The EU-project ERAPharm - Incentives for the further development of guidance documents? (4 pages)

-: Triggered by the detection of a large variety of pharmaceuticals in surface waters, soils and groundwaters across the world (e.g. Halling- Sørensen et al. 1998, Daughton & Ternes 1999, Jones et al. 2001, Heberer 2002) and the widespread occurrence of endocrine active compounds and related effects in the environment (e.g. Purdom et al. 1994, Tyler et al. 1998, Vethaak et al. 2002), pharmaceuticals in the environment have become an issue for both the scientific and the public community. During the last few years, our understanding of the fate and effects of pharmaceuticals in the environment has progressed significantly. However, there are still a number of uncertainties concerning the effects of pharmaceuticals on the environment and the assessment of potential exposure (e.g. Hanisch et al. 2004, Salomon 2005). These uncertainties will be addressed by the EU-project ‘Environmental risk assessment of pharmaceuticals' (ERAPharm). This project, a specific targeted research project, is carried out within the priority ‘Global change and ecosystems' of the 6th framework programme of the European Union. ERAPharm has started on 1st October 2004; the project duration is three year

Hipertensão arterial e diabetes mellitus: prevalência e impacto econômico em Goiânia e região metropolitana de 2008 a 2017

Objective: To estimate the prevalence of systemic arterial hypertension and diabetes mellitus, and to evaluate the average costs of hospitalizations for complications resulting from inadequate disease control. Methods: A cross-sectional study analyzed the prevalence and economic impact of systemic arterial hypertension and diabetes mellitus in Goiânia and metropolitan region from 2008 to 2017. We surveyed the referred diagnosis and average cost of hospitalizations due to complications of the two diseases from the following: Surveillance of Risk Factors and Protection for Chronic Diseases by Telephone and Hospital Inpatient Surveys of the Unified Health System. Results: The prevalence rate of both diseases was higher in women, ranging from 34.31% for systemic arterial hypertension and 8.64% for diabetes mellitus between 2008 and 2017. Concerning men, there was a variation of 28.88% for hypertension and 8.55% for diabetes mellitus. The average cost of hospitalizations for complications related to both diseases was R$1,392,973.40 in a decade, with the medium cost varying between them. Conclusion: There were high prevalence rates of systemic arterial hypertension and diabetes mellitus in resident adults of Goiânia and metropolitan regions during the investigated period. Also, there was a high average cost in hospitalizations associated with complications of the illness. The findings suggest the need for health surveillance actions aimed at structuring prevention strategies, encouraging treatment adherence and managing systemic arterial hypertension and diabetes mellitus.Objetivo: Estimar a prevalência de hipertensão arterial sistêmica e de diabetes mellitus e avaliar os custos médios de internações por complicações decorrentes do mau controle da doença. Métodos: Estudo observacional descritivo que analisou a prevalência e o impacto econômico da hipertensão arterial sistêmica e do diabetes mellitus em Goiânia e região metropolitana de 2008 a 2017. Foram analisados o diagnóstico referido e custo médio das internações por complicações das duas doenças, a partir dos bancos de dados Vigilância de Fatores de Risco e Proteção para Doenças Crônicas por Inquérito Telefônico e do Sistema de Internações Hospitalares do Sistema Único de Saúde. Resultados: A prevalência para as duas doenças foi maior em mulheres, variando 34,31$ em uma década, com custo médio variando entre os agravos. Conclusão: As taxas de prevalência de hipertensão arterial sistêmica e diabetes mellitus em adultos residentes de Goiânia e região metropolitana mostrou-se elevada durante o período analisado. Também verificou-se custo médio elevado nas internações hospitalares associadas a complicações da doença. Os achados deste estudo sugerem a necessidade de ações de vigilância em saúde, visando a estruturação de estratégias de prevenção, estímulo a adesão ao tratamento e controle da hipertensão arterial sistêmica e diabetes mellitus.&nbsp

Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer

Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls

Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group

Funder: U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)Funder: National Center for Research Resources under award number 1 C06 RR12463-01, VA Merit Review Award IBX004121A from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the DOD Prostate Cancer Idea Development Award (W81XWH-15-1-0558), the DOD Lung Cancer Investigator-Initiated Translational Research Award (W81XWH-18-1-0440), the DOD Peer Reviewed Cancer Research Program (W81XWH-16-1-0329), the Ohio Third Frontier Technology Validation Fund, the Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering and the Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University.Funder: Susan G Komen Foundation (CCR CCR18547966) and a Young Investigator Grant from the Breast Cancer Alliance.Funder: The Canadian Cancer SocietyFunder: Breast Cancer Research Foundation (BCRF), Grant No. 17-194Abstract: Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring

Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Funder: Breast Cancer Research Foundation (BCRF); doi: https://doi.org/10.13039/100001006Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting

The EU-project ERAPharm: Incentives for the further development of guidance documents?

ISSN:0944-1344ISSN:1614-749

Environmental risk assessment of human pharmaceuticals in the European Union: A case study with the beta-blocker atenolol

β-Adrenergic receptor blockers (b-blockers) are applied to treat high blood pressure, ischemic heart disease, and heart rhythm disturbances. Due to their widespread use and limited human metabolism, b-blockers are widely detected in sewage effluents and surface waters. b-Adrenergic receptors have been characterized in fish and other aquatic animals, so it can be expected that physiological processes regulated by these receptors in wild animals may be affected by the presence of bblockers. Because ecotoxicological data on b-blockers are scarce, it was decided to choose the β -blocker atenolol as a case study pharmaceutical within the project ERAPharm. A starting point for the assessment of potential environmental risks was the European guideline on the environmental risk assessment of medicinal products forhumanuse. In Phase I of the risk assessment, the initial predicted environmental concentration (PEC) of atenolol in surface water (500 ng L ) exceeded the action limit of 10 ng L . Thus, a Phase II risk assessment was conducted showing acceptable risks for surface water, for groundwater, and for aquatic microorganisms. Furthermore, atenolol showed a low potential for bioaccumulation as indicated by its low lipophilicity (log KOW0.16), a low potential for exposure of the terrestrial compartment via sludge (log KOC2.17), and a low affinity for sorption to the sediment. Thus, the risk assessment according to Phase II-Tier A did not reveal any unacceptable risk for atenolol. Beyond the requirements of the guideline, additional data on effects and fate were generated within ERAPharm. A2-generation reproduction test with the waterflea Daphnia magna resulted in the most sensitive no-observed-effect concentration (NOEC) of 1.8mg L . However, even with this NOEC, a risk quotient of 0.003 was calculated, which is still well below the risk threshold limit of 1. Additional studies confirm the outcome of the environmental risk assessment according to EMEA/CHMP (2006). However, atenolol should not be considered as representative for other b-blockers, such as metoprolol, oxprenolol, and propranolol, some of which show significantly different physicochemical characteristics and varying toxicological profiles in mammalian studies. Integr Environ Assess Manag 2010;6:514523