Status, trends and drivers of kelp forests in Europe: an expert assessment

A comprehensive expert consultation was conducted in order to assess the status, trends and the most important drivers of change in the abundance and geographical distribution of kelp forests in European waters. This consultation included an on-line questionnaire, results from a workshop and data provided by a selected group of experts working on kelp forest mapping and eco-evolutionary research. Differences in status and trends according to geographical areas, species identity and small-scale variations within the same habitat where shown by assembling and mapping kelp distribution and trend data. Significant data gaps for some geographical regions, like the Mediterranean and the southern Iberian Peninsula, were also identified. The data used for this study confirmed a general trend with decreasing abundance of some native kelp species at their southern distributional range limits and increasing abundance in other parts of their distribution (Saccharina latissima and Saccorhiza polyschides). The expansion of the introduced species Undaria pinnatifida was also registered. Drivers of observed changes in kelp forests distribution and abundance were assessed using experts’ opinions. Multiple possible drivers were identified, including global warming, sea urchin grazing, harvesting, pollutionand fishing pressure, and their impact varied between geographical areas. Overall, the results highlight major threats for these ecosystems but also opportunities for conservation. Major requirements to ensure adequate protection of coastal kelp ecosystems along European coastlines are discussed, based on the local to regional gaps detected in the study.

Status, trends and drivers of kelp forests in Europe: an expert assessment

A comprehensive expert consultation was conducted in order to assess the status, trends and the most important drivers of change in the abundance and geographical distribution of kelp forests in European waters. This consultation included an on-line questionnaire, results from a workshop and data provided by a selected group of experts working on kelp forest mapping and eco-evolutionary research. Differences in status and trends according to geographical areas, species identity and small-scale variations within the same habitat where shown by assembling and mapping kelp distribution and trend data. Significant data gaps for some geographical regions, like the Mediterranean and the southern Iberian Peninsula, were also identified. The data used for this study confirmed a general trend with decreasing abundance of some native kelp species at their southern distributional range limits and increasing abundance in other parts of their distribution (Saccharina latissima and Saccorhiza polyschides). The expansion of the introduced species Undaria pinnatifida was also registered. Drivers of observed changes in kelp forests distribution and abundance were assessed using experts’ opinions. Multiple possible drivers were identified, including global warming, sea urchin grazing, harvesting, pollutionand fishing pressure, and their impact varied between geographical areas. Overall, the results highlight major threats for these ecosystems but also opportunities for conservation. Major requirements to ensure adequate protection of coastal kelp ecosystems along European coastlines are discussed, based on the local to regional gaps detected in the study.

Comparing architectural styles for distributed expert knowledge modules in intelligent tutoring systems

Intelligent Tutoring Systems (ITSs) are computerized systems for learning-by-doing. These systems provide students with immediate and customized feedback on learning tasks. An ITS typically consists of several modules that are connected to each other. This research focuses on the distribution of the ITS module that provides expert knowledge services. For the distribution of such an expert knowledge module we need to use an architectural style because this gives a standard interface, which increases the reusability and operability of the expert knowledge module. To provide expert knowledge modules in a distributed way we need to answer the research question: ‘How can we compare and evaluate REST, Web services and Plug-in architectural styles for the distribution of the expert knowledge module in an intelligent tutoring system?’. We present an assessment method for selecting an architectural style. Using the assessment method on three architectural styles, we selected the REST architectural style as the style that best supports the distribution of expert knowledge modules. With this assessment method we also analyzed the trade-offs that come with selecting REST. We present a prototype and architectural views based on REST to demonstrate that the assessment method correctly scores REST as an appropriate architectural style for the distribution of expert knowledge modules.

Responsibility and Well-Being: Resource Integration Under Responsibilization in Expert Services

Responsibilization, or the shift of functions and risks from providers and producers to consumers, has become an increasingly common policy in service systems and marketplaces (e.g., financial, health, governmental). As responsibilization is often considered synonymous with consumer agency and well-being, the authors take a transformative service research perspective and draw on resource integration literature to investigate whether responsibilization is truly associated with well-being. The authors focus on expert services, for which responsibilization concerns are particularly salient, and question whether this expanding policy is in the public interest. In the process, they develop a conceptualization of resource integration under responsibilization that includes three levels of actors (consumer, provider, and service system), the identification of structural tensions to resource integration, and three categories of resource integration practices (access, appropriation, and management) necessary to negotiate responsibilization. The findings have important implications for health care providers, public and institutional policy makers, and other service systems, all of which must pay more active attention to the challenges consumers face in negotiating responsibilization and the resulting well-being outcomes.

