A perspective on polo-like kinase-1 inhibition for the treatment of rhabdomyosarcoma

Rhabdomyosarcomas are the most common pediatric soft tissue sarcoma and are a major cause of death from cancer in young patients requiring new treatment options to improve outcomes. High-risk patients include those with metastatic or relapsed disease and tumors with PAX3-FOXO1 fusion genes that encode a potent transcription factor that drives tumourigenesis through transcriptional reprogramming. Polo-Like Kinase-1 (PLK1) is a serine/threonine kinase that phosphorylates a wide range of target substrates and alters their activity. PLK1 functions as a pleiotropic master regulator of mitosis and regulates DNA replication after stress. Taken together with high levels of expression that correlate with poor outcomes in many cancers, including rhabdomyosarcomas, it is an attractive therapeutic target. This is supported in rhabdomyosarcoma models by characterization of molecular and phenotypic effects of reducing and inhibiting PLK1, including changes to the PAX3-FOXO1 fusion protein. However, as tumor re-growth has been observed, combination strategies are required. Here we review preclinical evidence and consider biological rationale for PLK1 inhibition in combination with drugs that promote apoptosis, interfere with activity of PAX3-FOXO1 and are synergistic with microtubule-destabilizing drugs such as vincristine. The preclinical effects of low doses of the PLK1 inhibitor volasertib in combination with vincristine, which is widely used in rhabdomyosarcoma treatment, show particular promise in light of recent clinical data in the pediatric setting that support achievable volasertib doses predicted to be effective. Further development of novel therapeutic strategies including PLK1 inhibition may ultimately benefit young patients with rhabdomyosarcoma and other cancers

A perspective on polo-like kinase-1 inhibition for the treatment of rhabdomyosarcoma

Rhabdomyosarcomas are the most common pediatric soft tissue sarcoma and are a major cause of death from cancer in young patients requiring new treatment options to improve outcomes. High-risk patients include those with metastatic or relapsed disease and tumors with PAX3-FOXO1 fusion genes that encode a potent transcription factor that drives tumourigenesis through transcriptional reprogramming. Polo-Like Kinase-1 (PLK1) is a serine/threonine kinase that phosphorylates a wide range of target substrates and alters their activity. PLK1 functions as a pleiotropic master regulator of mitosis and regulates DNA replication after stress. Taken together with high levels of expression that correlate with poor outcomes in many cancers, including rhabdomyosarcomas, it is an attractive therapeutic target. This is supported in rhabdomyosarcoma models by characterization of molecular and phenotypic effects of reducing and inhibiting PLK1, including changes to the PAX3-FOXO1 fusion protein. However, as tumor re-growth has been observed, combination strategies are required. Here we review preclinical evidence and consider biological rationale for PLK1 inhibition in combination with drugs that promote apoptosis, interfere with activity of PAX3-FOXO1 and are synergistic with microtubule-destabilizing drugs such as vincristine. The preclinical effects of low doses of the PLK1 inhibitor volasertib in combination with vincristine, which is widely used in rhabdomyosarcoma treatment, show particular promise in light of recent clinical data in the pediatric setting that support achievable volasertib doses predicted to be effective. Further development of novel therapeutic strategies including PLK1 inhibition may ultimately benefit young patients with rhabdomyosarcoma and other cancers

Optimising Antimicrobial Selection and Duration in the Treatment of Febrile Neutropenia in Children

Febrile neutropenia (FN) is a frequent complication of cancer treatment in children. Owing to the potential for overwhelming bacterial sepsis, the recognition and management of FN requires rapid implementation of evidenced-based management protocols. Treatment paradigms have progressed from hospitalisation with broad spectrum antibiotics for all patients, through to risk adapted approaches to management. Such risk adapted approaches aim to provide safe care through incorporating antimicrobial stewardship (AMS) principles such as implementation of comprehensive clinical pathways incorporating de-escalation strategies with the imperative to reduce hospital stay and antibiotic exposure where possible in order to improve patient experience, reduce costs and diminish the risk of nosocomial infection. This review summarises the principles of risk stratification in FN, the current key considerations for optimising empiric antimicrobial selection including knowledge of antimicrobial resistance patterns and emerging technologies for rapid diagnosis of specific infections and summarises existing evidence on time to treatment, investigations required and duration of treatment. To aid treating physicians we suggest the key features based on current evidence that should be part of any FN management guideline and highlight areas for future research. The focus is on treatment of bacterial infections although fungal and viral infections are also important in this patient group

Indeterminate Pulmonary Nodules at Diagnosis in Rhabdomyosarcoma: Are They Clinically Significant? A Report From the European Paediatric Soft Tissue Sarcoma Study Group

