Revealing chemical release from plastic debris in animals' digestive systems using nontarget and suspect screening and simulating digestive fluids.

Plastic debris in the environment are not only pollutants but may also be important sources of a variety of contaminants. This work simulated kinetics and potential of chemical leaching from plastic debris in animals' digestive systems by incubating polyvinyl chloride (PVC) cord particles in artificial digestive fluids combined with nontarget and suspect screening based on UHPLC-Orbitrap HRMS. Impacts of particle size, aging, and digestive fluid were investigated to elucidate mechanisms of chemical leaching. Thousands of chemical features were screened in the leachates of PVC cord particles in the artificial digestive fluids, among which >60% were unknown. Bisphenol A (BPA) and bis(2-ethylhexyl) phthalate (DEHP) were the dominant identified CL1 compounds. Finer size and aging of the PVC particles and prolonged incubation time enhanced chemical release, resulting in greater numbers, higher levels, and more complexity in components of the released chemicals. The gastrointestinal fluid was more favorable for chemical leaching than the gastric fluid, with greater numbers and higher levels. Hundreds to thousands of chemical features were screened and filtered in the leachates of consumer plastic products, including food contact products (FCPs) in the artificial bird gastrointestinal fluid. In addition to BPA and DEHP, several novel bisphenol analogues were identified in the leachate of at least one FCP. The results revealed that once plastic debris are ingested by animals, hundreds to thousands of chemicals may be released into animals' digestive tracts in hours, posing potential synergistic risks of plastic debris and chemicals to plastic-ingesting animals. Future research should pay more attentions to identification, ecotoxicities, and environmental fate of vast amounts of unknown chemicals potentially released from plastics in order to gain full pictures of plastic pollution in the environment.

Canakinumab in combination with docetaxel compared with docetaxel alone for the treatment of advanced non-small cell lung cancer following platinum-based doublet chemotherapy and immunotherapy (CANOPY-2): A multicenter, randomized, double-blind, phase 3 trial.

OBJECTIVES: Canakinumab, an interleukin-1 beta inhibitor, previously showed reduced lung cancer incidence and mortality (CANTOS). Here, we compare the efficacy/safety of canakinumab versus placebo in patients with advanced non-small cell lung cancer (NSCLC) who had progressed after platinum-based doublet chemotherapy (PDC) and immunotherapy. MATERIALS AND METHODS: CANOPY-2, a randomized, double-blind, phase 3 trial, enrolled adult patients with stage IIIB/IV NSCLC, without EGFR or ALK alterations, who had received one prior PDC regimen and one prior programmed death-1/programmed death-ligand 1 inhibitor and experienced subsequent disease progression. Patients were randomized to canakinumab plus docetaxel or placebo plus docetaxel. RESULTS: A total of 237 patients were randomly allocated: 120 (51 %) to canakinumab and 117 (49 %) to placebo, stratified by histology and prior lines of therapy. Three patients in the placebo arm did not receive study treatment. The trial did not meet its primary endpoint of overall survival: median 10.6 months (95 % confidence interval [CI], 8.2-12.4) for the canakinumab arm and 11.3 months (95 % CI, 8.5-13.8) for the placebo arm (hazard ratio, 1.06 [95 % CI, 0.76-1.48]; one-sided P-value = 0.633). AEs (any grade) were reported in 95 % of patients in the canakinumab group and in 98 % of patients in the placebo group. Grade 3-4 AEs were experienced by 62 % and 64 % of patients in the canakinumab and placebo groups, respectively, and grade 5 AEs were experienced by 8 % and 5 %. Prespecified, post-hoc subgroup analyses showed that patients with undetected circulating tumor DNA (ctDNA) and/or lower levels (< 10 mg/L) of C-reactive protein (CRP) achieved longer progression-free and overall survival than those with detected ctDNA or higher (≥ 10 mg/L) CRP levels. There was no association with treatment arm. CONCLUSION: Adding canakinumab to docetaxel did not provide additional benefit for patients with advanced NSCLC who had progressed after PDC and immunotherapy. CLINICAL REGISTRATION: NCT03626545.

