163 research outputs found
Impact of fusion gene status versus histology on riskâ stratification for rhabdomyosarcoma: Retrospective analyses of patients on UK trials
BackgroundLongâ term toxicities from current treatments are a major issue in paediatric cancer. Previous studies, including our own, have shown prognostic value for the presence of PAX3/7â FOXO1 fusion genes in rhabdomyosarcoma (RMS). It is proposed to introduce PAX3/7â FOXO1 positivity as a component of risk stratification, rather than alveolar histology, in future clinical trials.ProcedureTo assess the potential impact of this reclassification, we have determined the changes to risk category assignment of 210 histologically reviewed patients treated in the UK from previous malignant mesenchymal tumour clinical trials for nonâ metastatic RMS based on identification of PAX3/7â FOXO1 by fluorescence in situ hybridisation and/or reverse transcription PCR.ResultsUsing fusion gene positivity in the current risk stratification would reassign 7% of patients to different European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) risk groups. The next European trial would have 80% power to detect differences in eventâ free survival of 15% over 10 years and 20% over 5 years in reassigned patients. This would decrease treatment for over a quarter of patients with alveolar histology tumours that lack PAX3/7â FOXO1.ConclusionsFusion gene status used in stratification may result in significant numbers of patients benefitting from lower treatmentâ associated toxicity. Prospective testing to show this reassignment maintains current survival rates is now required and is shown to be feasible based on estimated recruitment to a future EpSSG trial. Together with developing novel therapeutic strategies for patients identified as higher risk, this may ultimately improve the outcome and quality of life for patients with RMS.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137481/1/pbc26386_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137481/2/pbc26386.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137481/3/pbc26386-sup-0002-FigureS2.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137481/4/pbc26386-sup-0001-FigureS1.pd
Metastatic Rhabdomyosarcoma: Results of the European Paediatric Soft Tissue Sarcoma Study Group MTS 2008 Study and Pooled Analysis With the Concurrent BERNIE Study
Rabdomiosarcoma metastásico; Sarcoma de tejido blandoRabdomiosarcoma metastàtic; Sarcoma de teixit touMetastatic rhabdomyosarcoma; Soft tissue sarcomaPURPOSE
Outcome for patients with metastatic rhabdomyosarcoma (RMS) is poor. This study presents the results of the MTS 2008 study with a pooled analysis including patients from the concurrent BERNIE study.
PATIENTS AND METHODS
In MTS 2008, patients with metastatic RMS received four cycles of ifosfamide, vincristine, and actinomycin D (IVA) plus doxorubicin, five cycles of IVA, and 12 cycles of maintenance chemotherapy (low-dose cyclophosphamide and vinorelbine). The BERNIE study randomly assigned patients to the addition or not of bevacizumab to the same chemotherapy. Local therapy (surgery/radiotherapy) was given to the primary tumor and all metastatic sites when feasible.
RESULTS
MTS 2008 included 270 patients (median age, 9.6 years; range, 0.07-20.8 years). With a median follow-up of 50.3 months, 3-year event-free survival (EFS) and overall survival (OS) were 34.9% (95% CI, 29.1 to 40.8) and 47.9% (95% CI, 41.6 to 53.9), respectively. In pooled analyses on 372 patients with a median follow-up of 55.2 months, 3-year EFS and OS were 35.5% (95% CI, 30.4 to 40.6) and 49.3% (95% CI, 43.9 to 54.5), respectively. Patients with ≤ 2 Oberlin risk factors (ORFs) had better outcome than those with ≥ 3 ORFs: 3-year EFS was 46.1% versus 12.5% (P < .0001) and 3-year OS 60.0% versus 26.0% (P < .0001). Induction chemotherapy and maintenance appeared tolerable; however, about two third of patients needed dose adjustments during maintenance.
