Formation of intermetallic PdIn nanoparticles: influence of surfactants on nanoparticle atomic structure.

Bimetallic nanoparticles have been extensively studied as electrocatalysts due to their superior catalytic activity and selectivity compared to their monometallic counterparts. The properties of bimetallic materials depend on the ordering of the metals in the structure, and to tailor-make materials for specific applications, it is important to be able to control the atomic structure of the materials during synthesis. Here, we study the formation of bimetallic palladium indium nanoparticles to understand how the synthesis parameters and additives used influence the atomic structure of the obtained product. Specifically, we investigate a colloidal synthesis, where oleylamine was used as the main solvent while the effect of two surfactants, oleic acid (OA) and trioctylphosphine (TOP) was studied. We found that without TOP included in the synthesis, a Pd-rich intermetallic phase with the Pd3In structure initially formed, which transformed into large NPs of the CsCl-structured PdIn phase. When TOP was included, the syntheses yielded both In2O3 and Pd3In. In situ X-ray total scattering with Pair Distribution Function analysis was used to study the formation process of PdIn bimetallic NPs. Our results highlight how seemingly subtle changes to material synthesis methods can have a large influence on the product atomic structure.

Molecular Representations in Machine-Learning-Based Prediction of PK Parameters for Insulin Analogs.

Therapeutic peptides and proteins derived from either endogenous hormones, such as insulin, or de novo design via display technologies occupy a distinct pharmaceutical space in between small molecules and large proteins such as antibodies. Optimizing the pharmacokinetic (PK) profile of drug candidates is of high importance when it comes to prioritizing lead candidates, and machine-learning models can provide a relevant tool to accelerate the drug design process. Predicting PK parameters of proteins remains difficult due to the complex factors that influence PK properties; furthermore, the data sets are small compared to the variety of compounds in the protein space. This study describes a novel combination of molecular descriptors for proteins such as insulin analogs, where many contained chemical modifications, e.g., attached small molecules for protraction of the half-life. The underlying data set consisted of 640 structural diverse insulin analogs, of which around half had attached small molecules. Other analogs were conjugated to peptides, amino acid extensions, or fragment crystallizable regions. The PK parameters clearance (CL), half-life (T1/2), and mean residence time (MRT) could be predicted by using classical machine-learning models such as Random Forest (RF) and Artificial Neural Networks (ANN) with root-mean-square errors of CL of 0.60 and 0.68 (log units) and average fold errors of 2.5 and 2.9 for RF and ANN, respectively. Both random and temporal data splittings were employed to evaluate ideal and prospective model performance with the best models, regardless of data splitting, achieving a minimum of 70% of predictions within a twofold error. The tested molecular representations include (1) global physiochemical descriptors combined with descriptors encoding the amino acid composition of the insulin analogs, (2) physiochemical descriptors of the attached small molecule, (3) protein language model (evolutionary scale modeling) embedding of the amino acid sequence of the molecules, and (4) a natural language processing inspired embedding (mol2vec) of the attached small molecule. Encoding the attached small molecule via (2) or (4) significantly improved the predictions, while the benefit of using the protein language model-based encoding (3) depended on the used machine-learning model. The most important molecular descriptors were identified as descriptors related to the molecular size of both the protein and protraction part using Shapley additive explanations values. Overall, the results show that combining representations of proteins and small molecules was key for PK predictions of insulin analogs.

Heterocyclic [9]Helicenes Exhibiting Bright Circularly Polarized Luminescence.