Synergistic Assembly of Charged Oligomers and Amino Acids at the Air-Water Interface: An Avenue toward Surface-Directed CO2 Capture.

Interfaces are considered a major bottleneck in the capture of CO2 from air. Efforts to design surfaces to enhance CO2 capture probabilities are challenging due to the remarkably poor understanding of chemistry and self-assembly taking place at these interfaces. Here, we leverage surface-specific vibrational spectroscopy, Langmuir trough techniques, and simulations to mechanistically elucidate how cationic oligomers can drive surface localization of amino acids (AAs) that serve as CO2 capture agents speeding up the apparent rate of absorption. We demonstrate how tuning these interfaces provides a means to facilitate CO2 capture chemistry to occur at the interface, while lowering surface tension and improving transport/reaction probabilities. We show that in the presence of interfacial AA-rich aggregates, one can improve capture probabilities vs that of a bare interface, which holds promise in addressing climate change through the removal of CO2 via tailored interfaces and associated chemistries.

Profile, Tissue Distribution, and Time Trend of Bisphenol Plastic Additives in Freshwater Wildlife of the Pearl River Ecosystem, China.

Plastic-related contaminants in the environment have attracted increasing attention, with plastic pollution becoming a serious issue globally. The present study investigated the potential bioaccumulation and biotransfer of bisphenol (BP) compounds that are widely added in various products such as plastics and other products in a freshwater ecosystem, China. Among commonly applied 14 BP analogues, bisphenol A (BPA), bisphenol F (BPF), and bisphenol S (BPS) were predominant, representing 64%-100% of the total concentrations of BPs (ΣBPs) in freshwater wildlife. Both the concentrations and analogue profiles in the fish showed seasonal differences and species dependence. Higher BP concentrations were observed in fish collected during the dry season than the wet season. Higher percentages of non-BPA analogues (e.g., BPS and BPF) were observed in fish collected during the wet season. Pelagic species accumulated notably higher levels of BPs than midwater and bottom species. The liver generally contained the highest ΣBPs, followed successively by the swim bladder, belly fat, and dorsal muscle. The analogue profile also showed some differences among tissues, varying by species and season. Lower ΣBPs but higher percentages of non-BPA analogues were observed in female than male common carp. Time trends of the BPA concentration in fish varied by species, probably related to habitats and diets of the fish. Habitats, feeding behaviors, and trophic transfer may have significant impacts on exposure of wildlife to BPs in natural ecosystems. The BPs did not demonstrate strong potential for bioaccumulation. More research is warranted about metabolism and transgenerational transfer of BPs in wildlife to fully reveal the bioaccumulation and consequently ecological risks of these chemicals in the environment. Environ Toxicol Chem 2023;42:2130-2142. © 2023 SETAC.

Long-Term Safety and Efficacy of Eltrombopag for Advanced Myelodysplastic Syndromes or Acute Myeloid Leukemia and Severe Thrombocytopenia: Results of the ASPIRE Extension Study.

ASPIRE, a three-part, international, phase 2 trial (ClinicalTrials.gov identifier: NCT01440374), investigated eltrombopag efficacy and safety in patients with advanced myelodysplastic syndrome or acute myeloid leukemia and grade 4 thrombocytopenia (<25 × 109 platelets/L). Approximately 30-65% of patients in this open-label extension phase experienced clinically relevant thrombocytopenic events; no conclusions could be made regarding long-term efficacy (non-randomized design, no placebo control), and survival rates may simply reflect advanced disease. Long-term safety was consistent with the double-blind phase and contrasted with earlier SUPPORT study findings in higher-risk patients, suggesting that eltrombopag may have a role in treating thrombocytopenia in patients with low-/intermediate-risk myelodysplastic syndrome.

Preparation of Polyethylene/α-Zirconium Phosphate Nanocomposites via a Well-Controlled Polyethylene-Grafted Interface.

