Incidence of childhood CNS tumours in Britain and variation in rates by definition of malignant behaviour: population-based study.

BACKGROUND: Intracranial and intraspinal tumours are the most numerous solid tumours in children. Some recently defined subtypes are relatively frequent in childhood. Many cancer registries routinely ascertain CNS tumours of all behaviours, while others only cover malignant neoplasms. Some behaviour codes have changed between revisions of the International Classification of Diseases for Oncology, including pilocytic astrocytoma, downgraded to uncertain behaviour in ICD-O-3. METHODS: We used data from the population-based National Registry of Childhood Tumours, which routinely included non-malignant CNS tumours, to document the occurrence of CNS tumours among children aged < 15 years in Great Britain during 2001-2010 and to document the descriptive epidemiology of childhood CNS tumours over the 40-year period 1971-2010, during which several new entities were accommodated in successive editions of the WHO Classification and revisions of ICD-O. Eligible cases were all those with a diagnosis included in Groups III (CNS tumours) and Xa (CNS germ-cell tumours) of the International Classification of Childhood Cancer, Third Edition. The population at risk was derived from annual mid-year estimates by sex and single year of age compiled by the Office for National Statistics and its predecessors. Incidence rates were calculated for age groups 0, 1-4, 5-9 and 10-14 years, and age-standardised rates were calculated using the weights of the world standard population. RESULTS: Age-standardised incidence in 2001-10 was 40.1 per million. Astrocytomas accounted for 41%, embryonal tumours for 17%, other gliomas for 10%, ependymomas for 7%, rarer subtypes for 20% and unspecified tumours for 5%. Incidence of tumours classified as malignant and non-malignant by ICD-O-3 increased by 30 and 137% respectively between 1971-75 and 2006-10. CONCLUSIONS: Total incidence was similar to that in other large western countries. Deficits of some, predominantly low-grade, tumours or differences in their age distribution compared with the United States and Nordic countries are compatible with delayed diagnosis. Complete registration regardless of tumour behaviour is essential for assessing burden of disease and changes over time. This is particularly important for pilocytic astrocytoma, because of its recent downgrading to non-malignant and time trends in the proportion of astrocytomas with specified subtype.

Overcoming challenges in the management of primary ciliary dyskinesia: the UK model.

Primary ciliary dyskinesia (PCD) is an autosomal recessive disease associated with bronchiectasis, chronic rhinosinusitis, infertility and situs inversus. Estimates of prevalence vary widely, but is probably between 1:10,000- 1:40,000 in most populations. A number of observational studies indicate that access to services to diagnose and manage patients with PCD vary both between and within countries. Diagnosis is often delayed and frequently missed completely. The prognosis of patients with PCD is variable, but evidence suggests that it is improved by early diagnosis and specialist care. This article briefly reviews the literature concerning PCD and the evidence that specialist care will improve healthcare outcomes. The article specifically refers to a new national service in the UK.

Our greatest untapped resource: our patients.

Healthcare is continually evolving to meet the changing needs of twenty-first century populations whilst striving to keeping pace with medical and technological advancements. Patients and clinicians remain the constants in this evolving environment, sitting at the cutting edge of new evidence and innovation and at the coalface of clinical services which need to address the increasingly challenging health priorities we face as a society. Patients and clinicians, positioned centre stage in this changing world, must adjust their relationships and partnerships to reduce the burden of illness and ensure that multifaceted care needs are all properly addressed. In rare diseases, this relationship between patients and professionals demands a new model of care, in which patients are active, valued partners in their own care and function not as 'enlightened self-interested' individuals but as experts by experience. The unique characteristics of rare diseases demand that care evolves beyond multidisciplinary team care to 'Networked-care', in which care is prescribed based upon the body of experience and expertise of a community of experts and patients (who are experts by experience). Healthcare models are being redrawn around a new norm of clinical practice based on true patient-clinical partnerships in care. A partnership with patients, when supported by proper investment, is a collaborative relationship that aligns both the medical and clinical perspectives of professionals with a holistic perspective of patients' life experiences. Such partnerships can (i) ensure that decisions around care and design of services are needs-led, (ii) reduce the fog of uncertainty that surrounds rare diseases, (iii) amplify the success of new discoveries, and (iv) create breakthrough innovations: in these ways, patient-clinical partnerships increase the efficiency and effectiveness of our work and build a more sustainable future for our healthcare services.

Elosulfase alfa in the treatment of mucopolysaccharidosis type IVA: insights from the first managed access agreement.