CONCLUSION
Outcome remains poor for patients with metastatic RMS and multiple ORFs. Because of the design of the studies, it was not possible to determine whether the intensive induction regimen and/or the addition of maintenance treatment resulted in apparent improvement of outcome compared with historical cohorts. Further studies, with novel treatment approaches are urgently needed, to improve outcome for the group of patients with adverse prognostic factors
‘Out There’: Developing a transition pathway for adolescents and young adults with cancer using Experience-Based Co-Design
Experience-based co-design (EBCD) provides the opportunity to embed patient experience and input into service design. EBCD was used in the adolescent and young adult oncology setting to develop a transition pathway from hospital for young adults completing cancer treatment
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
Chemotherapy responsiveness in a patient with multiply relapsed ameloblastic fibro-odontosarcoma of the maxilla
Ameloblastic fibro-odontosarcoma (AFOS) is an extremely rare malignant odontogenic tumor. Complete surgical excision is the treatment of choice. Deaths due to disease recurrence and/or progression are documented. Here, we report the case of a 15-year-old female with multiple recurrent AFOS. She responded to chemotherapy with ifosfamide and doxorubicin consolidated by stereotactic reirradiation using cyberknife and remained in complete remission 14 months from the end of reirradiation therapy. Chemotherapy with ifosfamide and doxorubicin should be considered in advanced cases of AFOS. (C) 2015 The Authors. Pediatric Blood & Cancer Published by Wiley Periodicals, Inc
Children's daily travel to school in Johannesburg-Soweto, South Africa: geography and school choice in the Birth to Twenty cohort study
This paper has two aims: to explore approaches to the measurement of children’s daily travel to school in a context of limited geospatial data availability, and to provide data regarding school choice and distance travelled to school in Soweto-Johannesburg, South Africa. The paper makes use of data from the Birth to Twenty cohort study (n=1428) to explore three different approaches to estimating school choice and travel to school. Firstly, straight-line distance between home and school is calculated. Secondly, census geography is used to determine whether a child's home and school fall in the same area. Thirdly, distance data are used to determine whether a child attends the nearest school. Each of these approaches highlights a different aspect of mobility, and all provide valuable data. Overall, primary school aged children in Soweto-Johannesburg are shown to be travelling substantial distances to school on a daily basis. Over a third travel more than 3km, one-way, to school, 60% attend schools outside of the suburb in which they live, and only 18% attend their nearest school. These data provide evidence for high levels of school choice in Johannesburg-Soweto, and that families and children are making substantial investments in pursuit of high quality educational opportunities. Additionally, these data suggest that two patterns of school choice are evident: one pattern involving travel of substantial distances and requiring a higher level of financial investment, and a second pattern, involving choice between more local schools, requiring less travel and a more limited financial investment
The Caenorhabditis elegans vab-10 spectraplakin isoforms protect the epidermis against internal and external forces
Morphogenesis of the Caenorhabditis elegans embryo is driven by actin microfilaments in the epidermis and by sarcomeres in body wall muscles. Both tissues are mechanically coupled, most likely through specialized attachment structures called fibrous organelles (FOs) that connect muscles to the cuticle across the epidermis. Here, we report the identification of new mutations in a gene known as vab-10, which lead to severe morphogenesis defects, and show that vab-10 corresponds to the C. elegans spectraplakin locus. Our analysis of vab-10 reveals novel insights into the role of this plakin subfamily. vab-10 generates isoforms related either to plectin (termed VAB-10A) or to microtubule actin cross-linking factor plakins (termed VAB-10B). Using specific antibodies and mutations, we show that VAB-10A and VAB-10B have distinct distributions and functions in the epidermis. Loss of VAB-10A impairs the integrity of FOs, leading to epidermal detachment from the cuticle and muscles, hence demonstrating that FOs are functionally and molecularly related to hemidesmosomes. We suggest that this isoform protects against forces external to the epidermis. In contrast, lack of VAB-10B leads to increased epidermal thickness during embryonic morphogenesis when epidermal cells change shape. We suggest that this isoform protects cells against tension that builds up within the epidermis
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