It is a daunting task to prepare polyolefin nanocomposites that contain well-exfoliated nanoplatelets due to the nonpolar and high crystallinity nature of polyolefins. In this research, a robust approach was developed to prepare polyethylene (PE) nanocomposites by grafting maleated polyethylene (MPE) onto pre-exfoliated α-zirconium phosphate (ZrP) nanoplatelets via a simple amine-anhydride reaction to form ZrP-g-MPE. Several variables, including maleic anhydride (MA) content, MPE graft density, MPE molecular weight, and PE matrix crystallinity, were investigated to determine how they influence ZrP-g-MPE dispersion in PE. It was found that grafted PE has a different morphology and that the long PE brushes with medium graft density on ZrP can achieve sufficient chain entanglement and cocrystallization with PE matrix to stabilize and maintain ZrP-g-MPE dispersion after solution or melt mixing. This leads to enhanced Young's modulus, yield stress, and ductility. The structure-property relationship of PE/ZrP-g-MPE nanocomposites and usefulness of this study for the preparation of high-performance polyolefin nanocomposites are discussed.

Aurora A kinase inhibition compromises its antitumor efficacy by elevating PD-L1 expression.

Aurora A plays a critical role in G2/M transition and mitosis, making it an attractive target for cancer treatment. Aurora A inhibitors showed remarkable antitumor effects in preclinical studies, but unsatisfactory outcomes in clinical trials have greatly limited their development. In this study, the Aurora A inhibitor alisertib upregulated programmed death ligand 1 (PD-L1) expression in a panel of tumor cells both in vitro and in vivo. Upregulation of the checkpoint protein PD-L1 reduced antitumor immunity in immune-competent mice, paradoxically inhibiting the antitumor effects of alisertib. Mechanistically, Aurora A directly bound to and phosphorylated cyclic GMP-AMP synthase (cGAS), suppressing PD-L1 expression in tumor cells. Aurora A inhibition by alisertib activated the cGAS/stimulator of IFN genes (STING)/NF-κB pathway and promoted PD-L1 expression. Combining alisertib with anti-PD-L1 antibody improved antitumor immunity and enhanced the antitumor effects of alisertib in immune-competent mice. Our results, which reveal the immunomodulatory functions of Aurora A inhibitors and provide a plausible explanation for the poor clinical outcomes with their use, offer a potential approach to improve the antitumor efficacy of these inhibitors.

Multi-residue determination of bisphenol analogues in organism tissues by ultra-high performance liquid chromatography-tandem mass spectrometry.

A reliable and sensitive analyzing method was developed and validated for determination of 13 novel bisphenol analogues (BPs) along with bisphenol A (BPA) in organism tissues. The complex organism tissues were treated by ultrasonic-assisted extraction using acetonitrile/formic acid (99:1, v/v), followed by successive purification using enhanced matrix removal-lipid sorbents and primary secondary amine sorbents. The BPs were finally determined by ultra-high performance liquid chromatography-tandem mass spectrometry after derivatization using pyridine-3-sulfonyl chloride. Satisfactory recoveries of 75 - 118% were obtained for the BPs, with good repeatability (RSD < 20%). Matrix interferences were efficiently diminished. The method quantification limits (MQLs) reached 0.003 - 0.1 ng g-1 dry weight (dw). The validated method was successfully applied to a preliminary investigation of the BPs in wild marine organisms collected from the nearshore waters along the coast of Guangdong, China. Besides BPA, novel BPs such as bisphenol F, bisphenol AF, and tetrabromobisphenol A were also detected at < MDL - 15.5 ng g-1 dw. This work laid a strong basis for further in-depth research on bioaccumulation of the novel BPs in the environment.

The effect of sulfur on the leaching of Cr3+, Cr6+, Pb2+ and Zn2+ from fly ash glass.

