Utility of carboplatin therapeutic drug monitoring for the treatment of neonate and infant retinoblastoma patients in the United Kingdom.

BACKGROUND: Retinoblastoma is the most common intra-ocular malignancy in children and frequently presents in very young patients who commonly require intravenous carboplatin. Delivering this is challenging due to a lack of uniform dosing recommendations, rapid changes in physiological function and the risk of side-effects. METHODS: We conducted a retrospective review of neonates and infants in the UK with retinoblastoma, who have undergone carboplatin therapeutic drug monitoring (TDM). We report on the pharmacokinetic, treatment efficacy and toxicity data. RESULTS: In total, 29 patients (median age 5 weeks at treatment onset) underwent a total of 74 TDM guided cycles of chemotherapy, involving real time sampling and dose adjustment. An additional 13 patients underwent TDM sampling to modify doses between cycles. Without the adoption of TDM guided dosing, carboplatin exposures would have been ≥20% outside the target AUC in 38/78 (49%) of treatment cycles. Excellent responses and a reassuringly low incidence of toxicities were observed following dose adjustment, despite the young patient age and the implementation of dose increases in the majority of cases. CONCLUSIONS: Real time TDM is safe, effective and deliverable for neonates and infants receiving carboplatin for retinoblastoma and should be considered standard of care up to the age of 6 months.

Surveillance for subsequent neoplasms of the CNS for childhood, adolescent, and young adult cancer survivors: a systematic review and recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Exposure to cranial radiotherapy is associated with an increased risk of subsequent CNS neoplasms among childhood, adolescent, and young adult (CAYA) cancer survivors. Surveillance for subsequent neoplasms can translate into early diagnoses and interventions that could improve cancer survivors' health and quality of life. The practice guideline presented here by the International Late Effects of Childhood Cancer Guideline Harmonization Group was developed with an evidence-based method that entailed the gathering and appraisal of published evidence associated with subsequent CNS neoplasms among CAYA cancer survivors. The preparation of these guidelines showed a paucity of high-quality evidence and highlighted the need for additional research to inform survivorship care. The recommendations are based on careful consideration of the evidence supporting the benefits, risks, and harms of the surveillance interventions, clinical judgment regarding individual patient circumstances, and the need to maintain flexibility of application across different health-care systems. Currently, there is insufficient evidence to establish whether early detection of subsequent CNS neoplasms reduces morbidity and mortality, and therefore no recommendation can be formulated for or against routine MRI surveillance. The decision to start surveillance should be made by the CAYA cancer survivor and health-care provider after careful consideration of the potential harms and benefits of surveillance for CNS neoplasms, including meningioma.

Adjuvant therapy of histopathological risk factors of retinoblastoma in Europe: A survey by the European Retinoblastoma Group (EURbG).

INTRODUCTION: Advanced intraocular retinoblastoma can be cured by enucleation, but spread of retinoblastoma cells beyond the natural limits of the eye is related to a high mortality. Adjuvant therapy after enucleation has been shown to prevent metastasis in children with risk factors for extraocular retinoblastoma. However, histological criteria and adjuvant treatment regimens vary and there is no unifying consensus on the optimal choice of treatment. METHOD: Data on guidelines for adjuvant treatment in European retinoblastoma referral centres were collected in an online survey among all members of the European Retinoblastoma Group (EURbG) network. Extended information was gathered via personal email communication. RESULTS: Data were collected from 26 centres in 17 countries. Guidelines for adjuvant treatment were in place at 92.3% of retinoblastoma centres. There was a consensus on indication for and intensity of adjuvant treatment among more than 80% of all centres. The majority of centres use no adjuvant treatment for isolated focal choroidal invasion or prelaminar optic nerve invasion. Patients with massive choroidal invasion or postlaminar optic nerve invasion receive adjuvant chemotherapy, while microscopic invasion of the resection margin of the optic nerve or extension through the sclera are treated with combined chemo- and radiotherapy. CONCLUSION: Indications and adjuvant treatment regimens in European retinoblastoma referral centres are similar but not uniform. Further biomarkers in addition to histopathological risk factors could improve treatment stratification. The high consensus in European centres is an excellent foundation for a common European study with prospective validation of new biomarkers.

Employment status and occupational level of adult survivors of childhood cancer in Great Britain: The British childhood cancer survivor study.

