RESUMEN
BACKGROUND: No biomarker is available for identifying cancer patients at risk of developing nephrotoxicity when treated with cisplatin. METHODS: We performed microRNA (miRNA) sequencing using plasma collected 5 days after cisplatin treatment (D5) from twelve patients with head and neck cancer with and without nephrotoxicity (grade ≥ 2 increased serum creatinine). The most differentially expressed miRNAs between the two groups were selected for quantification at baseline and D5 in a larger cohort of patients. The association between miRNAs and nephrotoxicity was evaluated by calculating the odds ratio (OR) from univariate logistic regression. Receiver operating characteristic curves (ROC) were used to estimate the area under the curve (AUC), sensitivity, and specificity. RESULTS: MiR-3168 (p = 1.98 × 10− 8 ), miR-4718 (p = 4.24 × 10− 5 ), and miR-6125 (p = 6.60 × 10− 5 ) were the most differentially expressed miRNAs and were further quantified in 43, 48, and 53 patients, respectively. The baseline expression of miR-3168 (p = 0.0456, OR = 1.03, 95% CI: 1.001.06) and miR-4718 (p = 0.0388, OR = 1.56, 95% CI: 1.03 2.46) were associated with an increased risk of nephrotoxicity, whereas miR-6125 showed a trend (p = 0.0618, OR = 1.73, 95% CI: 0.983.29). MiR-4718 showed the highest AUC (0.77, 95% CI: 0.610.93) with sensitivity of 66.76 and specificity of 79.49. CONCLUSIONS: We have provided evidence of baseline plasmatic expression of miR-3168, miR-6125, and miR-4718 as potential predictors of cisplatin-induced nephrotoxicity.
Asunto(s)
Cisplatino , MicroARNs , Enfermedades Renales , NeoplasiasRESUMEN
BACKGROUND: No biomarker is available for identifying cancer patients at risk of developing nephrotoxicity when treated with cisplatin. METHODS: We performed microRNA (miRNA) sequencing using plasma collected 5 days after cisplatin treatment (D5) from twelve patients with head and neck cancer with and without nephrotoxicity (grade ≥ 2 increased serum creatinine). The most differentially expressed miRNAs between the two groups were selected for quantification at baseline and D5 in a larger cohort of patients. The association between miRNAs and nephrotoxicity was evaluated by calculating the odds ratio (OR) from univariate logistic regression. Receiver operating characteristic curves (ROC) were used to estimate the area under the curve (AUC), sensitivity, and specificity. RESULTS: MiR-3168 (p = 1.98 × 10- 8), miR-4718 (p = 4.24 × 10- 5), and miR-6125 (p = 6.60 × 10- 5) were the most differentially expressed miRNAs and were further quantified in 43, 48, and 53 patients, respectively. The baseline expression of miR-3168 (p = 0.0456, OR = 1.03, 95% CI: 1.00-1.06) and miR-4718 (p = 0.0388, OR = 1.56, 95% CI: 1.03-2.46) were associated with an increased risk of nephrotoxicity, whereas miR-6125 showed a trend (p = 0.0618, OR = 1.73, 95% CI: 0.98-3.29). MiR-4718 showed the highest AUC (0.77, 95% CI: 0.61-0.93) with sensitivity of 66.76 and specificity of 79.49. CONCLUSIONS: We have provided evidence of baseline plasmatic expression of miR-3168, miR-6125, and miR-4718 as potential predictors of cisplatin-induced nephrotoxicity.
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Lesión Renal Aguda/epidemiología , Biomarcadores de Tumor/metabolismo , Cisplatino/efectos adversos , Neoplasias de Cabeza y Cuello/terapia , MicroARNs/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Lesión Renal Aguda/sangre , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/genética , Anciano , Biomarcadores de Tumor/sangre , Estudios de Casos y Controles , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Creatinina/sangre , Femenino , Perfilación de la Expresión Génica , Predisposición Genética a la Enfermedad , Neoplasias de Cabeza y Cuello/sangre , Neoplasias de Cabeza y Cuello/genética , Humanos , Masculino , MicroARNs/sangre , Persona de Mediana Edad , Curva ROC , Medición de Riesgo/métodos , Medición de Riesgo/estadística & datos numéricos , Análisis de Secuencia de ARN , Carcinoma de Células Escamosas de Cabeza y Cuello/sangre , Carcinoma de Células Escamosas de Cabeza y Cuello/genéticaRESUMEN
The protective antioxidant activity of acetylcysteine (NAC) against toxicity due to cisplatin has been reported in experimental models; however, its efficacy in patients has not been elucidated. The aim of this study was to investigate the possible protective effect of NAC on cisplatin-induced toxicity and the effect of NAC on clinical response and oxidative stress in patients treated for head and neck cancer. This was a randomized, double-blind, placebo-controlled trial conducted in patients receiving high-dose cisplatin chemotherapy concomitant to radiotherapy. Patients were randomly assigned to groups and received: (a) 600 mg NAC syrup, orally once daily at night for 7 consecutive days or (b) placebo, administered similarly to NAC. Nephro-, oto-, hepato-, myelo-, and gastrointestinal toxicities, clinical responses, and plasma and cellular markers of oxidative stress were evaluated. Fifty-seven patients were included (n = 28, NAC arm; and n = 29, placebo arm). A high prevalence of most types of toxicities was observed after cisplatin chemotherapy; however, the parameters were similar between the two groups. There was a predominance of partial response to treatment. In the cellular and plasmatic oxidative stress analyses, minor differences were observed. Overall, there was no statistically significant difference between the groups for all outcomes. These findings show that low-dose oral NAC does not protect patients with head and neck cancer from cisplatin-induced toxicities and oxidative stress. The antitumor efficacy of cisplatin was apparently not impaired by NAC.