This work assessed the capture and subsequent release of potentially harmful Cr(VI), Cr(III), Pb(II) and Zn(II) ions in and from dechlorinated fly ash glass. Differential scanning calorimetry, Fourier transform infrared spectroscopy, scanning electron microscopy - energy dispersive spectroscopy and inductively coupled plasma spectrometry along with other analytical techniques were used to explore the mechanism by which sulfur affected the immobilization and long-term leaching behavior of heavy metals in fly ash glass. Working with a CaO-MgO-Al2O3-SiO2-SO3 system, increasing the sulfur content was found to promote the leaching of Cr but had only a minimal effect on the loss of Pb and Zn. The concentrations of Pb and Zn in the leachate were found to remain at essentially nil over time while the Cr level increased up to 64 h and then decreased. The presence of Sulfur ions degraded the glass network and this promoted the leaching of S2-, Cr3+/Cr6+, Pb2+ and Zn2+. In addition, the S2- ions reacted with Pb2+ and Zn2+ to form needle-shaped and flocculent sulfide precipitates, thus trapping the Pb2+ and Zn2+. Si4+, Ca2+, Al3+ and Fe3+ were also found to migrate into the leaching solution where they combined to form a dendritic flocculent that adsorbed and encapsulated Cr. This phenomenon greatly reduced the concentration of Cr in the leachate. Thus, sulfur prevented the leaching of Cr, Pb and Zn via different mechanisms.

Fracture Behavior of Polyrotaxane-Toughened Poly(Methyl Methacrylate).

The fracture behavior of polyrotaxane (PR)-modified poly(methyl methacrylate) (PMMA) was investigated. PR is a supramolecule with rings threaded onto a linear backbone chain, which is capped by bulky end groups to prevent the rings from de-threading. The ring structure is α-cyclodextrin (CD), and it can be functionalized to enhance its affinity with the hosting polymer matrix. Adding only 1 wt % of PR containing methacrylate functional groups (mPR) at the terminal of some of the polycaprolactone-grafted chains on CD promotes massive crazing, resulting in a significant improvement in fracture toughness while maintaining the modulus and transparency of the PMMA matrix. Dynamic mechanical analysis and atomic force microscopy studies reveal that mPR strongly interact with PMMA, leading to higher molecular mobility and enhanced molecular cooperativity during deformation. This molecular cooperativity may be responsible for the formation of massive crazing in a PMMA matrix, which leads to greatly improved fracture toughness.

Neutrophil-to-lymphocyte ratio is associated with carotid intraplaque neovascularization in asymptomatic carotid stenosis patients.

BACKGROUND AND PURPOSE: Neutrophil-to-lymphocyte ratio (NLR) has been suggested as an available systemic inflammatory biomarker. This study aims to evaluate whether intraplaque neovascularization assessed by contrast-enhanced ultrasound (CEUS) is associated with NLR in asymptomatic carotid stenosis patients. MATERIALS AND METHODS: One hundred and forty-four asymptomatic patients with carotid luminal stenosis >30% were assessed using contrast-enhanced ultrasound imaging. The contrast enhancement within the plaque was classified on a visual semiquantitative grading scale. The data collected included the patient's risk factors, laboratory results, cardiovascular disease history, and drug use history. Univariate and multivariate analyses were assessed to identify independent factors related to intraplaque neovascularization with adjustment for potential confounders. RESULTS: Patients with CEUS grade 2 plaques had a higher level of LDL-C (p < .001), neutrophil count (p < .001), and blood glucose (p = .005), but lower level of lymphocyte count (p = .021). The presence of grade 2 plaques was significantly associated with high NLR values (OR 1.21, 95% CI 1.03-1.43, p = .017). Patients were divided into four groups according to the quartile of NLR values. Compared to the patients in the first quartile of NLR (<1.73), the patients in the fourth NLR quartile (≥3.38) were characterized by the most prevalence of CEUS grade 2 plaques (OR 4.55, 95% CI 1.69-12.25, p = .003). Multivariate logistic regression analysis after adjusting various variables demonstrated NLR remained an independent risk factor for the presence of CEUS grade 2 plaques. CONCLUSION: Intraplaque neovascularization is significantly associated with NLR in asymptomatic carotid stenosis patients.