We describe a concise synthetic strategy for the preparation of heterocyclic [9]helicenes and a simple preparative-scale protocol for the optical resolution of the resulting M- and P-enantiomers. The helicenes were characterized by single-crystal X-ray diffraction along with a range of spectroscopic and computational techniques. A fluorescence quantum yield of up to 65 % was observed, and the chiroptical properties of both M- and P-helicenes revealed large dissymmetry factors. The circularly polarized luminescence brightness reaches up to 17 M-1 cm-1 , as measured experimentally and verified computationally, which makes this the highest circularly polarized luminescence brightness among heterocyclic helicenes. We describe how chiroptical properties (both circular dichroism and circularly polarized luminescence) can be described and predicted using quantum chemical calculations. The synthetic approach also reveals by-products that originate from internal oxidation reactions, presumably mediated by the close proximity of the π-surfaces in the helicene structure.

Invisible strings. The first single crystal of the cTSAP form of [Eu(DOTA)(H2O)]- has an electronic structure similar to one of the reported cSAP forms.

The coordination geometry of lanthanide(III) ions is extremely sensitive to perturbation from the surrounding environment. Changes in the crystal field can be observed as spectral variations in the emission spectra of luminescent lanthanide(III) ions. Europium(III) ions are commonly used to correlate luminescence properties to the crystal field. In solution, kinetically inert complexes as [Ln(DOTA)(H2O)]- can fluctuate and give rise to different diastereomers (H4DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). The [Ln(DOTA)(H2O)]- complex adopts a capped square antiprism (cSAP) geometry but can rotate into a capped twisted square antiprism (cTSAP). The time scale of the solution dynamics in [Ln(DOTA)(H2O)]- is shorter than that of luminescence emission, thus, structural averages are observed in the emission spectra. For the first time, we were able to crystallise both forms of the [Eu(DOTA)(H2O)]- diastereomers. The single crystal structure was combined with single crystal luminescence spectroscopy to reveal the electronic structure of Eu(III) in each form of the complex. The coordination geometry of the crystallized cSAP and cTSAP forms of the complex was compared to ideal coordination polyhedra using a continuous symmetry measure in the AlignIt code. The diastereomers of [Eu(DOTA)(H2O)]- all demonstrate very little deviation from ideal geometries yet nearly identical electronic properties were observed from the two different forms.

Long story short: donor set symmetry in [Eu(DOTA)(H2O)]- crystals determines the electronic structure.

Lanthanide complexes of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid DOTA have been studied in great detail due to their use as MRI contrast agents. Since the first report from Desreux in 1980, the Ln[DOTA]- complexes of gadolinium(III) in particular have been thoroughly investigated. The forms of the nine-coordinated [Ln(DOTA)(H2O)]- complexes are well known, and the ligand backbone has been used extensively to create functional MRI contrast agents, luminescent probes, and as a model system for studying the properties of lanthanide(III) ions. In solution, the photophysical properties have been mapped, but as the structures are not known, direct structure-property relationships have not been created. Here, the electronic properties of two Eu[DOTA] compounds (1 and 2) and a Eu[DOTA]-like compound (3) were studied using single-crystal luminescence spectroscopy. The donor set in the three compounds is identical (4N 4O 1O), and using the symmetry deviation value σideal it was shown that the coordination geometry is close to identical. Nevertheless, the electronic properties evaluated using the luminescence spectrum were found to differ significantly between the three compounds. The magnitude of the crystal field splitting was found not to scale with the symmetry of the coordination geometry. It was concluded that the donor set dictates the splitting, yet the structure-property relationships governing the electronic properties of europium(III) ions still elude us.

We are never ever getting (back to) ideal symmetry: structure and luminescence in a ten-coordinated europium(III) sulfate crystal.

Our theoretical treatment of electronic structures in coordination complexes often rests on assumptions of symmetry. Experiments rarely provide fully symmetric systems to study. In solutions, fluctuations in solvation, variations in conformations, and even changes in constitution occur and complicate the picture. In crystals, lattice distortion, energy transfer, and phonon quenching play a role, but we are able to identify distinct symmetries. Yet the question remains: How is the real symmetry in a crystal compared to ideal symmetries?

Delicate, a study of the structural changes in ten-coordinated La(III), Ce(III), Pr(III), Nd(III), Sm(III) and Eu(III) sulfates.

