Transcriptional Subtyping and CD8 Immunohistochemistry Identifies Patients With Stage II and III Colorectal Cancer With Poor Prognosis Who Benefit From Adjuvant Chemotherapy

This work was funded by Cancer Research UK: C212/A13721 and C11884/A24387Peer reviewedPublisher PD

ESMO Leaders Generation Programme: an alumni insight.

info:eu-repo/semantics/publishe

Maximising clinical benefit with adequate patient management beyond the second line in mCRC

New therapeutic options for refractory metastatic colorectal cancer (mCRC) include trifluridine/tipiracil (TAS-102) and regorafenib. However, the optimal chemotherapeutic regimen for use of each agent beyond the second line for patients with mCRC remains unclear and various factors may influence treatment decision. Available efficacy data suggest treatment with either trifluridine/tipiracil or regorafenib may be appropriate as both can extend patient survival. Thus, the safety profiles of each agent, along with patient performance status, are likely to determine treatment choice. The safety profiles of trifluridine/tipiracil and regorafenib are markedly different: higher levels of non-haematological adverse events such as fatigue, diarrhoea, hypertension and hand-foot skin reaction are reported with regorafenib, while haematological events such as neutropaenia are more common with trifluridine/tipiracil. In general, neutropaenia is a manageable treatment-related toxicity, while hand-foot skin reaction can be troublesome for patients, affecting their ability to carry out everyday activities and get on with their lives, while also affecting treatment adherence. Thus, the occurrence of any potential adverse effects and patient adherence should be closely monitored at each clinic visit. As quality of life is an important issue for patients with mCRC, it is important to balance extended survival and the likely quality of this extended life. Likewise, discussing possible side effects along with treatment expectations with patients can greatly facilitate adherence to therapy, and ultimately improve patients' quality of life and eventual clinical outcomes.status: publishe

Multiple stressor effects on biodiversity and ecosystem functioning in a Mediterranean temporary river

The hydrological and biological complexity of temporary rivers as well as their importance in providing goods and services is increasingly recognized, as much as it is the vulnerability of the biotic communities in view of climate change and increased anthropogenic pressures. However, the effects of flow intermittency (resulting from both seasonal variations and rising hydrological pressure) and pollution on biodiversity and ecosystem functioning have been overlooked in these ecosystems. We explore the way multiple stressors affect biodiversity and ecosystem functioning, as well as the biodiversity-ecosystem functioning (B-EF) relationship in a Mediterranean temporary river. We measured diversity of benthic communities (i.e. diatoms and macroinvertebrates) and related ecosystem processes (i.e. resource use efficiency-RUE and organic matter breakdown-OMB) across a pollution and flow intermittency gradient. Our results showed decreases in macroinvertebrate diversity and the opposite trend in diatom assemblages, whereas ecosystem functioning was negatively affected by both pollution and flow intermittency. The explored B-EF relationships showed contrasting results: RUE decreased with higher diatom diversity, whereas OMB increased with increased macroinvertebrate diversity. The different responses suggest contrasting operating mechanisms, selection effects possibly driving the B-EF relationship in diatoms and complementarity effects driving the B-EF relationship in macroinvertebrates. The understanding of multiple stressor effects on diversity and ecosystem functioning, as well as the B-EF relationship in temporary rivers could provide insights on the risks affecting ecosystem functioning under global change. © 2018The authors would like to thank P. Kouraklis for field work, A. Vourka, C. Theodoropoulos, A. Andriopoulou and M. Koutsodimou for laboratory assistance in macroinvertebrate identification and E. Anastasopoulou for chemical analysis. This study was conducted within the frame of the European Communities 7th Framework Programme under Grant Agreement no 603629-ENV-2013-6.2.1-GLOBAQUA . Appendix APeer reviewe

Analysis of 52 pesticides in fresh fish muscle by QuEChERS extraction 1 followed by LC-MS/MS determination

