Buruli ulcer in West Africa: strategies for early detection and treatment in the antibiotic era

OBJECTIVE: Buruli ulcer (BU), caused by Mycobacterium ulcerans infection, has become one of the most rapidly emerging diseases in West Africa in recent decades. Until recently, the definitive treatment involved wide surgical excision. Recent data suggest that antibiotic therapy with rifampin and streptomycin may reduce the extent or prevent excision when initiated during the early phases of the disease. New strategies for BU control are needed, emphasizing early detection and increasing public awareness about the disease and treatment. Here we review current knowledge about BU and examine clinical, public health and anthropological research in the context of this new treatment paradigm to identify potential strategies for more effective control of this disease. METHODS: A comprehensive literature search for articles in English or French using the Medline and INIST databases, World Health Organization publications, and bibliographical references was undertaken using key words Buruli ulcer. Mycobacterium ulcerans, community surveillance, and public health. CONCLUSION: Studies to identify factors contributing to delayed presentation indicate that awareness of the disease is generally good in endemic regions, but wide variation exists in perceived cause of the disease, and the role of sorcery in its transmission and treatment. The use of traditional healers as first line therapy also contributes to delayed treatment, as do lack of awareness about the availability of effective treatment and financial concerns. Epidemiological data from existing BU control programs indicate that active public awareness campaigns are succcessful in increasing understanding and decreasing treatment delay and disease progression. Community-based surveillance and health education modeled after the village health worker programs used in the eradication of Guinea worm may be successfully applied in BU endemic areas

Vorinostat in combination with lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma

The addition of vorinostat to lenalidomide/dexamethasone represents a novel combination therapy in multiple myeloma (MM), informed by laboratory studies suggesting synergy. This was a phase I, multicenter, open-label, non-randomized, dose-escalating study in patients with relapsed or relapsed and refractory MM. Clinical evaluation, electrocardiogram, laboratory studies and adverse events were obtained and assessed. The maximum-tolerated dose was not reached owing to a non-occurrence of two dose-limiting toxicities per six patients tested at any of the dosing levels. Patients tolerated the highest dose tested (Level 5) and this was considered the maximum administered dose: at 400mg vorinostat on days 1-7 and 15-21, 25mg lenalidomide on days 1-21 and 40mg dexamethasone on days 1, 8, 15 and 22, per 28-day cycle. Drug-related adverse events were reported in 90% of patients serious adverse experiences were reported in 45% of the patients and 22% of all patients had adverse experiences considered, possibly related to study drug by the investigators. A confirmed partial response or better was reported for 14/30 patients (47%) evaluable for efficacy, including 31% of patients previously treated with lenalidomide. Vorinostat in combination with lenalidomide and dexamethasone proved tolerable with appropriate supportive care, with encouraging activity observed. © 2014 Macmillan Publishers Limited

Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): A multicentre, randomised, double-blind study

Background: We aimed to assess efficacy and tolerability of vorinostat in combination with bortezomib for treatment of patients with relapsed or refractory multiple myeloma. Methods: In our randomised, double-blind, placebo-controlled, phase 3 trial, we enrolled adults (≥18 years) at 174 university hospitals in 31 countries worldwide. Eligible patients had to have non-refractory multiple myeloma that previously responded to treatment (one to three regimens) but were currently progressing, ECOG performance statuses of 2 or less, and no continuing toxic effects from previous treatment. We excluded patients with known resistance to bortezomib. We randomly allocated patients (1:1) using an interactive voice response system to receive 21 day cycles of bortezomib (1·3 mg/m2 intravenously on days 1, 4, 8, and 11) in combination with oral vorinostat (400 mg) or matching placebo once-daily on days 1-14. We stratified patients by baseline tumour stage (International Staging System stage 1 or stage ≥2), previous bone-marrow transplantation (yes or no), and number of previous regimens (1 or ≥2). The primary endpoint was progression-free survival (PFS) in the intention-to-treat population. We assessed adverse events in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number 00773747. Findings: Between Dec 24, 2008, and Sept 8, 2011, we randomly allocated 317 eligible patients to the vorinostat group (315 of whom received at least one dose) and 320 to the placebo group (all of whom received at least one dose). Median PFS was 7·63 months (95% CI 6·87-8·40) in the vorinostat group and 6·83 months (5·67-7·73) in the placebo group (hazard ratio [HR] 0·77, 95% CI 0·64-0·94; p=0·0100). 312 (99%) of 315 patients in the vorinostat group and 315 (98%) of 320 patients in the placebo group had adverse events (300 [95%] adverse events in the vorinostat group and 282 [88%] in the control group were regarded as related to treatment). The most common grade 3-4 adverse events were thrombocytopenia (143 [45%] patients in the vorinostat group vs 77 [24%] patients in the placebo group), neutropenia (89 [28%] vs 80 [25%]), and anaemia (53 [17%] vs 40 [13%]). Interpretation: Although the combination of vorinostat and bortezomib prolonged PFS relative to bortezomib and placebo, the clinical relevance of the difference in PFS between the two groups is not clear. Different treatment schedules of bortezomib and vorinostat might improve tolerability and enhance activity. Funding: Merck. © 2013 Elsevier Ltd