We recently presented a new method that allows for a direct structural comparison of coordination complexes. The main difference from other methods is that our AlignIt approach uses common scaling and orientation of the complexes when computing the symmetry deviation, σideal, values. Here, six apparently isostructural lanthanide(III) sulfates K6[(Ln)2(SO4)6]/K5Na[(Ln)2(SO4)6] with ten-coordinated lanthanide(III) sites (Ln(O)10) were prepared, and single-crystal structures were determined and compared using the symmetry deviation (σideal) values. The six structures were shown to fall into two groups: Pr(III) and Eu(III) are identical (σideal = 0.04) bar in size. With a maximum σideal of 0.07, the same was found to be true for La(III), Ce(III), Nd(III), Sm(III) structures. The two groups are shown to be significantly different (σideal > 2.7), yet the coordination geometries of all six are best described as bicapped square antiprisms (σideal = 1.15-1.68). The structures differ in more than symmetry as the smaller lanthanides are shown to crystallize with one sodium and five potassium ions, while the larger lanthanides crystallize with six potassium ions. This does not change the structure and we postulate that the structural variation is due to delicate size matching between alkali and lanthanide ions. For the first six lanthanides, this structure is very robust, which is confirmed as seven doped systems readily crystallized. These doped systems were prepared in order to use europium(III) luminescence as a structural probe. Unsurprisingly, only the doped Eu-La and Eu-Ce systems were found to be luminescent. Between these two and all the europium(III) systems, the intricate structural differences were shown to be enough to change both crystal field splitting and luminescence lifetime. We conclude that even in simple dilution experiments, where luminescent lanthanide(III) ions are introduced in 'innocent' hosts materials, the structure can act as a modulator for the observed properties.

Health-Related Quality of Life in Colorectal Cancer Patients Treated With Liver Transplantation Compared to Chemotherapy.

Liver transplantation (LT) for patients with non-resectable colorectal liver metastases (CRLM) offers improved survival and has gained increased interest internationally the last years. The aim of this study was to describe the health-related quality of life (HRQoL) in patients with non-resectable CRLM receiving LT and how baseline HRQoL factors affect overall survival (OS). HRQoL data in the SECA (SEcondary CAncer) LT cohort was compared to data obtained from colorectal cancer patients starting first-line chemotherapy for metastatic disease in a clinical trial and data from a Norwegian normal population. HRQoL data from the QLQ-C30 questionnaire used in the SECA LT study and the NORDIC- VII study were reported. The relationship between patient-reported symptom burden at baseline and OS was investigated. In the SECA study longitudinal HRQoL assessment was used to describe the time until definitive deterioration as well as mean values at different time points. Patients in the SECA and NORDIC-VII studies reported similar baseline HRQoL. The median time until definitive deterioration in the transplanted patients was estimated to 36 months. In the SECA study appetite loss and pain at baseline had negative impact on OS (25.3 versus 71.7 months, p = 0.002 and 39.7 versus 71.7 months, p = 0.038, respectively). Despite a relapse in most of the LT patients the Global Health Score (GHS) remained good. Pain, and especially appetite loss at time of transplantation is associated with poor outcome after LT.

Revisiting the assignment of innocent and non-innocent counterions in lanthanide(III) solution chemistry.

