Miltefosine in the Treatment of Cutaneous Leishmaniasis Caused by Leishmania braziliensis in Brazil: A Randomized and Controlled Trial

Cutaneous leishmaniasis (CL) is characterized by skin ulcerations and occurs in rural poor areas of developing countries. It is treated with daily injections of antimony for 20 days, which is associated with irregular use and increasingly lower cure rates. Miltefosine is an oral medication with activity against the agent of CL (Leishmania). We have studied the efficacy and safety of miltefosine compared with antimony in patients with CL caused by Leishmania braziliensis in Bahia, Brazil. A total of 90 patients participated; 60 received miltefosine and 30 were treated with antimony. Six months after treatment, 75% of patients treated with miltefosine were cured, compared with 53% of the patients in the antimony group, a difference considered significant (p = 0.04). We also found that miltefosine was more effective than antimony in adults than in children. The incidence of side effects was similar with both drugs (76.7% vs. 78.3%), but all patients were able to finish the treatments. Our study shows that miltefosine is more effective than antimony for the treatment of CL in Bahia, Brazil and can contribute to the control of this disease due to its activity and easier administration

Methylation of HOXA9 and ISL1 predicts patient outcome in high-grade non-invasive bladder cancer

Introduction Inappropriate DNA methylation is frequently associated with human tumour development, and in specific cases, is associated with clinical outcomes. Previous reports of DNA methylation in low/intermediate grade non-muscle invasive bladder cancer (NMIBC) have suggested that specific patterns of DNA methylation may have a role as diagnostic or prognostic biomarkers. In view of the aggressive and clinically unpredictable nature of high-grade (HG) NMIBC, and the current shortage of the preferred treatment option (Bacillus:Calmette-Guerin), novel methylation analyses may similarly reveal biomarkers of disease outcome that could risk-stratify patients and guide clinical management at initial diagnosis. Methods Promoter-associated CpG island methylation was determined in primary tumour tissue of 36 initial presentation high-grade NMIBCs, 12 low/intermediate-grade NMIBCs and 3 normal bladder controls. The genes HOXA9, ISL1, NKX6-2, SPAG6, ZIC1 and ZNF154 were selected for investigation on the basis of previous reports and/or prognostic utility in low/intermediate-grade NMIBC. Methylation was determined by Pyrosequencing of sodium-bisulphite converted DNA, and then correlated with gene expression using RT-qPCR. Methylation was additionally correlated with tumour behaviour, including tumour recurrence and progression to muscle invasive bladder cancer or metastases. Results The ISL1 genes’ promoter-associated island was more frequently methylated in recurrent and progressive high-grade tumours than their non-recurrent counterparts (60.0% vs. 18.2%, p = 0.008). ISL1 and HOXA9 showed significantly higher mean methylation in recurrent and progressive tumours compared to non-recurrent tumours (43.3% vs. 20.9%, p = 0.016 and 34.5% vs 17.6%, p = 0.017, respectively). Concurrent ISL1/HOXA9 methylation in HG-NMIBC reliably predicted tumour recurrence and progression within one year (Positive Predictive Value 91.7%), and was associated with disease-specific mortality (DSM). Conclusions In this study we report methylation differences and similarities between clinical sub-types of high-grade NMIBC. We report the potential ability of methylation biomarkers, at initial diagnosis, to predict tumour recurrence and progression within one year of diagnosis. We found that specific biomarkers reliably predict disease outcome and therefore may help guide patient treatment despite the unpredictable clinical course and heterogeneity of high-grade NMIBC. Further investigation is required, including validation in a larger patient cohort, to confirm the clinical utility of methylation biomarkers in high-grade NMIBC