Pesticide pollution in water has been well described; however, little is known on pesticide accumulation by aquatic organisms, and to date, most studies in this line have been focused on persistent organochlorine pesticides. For this reason, a method based on QuEChERS extraction and subsequent liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis has been developed and validated for the determination of 52 medium to highly polar pesticides in fresh fish muscle. Target pesticides were selected on the basis of use and occurrence in surface waters. Quantification is carried out following an isotope dilution approach. The method developed is satisfactory in terms of accuracy (relative recoveries between 71 and 120%), precision (relative standard deviations below 21%) and sensitivity (limits of determination in the pg/g or low ng/g f.w. range for most compounds). The application of the validated methodology to fish specimens collected from the Adige River (Italy) revealed the presence of trace levels of diazinon, dichlorvos and diuron, and measurable levels of metolachlor, quinoxyfen, irgarol, terbutryn, and acetamiprid, but in all cases at concentrations below the default maximum residue level of 10 ng/g established for pesticides not specifically regulated in fish intended for human consumption. Metolachlor and quinoxyfen were both the most ubiquitous and abundant pesticides, in agreement with their high potential for bioaccumulation. Both are toxic to aquatic organisms, and therefore, their potential effects on aquatic ecosystems should be further explored. © 2018 Elsevier B.V.The authors thank the financial support of the EU ( FP7 projects GLOBAQUA ( 265264 ) and SOLUTIONS ( 603437 )) and the Generalitat de Catalunya (Consolidated Research Group “ 2017 SGR 1404 - Water and Soil Quality Unit”). Bekolut is acknowledged for the gift of QuEChERS kits. CP acknowledges support from the Swedish University of Agricultural Sciences through the August T Larsson Guest Researcher Programme. Appendix APeer reviewe

Association of Consensus Molecular Subtypes and Molecular Markers With Clinical Outcomes in Patients With Metastatic Colorectal Cancer: Biomarker Analyses From LUME-Colon 1.

INTRODUCTION: LUME-Colon 1 (NCT02149108) was a global, placebo-controlled phase III study of nintedanib in advanced colorectal cancer (CRC). Pre-specified biomarker analyses investigated the association of CRC consensus molecular subtypes (CMS) and tumor genomic and circulating biomarkers with clinical outcomes. MATERIALS AND METHODS: Archival tumor tissue, cell-free DNA (cfDNA), and plasma samples were collected for genomic, transcriptomic, and proteomic analyses to investigate potential associations between CRC CMS and other biomarkers with nintedanib response and clinical outcomes. RESULTS: Of the 765 treated patients, 735, 245, and 192 patient samples were analyzed in the circulating protein, tumor tissue, and cfDNA datasets, respectively. Patients were classified as CMS1 (1.7%), CMS2 (27.7%), CMS3 (0.9%), CMS4 (51.5%), or unclassified (18.2%). Unclassified/mixed CMS was associated with longer overall survival (OS) with nintedanib vs. CMS2 or CMS4 (interaction P-value = .0086); no association was observed for CMS4. Gene expression-based pathway analysis revealed an association between vascular endothelial growth factor-related signaling and OS for nintedanib (P = .0498). The most frequently detected somatic mutations were APC (72.0% [tumor tissue] vs. 56.8% [cfDNA]), TP53 (47.1% vs. 34.9%), KRAS (40.8% vs. 28.6%), and PIK3CA (16.6% vs. 11.5%); concordance rates were > 80%. Median OS differences were observed for APC and TP53 mutations vs. wild-type in cfDNA, indicating a potential prognostic value. Circulating ANG-2, CA-9, CEACAM1, collagen-IV, IGFBP-1, ICAM-1, IL-8, and uPAR were potentially prognostic for both OS and progression-free survival. CONCLUSION: We demonstrated the feasibility of large-scale biomarker analyses and CMS classification within a global clinical trial, and identified signals suggesting a potential for greater nintedanib treatment response in the unclassified/mixed CMS subgroup, despite these tumors showing heterogeneous patterns of CMS mixtures. Our results revealed a high degree of concordance in somatic mutations between tumor tissue and cfDNA. Associations with prognosis for cfDNA somatic mutations, as well as several protein-based biomarkers, may warrant further investigation in future trials.status: Published onlin

Health-related Quality of Life in the Phase III LUME-Colon 1 Study: Comparison and Interpretation of Results From EORTC QLQ-C30 Analyses