Preparation of Well-Exfoliated Poly(ethylene-co-vinyl acetate)/α-Zirconium Phosphate Nanocomposites.

Poly(ethylene-co-vinyl acetate) (PEVAc) nanocomposites containing exfoliated α-zirconium phosphate (ZrP) have been prepared using a simple solution mixing method to improve their barrier and mechanical properties. ZrP was pre-exfoliated with a surfactant, followed by additional targeted surface functionalization and surfactant exchange to allow for hydrogen bonding of ZrP with the acetate functionality on PEVAc and to improve ZrP surface hydrophobicity. The solvent is found to play an important role in stabilizing ZrP exfoliation in the presence of PEVAc to retain full exfoliation and homogeneous dispersion upon the removal of the solvent. The PEVAc/ZrP nanocomposite exhibits greatly improved oxygen barrier, melt strength, and mechanical properties. The usefulness of the present study for the preparation of olefinic polymer nanocomposites is discussed.

Lifetime bioaccumulation, gender difference, tissue distribution, and parental transfer of organophosphorus plastic additives in freshwater fish.

Plastic pollution has been a growing global issue. Various plastic additives may enter the environment with plastic debris, which could also become contaminants. Lifetime bioaccumulation, gender difference, tissue distribution, and parental transfer potential of commonly applied organophosphorus plastic additives (OPPAs) were investigated in wildlife fish of the Pearl River system, China. The OPPAs were widely detected in 7 consumable fish species. Tris (2-chloropropyl) phosphate was the predominant compound, with a median concentration of 18.8 ng/g lipid weight. The total OPPA concentrations (ΣOPPAs) were higher in the livers and swimming bladders, suggesting important roles of lipophilicity on the OPPAs accumulation in the fish. Besides, the livers were more abundant in the non-chlorinated OPPAs relative to the other tissues, indicating potentially stronger metabolism of the chlorinated OPPAs in the livers. Redbelly tilapia contained obviously lower ΣOPPAs than the other species. On the other hand, proportions of the chlorinated OPPAs were obviously lower in barbel chub and Guangdong black bream. For an individual species, higher ΣOPPAs were usually detected in the female than in the male fish. Furthermore, the females contained higher proportions of the non-chlorinated OPPAs. These results suggested potentially more accumulation of the OPPAs, particularly the non-chlorinated OPPAs in the female than in the male fish. Body weight dependence of the OPPAs accumulation showed varied patterns depending on species, tissue, and compound. Species-specific characteristics affected by both ecology and organisms' physiology should be considered in combination in assessing bioaccumulation of the OPPAs. The OPPAs were slightly bioaccumulative with LogBAFs of 1.2-3.3. The OPPAs did not show obvious inclination to be partitioned to biota from sediment. Omnipresence of the OPPAs in both egg/ovary and testis of the fish suggested potential transgenerational transfer of these chemicals, which can be a serious ecological issue and warrants further research.

α-Zirconium Phosphate Nanoplatelets with Covalent Modifiers for Exfoliation in Organic Media.

Nanocomposites with exfoliated 2D materials are highly sought after due to resulting material enhancement of barrier and increased modulus among others. In the past, this was achieved by using polyols that were effective but caused a significant drop in the glass transition temperature of the nanocomposite. In this contribution, α-zirconium phosphate (ZrP) nanoplatelets were covalently modified to allow for dispersion in solvents with varying hydrophobicity and poly(methyl methacrylate) (PMMA) for the first time. The nanoplatelets were prepared by using a polyetheramine surfactant to achieve exfoliation, followed by modification with epoxides. Combinations of different epoxides were shown capable of tuning the functionality and hydrophobicity of the exfoliated ZrP in organic media. After grafting glycidyl methacrylate and cyclohexene oxide to the surface of ZrP, an in situ free radical polymerization of MMA allowed for high concentrations of self-assembled exfoliated ZrP in a PMMA matrix.

Manipulation of Fracture Behavior of Poly(methyl methacrylate) Nanocomposites by Interfacial Design of a Metal-Organic-Framework Nanoparticle Toughener.

