BCAR4 induces antioestrogen resistance but sensitises breast cancer to lapatinib

BACKGROUND: High BCAR4 and ERBB2 mRNA levels in primary breast cancer associate with tamoxifen resistance and poor patient outcome. We determined whether BCAR4 expression sensitises breast cancer cells to lapatinib, and identifies a subgroup of patients who possibly may benefit from ERBB2-targeted therapies despite having tumours with low ERBB2 expression. METHODS: Proliferation assays were applied to determine the effect of BCAR4 expression on lapatinib treatment. Changes in cell signalling were quantified with reverse-phase protein microarrays. Quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) of ERBB2 and BCAR4 was performed in 1418 primary breast cancers. Combined BCAR4 and ERBB2 mRNA levels were evaluated for association with progression-free survival (PFS) in 293 oestrogen receptor-alpha (ER)-positive patients receiving t RESULTS: BCAR4 expression strongly sensitised ZR-75-1 and MCF7 breast cancer cells to the combination of lapatinib and antioestrogens. Lapatinib interfered with phosphorylation of ERBB2 and its downstream mediators AKT, FAK, SHC, STAT5, and STAT6. Reverse transcriptase-PCR analysis showed that 27.6% of the breast cancers were positive for BCAR4 and 22% expressed also low levels of ERBB2. The clinical significance of combining BCAR4 and ERBB2 mRNA status was underscored by the finding that the gr CONCLUSION: This study shows that BCAR4 expression identifies a subgroup of ER-positive breast cancer patients without overexpression of ERBB2 who have a poor outcome and might benefit from combined ERBB2-targeted and antioestrogen therapy. British Journal of Cancer (2012) 107, 947-955. doi:10.1038/bjc.2012.351 www.bjcancer.com Published online 14 August 2012 (C) 2012 Cancer Research U

Постанова загальних зборів Академії економічних наук України по звіту президії про роботу АЕН України з 15 травня 2010 р. по 13 травня 2011 p.

We study the response of firn to a stepwise surface temperature change, using a firn model that includes meltwater hydrology and is driven by an idealized surface climate. We find that adjustment of dry firn (i.e. without surface melt) to surface warming takes longer than a subsequent cooling to the original, colder climate, mainly because firn compacts faster at higher firn temperatures. In contrast, wet firn adjusts faster to a surface warming than to a cooling. Increased meltwater percolation enhances the downward transport of latent heat, whereas there is no such mechanism that can enhance the downward transport of a cooling signal. Thus, wastage of firn after surface warming is faster than its regeneration if the warming were reversed. Furthermore, the response of wet firn to temperature change exhibits a complex relation between accumulation rate and the steady-state deepfirn temperature. For high accumulation rates, the deep-firn temperature is higher because latent heat release upon refreezing is isolated by winter snow. As a result, the response of wet firn to a temperature change varies strongly with accumulation rate. In general, the magnitude and the rate of density change is larger in wet firn than in dry firn

Nationwide evaluation of mutation-tailored treatment of gastrointestinal stromal tumors in daily clinical practice

Background Molecular analysis of KIT and PDGFRA is critical for tyrosine kinase inhibitor treatment selection of gastrointestinal stromal tumors (GISTs) and hence recommended by international guidelines. We performed a nationwide study into the application of predictive mutation testing in GIST patients and its impact on targeted treatment decisions in clinical practice. Methods Real-world clinical and pathology information was obtained from GIST patients with initial diagnosis in 2017-2018 through database linkage between the Netherlands Cancer Registry and the nationwide Dutch Pathology Registry. Results Predictive mutation analysis was performed in 89% of the patients with high risk or metastatic disease. Molecular testing rates were higher for patients treated in expertise centers (96%) compared to non-expertise centers (75%, P < 0.01). Imatinib therapy was applied in 81% of the patients with high risk or metastatic disease without patient's refusal or adverse characteristics, e.g., comorbidities or resistance mutations. Mutation analysis that was performed in 97% of these imatinib-treated cases, did not guarantee mutation-tailored treatment: 2% of these patients had the PDGFRA p.D842V resistance mutation and 7% initiated imatinib therapy at the normal instead of high dose despite of having a KIT exon 9 mutation. Conclusion In conclusion, nationwide real-world data show that over 81% of the eligible high risk or metastatic disease patients receive targeted therapy, which was tailored to the mutation status as recommended in guidelines in 88% of cases. Therefore, still 27% of these GIST patients misses out on mutation-tailored treatment. The reasons for suboptimal uptake of testing and treatment require further study

Modelled glacier response to centennial temperature and precipitation trends on the Antarctic Peninsula