Managed access agreements provide a crucial mechanism whereby real-world data can be collected systematically to reduce uncertainty around available clinical and economic data, whilst providing the opportunity to identify patient sub-populations who are most likely to benefit from a new treatment. This manuscript aims to share learnings from the first managed access agreement, which was initiated following positive conditional approval in 2015 from the National Institute for Health and Care Excellence (NICE) for elosulfase alfa, an enzyme replacement therapy for the treatment of mucopolysaccharidosis type IVA (MPS IVA). This managed access agreement enabled the collection of comprehensive real-world data for patients with MPS IVA, with results demonstrating that patients starting elosulfase alfa treatment showed gains similar to those seen in the pivotal trial for outcomes including endurance, respiratory and cardiac function, pain, quality of life measures and urinary keratan sulfate levels. In addition, former trial patients continued to see benefits in both clinical assessments and quality of life/activities of daily living nine years after beginning treatment. Key strengths of the process included recruitment of a high proportion of MPS IVA patients treated in England (72/89 known eligible patients) with a wide range of ages (2-58 years). Participation of a patient organisation (the MPS society) ensured that the patient voice was present throughout the process, whilst a contract research organisation (Rare Disease Research Partners) ensured that patients were represented when interpreting agreement criteria and during patient assessment meetings. Longer-term follow-up will be required for several MPS IVA outcomes (e.g. skeletal measures) to further reduce uncertainty, and continued follow-up of patients who had stopped treatment was found to be challenging. The burden associated with this managed access agreement was found to be high for patients, physicians, patient organisations, NHS England and the manufacturer, therefore costs and benefits of future agreements should be considered carefully before initiation. Through evaluation of the strengths and limitations of this process, it is hoped that learnings from this managed access agreement can be used to inform future agreements.

Treatment perceptions in patients with asthma: Synthesis of factors influencing adherence.

BACKGROUND: Non-adherence to asthma treatment is a contributing factor for poorly controlled asthma. AIM: The aim of this systematic review is to explore patients' perceptions of their inhaled asthma treatment, and how these relate to adherence, using both qualitative and quantitative data. METHODS: Pre-determined search terms and inclusion criteria were used to search electronic databases (The Cochrane Library, MEDLINE, EMBASE and PsycINFO). Two researchers screened titles and abstracts using the Rayyan web app and data were extracted in relation to psychological components (beliefs about, and attitudes towards, medicines) and adherence. RESULTS: Of 1638 papers, 36 met the inclusion criteria. Key themes were: Perceived need for treatment - all 12 studies using the BMQ to measure patients' perceived need for treatment found that patients' beliefs about their necessity for treatment were associated with adherence-; Concerns about treatment - immediate and long-term side effects (58%), worries about safety (19%), and potential addiction to asthma medication (31%)-; and Perceived social stigma - 22% of studies reported that embarrassment contributed to poor adherence. CONCLUSIONS: Acknowledging and addressing patient treatment beliefs and perceptual barriers to adherence is integral to designing adherence interventions for asthma patients. Further research is needed to better our understanding of the relationship between treatment perceptions and adherence.

Comparison of survival between the UK and US after surgery for most common pediatric CNS tumors.

BACKGROUND: We report a population-based study examining long-term outcomes for common pediatric CNS tumors comparing results from the UK with the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) data set and with the literature. No such international study has previously been reported. METHODS: Data between 1996 and 2005 from the UK National Registry of Childhood Tumours (NRCT) and the SEER registry were analyzed. We calculated actuarial survival at each time point from histological diagnosis, with death from any cause as the endpoint. Kaplan-Meier estimation and log-rank testing (Cox proportional hazards regression analysis) were used to calculate survival differences among tumor subtypes, adjusting for age at diagnosis. RESULTS: Population-based outcomes for each tumor type are presented. Overall age-adjusted survival, stratifying for histology (combining pilocytic astrocytoma, anaplastic astrocytoma, glioblastoma, primitive neuroectodermal tumor, medulloblastoma, and ependymoma), is significantly lower for NRCT than SEER (hazard ratio 0.71, P < .001) and at 1, 5, and 10 years. Both NRCT and SEER outcomes are worse than those reported from trials. CONCLUSION: Analyzing data from comprehensive registries minimizes bias associated with trials and institutional studies. The reasons for the poorer outcomes in children treated in the UK are unclear. Likewise, the differences in outcomes between patients in trials and those not in trials need further investigation. We recommend that all children with CNS tumors be recruited into studies-even if these are observational studies. We also suggest that registries be suitably funded to publish independent outcome data (including morbidity) at both a national and an institutional level.

United Kingdom 30-day mortality rates after surgery for pediatric central nervous system tumors.

OBJECT: In an increasing culture of medical accountability, 30-day operative mortality rates remain one of the most objective measurements reported for the surgical field. The authors report population-based 30-day postoperative mortality rates among children who had undergone CNS tumor surgery in the United Kingdom. METHODS: To determine overall 30-day operative mortality rates, the authors analyzed the National Registry of Childhood Tumors for CNS tumors for the period 2004-2007. The operative mortality rate for each tumor category was derived. In addition, comparison was made with the 30-day operative mortality rates after CNS tumor surgery reported in the contemporary literature. Finally, by use of a funnel plot, institutional performance for 30-day operative mortality was compared for all units across the United Kingdom. RESULTS: The overall 30-day operative mortality rate for children undergoing CNS tumor surgery in the United Kingdom during the study period was 2.7%. When only malignant CNS tumors were analyzed, the rate increased to 3.5%. One third of the deaths occurred after discharge from the hospital in which the surgery had been performed. The highest 30-day operative mortality rate (19%) was for patients with choroid plexus carcinomas. A total of 20 institutions performed CNS tumor surgery during the study period. Rates for all institutions fell within 2 SDs. No trend associating operative mortality rates and institutional volume was found. In comparison, review of the contemporary literature suggests that the postoperative mortality rate should be approximately 1%. CONCLUSIONS: The authors believe this to be the first report of national 30-day surgical mortality rates specifically for children with CNS tumors. The study raises questions about the 30-day mortality rate among children undergoing surgery for CNS tumors. International consensus should be reached on a minimum data set for outcomes and should include 30-day operative mortality rates.