The interfacial region between nanoparticles and polymer matrix plays a critical role in influencing the mechanical behavior of polymer nanocomposites. In this work, a set of model systems based on poly(methyl methacrylate) (PMMA) matrix containing poly(alkyl glycidyl ether) brushes grafted on 50 nm metal-organic-framework (MOF) nanoparticles were synthesized and investigated. By systematically increasing the polymer brush length and graft density on the MOF nanoparticles, the fracture behavior of PMMA/MOF nanocomposite changes from forming only a few large crazes to generating massive crazing and to undergoing shear banding, which results in significant improvement in fracture toughness. The implication of the present finding for the interfacial design of the nanoparticles for the development of high-performance, multifunctional polymer nanocomposites is discussed.

Tissue Distribution, Growth Dilution, and Species-Specific Bioaccumulation of Organic Ultraviolet Absorbents in Wildlife Freshwater Fish in the Pearl River Catchment, China.

Tissue distributions and body-size dependent and species-specific bioaccumulation of 12 organic ultraviolet absorbents (UVAs) were investigated in 9 species of wildlife freshwater fish from the Pearl River catchment, South China. The concentrations of the 12 UVAs were from 109 to 2320 ng/g lipid weight in the fish tissue samples. The UVAs 2-hydroxy-4-methoxybenzophenone (BP-3), octocrylene (OCR), UV531, and 5 benzotriazole UV stabilizers (UVP, UV329, UV234, UV328, and UV327) were detected in more than half of the fish tissue samples. The UVA UV531 showed an obvious potential for bioaccumulation in the wild freshwater fish, with an estimated bioaccumulation factor (log BAF) and a biota-sediment accumulation factor (BSAF) of 4.54 ± 0.55 and 4.88 ± 6.78, respectively. Generally, liver (989 ± 464 ng/g lipid wt) contained the highest level of UVAs, followed in decreasing order by belly fat (599 ± 318 ng/g lipid wt), swimming bladder (494 ± 282 ng/g lipid wt), dorsal muscle (470 ± 240 ng/g lipid wt), and egg (442 ± 238 ng/g lipid wt). The bioaccumulation of UVAs in the freshwater wild fish was species specific and compound dependent. Bottom-dwelling detritus-ingesting omnivorous fish contained obviously higher UVA concentrations, suggesting that detritus/sediment ingestion is a significant pathway for exposure of the wild freshwater fish to the UVAs. The UVAs UV531 and BP-3 demonstrated a potential for growth dilution. Metabolism might play a significant role in elimination of the UVAs in the fish tissues, with the highest rate of metabolism in the liver. The UVAs did not demonstrate obvious trophic magnification in the freshwater ecosystem of the Pearl River catchment. More research is warranted to elucidate maternal transfer of the UVAs. Environ Toxicol Chem 2020;39:343-351. © 2019 SETAC.

Distribution, sedimentary record, and persistence of microplastics in the Pearl River catchment, China.

Microplastics (MPs) in the environment have become an issue worldwide. However, data about MPs in freshwater systems are still limited so far. This study investigated sources, fate, and seasonal and spatial distribution of MPs in the main stream Pearl River and its tributaries, as well as in the Pearl River Estuary (PRE), China. MPs were widely detected in the river water, river bed sediment, and estuarine sediment, with abundances of 0.57 ±â€¯0.71 items L-1, 685 ±â€¯342 items kg-1 dry weight (dw), and 258 ±â€¯133 items kg-1 dw, respectively. Sheet, fragmental, and fibrous polyethylene, polypropylene, and ethylene-propylene copolymers were predominant, suggesting that MPs in the Pearl River catchment be mainly derived from fragmentation of discarded plastic wastes. In addition, municipal wastewater was also an important MPs source, especially for polyethylene terephthalate (PET) fibers. Polymers of higher density, such as PET and polyvinyl alcohol were relatively more abundant in the sediment than in the river water, especially in the estuarine sediment. Upward increase of the MP abundance was observed in the sedimentary core, probably indicating increasing release of plastic wastes due to growing production and uses of plastic products. On the other hand, percentage of finer MPs increased with increasing depth. The results revealed persistence and potential downward dispersion of the fine MPs. The MPs abundance was positively related with population density and gross domestic product, demonstrating impacts of human activities and economic development on the MPs contamination. Higher MPs abundance was detected in dry season than in wet season in the river water, suggesting dilution effect of precipitation. It's estimated that 15963 tons of MPs could be released annually into the PRE from the main stream Pearl River and its tributaries.

