Multifactorial analysis of predictors of outcome in pediatric intracranial ependymoma

Pediatric ependymomas are enigmatic tumors, and their clinical management remains one of the more difficult in pediatric oncology. The identification of biological correlates of outcome and therapeutic targets remains a significant challenge in this disease. We therefore analyzed a panel of potential biological markers to determine optimal prognostic markers. We constructed a tissue microarray from 97 intracranial tumors from 74 patients (WHO grade II-III) and analyzed the candidate markers nucleolin, telomerase catalytic subunit (hTERT; antibody clone 44F12), survivin, Ki-67, and members of the receptor tyrosine kinase I (RTK-I) family by immunohistochemistry. Telomerase activity was determined using the in vitro-based telomere repeat amplification protocol assay, and telomere length was measured using the telomere restriction fragment assay. Primary tumors with low versus high nucleolin protein expression had a 5-year event-free survival of 74%+/-13% and 31%+/-7%, respectively. Multivariate analysis identified low nucleolin expression to be independently associated with a more favorable prognosis (hazard ratio=6.25; 95% confidence interval, 1.6-24.2; p=0.008). Ki-67 and survivin correlated with histological grade but not with outcome. Immunohistochemical detection of the RTK-I family did not correlate with grade or outcome. Telomerase activity was evident in 19 of 22 primary tumors, with telomere lengthening and/or maintenance occurring in five of seven recurrent cases. Low nucleolin expression was the single most important biological predictor of outcome in pediatric intracranial ependymoma. Furthermore, telomerase reactivation and maintenance of telomeric repeats appear necessary for childhood ependymoma progression. These findings require corroboration in a clinical trial setting.     

Prevalence and distribution of unintended pregnancy: the Understanding Fertility Management in Australia National Survey

Objective : Mistimed, unexpected or unwanted pregnancies occur in Australia, despite widespread contraception use. The objective was to estimate prevalence and ascertain modifiable social factors for prevention of unintended pregnancy. Methods : National population‐based survey of women and men aged 18–51 years recruited from a random sample of electors on the Australian Electoral Roll in 2013. Data were weighted to reduce non‐response bias. Factors associated with unintended pregnancy were identified in multivariable analyses. Results : Data from 2,235 completed questionnaires were analysed (Women: 69%; Men: 31%). Of those ever pregnant or partner in pregnancy (59%), 40% had experienced an unintended pregnancy. Adjusting for other risks, ever having experienced sexual coercion (AOR, 95%CI=Women 1.948; 1.458–2.601; Men 1.657, 1.014–2.708); socioeconomic disadvantage (AOR, 95%CI=Women 1.808, 1.373, 2.381; Men 1.360, 1.004–1.841), living in a rural area (AOR, 95%CI=Women 1.403, 1.056–1.864; Men 1.583, 1.161–2.159), and for men being born overseas (AOR, 95%CI 1.989, 1.317–3.002) were significantly associated with unintended pregnancy. Conclusions : Experiences of sexual coercion, social disadvantage, rural residence and overseas birth are independently associated with unintended pregnancy in Australia. Implications : Public health policy and health service initiatives should prioritise prevention of sexual coercion, reduction of social inequality and reduction of geographic inequality for those in rural areas.     

Sequence survey of receptor tyrosine kinases reveals mutations in glioblastomas

It is now clear that tyrosine kinases represent attractive targets for therapeutic intervention in cancer. Recent advances in DNA sequencing technology now provide the opportunity to survey mutational changes in cancer in a high-throughput and comprehensive manner. Here we report on the sequence analysis of members of the receptor tyrosine kinase (RTK) gene family in the genomes of glioblastoma brain tumors. Previous studies have identified a number of molecular alterations in glioblastoma, including amplification of the RTK epidermal growth factor receptor. We have identified mutations in two other RTKs: (i) fibroblast growth receptor 1, including the first mutations in the kinase domain in this gene observed in any cancer, and (ii) a frameshift mutation in the platelet-derived growth factor receptor-alpha gene. Fibroblast growth receptor 1, platelet-derived growth factor receptor-alpha, and epidermal growth factor receptor are all potential entry points to the phosphatidylinositol 3-kinase and mitogen-activated protein kinase intracellular signaling pathways already known to be important for neoplasia. Our results demonstrate the utility of applying DNA sequencing technology to systematically assess the coding sequence of genes within cancer genomes.     

