Biomarkers and new therapeutic targets in renal cell carcinoma.

OBJECTIVE: Renal Cell Carcinoma (RCC) is the most common malignancy in adult kidneys. The American Cancer Society estimated 62,700 new cases and 14,240 deaths in 2018. Although early detection has improved in recent years, the treatment remains a challenge and reliable biomarkers for poor outcomes become necessary for the prevention of metastases and improve the quality of patients' life during and after treatment. Then, the current status of the search for new RCC biomarkers was discussed, as well as the latest discoveries in the RCC risk and metastatic treatment were discussed in this review. MATERIALS AND METHODS: Extensive research was carried out in the online databases and full-free text articles published in the last 5 years, or more when convenient, were evaluated. Articles were included that addressed the proposed theme and were published in the English language. RESULTS: The present state of knowledge on biomarkers for RCC carcinogenesis and progression is still much to be understood about RCC risk factors and molecular pathways resulting in metastatic progression. Newest RCC target therapies were discussed, mainly in relation to immunological therapy, and vaccines that have been tested in numerous trials with different cancer types. CONCLUSIONS: The development of targeted therapies has revolutionized the treatment of advanced and metastatic cancers or non-responder patients. Combined therapy between classical chemotherapy and adjuvant immunotherapies has been modifying the cancer patients prognosis and bringing the hope of a cure in many cases.

Association of the GSTT1 polymorphism in upper aerodigestive tract cancer with tobacco smoking.

Polymorphisms in genes encoding xenobiotic-metabolizing enzymes might explain differences in the susceptibility to upper aerodigestive tract (UADT) cancers in individuals exposed to tobacco or other carcinogens. The present study aimed to evaluate the association of polymorphisms in the glutathione S-transferase (GST) candidate genes GSTM1, GSTT1, and GSTP1 with the risk of UADT cancers. GST gene polymorphisms were determined in 116 individuals with UADT cancer and 224 healthy controls using polymerase chain reaction-based methods. The GSTT1-null polymorphism was found to be a protective factor for UADT cancer [(odds ratio (OR) = 0.5, 95% confidence interval (CI) = 0.27-0.93)], although this association was not confirmed when adjusted for gender, age, smoking, alcoholism, and self-reported skin color in the multivariate logistic regression model (OR = 0.61, 95%CI = 0.29-1.28). The combined effect of GSTT1-positive genotypes with either the GSTP1 wild-type genotype (Ile/Ile) or the GSTP1 variant genotypes (Ile/Val or Val/Val) increased the risk for UADT cancer (OR = 4.34, 95%CI = 1.06-17.78 and OR = 4.55, 95%CI = 1.12-18.42, respectively). A significant interaction was observed among moderate smokers carrying the GSTT1-positive genotype. In this population, the significant gene-gene and gene-environment interactions of GST polymorphisms may confer a substantial risk to UADT cancers.

Efeito da sibutramina na redução do peso e no perfil metabólico em indivíduos obesos de uma população brasileira / Effects of sibutramine on weight reduction and metabolic profile in obese individuals in a brazilian population

O objetivo deste trabalho é avaliar a eficácia e a segurança da dose de 20 mg/dia de sibutramina em voluntários obesos, com IMC superior a 35, e compará-las com a dose de 10 mg/dia e à mudança de estilo de vida de pacientes com IMC inferior a 35 (a avaliação e a comparação foram realizadas em um período de 24 semanas). Foram submetidos a um estudo transversal 54 voluntários, distribuídos em três grupos de observação: grupo sem tratamento farmacológico (GMEV), grupo com IMC inferior a 35 e uma dose de 10 mg/ dia de sibutramina (G1) e grupo com IMC superior a 35 e dose de 20 mg/ dia de sibutramina (G2). Os parâmetros avaliados foram peso, circunferência abdominal e perfil metabólico. Os grupos submetidos ao tratamento farmacológico demonstraram maior redução do peso (G1: redução média de 9,4% ; G2: redução média de 20,6%) quando comparados a indivíduos sem tratamento farmacológico (GMEV: redução de 3,9%), assim como da circunferência abdominal (redução de 7,1%, 12,8% e 3,1% em G1, G2 e GMEV, respectivamente). Em relação aos achados laboratoriais, foram observados redução da glicemia de jejum (14,8%, 22,9% e 5% em G1, G2 e GMEV, respectivamente), aumento do HDL colesterol (31,2%, 40% e 14,2% em G1, G2 e GMEV, respectivamente) e redução do colesterol total (29,0%, 32,8% e 13,7% em G1, G2 e GMEV, respectivamente). Os resultados deste estudo demonstram que a dose de 20 mg de sibutramina é uma indicação segura e eficaz em pacientes obesos com IMC superior a 35