Lanthanides are found in critical applications from display technology to renewable energy. Often, these rare earth elements are used as alloys or functional materials, yet access to them is through solution processes. In aqueous solutions, the rare earths are found predominantly as trivalent ions and charge balance dictates that counterions are present. The fast ligand exchange and lack of directional bonding in lanthanide complexes have led to questions regarding the speciation of Ln3+ solvates in the presence of various counterions and the distinction between innocent = non-coordinating and non-innocent = coordinating counterions. There is limited agreement as to which group counterions belong to, which led to this report. By using Eu3+ luminescence, it was possible to clearly distinguish between coordinating and non-coordinating ions. To interpret the results, it was required to bridge the descriptions of ion pairing and coordination. The data-in the form of Eu3+ luminescence spectra and luminescence lifetimes from solutions with varying concentrations of acetate, chloride, nitrate, sulfate, perchlorate and triflate-was contrasted to those obtained with ethylenediaminetetraacetic acid (EDTA4-), which allowed for the distinction between three Ln3+-anion interaction types. It was possible to conclude which counterions are truly innocent (e.g. ClO4- and OTf-) and which clearly coordinate (e.g. NO3- and AcO-). Finally, a considerable amount of data from systems studied under similar conditions allowed the minimum perturbation arising from the inner sphere or outer sphere coordination in Eu3+ complexes to be identified.

[Use of the sentinel lymph node procedure in colorectal cancer].

The use of a sentinel lymph node procedure (SN) in various cancer treatments including breast cancer is well examined. Little is known however, regarding the use of SN in colorectal cancer treatment. In this review, we explain the use of SN and its implications for future colorectal cancer treatment.

Breaking with the Principles of Coreduction to Form Stoichiometric Intermetallic PdCu Nanoparticles.

Intermetallic nanoparticles (NPs) have shown enhanced catalytic properties as compared to their disordered alloy counterparts. To advance their use in green energy, it is crucial to understand what controls the formation of intermetallic NPs over alloy structures. By carefully selecting the additives used in NP synthesis, it is here shown that monodisperse, intermetallic PdCu NPs can be synthesized in a controllable manner. Introducing the additives iron(III) chloride and ascorbic acid, both morphological and structural control can be achieved. Combined, these additives provide a synergetic effect resulting in precursor reduction and defect-free growth; ultimately leading to monodisperse, single-crystalline, intermetallic PdCu NPs. Using in situ X-ray total scattering, a hitherto unknown transformation pathway is reported that diverges from the commonly reported coreduction disorder-order transformation. A Cu-rich structure initially forms, which upon the incorporation of Pd(0) and atomic ordering forms intermetallic PdCu NPs. These findings underpin that formation of stoichiometric intermetallic NPs is not limited by standard reduction potential matching and coreduction mechanisms, but is instead driven by changes in the local chemistry. Ultimately, using the local chemistry as a handle to tune the NP structure might open new opportunities to expand the library of intermetallic NPs by exploiting synthesis by design.

Atorvastatin does not ameliorate nephrogenic diabetes insipidus induced by lithium or potassium depletion in mice.

Acquired forms of nephrogenic diabetes insipidus (NDI) include lithium (Li)-induced and hypokalemia-induced NDI. Both forms are associated with AQP2 downregulation and collecting duct (CD) cellular remodeling. Statins are cholesterol-lowering drugs appearing to increase AQP2 membrane-translocation and improve urine concentration in other NDI models. We have investigated if statins are able to prevent or rescue the Li-induced changes in mice and in a mouse cortical CD cell line (mCCDc1l ). Biotinylation assays showed that acute (1hr) atorvastatin, simvastatin, or fluvastatin increased AQP2 membrane accumulation in mCCDc1l cells showing that the cell line responds to acute statin treatment. To see whether chronic statin treatment abolish the Li effects, mCCDc1l cells were treated with 48 h Li, combined Li/atorvastatin or combined Li/simvastatin. Li reduced AQP2, but combined Li/atorvastatin or Li/simvastatin did not prevent AQP2 downregulation. In mice, chronic (21 days) Li increased urine output and reduced urine osmolality, but combined Li/atorvastatin did not prevent these effects. In inner medulla (IM), Li reduced total AQP2 and increased pS261-AQP2. Combined Li/atorvastatin did not abolish these changes. Atorvastatin did not prevent a Li-induced increase in intercalated cells and proliferation in IM. In mice with already established NDI, atorvastatin had no effect on the Li-induced changes either. Mice subjected to 14 days of potassium-deficient diet developed polyuria and AQP2 downregulation in IM. Co-treatment with atorvastatin did not prevent this. In conclusion, atorvastatin does not appear to be able to prevent or rescue Li-NDI or to prevent hypokalemic-induced NDI.