Monitoring access to nationally commissioned services in England.

BACKGROUND: For over 20 years, the National Health Service in England has run a system of national planning for highly specialised healthcare services. The aim is to ensure that very rare diseases are treated, and very complex procedures performed, in only a few centres, each of which maintains a volume high enough to maintain excellent outcomes. The commissioning strategy for the provision of these national services in England is strongly centralising. Centralising does however create a duty to ensure that patients distant from the treatment centres are not thereby disadvantaged. The commissioning process ensures sufficient capacity to treat the entire national caseload of clinically eligible patients. The aim of this paper is to apply the Systematic Component of Variation (SCV) to study access to services commissioned by the National Specialised Commissioning Team (NSCT) in England. The discussion focuses on the potential explanations for a high level of systematic variation between areas and on the use of the SCV to support the monitoring and development of these nationally commissioned services. METHOD: Data from nationally commissioned services for the year ending 2011 were received from treating hospital. Mid year age and sex appropriate population estimates were then obtained to provide denominator data. Data were analysed at the geographic level of strategic health authority. RESULTS: 30 services met all requirements for analysis. There is no apparent relationship between SCV and number of locations from which the service is provided. On inspection high SCV is more common among recently commissioned services. DISCUSSION: The importance of the SCV lies in its ability to support the development of highly specialised services. Once the random variation has been accounted for, the reasons for a systematic component can be explored. While no absolute cut- off exists, the SCV can be used to gauge and explore services that are potentially not covering the national caseload. The reason for a high SCV may not be immediately apparent; thus the SCV can aid those responsible for commissioning the service to seek potential explanations and identify improvements. CONCLUSION: We have reviewed spatial variation in access to a set of highly specialised services in England. On inspecting our results, we believe that they suggest that equity of access can usually be achieved at about five years after establishing a service, and this is not dependent, within the geography of England, on the number of centres designated.

Immunological orchestration of liver fibrosis.

Fibrosis represents the main pathophysiological consequence of all chronic inflammatory liver diseases and ultimately leads to the life-threatening clinical consequences of cirrhosis. Regardless of the underlying etiology, fibrosis involves interplay between cells of the immune systems and the direct mediators of fibrosis, including hepatic stellate cells. However, the precise physiological mechanism of liver fibrosis remains largely on enigma. Primary biliary cirrhosis (PBC) is a unique chronic, fibrosing liver disease affecting predominantly women and characterized by an immune-mediated specific destruction of the small intrahepatic bile ducts. The presence of highly specific anti-mitochondrial autoantibodies (AMA) as well as T cell responses directed agonist the pyruvate dehydrogenase E2 complex (PDC-E2) provides a unique opportunity to assess the interaction between specific immune responses and fibrogenesis. In addition, mouse models of PBC have been developed allowing the dissection of mechanisms involved in breakdown of immune tolerance, bile duct injury, and fibrosis. Recently, we reported that liver fibrosis could be induced in a xenobiotic-induced murine model of PBC by polyinosinic-polycytidylic acid (poly I:C) treatment as well as with the administration of α-galactosylceramide (α-GalCer). The aim of this article is to provide a current perspective of the immunological mechanisms that are significant in the fibrogenic processes, and potentially, for its regression by comparing PBC with other chronic inflammatory liver diseases.

Atypical haemolytic uraemic syndrome presenting initially as suspected meningococcal disease: a case report.

BACKGROUND: Haemolytic uraemic syndrome (HUS) is the most common cause of acute renal failure in children and is usually linked with Escherichia coli O157 infection. With a fatality rate of around 5%, some reports have associated antibiotic treatment with a worsening prognosis. CASE PRESENTATION: We describe a female infant patient, initially treated for suspected meningococcal septicaemia, who went on to develop renal complications and thrombocytopenia characteristic of HUS. A subsequent positive stool sample for E. coli O157 confirmed HUS as an appropriate diagnosis, although there was no evidence of diarrhoea or vomiting throughout the course of her management. CONCLUSION: The urgency of early recognition and treatment for suspected meningococcal disease in very young children while entirely appropriate can initially divert attention from other serious conditions. Evidence of infection with E. coli O157 infection in this case also highlights what can be a blurred distinction between atypical (non-diarrhoeal) HUS from classical HUS of infective origin.