The northern Antarctic Peninsula is currently undergoing rapid atmospheric warming1. Increased glacier-surface melt during the twentieth century2, 3 has contributed to ice-shelf collapse and the widespread acceleration4, thinning and recession5 of glaciers. Therefore, glaciers peripheral to the Antarctic Ice Sheet currently make a large contribution to eustatic sea-level rise6, 7, but future melting may be offset by increased precipitation8. Here we assess glacier–climate relationships both during the past and into the future, using ice-core and geological data and glacier and climate numerical model simulations. Focusing on Glacier IJR45 on James Ross Island, northeast Antarctic Peninsula, our modelling experiments show that this representative glacier is most sensitive to temperature change, not precipitation change. We determine that its most recent expansion occurred during the late Holocene ‘Little Ice Age’ and not during the warmer mid-Holocene, as previously proposed9. Simulations using a range of future Intergovernmental Panel on Climate Change climate scenarios indicate that future increases in precipitation are unlikely to offset atmospheric-warming-induced melt of peripheral Antarctic Peninsula glaciers

Oceanic Controls on the Mass Balance of Wilkins Ice Shelf, Antarctica

Several Antarctic Peninsula (AP) ice shelves have lost significant fractions of their volume over the past decades, coincident with rapid regional climate change. Wilkins Ice Shelf (WIS), on the western side of the AP, is the most recent, experiencing a sequence of large calving events in 2008 and 2009. We analyze the mass balance for WIS for the period 1992-2008 and find that the averaged rate of ice-shelf thinning was similar to 0.8 m a(-1), driven by a mean basal melt rate of \u3c w(b)\u3e = 1.3 +/- 0.4 m a(-1). Interannual variability was large, associated with changes in both surface mass accumulation and \u3c w(b)\u3e. Basal melt rate declined significantly around 2000 from 1.8 +/- 0.4 m a(-1) for 1992-2000 to similar to 0.75 +/- 0.55 m a(-1) for 2001-2008; the latter value corresponding to approximately steady-state ice-shelf mass. Observations of ocean temperature T obtained during 2007-2009 by instrumented seals reveal a cold, deep halo of Winter Water (WW; T approximate to - 1.6 degrees C) surrounding WIS. The base of the WW in the halo is similar to 170 m, approximately the mean ice draft for WIS. We hypothesize that the transition in \u3c w(b)\u3e in 2000 was caused by a small perturbation (similar to 10-20 m) in the relative depths of the ice base and the bottom of the WW layer in the halo. We conclude that basal melting of thin ice shelves like WIS is very sensitive to upper-ocean and coastal processes that act on shorter time and space scales than those affecting basal melting of thicker West Antarctic ice shelves such as George VI and Pine Island Glacier

Cost-Effectiveness of Parallel Versus Sequential Testing of Genetic Aberrations for Stage IV Non-Small-Cell Lung Cancer in the Netherlands

PURPOSE: A large number of targeted treatment options for stage IV nonsquamous non–small-cell lung cancer with specific genetic aberrations in tumor DNA is available. It is therefore important to optimize diagnostic testing strategies, such that patients receive adequate personalized treatment that improves survival and quality of life. The aim of this study is to assess the efficacy (including diagnostic costs, turnaround time (TAT), unsuccessful tests, percentages of correct findings, therapeutic costs, and therapeutic effectiveness) of parallel next generation sequencing (NGS)–based versus sequential single-gene–based testing strategies routinely used in patients with metastasized non–small-cell lung cancer in the Netherlands. METHODS: A diagnostic microsimulation model was developed to simulate 100,000 patients with prevalence of genetic aberrations, extracted from real-world data from the Dutch Pathology Registry. These simulated patients were modeled to undergo different testing strategies composed of multiple tests with different test characteristics including single-gene and panel tests, test accuracy, the probability of an unsuccessful test, and TAT. Diagnostic outcomes were linked to a previously developed treatment model, to predict average long-term survival, quality-adjusted life-years (QALYs), costs, and cost-effectiveness of parallel versus sequential testing. RESULTS: NGS-based parallel testing for all actionable genetic aberrations is on average €266 cheaper than single-gene–based sequential testing, and detects additional relevant targetable genetic aberrations in 20.5% of the cases, given a TAT of maximally 2 weeks. Therapeutic costs increased by €8,358, and 0.12 QALYs were gained, leading to an incremental cost-effectiveness ratio of €69,614/QALY for parallel versus sequential testing. CONCLUSION: NGS-based parallel testing is diagnostically superior over single-gene–based sequential testing, as it is cheaper and more effective than sequential testing. Parallel testing remains cost-effective with an incremental cost-effectiveness ratio of 69,614 €/QALY upon inclusion of therapeutic costs and long-term outcomes