Responsibility and Well-being: Resource Integration under Responsibilization in Expert Services

Responsibilization, or the shift in functions and risks from providers and producers to the consumer, has become an increasingly common policy in service systems and marketplaces (e.g., financial, health, governmental). Responsibilization is often presented as synonymous with consumer agency and well-being. We take a transformative service research perspective and utilize the resource integration framework to investigate whether responsibilization is truly associated with well-being. We focus on expert services, where responsibilization concerns are particularly salient, and question whether this expanding policy is in the public interest. In the process, we develop a conceptualization of resource integration under responsibilization that includes three levels of actors (consumer, provider and service system), the identification of structural tensions to resource integration and three categories of resource integration practices (access, appropriation and management) necessary to negotiate responsibilization. Our findings have important implications for health care providers, public policy makers, and other service systems, all of which must pay more active attention to the challenges consumers face in negotiating responsibilization and the resulting well-being outcomes.

Prognostic role of the LCS6 KRAS variant in locally advanced rectal cancer: results of the EXPERT-C trial.

Background: Lethal-7 (let-7) is a tumour suppressor miRNA which acts by down-regulating several oncogenes including KRAS. A single-nucleotide polymorphism (rs61764370, T > G base substitution) in the let-7 complementary site 6 (LCS-6) of KRAS mRNA has been shown to predict prognosis in early-stage colorectal cancer (CRC) and benefit from anti-epidermal growth factor receptor monoclonal antibodies in metastatic CRC. Patients and methods: We analysed rs61764370 in EXPERT-C, a randomised phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX plus or minus cetuximab in locally advanced rectal cancer. DNA was isolated from formalin-fixed paraffin-embedded tumour tissue and genotyped using a PCR-based commercially available assay. Kaplan–Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms. Results: A total of 155/164 (94.5%) patients were successfully analysed, of whom 123 (79.4%) and 32 (20.6%) had the LCS-6 TT and LCS-6 TG genotype, respectively. Carriers of the G allele were found to have a statistically significantly higher rate of complete response (CR) after neoadjuvant therapy (28.1% versus 10.6%; P = 0.020) and a trend for better 5-year progression-free survival (PFS) [77.4% versus 64.5%: hazard ratio (HR) 0.56; P = 0.152] and overall survival (OS) rates (80.3% versus 71.9%: HR 0.59; P = 0.234). Both CR and survival outcomes were independent of the use of cetuximab. The negative prognostic effect associated with KRAS mutation appeared to be stronger in patients with the LCS-6 TT genotype (HR PFS 1.70, P = 0.078; HR OS 1.79, P = 0.082) compared with those with the LCS-6 TG genotype (HR PFS 1.33, P = 0.713; HR OS 1.01, P = 0.995). Conclusion: This analysis suggests that rs61764370 may be a biomarker of response to neoadjuvant treatment and an indicator of favourable outcome in locally advanced rectal cancer possibly by mitigating the poor prognosis of KRAS mutation. In this setting, however, this polymorphism does not appear to predict cetuximab benefit.

TP53 mutational status and cetuximab benefit in rectal cancer: 5-year results of the EXPERT-C trial.

In this updated analysis of the EXPERT-C trial we show that, in magnetic resonance imaging-defined, high-risk, locally advanced rectal cancer, adding cetuximab to a treatment strategy with neoadjuvant CAPOX followed by chemoradiotherapy, surgery, and adjuvant CAPOX is not associated with a statistically significant improvement in progression-free survival (PFS) and overall survival (OS) in both KRAS/BRAF wild-type and unselected patients. In a retrospective biomarker analysis, TP53 was not prognostic but emerged as an independent predictive biomarker for cetuximab benefit. After a median follow-up of 65.0 months, TP53 wild-type patients (n = 69) who received cetuximab had a statistically significant better PFS (89.3% vs 65.0% at 5 years; hazard ratio [HR] = 0.23; 95% confidence interval [CI] = 0.07 to 0.78; two-sided P = .02 by Cox regression) and OS (92.7% vs 67.5% at 5 years; HR = 0.16; 95% CI = 0.04 to 0.70; two-sided P = .02 by Cox regression) than TP53 wild-type patients who were treated in the control arm. An interaction between TP53 status and cetuximab effect was found (P <.05) and remained statistically significant after adjusting for statistically significant prognostic factors and KRAS.

RAS mutations and cetuximab in locally advanced rectal cancer: results of the EXPERT-C trial.

Background: RAS mutations predict resistance to anti-epidermal growthfactor receptor (EGFR) monoclonal antibodies in metastatic colorectal cancer. We analysed RAS mutations in 30 non-metastatic rectal cancer patients treated with or without cetuximab within the 31 EXPERT-C trial.