Occurrence and Species-Specific Distribution of Plastic Debris in Wild Freshwater Fish from the Pearl River Catchment, China.

Freshwater systems are an important source and vector of plastic debris found in oceans. However, plastic debris in freshwater organisms has not been well studied. The occurrence, characterization, polymer composition, and seasonal and spatial distribution of plastic debris were investigated in 9 species of wild freshwater fish from the Pearl River catchment, south China. Approximately 50% of the total fish (n = 279) belonging to 9 species were found to ingest plastic debris with an average abundance of 7.0 ± 23.8 items/individual, indicating wide plastic contamination in the Pearl River catchment. Plastic debris were predominantly transparent or white in color, fibers or fragments in shape, and polyethylene, polypropylene, ethylene-propylene copolymer (PE-PP), and polyethylene terephthalate (PET) in polymer composition. A species-specific distribution of the plastic debris was observed in terms of abundance, shape, and polymer composition. Redbelly tilapia had the highest (27.4 ± 54.0 items/individual), whereas common carp had the lowest (0.2 ± 0.4 items/individual) abundance of the plastic debris in their gastrointestinal tracts. Fibers of PET were predominant in the freshwater species except in barbel chubs, which had mostly PE-PP fragments. Omnivores and bottom-dwellers were more likely to ingest plastic debris. Seasonal variation was observed, with generally higher abundance of plastic debris in fish collected in the dry season than in the wet season. Environ Toxicol Chem 2019;38:1504-1513. © 2019 SETAC.

Effect of crizanlizumab on pain crises in subgroups of patients with sickle cell disease: A SUSTAIN study analysis.

The cell adhesion molecule P-selectin plays a key role in the pathogenesis of a vaso-occlusive crisis (VOC) in patients with sickle cell disease (SCD). In the double-blind, placebo-controlled phase 2 SUSTAIN study, crizanlizumab (humanized, anti-P-selectin monoclonal antibody) 5 mg/kg significantly lowered the rate of VOC in patients with SCD by 45% vs placebo. In SUSTAIN, patients with SCD were randomized to crizanlizumab 2.5 mg/kg, crizanlizumab 5 mg/kg, or placebo intravenously 14 times over 52 weeks. The primary endpoint was the annual rate of VOC with crizanlizumab vs placebo. This post hoc descriptive analysis evaluated the proportion of patients who did not experience a VOC during the study in the following subgroups: VOCs in the year prior to study entry (2-4/5-10), SCD genotype (HbSS/non-HbSS), and concomitant hydroxyurea use (yes/no). More patients were VOC event-free in the crizanlizumab 5 mg/kg arm than in the placebo arm, including those with more frequent prior VOCs (ie, 5-10; 28.0% vs 4.2%), the HbSS genotype (31.9% vs 17.0%) and/or using concomitant hydroxyurea (33.3% vs 17.5%). Further analyses of secondary endpoints demonstrated that crizanlizumab treatment significantly increased time-to-first VOC vs placebo in these subgroups. The rates of treatment-emergent adverse events were similar between treatment arms across all subgroups. This post hoc analysis of SUSTAIN shows that in patients with a high number of prior VOCs, on concomitant hydroxyurea and/or with the HbSS genotype, crizanlizumab treatment increases the likelihood of patients being VOC event-free and delays time-to-first VOC.

Eltrombopag for advanced myelodysplastic syndromes or acute myeloid leukaemia and severe thrombocytopenia (ASPIRE): a randomised, placebo-controlled, phase 2 trial.