Utilizing Selective Chlorination to Synthesize New Triangulenium Dyes.

Functionalization of new sites on the triangulenium structure has been achieved by early-stage chlorination with N-chlorosuccinimide (NCS), giving rise to two new triangulenium dyes (1 and 3). By introducing the chlorine functionalities in the acridinium precursor, positions complementary to those previously obtained by electrophilic aromatic substitution on the final dyes are accessed. The chlorination is selective, giving only one regioisomer for both mono- and dichlorination products. For the monochlorinated acridinium compound, a highly selective ring-closing reaction was discovered, generating a single regioisomer of the cationic [4]helicene product. Further investigations into the mechanism of the [4]helicene formation lead to the first isolation of the previously proposed intermediate of the two-step SNAr reaction, key to all aza-bridged triangulenium and helicenium systems. Late-stage functionalization of DAOTA+ with NCS gave rise to a different dichlorinated compound (2). The fully ring closed chlorinated triangulenium dyes 1, 2, and 3 show a redshift in absorption and emission, while maintaining relatively high fluorescence quantum yields of 36%, 26%, and 41% and long fluorescence lifetimes of 15, 12.5, and 16 ns, respectively. Cyclic voltammetry shows that chlorination of the triangulenium dyes significantly lowers reduction potentials and thus allows for efficient tuning of redox and photoredox properties.

Crystal structure and optical properties of a two-sited EuIII compound: an EuIII ion coordinated by two [EuIII(DOTA)]- complexes (DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate).

The structure and solid-state luminescence properties of an EuIII compound with two different lanthanide sites, [Eu(µ-O)5(OH)(H2O)2][Eu(DOTA)(H2O)]2 (DOTA is 1,4,7,10-tetrazacyclododecane-1,4,7,10-tetraacetate, C16H24N4O8), were determined. The compound crystallizes in a laminar structure in the triclinic space group P-1, where the two sites are a free europium(III) ion and an [Eu(DOTA)(H2O)]- complex. The crystal structure was determined using complex data treatment due to nonmerohedral twinning. Experimental data sets were recorded with large redundancy and separated according to scattering domains in order to obtain a reliable structure. In the first site, the [Eu(DOTA)(H2O)]- complex was found to adopt a capped twisted square-antiprismatic (cTSAP) conformation, where a capping water molecule increased the coordination number of the europium(III) site to nine (CN = 9). In the second site, the europium(III) ion was found to be coordinated by two water molecules, one hydroxide group and five oxide groups from neighbouring [Eu(DOTA)(H2O)]- complexes. The coordination geometry of this site was found to be a compressed square antiprism (SAP) and the coordination number of the europium(III) ion was found to be eight (CN = 8). A large increase in the rate constant of luminescence was observed for EuIII in [Eu(DOTA)(H2O)]- in solid-state luminescence spectroscopy measurements compared to in solution, which led to investigations of single crystals in deuterated media to exclude additional effects of quenching. We conclude that the most probable cause of the decrease in the observed luminescence lifetimes is the high asymmetry of the coordination environment of [Eu(DOTA)(D2O)]- in the [Eu(µ-O)5(OD)(D2O)2][Eu(DOTA)(D2O)]2 crystals.

Three-wavelength broadband soot pyrometry technique for axisymmetric flames.