INTRODUCTION: We used European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) data from the LUME-Colon 1 study to illustrate different methods of statistical analysis for health-related quality of life (HRQoL), and compared the results. PATIENTS AND METHODS: Patients were randomized 1:1 to receive nintedanib 200 mg twice daily plus best supportive care (n = 386) or matched placebo plus best supportive care (n = 382). Five methods (mean treatment difference averaged over time, using a mixed-effects growth curve model; mixed-effects models for repeated measurements (MMRM); time-to-deterioration (TTD); status change; and responder analysis) were used to analyze EORTC QLQ-C30 global health status (GHS)/QoL and scores from functional scales. RESULTS: Overall, GHS/QoL and physical functioning deteriorated over time. Mean treatment difference slightly favored nintedanib over placebo for physical functioning (adjusted mean, 2.66; 95% confidence interval [CI], 0.97-4.34) and social functioning (adjusted mean, 2.62; 95% CI, 0.66-4.47). GHS/QoL was numerically better with nintedanib versus placebo (adjusted mean, 1.61; 95% CI, -0.004 to 3.27). MMRM analysis had similar results, with better physical functioning in the nintedanib group at all timepoints. There was no significant delay in GHS/QoL deterioration (10%) and physical functioning (16%) with nintedanib versus placebo (TTD analysis). Status change analysis showed a higher proportion of patients with markedly improved GHS/QoL and physical functioning in the nintedanib versus placebo groups. Responder analysis showed a similar, less pronounced pattern. CONCLUSION: Analyses of EORTC QLQ-C30 data showed that HRQoL was not impaired by treatment with nintedanib versus placebo. Analysis and interpretation of HRQoL endpoints should consider symptom type and severity and course of disease.status: publishe

Ecotoxicological tools to assess the impact pollution of tributaries to the Alqueva Reservoir (Southern Portugal)

Degradation of surface waters and biodiversity loss at different spatial and temporal scales occurs through multiple stressors whose effects are difficult to separate and identify. Efficient management of water bodies depends on the development and selection of robust, sensitive and easily applicable tools that allow prioritizing the pressures and stressors that act in a basin, and mitigate their effects. The Alqueva reservoir constitutes the most important water supply source in southern Portugal, a semi-arid region with high levels of water scarcity and where agriculture is one of the main activities. The aim of the present study was to assess the use of an ecotoxicological tool-box in tributaries of the Alqueva reservoir for detecting chemical alterations that may influence the water quality of the reservoir. Water samples were collected along 2017 at four tributaries of Alqueva (streams of Zebro, Álamos, Amieira and Lucefécit) and analyzed for: (i) physical chemical support elements (pH, temperature, dissolved oxygen, conductivity, chloride, total phosphorus, Kjeldahl nitrogen, ammonium, nitrite, nitrate, BOD, COD), (ii) hazardous substances (pesticides), and (iii) ecotoxicological endpoints, using bioindicators representing different trophic levels (Vibrio fischeri, Thamnocephalus platyurus, Daphnia magna). In general, Zebro and Lucefécit presented concentrations of BOD (Zebro: 4.0-35.5 mg L-1; Lucefécit: 2.3-7.5 mg L-1) and total phosphorus (Zebro: 0.18-6.23 mg L-1; Lucefécit: 0.02-1.92 mg L-1) that compromise the support of biological life, with regard to nutrient and oxygenation conditions. As regards pesticides, the concentrations detected were low, being bentazone the compound quantified at highest levels. Lucefécit was the tributary that presented higher concentrations of pesticides (with values of bentazone of 1.94 µg L-1), probably due to the intensive agriculture crops around it. Concerning to ecotoxicological analysis, the results highlighted the toxicity in sublethal parameters (reproduction, feed inhibition or growth inhibition) induced, mainly, by samples from Zebro and Lucefécit streams. So, the results from the ecotoxicological tool-box allowed identifying the streams that promote a higher chemical impact to the reservoir, which is essential to delineate management actions to improve the water quality of the reservoir.This work was co-funded by the European Union through the European Regional Development Fund, framed in COMPETE 2020 (Operational Programme Competitiveness and Internationalization), through the ICT project (UID/GEO/04683/2013) with reference POCI-01-0145-FEDER-007690 and the ALOP project (ALT20-03-0145-FEDER-000004