The British Childhood Cancer Survivor Study (BCCSS) provides the first detailed investigation of employment and occupation to be undertaken in a large population-based cohort. Previous studies have been limited by design issues such as using small numbers of survivors with specific diagnoses, and involved limited assessment of employment status and occupational level. The BCCSS includes 17,981 5-year survivors of childhood cancer. Employment status and occupational level were ascertained by questionnaire from eligible survivors (n = 14,836). Multivariate logistic regression was used to explore factors associated with employment and occupation, and to compare survivors to their demographic peers in the general population. Employment status was available for 10,257 survivors. Gender, current age, cancer type, radiotherapy, age at diagnosis and epilepsy were consistently associated with being: employed; unable to work; in managerial or non-manual occupations. Overall, survivors were less likely to be working than expected (OR (99% CI): 0.89 (0.81-0.98)), and this deficit was greatest for irradiated CNS neoplasm survivors (0.34 (0.28-0.41)). Compared to the general population, survivors were fivefold more likely to be unable to work due to illness/disability; the excess was 15-fold among CNS neoplasm survivors treated with radiotherapy. Overall survivors were less likely to be in managerial occupations than expected (0.85 (0.77-0.94)). However, bone sarcoma survivors were more likely to be in these occupations than expected (1.37 (1.01-1.85)) and also similarly for non-manual occupations (1.90 (1.37-2.62)). Survivors of retinoblastoma (1.55 (1.20-2.01)) and 'other' neoplasm group (1.62 (1.30-2.03)) were also more likely to be in non-manual occupations than expected.

Metabolite profiling in retinoblastoma identifies novel clinicopathological subgroups.

BACKGROUND: Tumour classification, based on histopathology or molecular pathology, is of value to predict tumour behaviour and to select appropriate treatment. In retinoblastoma, pathology information is not available at diagnosis and only exists for enucleated tumours. Alternative methods of tumour classification, using noninvasive techniques such as magnetic resonance spectroscopy, are urgently required to guide treatment decisions at the time of diagnosis. METHODS: High-resolution magic-angle spinning magnetic resonance spectroscopy (HR-MAS MRS) was undertaken on enucleated retinoblastomas. Principal component analysis and cluster analysis of the HR-MAS MRS data was used to identify tumour subgroups. Individual metabolite concentrations were determined and were correlated with histopathological risk factors for each group. RESULTS: Multivariate analysis identified three metabolic subgroups of retinoblastoma, with the most discriminatory metabolites being taurine, hypotaurine, total-choline and creatine. Metabolite concentrations correlated with specific histopathological features: taurine was correlated with differentiation, total-choline and phosphocholine with retrolaminar optic nerve invasion, and total lipids with necrosis. CONCLUSIONS: We have demonstrated that a metabolite-based classification of retinoblastoma can be obtained using ex vivo magnetic resonance spectroscopy, and that the subgroups identified correlate with histopathological features. This result justifies future studies to validate the clinical relevance of these subgroups and highlights the potential of in vivo MRS as a noninvasive diagnostic tool for retinoblastoma patient stratification.

Aspects of mental health dysfunction among survivors of childhood cancer.

BACKGROUND: Some previous studies have reported that survivors of childhood cancer are at an increased risk of developing long-term mental health morbidity, whilst others have reported that this is not the case. Therefore, we analysed 5-year survivors of childhood cancer using the British Childhood Cancer Survivor Study (BCCSS) to determine the risks of aspects of long-term mental health dysfunction. PROCEDURE: Within the BCCSS, 10 488 survivors completed a questionnaire that ascertained mental health-related information via 10 questions from the Short Form-36 survey. Internal analyses were conducted using multivariable logistic regression to determine risk factors for mental health dysfunction. External analyses were undertaken using direct standardisation to compare mental health dysfunction in survivors with UK norms. RESULTS: This study has shown that overall, childhood cancer survivors had a significantly higher prevalence of mental health dysfunction for 6/10 questions analysed compared to UK norms. Central nervous system (CNS) and bone sarcoma survivors reported the greatest dysfunction, compared to expected, with significant excess dysfunction in 10 and 6 questions, respectively; the excess ranged from 4.4-22.3% in CNS survivors and 6.9-15.9% in bone sarcoma survivors. Compared to expected, excess mental health dysfunction increased with attained age; this increase was greatest for reporting 'limitations in social activities due to health', where the excess rose from 4.5% to 12.8% in those aged 16-24 and 45+, respectively. Within the internal analyses, higher levels of educational attainment and socio-economic classification were protective against mental health dysfunction. CONCLUSIONS: Based upon the findings of this large population-based study, childhood cancer survivors report significantly higher levels of mental health dysfunction than those in the general population, where deficits were observed particularly among CNS and bone sarcoma survivors. Limitations were also observed to increase with age, and thus it is important to emphasise the need for mental health evaluation and services across the entire lifespan. There is evidence that low educational attainment and being unemployed or having never worked adversely impacts long-term mental health. These findings provide an evidence base for risk stratification and planning interventions.