Methods: Ninety of 149 patients with tumours available for analysis were KRAS/BRAF wild-type, and randomly assigned to capecitabine plus oxaliplatin (CAPOX) followed by chemoradiotherapy, surgery and adjuvant CAPOX or the same regimen plus cetuximab (CAPOX-C). Of these, four had a mutation of NRAS exon 3, and 84 were retrospectively analysed for additional KRAS (exon 4) and NRAS (exons 2/4) mutations by using bi-directional Sanger sequencing. The effect of cetuximab on study end-points in the RAS wild-type population was analysed.

Results: Eleven (13%) of 84 patients initially classified as KRAS/BRAF wild-type were found to have a mutation in KRAS exon 4 (11%) or NRAS exons 2/4 (2%). Overall, 78/149 (52%) assessable patients were RAS wild-type (CAPOX, n = 40; CAPOX-C, n = 38). In this population, after a median follow-up of 63.8 months, in line with the initial analysis, the addition of cetuximab was associated with numerically higher, but not statistically significant, rates of complete response (15.8% versus 7.5%, p = 0.31), 5-year progression-free survival (75.5% versus 67.5%, hazard ratio (HR) 0.61, p = 0.25) and 5-year overall survival (83.8% versus 70%, HR 0.54, p = 0.20).

Conclusions: RAS mutations beyond KRAS exon 2 and 3 were identified in 17% of locally advanced rectal cancer patients. Given the small sample size, no definitive conclusions on the effect of additional RAS mutations on cetuximab treatment in this setting can be drawn and further investigation of RAS in larger studies is warranted.

HER2 in high-risk rectal cancer patients treated in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab.

BACKGROUND: HER2 is an established therapeutic target in breast and gastric cancers. The role of HER2 in rectal cancer is unclear, as conflicting data on the prevalence of HER2 expression in this disease have been reported. We evaluated the prevalence of HER2 and its impact on the outcome of high-risk rectal cancer patients treated with neoadjuvant CAPOX and CRT±cetuximab in the EXPERT-C trial. PATIENTS AND METHODS: Eligible patients with available tumour tissue for HER2 analysis were included. HER2 expression was determined by immunohistochemistry (IHC) in pre-treatment biopsies and/or surgical specimens (score 0-3+). Immunostaining was scored according to the consensus panel recommendations on HER2 scoring for gastric cancer. Tumours with equivocal IHC result (2+) were tested for HER2 amplification by D-ISH. Tumours with IHC 3+ or D-ISH ratio ≥2.0 were classified as HER2+. The impact of HER2 on primary and secondary end points of the study was analysed. RESULTS: Of 164 eligible study patients, 104 (63%) biopsy and 114 (69%) surgical specimens were available for analysis. Only 3 of 104 (2.9%) and 3 of 114 (2.6%) were HER2+, respectively. In 77 patients with paired specimens, concordance for HER2 status was found in 74 (96%). Overall, 141 patients were assessable for HER2 and 6 out of 141 (4.3%) had HER2 overexpression and/or amplification. The median follow-up was 58.6 months. HER2 was not associated with a difference in the outcome for any of the study end points, including in the subset of 90 KRAS/BRAF wild-type patients treated±cetuximab. CONCLUSIONS: Based on the low prevalence of expression as recorded in the EXPERT-C trial, HER2 does not appear to represent a useful therapeutic target in high-risk rectal cancer. However, the role of HER2 as a potential predictive biomarker of resistance to anti-EGFR-based treatments and a therapeutic target in anti-EGFR refractory metastatic colorectal cancer (CRC) warrants further investigation. TRIAL REGISTRATION: ISRCTN Register: 99828560.

BRAF mutation testing algorithm for vemurafenib treatment in melanoma: recommendations from an expert panel.

The incidence of melanoma has increased rapidly over the past 30 years, and the disease is now the sixth most common cancer among men and women in the U.K. Many patients are diagnosed with or develop metastatic disease, and survival is substantially reduced in these patients. Mutations in the BRAF gene have been identified as key drivers of melanoma cells and are found in around 50% of cutaneous melanomas. Vemurafenib (Zelboraf(®) ; Roche Molecular Systems Inc., Pleasanton, CA, U.S.A.) is the first licensed inhibitor of mutated BRAF, and offers a new first-line option for patients with unresectable or metastatic melanoma who harbour BRAF mutations. Vemurafenib was developed in conjunction with a companion diagnostic, the cobas(®) 4800 BRAF V600 Mutation Test. The purpose of this paper is to make evidence-based recommendations to facilitate the implementation of BRAF mutation testing and targeted therapy in patients with metastatic melanoma in the U.K. The recommendations are the result of a meeting of an expert panel and have been reviewed by melanoma specialists and representatives of the National Cancer Research Network Clinical Study Group on behalf of the wider melanoma community. This article is intended to be a starting point for practical advice and recommendations, which will no doubt be updated as we gain further experience in personalizing therapy for patients with melanoma.