Elevation change of the Greenland Ice Sheet due to surface mass balance and firn processes, 1960–2014

© The Author(s), 2015. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in The Cryosphere 9 (2015): 2009-2025, doi:10.5194/tc-9-2009-2015.Observed changes in the surface elevation of the Greenland Ice Sheet are caused by ice dynamics, basal elevation change, basal melt, surface mass balance (SMB) variability, and by compaction of the overlying firn. The last two contributions are quantified here using a firn model that includes compaction, meltwater percolation, and refreezing. The model is forced with surface mass fluxes and temperature from a regional climate model for the period 1960–2014. The model results agree with observations of surface density, density profiles from 62 firn cores, and altimetric observations from regions where ice-dynamical surface height changes are likely small. In areas with strong surface melt, the firn model overestimates density. We find that the firn layer in the high interior is generally thickening slowly (1–5 cm yr−1). In the percolation and ablation areas, firn and SMB processes account for a surface elevation lowering of up to 20–50 cm yr−1. Most of this firn-induced marginal thinning is caused by an increase in melt since the mid-1990s and partly compensated by an increase in the accumulation of fresh snow around most of the ice sheet. The total firn and ice volume change between 1980 and 2014 is estimated at −3295 ± 1030 km3 due to firn and SMB changes, corresponding to an ice-sheet average thinning of 1.96 ± 0.61 m. Most of this volume decrease occurred after 1995. The computed changes in surface elevation can be used to partition altimetrically observed volume change into surface mass balance and ice-dynamically related mass changes.P. Kuipers Munneke received financial support from the Netherlands Polar Programme (NPP) of the Netherlands Institute for Scientific Research (NWO). ECMWF at Reading (UK) is acknowledged for use of the Cray supercomputing system. The J. E. Box contribution is supported by Det Frie Forskningsråd grant 4002-00234 and Geocenter Denmark

Climate and surface mass balance of coastal West Antarctica resolved by regional climate modelling

West Antarctic climate and surface mass balance (SMB) records are sparse. To fill this gap, regional atmospheric climate modelling is useful, providing that such models are employed at sufficiently high horizontal resolution and coupled with a snow model. Here we present the results of a high-resolution (5.5 km) regional atmospheric climate model (RACMO2) simulation of coastal West Antarctica for the period 1979–2015. We evaluate the results with available in situ weather observations, remote-sensing estimates of surface melt, and SMB estimates derived from radar and firn cores. Moreover, results are compared with those from a lower-resolution version, to assess the added value of the resolution. The high-resolution model resolves small-scale climate variability invoked by topography, such as the relatively warm conditions over ice-shelf grounding zones, and local wind speed accelerations. Surface melt and SMB are well reproduced by RACMO2. This dataset will prove useful for picking ice core locations, converting elevation changes to mass changes, for driving ocean, ice-sheet and coupled models, and for attributing changes in the West Antarctic Ice Sheet and shelves to changes in atmospheric forcing

Micro-costing diagnostics in oncology: From single-gene testing to whole genome sequencing

Purpose: Predictive diagnostics play an increasingly important role in personalized medicine for cancer treatment. Whole genome sequencing (WGS) based treatment selection is expected to rapidly increase worldwide. Detailed and comparative cost analyses of diagnostic techniques are an essential element in decision-making. This study aimed to calculate and compare the total cost of currently used diagnostic techniques and of WGS in treatment of non-small cell lung carcinoma (NSCLC), melanoma, colorectal cancer (CRC) and gastrointestinal stromal tumor (GIST) in the Netherlands. Methods: The activity-based costing (ABC) method was conducted to calculate the total cost of included diagnostic techniques based on data provided by Dutch pathology laboratories and the Dutch centralized cancer WGS facility. Costs were allocated to four categories: capital costs, maintenance costs, software costs and operational costs. Outcome measures were total cost per cancer patient per included technique, and the total cost per cancer patient per most commonly applied technique (combination) for each cancer type. Results: The total cost per cancer patient per technique varied from € 58 (Sanger sequencing, 3 amplicons) to € 4738 (paired tumor-normal WGS). The operational costs accounted for the vast majority over 90 % of the total per cancer patient technique costs. The most important operational cost drivers were consumables followed by personnel (for sample preparation and primary data analysis). Conclusion: This study outlined in detail all costing aspects and cost prices of current and new diagnostic modalities used in treatment of NSCLC, melanoma, CRC and GIST in the Netherlands. Detailed cost differences and value comparisons between these diagnostic techniques enable future economic evaluations to support decision-making on implementation of WGS and other diagnostic modalities in routine clinical practice