Sequence-dependent cross-resistance of combined radiotherapy plus BRAFV600E inhibition in melanoma.

INTRODUCTION: Treatment of patients with metastatic melanoma is hampered by drug-resistance and often requires combination with radiotherapy as last-resort option. However, also after radiotherapy, clinical relapses are common. METHODS & RESULTS: Our preclinical models indicated a higher rate of tumour relapse when melanoma cells were first treated with BRAFV600E inhibition (BRAFi) followed by radiotherapy as compared to the reverse sequence. Accordingly, retrospective follow-up data from 65 stage-IV melanoma patients with irradiated melanoma brain metastases confirmed a shortened duration of local response of mitogen-activated protein kinase (MAPK)-inhibitor-pretreated compared with MAPK-inhibitor-naïve intracranial metastases. On the molecular level, we identified JARID1B/KDM5B as a cellular marker for cross-resistance between BRAFi and radiotherapy. JARID1Bhigh cells appeared more frequently under upfront BRAFi as compared with upfront radiation. JARID1B favours cell survival by transcriptional regulation of genes controlling cell cycle, DNA repair and cell death. CONCLUSION: The level of cross-resistance between combined MAPK inhibition and radiotherapy is dependent on the treatment sequence. JARID1B may represent a novel therapy-overarching resistance marker.

[Systemic treatment of distant metastatic malignant melanoma]. / Systemische Therapie des fernmetastasierten malignen Melanoms.

CONTEXT: Systemic therapy of advanced metastatic malignant melanoma has been considerably changed by the approval of new drugs in recent years. The targeted therapy with the B-RAF inhibitors vemurafenib and dabrafenib achieves rapid tumor reduction but is often followed by the development of resistance in the further course of therapy. By immunotherapy with ipilimumab, on the other hand, a plateau effect becomes apparent in the survival curves. OBJECTIVE: The aim of this article is to discuss the treatment options for patients with advanced melanoma with special reference to new treatment options and substances for which approval is soon to be expected. METHODS: Treatment recommendations, taking into account the S3 guidelines on diagnosis, treatment and follow-up of melanoma and recent publications (Pubmed and manual search) are presented. RESULTS: In patients with B-RAF mutations, targeted therapy with the B-RAF inhibitor vemurafenib achieves response rates of 50-60 %, comparable with the B-RAF inhibitor dabrafenib, yet resistance often occurs after approximately 7 months. By immunotherapy with ipilimumab long-term survival can be achieved in approximately 20 % of patients. CONCLUSION: The treatment options for patients with metastatic melanoma have considerably improved in recent years. Several highly effective substances have recently become available and the approval of more potent substances is expected this year.

Improvement of walking abilities after robotic-assisted locomotion training in children with cerebral palsy.

OBJECTIVE: To measure functional gait improvements of robotic-assisted locomotion training in children with cerebral palsy (CP). DESIGN: Single-case experimental A-B design. SETTINGS: Rehabilitation Centre Affoltern am Albis, Children's University Hospital Zurich, Switzerland (inpatient group) and Neurology Department of the Dr von Haunersches Children's Hospital Munich, Germany (outpatient group). PARTICIPANTS: 22 children (mean age 8.6 years, range 4.6-11.7) with CP and a Gross Motor Function Classification System level II to IV. INTERVENTIONS: 3 to 5 sessions of 45-60 minutes/week during a 3-5-week period of driven gait orthosis training. MAIN OUTCOME MEASURES: 10-metre walk test (10MWT), 6-minute walk test (6MinWT), Gross Motor Function Measure (GMFM-66) dimension D (standing) and dimension E (walking), and Functional Ambulation Categories (FAC). RESULTS: The mean (SD) maximum gait speed (0.78 (0.57) to 0.91 (0.61) m/s; p<0.01) as well as the mean (SD) dimension D of the GMFM-66 (40.3% (31.3%) to 46.6% (28.7%); p<0.05) improved significantly after the intervention period. The mean (SD) 6MinWT (176.3 (141.8) to 199.5 (157.7) m), the mean FAC (2.6 (1.7) to 3.0 (1.6)) and the mean (SD) dimension E of the GMFM-66 (29.5% (30.3%) to 31.6% (29.2%)) also showed an increase, but did not reach a statistically significant level. CONCLUSION: These results suggest that children with CP benefit from robotic-assisted gait training in improving functional gait parameters.

High-dose intravenous immunoglobulin therapy in juvenile myasthenia gravis.

Autoimmune neurologic disease management has been significantly modified by the use of high-dose intravenous immunoglobulin (HDIVIG) during the past 15 years. Venous access, readily available IgG (until recently), and the relative lack of serious identifiable complications have prompted its use in myasthenia gravis. In adults, its effectiveness has been inconsistent, with variable acetylcholine receptor (AChR) antibody responses. Ten children were evaluated for clinical responses to, and complications of, HDIVIG. Weekly anti-AChR antibody titers in three patients were obtained. The HDIVIG dosage was 2 gm/kg body weight, infused at variable rates of 2 gm/kg for 1 day, 0.66 gm/kg daily for 3 days, and 0.5 g/kg daily for 4 days; in one patient the total dose was 0.8 gm/kg to correct to the ideal body weight. All children but one tolerated HDIVIG without complications. Eight patients exhibited definite improvement in functional strength after HDIVIG, but a decreasing response to HDIVIG was evident after multiple monthly treatments, warranting the additional use of corticosteroids in two patients. A decrease in anti-AChR antibody levels was observed in the three patients tested, but this decrease was constant in one patient. No correlation was observed between clinical response and antibody titers. HDIVIG is safe and effective in most patients for short-term management of juvenile myasthenia gravis, in myasthenic crises, and in preparing patients for surgery but appears to be of limited long-term benefit.

Childhood lumbosacral plexus neuropathy.

Primary lumbosacral plexus neuropathy without underlying disease is a well-defined syndrome characterized by pain, weakness, and atrophy in the distribution of the lumbosacral plexus. It generally affects adults and rarely occurs in children. We report 2 children with primary lumbosacral plexus neuropathy evaluated at our institution and review the literature. This syndrome, despite initially severe symptoms, appears to be benign with a favorable prognosis in children.