Access to essential anticancer medicines for children and adolescents in Europe.

BACKGROUND: Essential anticancer medicines are an indispensable component of multidisciplinary treatment of paediatric malignancies. A European Society for Medical Oncology (ESMO) study reported inequalities in the availability of anticancer medicines for adult solid tumours and provided a model for the present survey. The aim of this survey was to assess the accessibility of essential medicines used in paediatric cancer patients aged 0 to 18 years across Europe from 2016 to 2018. METHODS: A list of medicines was drawn with input from the European Society for Paediatric Oncology (SIOP Europe) Clinical Research Council referring to the World Health Organization Model List of Essential Medicines for Children (WHO EMLc) 2017. A survey was sent to nominated national clinician and pharmacist rapporteurs and parent associations in up to 37 countries; answers were obtained from 34 countries. RESULTS: The full survey list contained 68 medicines, including 24 on the WHO EMLc 2017. Health professionals reported that 35% of all medicines were prescribed off-label in at least one country and that 44% were always available in >90% of countries. Only 63% of the EMLc 2017 medicines were reported as always available. The main determinant of unavailability was shortages, reported for 72% of medicines in at least one country. Out-of-pocket costs were reported in eight countries. Twenty-seven percent of orally administered medicines were never available in child-friendly formulations. Parents detailed individual efforts and challenges of facilitating ingestion of oral medicines as prescribed. Inequalities in access to pain control during procedures were reported by parents across Europe. CONCLUSIONS: Children and adolescents with cancer in Europe experience lack of access to essential medicines. Urgent actions are needed to address shortages, financial accessibility, availability of safe age-appropriate oral formulations, and pain management across Europe.

A phase I/II trial of AT9283, a selective inhibitor of aurora kinase in children with relapsed or refractory acute leukemia: challenges to run early phase clinical trials for children with leukemia.

Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies.

The dual-acting chemotherapeutic agent Alchemix induces cell death independently of ATM and p53.

Topoisomerase inhibitors are in common use as chemotherapeutic agents although they can display reduced efficacy in chemotherapy-resistant tumours, which have inactivated DNA damage response (DDR) genes, such as ATM and TP53. Here, we characterise the cellular response to the dual-acting agent, Alchemix (ALX), which is a modified anthraquinone that functions as a topoisomerase inhibitor as well as an alkylating agent. We show that ALX induces a robust DDR at nano-molar concentrations and this is mediated primarily through ATR- and DNA-PK- but not ATM-dependent pathways, despite DNA double strand breaks being generated after prolonged exposure to the drug. Interestingly, exposure of epithelial tumour cell lines to ALX in vitro resulted in potent activation of the G2/M checkpoint, which after a prolonged arrest, was bypassed allowing cells to progress into mitosis where they ultimately died by mitotic catastrophe. We also observed effective killing of lymphoid tumour cell lines in vitro following exposure to ALX, although, in contrast, this tended to occur via activation of a p53-independent apoptotic pathway. Lastly, we validate the effectiveness of ALX as a chemotherapeutic agent in vivo by demonstrating its ability to cause a significant reduction in tumour cell growth, irrespective of TP53 status, using a mouse leukaemia xenograft model. Taken together, these data demonstrate that ALX, through its dual action as an alkylating agent and topoisomerase inhibitor, represents a novel anti-cancer agent that could be potentially used clinically to treat refractory or relapsed tumours, particularly those harbouring mutations in DDR genes.

Diffuse intrinsic pontine glioma treated with prolonged temozolomide and radiotherapy--results of a United Kingdom phase II trial (CNS 2007 04).

Diffuse intrinsic pontine glioma (DIPG) has a dismal prognosis with no chemotherapy regimen so far resulting in any significant improvement over standard radiotherapy. In this trial, a prolonged regimen (21/28d) of temozolomide was studied with the aim of overcoming O(6)-methylguanine methyltransferase (MGMT) mediated resistance. Forty-three patients with a defined clinico-radiological diagnosis of DIPG received radiotherapy and concomitant temozolomide (75 mg/m(2)) after which up to 12 courses of 21d of adjuvant temozolomide (75-100mg/m(2)) were given 4 weekly. The trial used a 2-stage design and passed interim analysis. At diagnosis median age was 8 years (2-20 years), 81% had cranial nerve abnormalities, 76% ataxia and 57% long tract signs. Median Karnofsky/Lansky score was 80 (10-100). Patients received a median of three courses of adjuvant temozolomide, five received all 12 courses and seven did not start adjuvant treatment. Three patients were withdrawn from study treatment due to haematological toxicity and 10 had a dose reduction. No other significant toxicity related to temozolomide was noted. Overall survival (OS) (95% confidence interval (CI)) was 56% (40%, 69%) at 9 months, 35% (21%, 49%) at 1 year and 17% (7%, 30%) at 2 years. Median survival was 9.5 months (range 7.5-11.4 months). There were five 2-year survivors with a median age of 13.6 years at diagnosis. This trial demonstrated no survival benefit of the addition of dose dense temozolomide, to standard radiotherapy in children with classical DIPG. However, a subgroup of adolescent DIPG patients did have a prolonged survival, which needs further exploration.

