A Canadian Study of Cisplatin Metabolomics and Nephrotoxicity (ACCENT): A Clinical Research Protocol

Background: Cisplatin, a chemotherapy used to treat solid tumors, causes acute kidney injury (AKI), a known risk factor for chronic kidney disease and mortality. AKI diagnosis relies on biomarkers which are only measurable after kidney damage has occurred and functional impairment is apparent; this prevents timely AKI diagnosis and treatment. Metabolomics seeks to identify metabolite patterns involved in cell tissue metabolism related to disease or patient factors. The A Canadian study of Cisplatin mEtabolomics and NephroToxicity (ACCENT) team was established to harness the power of metabolomics to identify novel biomarkers that predict risk and discriminate for presence of cisplatin nephrotoxicity, so that early intervention strategies to mitigate onset and severity of AKI can be implemented. Objective: Describe the design and methods of the ACCENT study which aims to identify and validate metabolomic profiles in urine and serum associated with risk for cisplatin-mediated nephrotoxicity in children and adults. Design: Observational prospective cohort study. Setting: Six Canadian oncology centers (3 pediatric, 1 adult and 2 both). Patients: Three hundred adults and 300 children planned to receive cisplatin therapy. Measurements: During two cisplatin infusion cycles, serum and urine will be measured for creatinine and electrolytes to ascertain AKI. Many patient and disease variables will be collected prospectively at baseline and throughout therapy. Metabolomic analyses of serum and urine will be done using mass spectrometry. An untargeted metabolomics approach will be used to analyze serum and urine samples before and after cisplatin infusions to identify candidate biomarkers of cisplatin AKI. Candidate metabolites will be validated using an independent cohort. Methods: Patients will be recruited before their first cycle of cisplatin. Blood and urine will be collected at specified time points before and after cisplatin during the first infusion and an infusion later during cancer treatment. The primary outcome is AKI, defined using a traditional serum creatinine-based definition and an electrolyte abnormality-based definition. Chart review 3 months after cisplatin therapy end will be conducted to document kidney health and survival. Limitations: It may not be possible to adjust for all measured and unmeasured confounders when evaluating prediction of AKI using metabolite profiles. Collection of data across multiple sites will be a challenge. Conclusions: ACCENT is the largest study of children and adults treated with cisplatin and aims to reimagine the current model for AKI diagnoses using metabolomics. The identification of biomarkers predicting and detecting AKI in children and adults treated with cisplatin can greatly inform future clinical investigations and practices

Measurement of ϕ\phi-meson production in Cu++Au at sNN=200\sqrt{s_{_{NN}}}=200 GeV and U++U at sNN=193\sqrt{s_{_{NN}}}=193 GeV

The PHENIX experiment reports systematic measurements at the Relativistic Heavy Ion Collider of $\phi$-meson production in asymmetric Cu$+$Au collisions at $\sqrt{s_{_{NN}}}$=200 GeV and in U$+$U collisions at $\sqrt{s_{_{NN}}}$=193 GeV. Measurements were performed via the $\phi\rightarrow K^{+}K^{-}$ decay channel at midrapidity $|\eta|<0.35$. Features of $\phi$-meson production measured in Cu$+$Cu, Cu$+$Au, Au$+$Au, and U$+$U collisions were found to not depend on the collision geometry, which was expected because the yields are averaged over the azimuthal angle and follow the expected scaling with nuclear-overlap size. The elliptic flow of the $\phi$ meson in Cu$+$Au, Au$+$Au, and U$+$U collisions scales with second order participant eccentricity and the length scale of the nuclear overlap region (estimated with the number of participating nucleons). At moderate $p_T$, $\phi$-meson production measured in Cu$+$Au and U$+$U collisions is consistent with coalescence-model predictions, whereas at high $p_T$ the production is in agreement with expectations for in-medium energy loss of parent partons prior to their fragmentation. The elliptic flow for $\phi$ mesons measured in Cu$+$Au and U$+$U collisions is well described by a (2+1)D viscous-hydrodynamic model with specific-shear viscosity $\eta/s=1/4\pi$.Comment: 411 authors from 76 institutions, 16 pages, 12 figures, 9 tables, 2012 data. v1 is version submitted to Physical Review C. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

A Canadian Study of Cisplatin Metabolomics and Nephrotoxicity (ACCENT): A Clinical Research Protocol.

BackgroundCisplatin, a chemotherapy used to treat solid tumors, causes acute kidney injury (AKI), a known risk factor for chronic kidney disease and mortality. AKI diagnosis relies on biomarkers which are only measurable after kidney damage has occurred and functional impairment is apparent; this prevents timely AKI diagnosis and treatment. Metabolomics seeks to identify metabolite patterns involved in cell tissue metabolism related to disease or patient factors. The A Canadian study of Cisplatin mEtabolomics and NephroToxicity (ACCENT) team was established to harness the power of metabolomics to identify novel biomarkers that predict risk and discriminate for presence of cisplatin nephrotoxicity, so that early intervention strategies to mitigate onset and severity of AKI can be implemented.ObjectiveDescribe the design and methods of the ACCENT study which aims to identify and validate metabolomic profiles in urine and serum associated with risk for cisplatin-mediated nephrotoxicity in children and adults.DesignObservational prospective cohort study.SettingSix Canadian oncology centers (3 pediatric, 1 adult and 2 both).PatientsThree hundred adults and 300 children planned to receive cisplatin therapy.MeasurementsDuring two cisplatin infusion cycles, serum and urine will be measured for creatinine and electrolytes to ascertain AKI. Many patient and disease variables will be collected prospectively at baseline and throughout therapy. Metabolomic analyses of serum and urine will be done using mass spectrometry. An untargeted metabolomics approach will be used to analyze serum and urine samples before and after cisplatin infusions to identify candidate biomarkers of cisplatin AKI. Candidate metabolites will be validated using an independent cohort.MethodsPatients will be recruited before their first cycle of cisplatin. Blood and urine will be collected at specified time points before and after cisplatin during the first infusion and an infusion later during cancer treatment. The primary outcome is AKI, defined using a traditional serum creatinine-based definition and an electrolyte abnormality-based definition. Chart review 3 months after cisplatin therapy end will be conducted to document kidney health and survival.LimitationsIt may not be possible to adjust for all measured and unmeasured confounders when evaluating prediction of AKI using metabolite profiles. Collection of data across multiple sites will be a challenge.ConclusionsACCENT is the largest study of children and adults treated with cisplatin and aims to reimagine the current model for AKI diagnoses using metabolomics. The identification of biomarkers predicting and detecting AKI in children and adults treated with cisplatin can greatly inform future clinical investigations and practices