Intravenous thrombolysis for acute ischaemic stroke: from randomised clinical trials to daily practice

In the Netherlands, as in most Western countries, stroke is a major contributor to the total burden of disease, with an estimated 39,600 hospital admissions, 9,000 deaths, and approximately 241,600 people living with the consequences of a stroke in 2009.1 Fortunately, improvements are observed, stroke mortality is declining; due to a both declines in incidence of stroke as well as in case fatality.2,3 New treatments like thrombolysis for acute ischaemic stroke are highly effective, but the main cause of increased survival rates after stroke is a better coordination of care, through widespread implementation of stroke units.4,5 Thrombolysis refers to the breakdown of blood clots by stimulating fibrinolysis. In 1995 a large American study on the effectiveness of thrombolysis with intravenous alteplase (recombinant tissue plasminogen activator, rTPA) for patients with acute ischaemic stroke was published. Patients treated with intravenous alteplase had a better functional outcome at three months.6 However two European trials (MAST I and MAST E) had unfavourable results and the ECASS I had inconclusive results.7-9 The higher complication rate was attributed to a too high dose of thrombolytic and the lack of improvement was attributed to the extended time window of 6 hours. In 1998 the ECASS II trial was published, but it also showed inconclusive results.10 A few years later in 2000 the Cochrane Review (including all the trials mentioned above) was published and showed that thrombolytic therapy appears to result in a significant net reduction in the proportion of dependency or death. The relative reduction in risk of poor outcome, defined as a modified Rankin Score >2, was 17.5% (95% CI: 7 to 26%).11 The scepticism about treatment with rTPA gradually declined. Steadily but slowly, more and more hospitals started to treat acute ischaemic stroke patients with thrombolysis, but in daily practice, several circumstances and causes put a constraint on the number of patients who could be treated, the most important cause being the narrow time window for treatment. Taking that narrow time window into account, it was estimated that up to 24% of the stroke patients presenting at the emergency care might be eligible for thrombolysis. 12 In 2002-2003 however, the rate of thrombolysis in Dutch hospitals varied between 1% and 8%, with a few exceptions.13 Clearly, improvements could be made. In addition, concern about bleeding complications remained an issue. A European license for alteplase was provided on the condition that safety and effectiveness would be monitored in a European registry. This resulted in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST)

International Paediatric Mitochondrial Disease Scale

Objective: There is an urgent need for reliable and universally applicable outcome measures for children with mitochondrial diseases. In this study, we aimed to adapt the currently available Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) to the International Paediatric Mitochondrial Disease Scale (IPMDS) during a Delphi-based process with input from international collaborators, patients and caretakers, as well as a pilot reliability study in eight patients. Subsequently, we aimed to test the feasibility, construct validity and reliability of the IPMDS in a multicentre study. Methods: A clinically, biochemically and genetically heterogeneous group of 17 patients (age 1.6–16 years) from five different expert centres from four different continents were evaluated in this study. Results: The feasibility of the IPMDS was good, as indicated by a low number of missing items (4 %) and the positive evaluation of patients, parents and users. Principal component analysis of our small sample identified three factors, which explained 57.9 % of the variance. Good construct validity was found using hypothesis testing. The overall interrater reliability was good [median intraclass correlation coefficient for agreement between raters (ICCagreement) 0.85; range 0.23–0.99). Conclusion: In conclusion, we suggest using the IPMDS for assessing natural history in children with mitochondrial diseases. These data should be used to further explore construct validity of the IPMDS and to set age limits. In parallel, responsiveness and the minimal clinically important difference should be studied to facilitate sample size calculations in future clinical trials

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association wit

International Paediatric Mitochondrial Disease Scale

OBJECTIVE : There is an urgent need for reliable and universally applicable outcome measures for children with mitochondrial diseases. In this study, we aimed to adapt the currently available Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) to the International Paediatric Mitochondrial Disease Scale (IPMDS) during a Delphi-based process with input from international collaborators, patients and caretakers, as well as a pilot reliability study in eight patients. Subsequently, we aimed to test the feasibility, construct validity and reliability of the IPMDS in a multicentre study. METHODS : A clinically, biochemically and genetically heterogeneous group of 17 patients (age 1.6–16 years) from five different expert centres from four different continents were evaluated in this study. RESULTS : The feasibility of the IPMDS was good, as indicated by a low number of missing items (4 %) and the positive evaluation of patients, parents and users. Principal component analysis of our small sample identified three factors, which explained 57.9 % of the variance. Good construct validity was found using hypothesis testing. The overall interrater reliability was good [median intraclass correlation coefficient for agreement between raters (ICCagreement) 0.85; range 0.23–0.99). CONCLUSION : In conclusion, we suggest using the IPMDS for assessing natural history in children with mitochondrial diseases. These data should be used to further explore construct validity of the IPMDS and to set age limits. In parallel, responsiveness and the minimal clinically important difference should be studied to facilitate sample size calculations in future clinical trials.The work of SK and JS was sponsored by ZonMW (The Netherlands Organization for Health Research and Development).http://link.springer.com/journal/10545am2017Paediatrics and Child Healt