The aim of this study is to assess the efficacy and safety of an oral daily dose of 20 mg sibutramine in obese volunteers (BMI > 35), in comparison with a dose of 10 mg/day and changed lifestyle in patients whose BMI is less than 35. The testing and comparison were performed over 24 weeks. The 54 volunteers were subjected to a cross-sectional study in three observation groups: a reference group without pharmacological treatment (GMEV), a group with BMI < 35, treated with 10 mg ?day sibutramine (G1), and another with BMI ? 35, on a dose of 20 mg? day (G2). The variables assessed were weight, abdominal circumference and metabolic profile. The groups subjected to the drug treatments exhibited greater weight losses (G1: -9.4% and G2: -20.6%) than the group that took no drugs (GMEV: -3.9%). The abdominal circumference was reduced by 7.1%, 12.8% and 3.1% in G1, G2 and GMEV, respectively. Regarding the biochemical variables, there was a reduction in fasting glucose levels (-14.8%, -22.9% and -5% in G1, G2 and GMEV, respectively); an increase in HDL cholesterol (+31.2%, +40% and +14.2% in G1, G2 and GMEV, respectively) and a reduction in total cholesterol (-29.0%, -32.8% and ?13.7% in G1, G2 and GMEV, respectively). The results of this study show that sibutramine, in doses of 20 mg/ day, is a safe and efficient drug for obesity treatment in patients whose BMI exceeds 35.

A simple HPLC-fluorescence method for the measurement of R,S-sotalol in the plasma of patients with life-threatening cardiac arrhythmias.

R,S-sotalol, a ss-blocker drug with class III antiarrhythmic properties, is prescribed to patients with ventricular, atrial and supraventricular arrhythmias. A simple and sensitive method based on HPLC-fluorescence is described for the quantification of R,S-sotalol racemate in 500 microl of plasma. R,S-sotalol and its internal standard (atenolol) were eluted after 5.9 and 8.5 min, respectively, from a 4-micron C18 reverse-phase column using a mobile phase consisting of 80 mM KH2PO4, pH 4.6, and acetonitrile (95:5, v/v) at a flow rate of 0.5 ml/min with detection at lambdaex = 235 nm and lambdaem = 310 nm, respectively. This method, validated on the basis of R,S-sotalol measurements in spiked blank plasma, presented 20 ng/ml sensitivity, 20-10,000 ng/ml linearity, and 2.9 and 4.8% intra- and interassay precision, respectively. Plasma sotalol concentrations were determined by applying this method to investigate five high-risk patients with atrial fibrillation admitted to the Emergency Service of the Medical School Hospital, who received sotalol, 160 mg po, as loading dose. Blood samples were collected from a peripheral vein at zero, 0.5, 1.0, 1.5, 2.0, 3.0, 4. 0, 6.0, 8.0, 12.0 and 24.0 h after drug administration. A two-compartment open model was applied. Data obtained, expressed as mean, were: C MAX = 1230 ng/ml, T MAX = 1.8 h, AUC T = 10645 ng h-1 ml-1, Kab = 1.23 h-1, alpha = 0.95 h-1, ss = 0.09 h-1, t((1/2))ss = 7.8 h, ClT/F = 3.94 ml min-1 kg-1, and Vd/F = 2.53 l/kg. A good systemic availability and a fast absorption were obtained. Drug distribution was reduced to the same extent in terms of total body clearance when patients and healthy volunteers were compared, and consequently elimination half-life remained unchanged. Thus, the method described in the present study is useful for therapeutic drug monitoring purposes, pharmacokinetic investigation and pharmacokinetic-pharmacodynamic sotalol studies in patients with tachyarrhythmias.