PURPOSE: To evaluate the clinical significance of indeterminate pulmonary nodules at diagnosis (defined as ≤ 4 pulmonary nodules < 5 mm or 1 nodule measuring ≥ 5 and < 10 mm) in patients with pediatric rhabdomyosarcoma (RMS). PATIENTS AND METHODS: We selected patients with supposed nonmetastatic RMS treated in large pediatric oncology centers in the United Kingdom, France, Italy, and the Netherlands, who were enrolled in the European Soft Tissue Sarcoma Study Group (E pSSG) RMS 2005 study. Patients included in the current study received a diagnosis between September 2005 and December 2013, and had chest computed tomography scans available for review that were done at time of diagnosis. Local radiologists were asked to review the chest computed tomography scans for the presence of pulmonary nodules and to record their findings on a standardized case report form. In the E pSSG RMS 2005 Study, patients with indeterminate pulmonary nodules were treated identically to patients without pulmonary nodules, enabling us to compare event-free survival and overall survival between groups by log-rank test. RESULTS: In total, 316 patients were included; 67 patients (21.2%) had indeterminate pulmonary nodules on imaging and 249 patients (78.8%) had no pulmonary nodules evident at diagnosis. Median follow-up for survivors (n = 258) was 75.1 months; respective 5-year event-free survival and overall survival rates (95% CI) were 77.0% (64.8% to 85.5%) and 82.0% (69.7% to 89.6%) for patients with indeterminate nodules and 73.2% (67.1% to 78.3%) and 80.8% (75.1% to 85.3%) for patients without nodules at diagnosis ( P = .68 and .76, respectively). CONCLUSION: Our study demonstrated that indeterminate pulmonary nodules at diagnosis do not affect outcome in patients with otherwise localized RMS. There is no need to biopsy or upstage patients with RMS who have indeterminate pulmonary nodules at diagnosis

The physical meaning of scattering matrix singularities in coupled-channel formalisms

The physical meaning of bare and dressed scattering matrix singularities has been investigated. Special attention has been attributed to the role of well known invariance of scattering matrix with respect to the field transformation of the effective Lagrangian. Examples of evaluating bare and dressed quantities in various models are given.Comment: 14 pages, Summary of the BRAG2007 worksho

Transforming training into practice with the conflict management framework: a mixed methods study

Objective To implement and evaluate the use of the conflict management framework (CMF) in four tertiary UK paediatric services. Design Mixed methods multisite evaluation including prospective pre and post intervention collection of conflict data alongside semistructured interviews. Setting Eight inpatient or day care wards across four tertiary UK paediatric services. Interventions The two-stage CMF was used in daily huddles to prompt the recognition and management of conflict. Results Conflicts were recorded for a total of 67 weeks before and 141 weeks after implementation of the CMF across the four sites. 1000 episodes of conflict involving 324 patients/families across the four sites were recorded. After implementation of the CMF, time spent managing episodes of conflict around the care of a patient was decreased by 24% (p < 0.001) (from 73 min to 55 min) and the estimated cost of this staff time decreased by 20% (p < 0.02) (from £26 to £21 sterling per episode of conflict). This reduction occurred despite conflict episodes after implementation of the CMF having similar severity to those before implementation. Semistructured interviews highlighted the importance of broad multidisciplinary leadership and training to embed a culture of proactive and collaborative conflict management. Conclusions The CMF offers an effective adjunct to conflict management training, reducing time spent managing conflict and the associated staff costs

Teaching of Energy Issues: A debate proposal for a GLobal Reorientation

The growing awareness of serious difficulties in the learning of energy issues has produced a great deal of research, most of which is focused on specific conceptual aspects. In our opinion, the difficulties pointed out in the literature are interrelated and connected to other aspects (conceptual as well as procedural and axiological), which are not sufficiently taken into account in previous research. This paper aims to carry out a global analysis in order to avoid the more limited approaches that deal only with individual aspects. From this global analysis we have outlined 24 propositions that are put forward for debate to lay the foundations for a profound reorientation of the teaching of energy topics in upper high school courses, in order to facilitate a better scientific understanding of these topics, avoid many students' misconceptions and enhance awareness of the current situation of planetary emergency

Influenza vaccination for immunocompromised patients: systematic review and meta-analysis from a public health policy perspective.

Immunocompromised patients are vulnerable to severe or complicated influenza infection. Vaccination is widely recommended for this group. This systematic review and meta-analysis assesses influenza vaccination for immunocompromised patients in terms of preventing influenza-like illness and laboratory confirmed influenza, serological response and adverse events

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements