five separate monogenetic cones within the Tolbachik volcanic field. These high-Al composition magmas likely reflect the homogenised fractionation products of primitive intermediate-Mg melt compositions, stored at shallow depths after significant fractional crystallisation. Boron isotope compositions and incompatible trace element ratios of the melt inclusions suggest a deeper plumbing system that is dominated by extensive fractional crystallisation and fed by melts derived from an isotopically homogeneous parental magma composition. Volatile components (H2O, CO2, S, Cl, F) show that magmas feeding different monogenetic cones had variable initial volatile contents and subsequently experienced different fluid-saturated storage conditions and degassing histories. We also show that melts supplying the Tolbachik volcanic field are strongly enriched in Cu compared with almost all other Kamchatka rocks, including samples from the Tolbachik central stratocones, and other volcanoes situated in close proximity in the Central Kamchatka Depression. The melt inclusions record Cu concentrations ≥450 μg/g at ca. 4–5 wt.% MgO, which can only be explained by bulk incompatible partitioning behaviour of Cu, i.e. evolution under sulphide-undersaturated conditions. We suggest that initial mantle melting in this region exhausted mantle sulphides, leading to sulphide undersaturated primitive melts. This sulphide-free model for the high-Al cone melts is further supported by S/Se and Cu/Ag values that overlap those of the primitive mantle and MORB array, with bulk rock Cu/Ag ratios also overlapping other with other global arc datasets for magma evolution prior to fractionation of a monosulfide solid solution. We therefore demonstrate that the combination of novel chalcophile metal analyses with trace element, isotopic, and volatile data is a powerful tool for deciphering complex magmatic evolution conditions across the entire volcanic field

Report of two protocol planned interim analyses in a randomised multicentre phase III study comparing capecitabine with fluorouracil and oxaliplatin with cisplatin in patients with advanced oesophagogastric cancer receiving ECF

The purpose of the study was to establish the optimal dose of capecitabine (X) to be used within a multicentre, randomised study evaluating the potential roles of oxaliplatin (O) and X in chemonaive patients (pts) with advanced oesophagogastric cancer. Two by two design was used, and pts were randomised to one of four regimens and stratified for extent of disease, performance status (PS) and centre. The treatment regimens are epirubicin, cisplatin, 5-fluorouracil (ECF), EOF, ECX or EOX. Doses: E 50 mg m-2, C 60 mg m-2 and O 130 mg m-2 i.v. 3 weekly; F 200 mg m-2 day-1 i.v. and X 500 mg m-2 b.i.d.-1 (escalated to 625 mg m-2 b.i.d.-1 after results of first interim analysis) p.o., continuously. First interim analysis was performed when 80 pts had been randomised. Dose-limiting fluoropyrimidine toxicities were stomatitis, palmar plantar erythema (PPE) and diarrhoea; 5.1% of X-treated pts experienced grade 3/4 toxicity. Protocol planned dose escalation of X to 625 mg m-2 b.i.d.-1 was instituted and a second interim analysis has been performed; results are presented in this paper. A total of 204 pts were randomised at the time of the protocol planned 2nd interim analysis. Grade 3/4 fluoropyrimidine-related toxicity was seen in 13.7% pts receiving F, 8.4% pts receiving X 500 mg m-2 b.i.d.-1 and 14.7% pts receiving X 625 mg m-2 b.i.d.-1. Combined complete and partial response rates were ECF 31% (95% CI 18.7-46.3), EOF 39% (95% CI 25.9-53.1), ECX 35% (95% CI 21.4-50.3), EOX 48% (95% CI 33.3-62.8). Grade 3/4 fluoropyrimidine toxicity affected 14.7% of pts treated with X 625 mg m-2 b.i.d.-1, which is similar to that observed with F, confirming this to be the optimal dose. The replacement of C by O and F by X does not appear to impair efficacy. The trial continues to total accrual of 1000 pts

Application of urine proteomics for biomarker discovery in drug-induced liver injury

Abstract The leading cause of hepatic damage is drug-induced liver injury (DILI), for which currently no adequate predictive biomarkers are available. Moreover, for most drugs related to DILI, the mechanisms underlying the adverse reaction have not yet been elucidated. Urinary protein biomarker candidates for DILI have emerged in the past few years and correlate well with clinical studies for serum DILI biomarkers. The goal of this review was to investigate the use of urine as a source of protein biomarkers for drug-induced liver injury. Finally, we discuss some of the current strategies required to advance the field of biomarker discovery for DILI with respect to appropriate clinical biobanking and adequate translational research