BACKGROUND: Thrombocytopenia is a life-threatening complication in patients with advanced myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML). In this study (ASPIRE), we aimed to assess eltrombopag, an oral thrombopoietin receptor agonist, for thrombocytopenia (grade 4) treatment in adult patients with advanced MDS or AML. METHODS: ASPIRE consisted of an open-label, double-blind phase for 8 weeks and a randomised, double-blind phase (parts 1 and 2, reported here) for 12 weeks, and an open-label extension (part 3). Eligible patients were men and women aged 18 years or older, with intermediate-2 or high-risk MDS or AML, with bone marrow blasts of 50% or less, and had either grade 4 thrombocytopenia due to bone marrow insufficiency (platelet counts <25 × 109 per L) or grade 4 thrombocytopenia before platelet transfusion, with 25 × 109 platelets per L or greater after transfusion. Additionally, eligible patients had at least one of the following within the screening period of 4 weeks: platelet transfusion, symptomatic bleeding, or platelet count of less than 10 × 109 per L. During part 1, patients received eltrombopag, and dose-escalation criteria for part 2 were determined. In part 2, we randomly allocated patients 2:1 using an interactive voice-response system to eltrombopag or placebo, stratified by baseline platelet count (<10 × 109 platelets per L vs ≥10 × 109 platelets per L) and disease (MDS vs AML). In parts 1 and 2, patients received supportive standard of care and initiated eltrombopag or placebo at 100 mg per day (50 mg per day for patients of east-Asian heritage) to a maximum of 300 mg per day (150 mg per day for patients of east-Asian heritage). The part 2 primary objective was assessed by a composite primary endpoint of clinically relevant thrombocytopenic events (CRTE) during weeks 5-12, defined as one of the following events, either alone or in combination: grade 3 or worse haemorrhagic adverse events; platelet counts of less than 10 × 109 per L; or platelet transfusions. Efficacy analyses were based on intention to treat; clinically meaningful efficacy was defined as 30% absolute difference between groups. This trial is registered with ClinicalTrials.gov, number NCT01440374. FINDINGS: In part 1, 17 patients received eltrombopag and 11 patients completed treatment; four experienced significantly increased platelet counts, and ten had reduced platelet transfusion requirements. In part 2 we randomly allocated 145 patients to receive supportive care plus eltrombopag (n=98) or placebo (n=47); similar proportions had MDS (50 [51%] patients to eltrombopag, 22 (47%) patients to placebo) or AML (48 [49%] patients to eltrombopag, 25 [53%] patients to placebo). Average weekly CRTE proportions from weeks 5-12 were significantly lower with eltrombopag (54% [95% CI 43-64]) than with placebo (69% [57-80], odds ratio [OR] 0·20, 95% CI 0·05-0·87; p=0·032) although the difference between treatment groups was less than 30%. The most common grade 3 and grade 4 adverse events were fatigue (six [6%] in the eltrombopag group and one [2%] in the placebo group), hypokalaemia (six [6%] and two [4%]), pneumonia (five [5%] and five [11%]), and febrile neutropenia (five [5%] and six [13%]). Serious adverse events were reported in 56 (58%) eltrombopag-treated patients and 32 (68%) placebo-treated patients. Seven eltrombopag recipients and two placebo recipients had serious adverse events that were suspected to be study drug-related (eltrombopag: acute kidney injury, arterial thrombosis, bone pain, diarrhoea, myocardial infarction, pyrexia, retinal vein occlusion, n=1 each; placebo: vomiting, white blood cell count increased, n=1 each). Two eltrombopag recipients (arterial thrombosis n=1; myocardial infarction n=1) and no placebo recipients experienced fatal serious adverse events suspected to be study drug-related. INTERPRETATION: No new safety concerns were noted with eltrombopag and the trial met the primary objective of a reduction in CRTEs; eltrombopag might be a treatment option for thrombocytopenic patients with AML or MDS who are ineligible for other treatment and who are not receiving disease-modifying treatment. FUNDING: Novartis Pharma AG.