High throughput screening aids clinical decision-making in refractory acute myeloid leukaemia.

BACKGROUND: Despite advances in therapeutics for adverse-risk acute myeloid leukaemia (AML), overall survival remains poor, especially in refractory disease. Comprehensive tumour profiling and pre-clinical drug testing can identify effective personalised therapies. CASE: We describe a case of ETV6-MECOM fusion-positive refractory AML, where molecular analysis and in vitro high throughput drug screening identified a tolerable, novel targeted therapy and provided rationale for avoiding what could have been a toxic treatment regimen. Ruxolitinib combined with hydroxyurea led to disease control and enhanced quality-of-life in a patient unsuitable for intensified chemotherapy or allogeneic stem cell transplantation. CONCLUSION: This case report demonstrates the feasibility and role of combination pre-clinical high throughput screening to aid decision making in high-risk leukaemia. It also demonstrates the role a JAK1/2 inhibitor can have in the palliative setting in select patients with AML.

Resistance mechanisms in BRAFV600E paediatric high-grade glioma and current therapeutic approaches.

Paediatric high-grade gliomas (pHGG) are aggressive central nervous system tumours with a poor prognosis. BRAFV600E mutant pHGGs can be treated with targeted BRAF inhibitors, which have shown both preclinical activity and potent clinical efficacy. Unfortunately, the development of drug resistance results in disease relapse or progression and is the primary cause of treatment failure. While there is a lot of data to explain mechanisms of resistance in other BRAFV600E tumours, comparatively little is known about the mechanisms of BRAF inhibitor resistance in BRAFV600E pHGG. Recent literature has identified aberrations in members of the RAS/RAF/ERK pathway, the PI3K/AKT/MTOR pathway and the cell cycle as major contributors to the resistance profile. A range of novel therapies have been suggested to overcome BRAF inhibitor drug resistance in BRAFV600E pHGG. This review will discuss the current literature available for BRAF inhibitor resistant BRAFV600E pHGGs and provide an overview of the currently available and proposed therapies.

Early-phenotype CAR-T cells for the treatment of pediatric cancers.

Chimeric antigen receptor (CAR)-T-cell therapy is a promising approach for the treatment of childhood cancers, particularly high-risk tumors that fail to respond to standard therapies. CAR-T cells have been highly successful in treating some types of hematological malignancies. However, CAR-T cells targeting solid cancers have had limited success so far for multiple reasons, including their poor long-term persistence and proliferation. Evidence is emerging to show that maintaining CAR-T cells in an early, less-differentiated state in vitro results in superior persistence, proliferation, and antitumor effects in vivo. Children are ideal candidates for receiving less-differentiated CAR-T cells, because their peripheral T-cell pool primarily comprises naïve cells that could readily be harvested in large numbers to generate early-phenotype CAR-T cells. Although several studies have reported different approaches to successfully generate early CAR-T cells, there are only a few clinical trials testing these in adult patients. No trials are currently testing early CAR-T cells in children. Here, we summarize the different strategies used to maintain CAR-T cells in an early phenotypic stage and present evidence suggesting that this approach may be particularly relevant to treating childhood cancers.

Healthcare professionals' attitudes toward cancer precision medicine: A systematic review.

Use of precision medicine in oncology is burgeoning and can provide patients with new treatment options. However, it is not clear how precision medicine is impacting healthcare professionals (HCPs), particularly with regards to their concerns about this new approach. We therefore synthesized the existing literature on HCPs' attitudes toward cancer precision medicine. We searched four databases for relevant articles. Two reviewers screened eligible articles and extracted data. We assessed the quality of each article using the QualSyst tool. We found 22 articles, representing 4,321 HCPs (63.7% cancer specialists). HCPs held largely positive attitudes toward cancer precision medicine, including their capacity to facilitate treatment decisions and provide prognostic information. However, they also had concerns regarding costs, insurance coverage, limited HCP knowledge about precision medicine, potential misuse, difficulties accessing the tests, and delays in receiving test results. Most HCPs felt that test-related decisions should be shared between families and HCPs. HCPs intended to disclose actionable results but were less inclined to disclose negative/secondary findings. HCPs had a strong preference for genetic counselor involvement when disclosing germline findings. Most HCPs intended to use somatic and germline tests in their future practice but the extent to which pharmacogenomic tests will be used is uncertain. HCPs indicated that additional evidence supporting test utility and increased availability of treatment guidelines could facilitate the use of testing. HCPs held generally positive attitudes toward cancer precision medicine, however there were some key concerns. Addressing concerns early, devising educational support for HCPs and developing guidelines may facilitate the successful implementation of precision medicine trials in the future.

The wide-ranging clinical implications of the short telomere syndromes.

There is an increasing number of inherited disorders in which excessive telomere shortening underlies the molecular defect, with dyskeratosis congenita (DC) being the archetypal short telomere syndrome. DC is classically described as a mucocutaneous triad of oral leukoplakia, nail dystrophy and abnormal skin pigmentation. However, excessive telomere shortening can affect almost any organ system, so the clinical manifestations are protean, including developmental delay, cerebellar hypoplasia, exudative retinopathy, aplastic anaemia, acute myeloid leukaemia, idiopathic pulmonary fibrosis, idiopathic hepatic cirrhosis, head and neck cancer and dental abnormalities, and may be multi-systemic. Undiagnosed patients may be seen by essentially any medical subspecialist. Correct diagnosis is important to ensure appropriate management, and for initiating investigations to identify affected family members. Treatment is often supportive, with transplantation offering cure for pulmonary fibrosis or bone marrow failure. Higher rates of mortality and morbidity with transplantation often require regimen alterations, underscoring the need for correct diagnosis. Short telomeres result from mutations in genes essential for telomere maintenance (e.g. genes encoding subunits of the telomerase enzyme complex). Disease severity reflects not only the severity of the defect, but also the inheritance of short telomeres, giving rise to incomplete penetrance and genetic anticipation. Attendees of the inaugural Australian Short Telomere Syndrome Conference were updated on the current scientific and clinical understanding of these disorders, and discussed the best approach for management of these patients in the Australian context. This review will include recommendations from the conference and aims to increase awareness of short telomere disorders.

Reduced incidence of second solid tumors in survivors of childhood Hodgkin's lymphoma treated without radiation therapy.

BACKGROUND: We assessed the risk of developing second malignancies in children treated for Hodgkin's lymphoma (HL), the majority of whom received chemotherapy only. PATIENTS AND METHODS: The development of second malignancies in children with HL, treated between 1960 and 1999, was assessed. Results were obtained by both chart review and linkage with a centralized cancer registry. Tumor incidence was compared for patients treated with and without radiotherapy (RT) and with the general population. Risk factors for developing second tumors were assessed by multivariate analysis. RESULTS: Of 142 childhood HL patients, 63 had received RT and 79 had not. Overall survival was similar for both groups. Fourteen patients developed second solid tumors, 12 who had received RT and 2 treated with chemotherapy only (P <0.001), with a 30-year cumulative incidence of 24.7% [95% confidence interval (CI) 7.27-47.4] and 5.8% (95% CI 0-58.9), respectively (P = 0.01). The standardized incidence ratio for second solid tumors was 236 (95% CI 112.2-359.0) versus 43.6 (95% CI 0-103.9), respectively. Multivariate analysis showed treatment with RT was the only significant risks factor for developing second solid tumors. CONCLUSIONS: Children with HL without RT have a substantially lower incidence of second tumors than those treated with RT.