Soot temperature measurements in laminar flames are often performed through two-color broadband emission pyrometry (BEMI) or modulated absorption/emission (BMAE) techniques, using models to relate the ratio between flame intensities at two different wavelengths with soot temperature. To benefit from wider spectral range and increase the accuracy of experimental estimation of soot temperature, this work proposes a new approach that uses three-color broadband images captured with a basic color camera. The methodology is first validated through simulations using numerically generated flames from the CoFlame code and then used to retrieve soot temperature in an experimental campaign. The experimental results show that using three-color and BEMI provides smoother reconstruction of soot temperature than two-color and BMAE when small disturbances exist in the measured signals due to a reduced experimental noise effect. A sensitivity analysis shows that the retrieved temperature from three-color BEMI is more resilient to variations on the ratio of measured signals than BMAE, which is confirmed by an error propagation analysis based on a Monte Carlo approach.

Economic assessment of rewilding versus agri-environmental nature management.

Policies aiming at improving biodiversity often consist of costly agri-environmental schemes, i.e. subsidized grazing or mowing of semi-natural areas. However, these practices have widely been found to be insufficient to mitigate biodiversity loss. Rewilding, i.e. restoring natural processes in self-sustaining biodiverse ecosystems, has been proposed as an alternative and is hypothesized to be a more cost-efficient approach to promote biodiversity conservation. Rewilding requires the availability of large natural areas which are not allocated for farming, forestry, and infrastructure to avoid potential conflicts over the use of the area. We perform an ex-ante private cost-benefit analysis of the establishment of four large nature reserves for rewilding in Denmark. We analyse the economic effects of changing from summer grazing in nature areas in combination with cultivated fields and forestry to the establishment of nature reserves in four case areas. We consider two scenarios involving conversion of agriculture and forestry areas into natural areas in combination with either extensive year-round cattle grazing or rewilding with wild large herbivores. In two case areas, it appears possible to establish large nature areas without incurring extra costs. Additionally, rewilding further reduces costs compared to year-round cattle grazing. Two opposing effects were dominant: increased economic rent occurred from the shift from summer grazing to year-round grazing or rewilding, while cessation of agriculture and forestry caused opportunity costs.

Buoyancy effects on concurrent flame spread over thick PMMA.

The flammability of combustible materials in a spacecraft is important for fire safety applications because the conditions in spacecraft environments differ from those on earth. Experimental testing in space is difficult and expensive. However, reducing buoyancy by decreasing ambient pressure is a possible approach to simulate on-earth the burning behavior inside spacecraft environments. The objective of this work is to determine that possibility by studying the effect of pressure on concurrent flame spread, and by comparison with microgravity data, observe up to what point low-pressure can be used to replicate flame spread characteristics observed in microgravity. Specifically, this work studies the effect of pressure and microgravity on upward/concurrent flame spread over 10 mm thick polymethyl methacrylate (PMMA) slabs. Experiments in normal gravity were conducted over pressures ranging between 100 and 40 kPa and a forced flow velocity of 200 mm/s. Microgravity experiments were conducted during NASA's Spacecraft Fire Experiment (Saffire II), on board the Cygnus spacecraft at 100 kPa with an air flow velocity of 200 mm/s. Results show that reductions of pressure slow down the flame spread over the PMMA surface approaching that in microgravity. The data is correlated in terms of a non-dimensional mixed convection analysis that describes the convective heat transferred from the flame to the solid, and the primary mechanism controlling the spread of the flame. The extrapolation of the correlation to low pressures predicts well the flame spread rate obtained in microgravity in the Saffire II experiments. Similar results were obtained by the authors with similar experiments with a thin composite cotton/fiberglass fabric (published elsewhere). Both results suggest that reduced pressure can be used to approximately replicate flame behavior of untested gravity conditions for the burning of thick and thin solids. This work could provide guidance for potential ground-based testing for fire safety design in spacecraft and space habitats.

Danish medical schools do not meet international recommendations for teaching palliative medicine.

