RESUMEN
PURPOSE: Common side effects of taxane chemotherapy are nail toxicity and peripheral neuropathy (CIPN) causing severe impact on the quality of life. Different methods of cryotherapy to prevent these side effects have been tested. We investigated the use of machine-controlled cooling of hands and feet to reduce nail toxicity and CIPN in patients receiving taxane chemotherapy. METHODS: Patients receiving Docetaxel (planned dose ≥ 300 mg/m2) or Paclitaxel (planned dose ≥ 720 mg/m2 - ) in the adjuvant or palliative setting of different cancers were included. The dominant hand and foot were cooled to approximately 10 °C using the Hilotherapy machine. The contralateral hand and foot were used as intrapatient comparison. The primary endpoint was the occurrence of any CIPN due to paclitaxel or nail toxicity due to Docetaxel. Both the intention to treat population (ITT) and the per protocol population (PPP) were analyzed. RESULTS: A total of 69 patients, 21 treated with Docetaxel and 48 with Paclitaxel, were included at our centre between 08/2020 and 08/2022. Nail toxicity due to Docetaxel was overall not significantly improved by cooling in the ITT or PPP but a significant benefit across visits was found for the ITT. CIPN due to Paclitaxel was numerically better in the ITT and significantly better in the PPP. A significant benefit of cooling on CIPN occurrence across visits was found for the ITT and the PPP. Cooling was very well tolerated. CONCLUSION: Cooling of hands and feet has a clinically meaningful impact on reducing occurrence of CIPN and nail toxicity on treatment with taxanes. Effects are more significant over time and are dose dependent. TRIAL REGISTRATION NUMBER: 2020-00381. Date of registration. 24th February 2020.
Asunto(s)
Docetaxel , Enfermedades de la Uña , Paclitaxel , Enfermedades del Sistema Nervioso Periférico , Humanos , Femenino , Estudios Prospectivos , Persona de Mediana Edad , Masculino , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/prevención & control , Anciano , Docetaxel/administración & dosificación , Docetaxel/efectos adversos , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Enfermedades de la Uña/terapia , Enfermedades de la Uña/inducido químicamente , Neoplasias/tratamiento farmacológico , Adulto , Taxoides/efectos adversos , Taxoides/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/administración & dosificación , Crioterapia/métodos , Calidad de VidaRESUMEN
BACKGROUND & AIMS: The organic anion-transporting polypeptide 1B1 (OATP1B1) is an anion exchanger expressed at the hepatocyte sinusoidal membrane, which mediates the uptake of several endogenous metabolites and drugs. OATP1B1 expression level and activity are major sources of inter-patient variability of pharmacokinetics and pharmacodynamics of several drugs. Besides the genotype, factors that contribute to the inter-individual variability in OATP1B1 expression level are practically unknown. The aim of this work was to uncover novel epigenetic mechanisms of OATP1B1 regulation. METHODS: A functional screening strategy to assess the effect of microRNAs on the uptake of estrone-3-sulphate, an OATP1B1 substrate, into human hepatocellular carcinoma (Huh-7) cells was used. microRNA-206 (miR-206) expression in human liver tissues was measured by real-time RT-PCR. OATP1B1 expression in Huh-7 and in human liver tissues was assessed by real-time RT-PCR, Western blotting and immunostaining. The mRNA-miRNA interaction was assessed by reporter assay. RESULTS: miR-206 mimic repressed mRNA and protein expression of OATP1B1 in Huh-7 cells. The intracellular accumulation of estrone-3-sulphate was reduced by 30% in cells overexpressing miR-206. The repressive effect of miR-206 on the activity of the firefly luciferase gene 2 under the control of the OATP1B1 3' untranslated region was lost upon deletion of the predicted miR-206 binding site. Hepatic miR-206 level negatively correlated with OATP1B1 mRNA and protein levels extracted from normal human liver tissues. CONCLUSIONS: miR-206 exerts a suppressive effect on OATP1B1 expression by an epigenetic mechanism. Individuals with high hepatic levels of miR-206 appear to display lower level of OATP1B1.
Asunto(s)
Estrona/análogos & derivados , Transportador 1 de Anión Orgánico Específico del Hígado/metabolismo , Hígado/metabolismo , MicroARNs/metabolismo , Animales , Células CHO , Línea Celular Tumoral , Simulación por Computador , Cricetulus , Estrona/metabolismo , Femenino , Humanos , Transportador 1 de Anión Orgánico Específico del Hígado/genética , Masculino , Persona de Mediana EdadRESUMEN
Associations between leisure time physical activity (LTPA) and all-cause mortality seem quite strong, however, less is known about the association of LTPA and cause-specific mortality. To examine this association data from the Third National Health and Nutrition Examination Survey (NHANES III), including 15,307 individuals of the non-institutionalized civilian United States population, were used. Data were collected from 1988 to 1994 with a mortality follow-up until 2006. LTPA was assessed during home interviews in which participants specified their LTPA and the performed frequency during the past month. Cox proportional hazards regression models were applied to analyze the risk of cause-specific mortality regarding LTPA. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed. An inverse association of LTPA with CVD mortality was observed for men and women combined for irregular (HR 0.66; 95% CI 0.51-0.85), and for regular activity (HR 0.58; 95% CI 0.47-0.72). An inverse association of LTPA with CVD mortality was observed only in women for irregular (HR 0.64; 95% CI 0.49-0.84) and for regular activity (HR 0.55; 95% CI 0.43-0.72). In men, no significant associations were seen. For mortality caused by respiratory diseases, a decreased mortality was also observed in the combined group (men and women) but after separating according to sex a decreased mortality was only observed in women. No statistically significant association of LTPA with cancer mortality was observed. Our data support an inverse association between LTPA and CVD and respiratory disease mortality in women, but not in men, and no associations with cancer.
Asunto(s)
Ejercicio Físico/fisiología , Actividades Recreativas , Mortalidad , Adulto , Enfermedades Cardiovasculares/mortalidad , Femenino , Humanos , Masculino , Neoplasias/mortalidad , Encuestas Nutricionales , Factores de Riesgo , Factores Sexuales , Estados UnidosRESUMEN
Bedside manufacturing is having a revival in healthcare, with a promise to revolutionize personalized medicine through on-site drug production. While this concept holds considerable promise, it also encounters a complex web of legal uncertainties. The current regulatory framework in Switzerland and the EU, which includes the Swiss Therapeutic Products Act and the EU directives, regulations, and guidelines, fails to adequately address its distinct challenges. Rising new technologies underscore the urgent need for regulatory reform. These technologies highlight the pressing demand for comprehensive legal frameworks that can reconcile the rapid pace of innovation with the imperatives of patient safety and product efficacy. Legal concerns extend beyond mere compliance; they encapsulate quality assurance, and liability in cases of human error. This study outlines the call for a recalibrated legal landscape that prioritizes patient-centered care while fostering the growth of bedside manufacturing. It is crucial for the legal system to evolve in tandem with these medical advancements, ensuring a secure, efficacious, and equitable integration of bedside manufacturing into healthcare.