BET inhibition as a single or combined therapeutic approach in primary paediatric B-precursor acute lymphoblastic leukaemia.

Paediatric B-precursor ALL is a highly curable disease, however, treatment resistance in some patients and the long-term toxic effects of current therapies pose the need for more targeted therapeutic approaches. We addressed the cytotoxic effect of JQ1, a highly selective inhibitor against the transcriptional regulators, bromodomain and extra-terminal (BET) family of proteins, in paediatric ALL. We showed a potent in vitro cytotoxic response of a panel of primary ALL to JQ1, independent of their prognostic features but dependent on high MYC expression and coupled with transcriptional downregulation of multiple pro-survival pathways. In agreement with earlier studies, JQ1 induced cell cycle arrest. Here we show that BET inhibition also reduced c-Myc protein stability and suppressed progression of DNA replication forks in ALL cells. Consistent with c-Myc depletion and downregulation of pro-survival pathways JQ1 sensitised primary ALL samples to the classic ALL therapeutic agent dexamethasone. Finally, we demonstrated that JQ1 reduces ALL growth in ALL xenograft models, both as a single agent and in combination with dexamethasone. We conclude that targeting BET proteins should be considered as a new therapeutic strategy for the treatment of paediatric ALL and particularly those cases that exhibit suboptimal responses to standard treatment.

Gene expression profiling identifies different sub-types of retinoblastoma.

BACKGROUND: Mutation of the RB1 gene is necessary but not sufficient for the development of retinoblastoma. The nature of events occurring subsequent to RB1 mutation is unclear, as is the retinal cell-of-origin of this tumour. METHODS: Gene expression profiling of 21 retinoblastomas was carried out to identify genetic events that contribute to tumorigenesis and to obtain information about tumour histogenesis. RESULTS: Expression analysis showed a clear separation of retinoblastomas into two groups. Group 1 retinoblastomas express genes associated with a range of different retinal cell types, suggesting derivation from a retinal progenitor cell type. Recurrent chromosomal alterations typical of retinoblastoma, for example, chromosome 1q and 6p gain and 16q loss were also a feature of this group, and clinically they were characterised by an invasive pattern of tumour growth. In contrast, group 2 retinoblastomas were found to retain many characteristics of cone photoreceptor cells and appear to exploit the high metabolic capacity of this cell type in order to promote tumour proliferation. CONCLUSION: Retinoblastoma is a heterogeneous tumour with variable biology and clinical characteristics.

Novel therapies for children with acute myeloid leukaemia.

Significant improvements in survival for children with acute myeloid leukaemia (AML) have been made over the past three decades, with overall survival rates now approximately 60-70%. However, these gains can be largely attributed to more intensive use of conventional cytotoxics made possible by advances in supportive care, and although over 90% of children achieve remission with frontline therapy, approximately one third in current protocols relapse. Furthermore, late effects of therapy cause significant morbidity for many survivors. Novel therapies are therefore desperately needed. Early-phase paediatric trials of several new agents such as clofarabine, sorafenib and gemtuzumab ozogamicin have shown encouraging results in recent years. Due to the relatively low incidence of AML in childhood, the success of paediatric early-phase clinical trials is largely dependent upon collaborative clinical trial design by international cooperative study groups. Successfully incorporating novel therapies into frontline therapy remains a challenge, but the potential for significant improvement in the duration and quality of survival for children with AML is high.

A comparison of McGrath and Macintosh laryngoscopes in novice users: a manikin study.

Direct laryngoscopy using the Macintosh laryngoscope is a difficult skill to acquire. Videolaryngoscopy is a widely accepted airway management technique that may be easier for novices to learn. We compared the McGrath videolaryngoscope and Macintosh laryngoscope by studying the performance of 25 medical students with no previous experience of performing tracheal intubation using an easy intubation scenario in a manikin. The order of device use was randomised for each student. After brief instruction each participant performed eight tracheal intubations with one device and then eight tracheal intubations with the other laryngoscope. Novices achieved a higher overall rate of successful tracheal intubation, avoided oesophageal intubation and produced less dental trauma when using the McGrath. The view at laryngoscopy was significantly better with the McGrath. Intubation times were similar for both laryngoscopes and became shorter with practice. There was no difference in participants' rating of overall ease of use for each laryngoscope.

The not-so-lazy-T: a modification of medial ectropion repair.

Medial involutional ectropion without excessive lateral canthal tendon laxity is often corrected using the lazy-T procedure. This procedure however carries a potential risk of canalicular damage, and locating the lower lid retractors can be difficult. We have developed a modification. Replacing the tarso-conjunctival diamond with a subconjuctival pocket posterior and inferior to the punctum, into which the lower lid retractors are advanced from the base of the wedge excision, which effectively ensures plication of the lower lid retractors while maintaining a straightforward procedure. The follow-up data on five procedures showed surgical and symptomatic success in all patients, without complications. These results confirm the efficacy of this modification of the lazy-T procedure in the correction of medial lower lid ectropion.