Docetaxel skin exposure and micronucleation contributes to skin toxicity caused by cpc634

Docetaxel entrapped nanoparticle CPC634 is associated with dose-related skin toxicity that resembles conventional docetaxel (Cd)-related skin toxicity. This study compared the cutaneous pharmacokinetics and pharmacodynamics of docetaxel and CPC634. In this randomised cross-over study, patients with solid tumours received one cycle of CPC634 and Cd (both at 75 mg/m2). Skin biopsies were taken at baseline and at day 8 of both cycles. Released and total docetaxel (released docetaxel plus entrapped docetaxel) concentrations and histopathological changes in the skin biopsies were evaluated. Twenty patients underwent paired skin biopsies for pharmacokinetic analysis and 10 patients had biopsies available for histopathological assessment. The total skin docetaxel concentration was 369% (95%CI: 229% to 569%, p < 0.001) higher after CPC634 administration compared to Cd while the released docetaxel concentrations were not statistically different (95%CI: −9% to 63%, p = 0.169). The CPC634 released docetaxel concentration in the skin was positively correlated with plasma concentrations (Pearson’s correlation 0.48, p = 0.03). Histopathological examination revealed increased apoptosis, mitotic cells with nuclear atypia, and micronucleation with an enhanced Ki-67 index for both compounds. In conclusion, both CPC634 and Cd treatment result in docetaxel exposure in the skin causing cutaneous anti-mitotic effects such as micronucleation, which could induce an inflammatory reaction leading to skin toxicity

Docetaxel skin exposure and micronucleation contributes to skin toxicity caused by cpc634

Docetaxel entrapped nanoparticle CPC634 is associated with dose-related skin toxicity that resembles conventional docetaxel (Cd)-related skin toxicity. This study compared the cutaneous pharmacokinetics and pharmacodynamics of docetaxel and CPC634. In this randomised cross-over study, patients with solid tumours received one cycle of CPC634 and Cd (both at 75 mg/m2). Skin biopsies were taken at baseline and at day 8 of both cycles. Released and total docetaxel (released docetaxel plus entrapped docetaxel) concentrations and histopathological changes in the skin biopsies were evaluated. Twenty patients underwent paired skin biopsies for pharmacokinetic analysis and 10 patients had biopsies available for histopathological assessment. The total skin docetaxel concentration was 369% (95%CI: 229% to 569%, p &lt; 0.001) higher after CPC634 administration compared to Cd while the released docetaxel concentrations were not statistically different (95%CI: −9% to 63%, p = 0.169). The CPC634 released docetaxel concentration in the skin was positively correlated with plasma concentrations (Pearson’s correlation 0.48, p = 0.03). Histopathological examination revealed increased apoptosis, mitotic cells with nuclear atypia, and micronucleation with an enhanced Ki-67 index for both compounds. In conclusion, both CPC634 and Cd treatment result in docetaxel exposure in the skin causing cutaneous anti-mitotic effects such as micronucleation, which could induce an inflammatory reaction leading to skin toxicity.</p

Non-cardiac comorbidities in heart failure with reduced, mid-range and preserved ejection fraction

Background: Comorbidities play a major role in heart failure. Whether prevalence and prognostic importance of comorbidities differ between heart failure with preserved ejection fraction (HFpEF), mid-range (HFmrEF) or reduced ejection fraction (HFrEF) is unknown. Methods: Patients from index (n = 2516) and validation cohort (n = 1738) of The BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) were pooled. Eight non-cardiac comorbidities were assessed; diabetes mellitus, thyroid dysfunction, obesity, anaemia, chronic kidney disease (CKD, estimated glomerular filtration rate &amp;lt; 60 mL/min/1.73 m 2 ), COPD, stroke and peripheral arterial disease. Patients were classified based on ejection fraction. The association of each comorbidity with quality of life (QoL), all-cause mortality and hospitalisation was evaluated. Results: Patients with complete comorbidity data were included (n = 3499). Most prevalent comorbidity was CKD (50%). All comorbidities showed the highest prevalence in HFpEF, except for stroke. Prevalences of HFmrEF were in between the other entities. COPD was the comorbidity associated with the greatest reduction in QoL. In HFrEF, almost all were associated with a significant reduction in QoL, while in HFpEF only CKD and obesity were associated with a reduction. Most comorbidities in HFrEF were associated with an increased mortality risk, while in HFpEF only CKD, anaemia and COPD were associated with higher mortality risks. Conclusions: The highest prevalence of comorbidities was seen in patients with HFpEF. Overall, comorbidities were associated with a lower QoL, but this was more pronounced in patients with HFrEF. Most comorbidities were associated with higher mortality risks, although the associations with diabetes were only present in patients with HFrEF. © 2018 The Author

The Netherlands Heart Tissue Bank Strengthening the cardiovascular research infrastructure with an open access Cardiac Tissue Repository

Aim Cardiac diseases remain a leading cause of cardiovascular disease (CVD) related hospitalisation and mortality. That is why research to improve our understanding of pathophysiological processes underlying cardiac diseases is of great importance. There is a strong need for healthy and diseased human cardiac tissue and related clinical data to accomplish this, since currently used animal and in vitro disease models do not fully grasp the pathophysiological processes observed in humans. This design paper describes the initiative of the Netherlands Heart Tissue Bank (NHTB) that aims to boost CVD-related research by providing an open-access biobank. Methods The NHTB, founded in June 2020, is a non-profit biobank that collects and stores biomaterial (including but not limited to myocardial tissue and blood samples) and clinical data of individuals with and without previously known cardiac diseases. All individuals aged >= 18 years living in the Netherlands are eligible for inclusion as a potential future donor. The stored samples and clinical data will be available upon request for cardiovascular researchers. Conclusion To improve the availability of cardiac tissue for cardiovascular research, the NHTB will include extensive (cardiac) biosamples, medical images, and clinical data of donors with and without a previously known cardiac disease. As such, the NHTB will function as a translational bridge to boost a wide range of cardiac disease-related fundamental and translational studies

The Netherlands Heart Tissue Bank : Strengthening the cardiovascular research infrastructure with an open access Cardiac Tissue Repository.

AIM: Cardiac diseases remain a leading cause of cardiovascular disease (CVD) related hospitalisation and mortality. That is why research to improve our understanding of pathophysiological processes underlying cardiac diseases is of great importance. There is a strong need for healthy and diseased human cardiac tissue and related clinical data to accomplish this, since currently used animal and in vitro disease models do not fully grasp the pathophysiological processes observed in humans. This design paper describes the initiative of the Netherlands Heart Tissue Bank (NHTB) that aims to boost CVD-related research by providing an open-access biobank. METHODS: The NHTB, founded in June 2020, is a non-profit biobank that collects and stores biomaterial (including but not limited to myocardial tissue and blood samples) and clinical data of individuals with and without previously known cardiac diseases. All individuals aged ≥ 18 years living in the Netherlands are eligible for inclusion as a potential future donor. The stored samples and clinical data will be available upon request for cardiovascular researchers. CONCLUSION: To improve the availability of cardiac tissue for cardiovascular research, the NHTB will include extensive (cardiac) biosamples, medical images, and clinical data of donors with and without a previously known cardiac disease. As such, the NHTB will function as a translational bridge to boost a wide range of cardiac disease-related fundamental and translational studies