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Acetilcisteína/administración & dosificación , Cisplatino/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Neoplasias de Cabeza y Cuello/terapia , Estrés Oxidativo/efectos de los fármacos , Acetilcisteína/farmacología , Administración Oral , Anciano , Quimioradioterapia/efectos adversos , Cisplatino/uso terapéutico , Método Doble Ciego , Esquema de Medicación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
WHAT IS KNOWN AND OBJECTIVE: Polymyxins, especially polymyxin B, has become the last line of therapy against Gram-negative pathogens' carbapenemase producers. However, given increasing use of polymyxin B in clinical settings its therapeutic value has been evaluated worldwide due to its toxic effects. The aim of this study was to assess the efficacy and safety of antimicrobial therapy with polymyxin B in patients with multidrug-resistant bacteria in Brazil. METHODS: This was a prospective cohort study in a 403-bed academic tertiary care centre, located in the countryside of Brazil. Patients receiving polymyxin B intravenous treatment for at least 72 hours were eligible for the study. Antimicrobial susceptibility, adverse reactions and clinical outcomes were submitted for descriptive analysis. Main outcomes measure the following: Patients' conditions following treatment (Treatment Success, Mortality, Treatment Failure, Inadequate Empiric Treatment or Indeterminate Response) and toxicities induced by polymyxin B (nephrotoxicity and skin hyperpigmentation). RESULTS AND DISCUSSION: Among 247 patients, treatment success was achieved in 25.1%, while mortality was observed in 32.8%. Empirical therapy was prescribed for 26.3% of the patients. Nephrotoxicity was reported in 40.5%. The carbapenemase producer, Klebsiella pneumonia, was the bacterium most associated with mortality (22.2%). CONCLUSIONS: Even though polymyxin B is currently the main therapy against carbapenemase producers, its use demands robust criteria to lead to positive clinical outcomes.
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Antibacterianos/uso terapéutico , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Polimixina B/uso terapéutico , Administración Intravenosa , Antibacterianos/efectos adversos , Brasil , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Femenino , Humanos , Hiperpigmentación/inducido químicamente , Masculino , Pruebas de Sensibilidad Microbiana/métodos , Persona de Mediana Edad , Polimixina B/efectos adversos , Estudios Prospectivos , Resultado del TratamientoRESUMEN
Cisplatin is a widely used antineoplastic agent in the treatment of head and neck cancer. However, it is highly nephrotoxic. Oxidative stress is the main mechanism responsible for cisplatin-induced nephrotoxicity. The aim of this study was to characterize cisplatin-induced nephrotoxicity, oxidative stress in peripheral blood mononuclear cells, and the relationship between them. Twenty-four patients were included in the study. Patients had their blood collected prior to cisplatin administration, and 5 and 20 days after initiating therapy, to assess renal function and to determine oxidative stress with MitoSOX™Red, H2DCF-DA, and Amplex® Red tests. Renal function was assessed by measuring serum creatinine, creatinine clearance, and blood urea nitrogen (BUN). Serum creatinine and creatinine clearance were used to grade nephrotoxicity using Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Compared to baseline values, the mean BUN and serum creatinine increased 135 and 100%, respectively, 5 days after cisplatin infusion. Mean creatinine clearance showed a 43% decrease compared to baseline value. Non-statistically significant changes in superoxide anion (O 2â¢- ), hydrogen peroxide (H2O2), and general reactive oxygen species production occurred. A higher production of H2O2 was correlated with variation in serum creatinine, and was associated with higher grades for serum creatinine increases and creatinine clearance reductions. Linear regression analyses showed an association between H2O2 production and serum creatinine, creatinine clearance, and BUN levels. These results were observed for 5 days following cisplatin administration. In conclusion, H2O2 production was significantly related to changes in all renal parameters that were evaluated, following the cisplatin infusion.
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Cisplatino , Neoplasias de Cabeza y Cuello , Peróxido de Hidrógeno/sangre , Enfermedades Renales , Leucocitos Mononucleares , Estrés Oxidativo/efectos de los fármacos , Adulto , Anciano , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Femenino , Neoplasias de Cabeza y Cuello/sangre , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/patología , Humanos , Enfermedades Renales/sangre , Enfermedades Renales/inducido químicamente , Enfermedades Renales/patología , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/patología , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: The aim of this study was to determine the impact of two resolutions to restrict antibiotic use (RDCs no. 44/2010 and 20/2011) in the Campinas metropolitan area (Sao Paulo, Brazil) on antibiotic consumption, resistance rates, and trends in Escherichia coli-causing community-acquired urinary tract infection (UTI). METHODS: The annual retail sale information of antibiotics from drugstores in the Campinas metropolitan area between 2008 and 2012 were obtained through the Intercontinental Medical Statistics Health of Brazil. The daily-defined dose (DDD)/1000 inhabitants/day was calculated from these data to measure consumption. To examine resistance rates, we performed an observational retrospective study in a Campinas teaching hospital, where urinary cultures from outpatients with a clinical suspicion of UTI between October 2009 and September 2015 were analyzed. RESULTS: We observed an increase in rates of antibiotic sales from 2008 to 2011 (cephalosporin: 216.8%, quinolones: 170.9%, aminopenicillins: 140.9%), followed by a decrease in sales in 2012 (cephalosporin: 19.4%, quinolones: 12.7%, aminopenicillins: 11.1%). Sale of nitrofurans, however, did not significantly change during this period. In the retrospective analysis, we observed a significant increasing trend of E. coli resistance for all antibiotic classes, except nitrofurans and folate pathway inhibitors. CONCLUSIONS: We found changes in antibiotic consumption, with an initial increase, followed by a decrease in sales after implementation of the resolutions. However, bacterial resistance does not appear to be affected by the RDCs.