Mitoxantrone treatment in multiple sclerosis: a 5-year clinical and MRI follow-up

Mitoxantrone (MTX) is an antineoplastic agent approved for treatment of secondary progressive and rapidly worsening relapsing-remitting multiple sclerosis (MS). We designed a longitudinal open-label prospective study to evaluate the efficacy and toxicity of MTX over a 2-year treatment period with a further 3-year follow-up. Fifty consecutive MS patients were included and received MTX intravenously (8 mg/m(2) every 2 months for a total of 12 infusions). Efficacy was assessed clinically and by brain MRI performed before MTX therapy, at the end of treatment and at the end of each year of follow-up. Forty-nine patients completed the 5-year study, 44 (89.8%) completed the MTX course, five (10.2%) interrupted the treatment because of side effects. Fifteen (30.6%) patients showed Expanded Disability Status Scale (EDSS) progression on treatment and nine (18.4%) during follow-up. Seventeen (34.7%) patients had enhancing lesions at baseline, nine (18.4%) at the end of treatment, but none at the end of follow-up. In conclusion, we observed EDSS progression in about 1/3 of the patients during the treatment period and in 115 during the further 3-year follow-up period. This evidence suggests a delayed beneficial effect after MTX treatment is completed with only a minority of patients showing disability progression once the drug was suspended

Mutations in the gene encoding the lamin B receptor produce an altered nuclear morphology in granulocytes (Pelger-Huet anomaly)

Pelger-Huet anomaly (PHA; OMIM *169400) is an autosomal dominant disorder characterized by abnormal nuclear shape and chromatin organization in blood granulocytes. Affected individuals show hypolobulated neutrophil nuclei with coarse chromatin. Presumed homozygous individuals have ovoid neutrophil nuclei, as well as varying degrees of developmental delay, epilepsy and skeletal abnormalities. Homozygous offspring in an extinct rabbit lineage showed severe chondrodystrophy, developmental anomalies and increased pre- and postnatal mortality. Here we show, by carrying out a genome-wide linkage scan, that PHA is linked to chromosome 1q41-43. We identified four splice-site, two frameshift and two nonsense mutations in LBR, encoding the lamin B receptor. The lamin B receptor (LBR), a member of the sterol reductase family, is evolutionarily conserved and integral to the inner nuclear membrane; it targets heterochromatin and lamins to the nuclear membrane. Lymphoblastoid cells from heterozygous individuals affected with PHA show reduced expression of the lamin B receptor, and cells homozygous with respect to PHA contain only trace amounts of it. We found that expression of the lamin B receptor affects neutrophil nuclear shape and chromatin distribution in a dose-dependent manner. Our findings have implications for understanding nuclear envelope-heterochromatin interactions, the pathogenesis of Pelger-like conditions in leukemia, infection and toxic drug reactions, and the evolution of neutrophil nuclear shape

Treatment-related cardiotoxicity in survivors of childhood cancer

Treatment advances and higher participation rates in clinical trials have rapidly increased the number of survivors of childhood cancer. However, chemotherapy and radiation treatments are cardiotoxic and can cause cardiomyopathy, conduction defects, myocardial infarction, hypertension, stroke, pulmonary oedema, dyspnoea and exercise intolerance later in life. These cardiotoxic effects are often progressive and irreversible, emphasizing a need for effective prevention and treatment to reduce or avoid cardiotoxicity. Medical interventions, such as angiotensin-converting enzyme inhibitors, β-blockers, and growth hormone therapy, might be used to treat cardiotoxicity in childhood cancer survivors. Preventative strategies should include the use of dexrazoxane, which provides cardioprotection without reducing the oncological efficacy of doxorubicin chemotherapy; less-toxic anthracycline derivatives and the use of antioxidant nutritional supplements might also be beneficial. Continuous-infusion doxorubicin provides no benefit over bolus infusion in children. Identifying patient-related (for example, obesity and hypertension) and drug-related (for example, cumulative dose) risk factors for cardiotoxicity could help tailor treatments to individual patients. However, all survivors of childhood cancer are at increased risk of cardiotoxicity, suggesting that survivor screening recommendations for assessment of global risk of premature cardiovascular disease should apply to all survivors. Optimal, evidence-based monitoring strategies and multiagent preventative treatments still need to be identified