Association of single nucleotide polymorphisms in klotho with priapism in sickle cell anaemia

The complications of sickle cell disease are probably determined by genes whose products modify the pathophysiology initiated by the sickle haemoglobin mutation. Priapism, one vaso-occlusive manifestation of sickle cell disease, affects more than 30% of males with the disease. We examined the possible association of single nucleotide polymorphisms (SNPs) in 44 candidate genes of different functional classes for an association with the occurrence of priapism. One hundred and forty-eight patients with sickle cell anaemia and incident or a confirmed history of priapism were studied, along with 529 controls that had not developed priapism. Polymorphisms in the KLOTHO gene (KL; 13q12) showed an association with priapism by genotypic [reference SNP cluster identifier number (rs)2249358; odds ratio (OR) = 2.6 (1.4-5.5); rs211239; OR = 1.7 (1.2-2.6)] and haplotype analyses [rs211234 and rs211239; OR = 2.3 (1.5-3.4)]. These findings may have broader implications in sickle cell disease, as KL encodes a membrane protein that regulates many vascular functions, including vascular endothelial growth factor expression and endothelial nitric oxide release.     

Acquired Fanconi syndrome is an indolent disorder in the absence of overt multiple myeloma

Adult-acquired Fanconi syndrome (FS) is a rare complication of monoclonal gammopathy. We retrospectively reviewed 32 patients diagnosed with adult-acquired FS between April 1968 and June 2002 at Mayo Clinic (Rochester, MN). At diagnosis, most patients had monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM), with a median creatinine level of 176.8 microM (2.0 mg/dL; range, 79.56-327.08 microM [0.9-3.7 mg/dL]) and evidence of osteomalacia. During the average 65 months (range, 2-238 months) of follow-up, 5 patients developed end-stage renal disease (ESRD) and only 1 of 14 patients with MGUS transformed to multiple myeloma (MM). Also, 14 deaths occurred, with only 1 from ESRD but 4 from alkylator-related leukemia or myelodysplastic syndrome. Chemotherapy offered little benefit on renal functions of MGUS or SMM patients. In conclusion, FS associated with monoclonal gammopathy does not appear to confer an additional risk of subsequent evolution to MM. ESRD occurs late in the disease process.     

Addressing complex healthcare problems in diverse settings: insights from activity theory

In the U.K., approaches to policy implementation, service improvement and quality assurance treat policy, management and clinical care as separate, hierarchical domains. They are often based on the central knowledge transfer (KT) theory idea that best practice solutions to complex problems can be identified and 'rolled out' across organisations. When the designated 'best practice' is not implemented, this is interpreted as local--particularly management--failure. Remedial actions include reiterating policy aims and tightening performance management of solution implementation, frequently to no avail. We propose activity theory (AT) as an alternative approach to identifying and understanding the challenges of addressing complex healthcare problems across diverse settings. AT challenges the KT conceptual separations between levels of policy, management and clinical care. It does not regard knowledge and practice as separable, and does not understand them in the commodified way that has typified some versions of KT theory. Instead, AT focuses on "objects of activity" which can be contested. It sees new practice as emerging from contradiction and understands knowledge and practice as fundamentally entwined, not separate. From an AT perspective, there can be no single best practice. The contributions of AT are that it enables us to understand the dynamics of knowledge-practice in activities rather than between levels. It shows how efforts to reduce variation from best practice may paradoxically remove a key source of practice improvement. After explaining the principles of AT we illustrate its explanatory potential through an ethnographic study of primary healthcare teams responding to a policy aim of reducing inappropriate hospital admissions of older people by the 'best practice' of rapid response teams.     

Specialist palliative care: patients' experiences

BACKGROUND: Nursing research generally, and palliative care research in particular, has been criticized for generating numerous small scale, often qualitative and/or evaluative studies, from which it is difficult to draw generalizations. AIMS: Our aim in this study was to conduct a synthesis of three evaluative studies of palliative care services in the United Kingdom (UK), to ascertain patients' reported expectations and experiences of specialist care. We also demonstrate how secondary data analysis and synthesis can identify commonalities and differences between services. METHODS: Secondary qualitative data analysis was conducted on interview data gathered from 37 patients during three evaluation studies of specialist palliative care services. All studies used formative evaluation methodology. FINDINGS: Four themes were identified: (1) knowledge and information about services, (2) meeting practical and psychosocial needs, (3) lack of control, and (4) family atmosphere. Data are presented to illustrate the presence or absence of these themes in patients' accounts of their expectations and experiences of each service. STUDY LIMITATIONS: Data were collected at different times between 1998 and 2000, and interviews were conducted by different researchers. CONCLUSIONS: Synthesizing findings from small scale qualitative studies offers the possibility of demonstrating their applicability beyond local and specific contexts. It is imperative to listen to the experiences of patients and carers as a basis for developing interventions and guidelines for services. The methods proposed in this paper offer the potential for these voices of experience to be heard more widely.