INTRODUCTION: Denmark has been ranked low regarding the extent of teaching in palliative care (PC) at medical schools although the Danish Health Authority recommends that all doctors have basic knowledge of PC. The aim of this study was to investigate the contents of and time spent on teaching in PC at the four Danish medical schools and to compare results with recommendations from the European Association of Palliative Care (EAPC). METHODS: Data were collected by examining university curricula, course catalogues, etc., using search words based on recommendations from the Palliative Education Assessment Tool and by a questionnaire survey among the university employees responsible for semesters or courses in Danish medical schools. RESULTS: Teaching in palliative medicine at Danish medical schools is generally sparse and mainly deals with pain management and general aspects of PC. Compared to European recommendations, teaching in, e.g., ethics, spirituality, teamwork and self-reflection is lacking. Furthermore, PC training does not reach the recommended minimum of 40 hours, and examinations in PC are not held. As from the autumn of 2017, the University of Southern Denmark has offered a course that expands teaching in PC and thereby improves compliance with EAPC recommendations; the remaining three medical schools do not, to our knowledge, have any specific plans to increase the extent of teaching activities in palliative medicine. CONCLUSIONS: Teaching in palliative medicine is sparse at all four medical schools in Denmark and should be strengthened to meet Danish as well as European recommendations. FUNDING: No funding was used for this study. TRIAL REGISTRATION: not relevant.

Harvest Strategies for Optimization of the Content of Bioactive Alkamides and Caffeic Acid Derivatives in Aerial Parts and in Roots of Echinacea purpurea.

Aerial parts and roots of Echinacea purpurea were harvested consecutively in order to find the best strategy for harvest of both types of plant material for an optimal content of bioactive alkamides and caffeic acid derivatives. Four caffeic acid derivatives and 15 alkamides were identified and quantified. The aerial parts were harvested in bud, bloom, and wilting stage and the roots were harvested 1 week, 1 month, and 3 months after each harvest of aerial parts. The highest yield per area of both alkamides and caffeic acid derivatives is achieved when the aerial parts are harvested late (wilting stage). To obtain an optimal content of alkamides and caffeic acid derivatives it is not recommendable to harvest the aerial parts and the roots in the same year. If the aerial parts must be harvested, the roots should be harvested 1 week after because this will result in the most optimal concentration of bioactive compounds in both products.

Prognostic role of carcinoembryonic antigen and carbohydrate antigen 19-9 in metastatic colorectal cancer: a BRAF-mutant subset with high CA 19-9 level and poor outcome.

BACKGROUND: Mutation status of RAS and BRAF, as well as serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9), are biomarkers used in clinical management of patients with gastrointestinal cancers. This study aimed to examine the prognostic role of these biomarkers in a patient population that started first-line chemotherapy for unresectable metastatic colorectal cancer (mCRC) in the NORDIC-VII study. METHODS: CEA and CA 19-9 were measured in serum samples from 545 patients obtained before the start of chemotherapy. Four hundred and ninety-four patients had detectable levels of carbohydrate antigen 19-9 (CA 19-9). RAS (exons 2-4) and BRAF (V600E) mutation status were available from 440 patients. Overall survival (OS) was estimated in patient groups defined by serum CEA or CA 19-9 levels using cut-off values of 5 µg/L and 35 kU/L, respectively, in the total population and in subgroups according to RAS and BRAF mutation status. RESULTS: For both CEA and CA 19-9, elevated serum levels were associated with reduced OS in adjusted analyses which included RAS and BRAF mutation status, baseline World Health Organization performance status, and levels of alkaline phosphatase and C-reactive protein. The negative prognostic information provided by an elevated CA 19-9 level was particularly marked in patients with BRAF mutation (hazard ratio = 4.35, interaction P = 0.003, in an adjusted model for OS). CONCLUSIONS: High baseline serum concentrations of CEA and CA 19-9 provide independent information of impaired prognosis in mCRC. In patients with BRAF-mutant tumours, elevated serum CA 19-9 may identify a subgroup with highly aggressive disease and could contribute to improving therapeutic decisions.