Long-term retinoblastoma follow-up with or without general anaesthesia.

BACKGROUND: Children with treated retinoblastoma undergo frequent examinations to monitor for recurrent or new tumours. Examinations under anaesthesia allow a more complete examination in younger children, however they are stressful for the family, subject the child to medical risk and consume resources. The risk of recurrent or new tumours declines with age and it is common practice to examine older children without general anaesthesia. There are no studies on the safety and cost effectiveness of this practice, or guidelines on when examination without anaesthesia (EWA) can be safely commenced. PROCEDURE: Retrospective case note review of 128 sequential patients treated for retinoblastoma in a national referral centre over 10 years. RESULTS: Following exclusions, 113 eyes of 84 children were analysed. The mean age at diagnosis was 20 months (range birth to 71 months). There were 55 unilateral and 29 bilateral cases. The mean follow-up was 77.7 months (range 12-178 months). EWA was commenced at a mean age of 53 months (range 12-98 months). The age of conversion to EWA was largely dependent on child cooperation and disease activity. Tumour activity was detected on EWA in one child at the age of 86 months, 9 months after the last active treatment and treated successfully. CONCLUSIONS: Examination without general anaesthesia does not appear to expose children to an increased risk of undetected tumour growth. This study highlights the important factors to be considered when deciding a safe time to commence EWA.

Genetic Diagnosis of Retinoblastoma Using Aqueous Humour-Findings from an Extended Cohort.

The identification of somatic RB1 variation is crucial to confirm the heritability of retinoblastoma. We and others have previously shown that, when tumour DNA is unavailable, cell-free DNA (cfDNA) derived from aqueous humour (AH) can be used to identify somatic RB1 pathogenic variation. Here we report RB1 pathogenic variant detection, as well as cfDNA concentration in an extended cohort of 75 AH samples from 68 patients. We show cfDNA concentration is highly variable and significantly correlated with the collection point of the AH. Cell-free DNA concentrations above 5 pg/µL enabled the detection of 93% of known or expected RB1 pathogenic variants. In AH samples collected during intravitreal chemotherapy treatment (Tx), the yield of cfDNA above 5 pg/µL and subsequent variant detection was low (≤46%). However, AH collected by an anterior chamber tap after one to three cycles of primary chemotherapy (Dx1+) enabled the detection of 75% of expected pathogenic variants. Further limiting our analysis to Dx1+ samples taken after ≤2 cycles (Dx ≤ 2) provided measurable levels of cfDNA in all cases, and a subsequent variant detection rate of 95%. Early AH sampling is therefore likely to be important in maximising cfDNA concentration and the subsequent detection of somatic RB1 pathogenic variants in retinoblastoma patients undergoing conservative treatment.

Risk Factors for Primary Bone Cancer After Childhood Cancer: A PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies Nested Case-Control Study.

PURPOSE: Radiation to the bone and exposure to alkylating agents increases the risk of bone cancer among survivors of childhood cancer, but there is uncertainty regarding the risks of bone tissue radiation doses below 10 Gy and the dose-response relationship for specific types of chemotherapy. METHODS: Twelve European countries contributed 228 cases and 228 matched controls to a nested case-control study within a cohort of 69,460 5-year survivors of childhood cancer. Odds ratios (ORs) of developing bone cancer for different levels of cumulative radiation exposure and cumulative doses of specific types of chemotherapy were calculated. Excess ORs were calculated to investigate the shape and extent of any dose-response relationship. RESULTS: The OR associated with bone tissue exposed to 1-4 Gy was 4.8-fold (95% CI, 1.2 to 19.6) and to 5-9 Gy was 9.6-fold (95% CI, 2.4 to 37.4) compared with unexposed bone tissue. The OR increased linearly with increasing dose of radiation (Ptrend < .001) up to 78-fold (95% CI, 9.2 to 669.9) for doses of ≥40 Gy. For cumulative alkylating agent doses of 10,000-19,999 and ≥20,000 mg/m2, the radiation-adjusted ORs were 7.1 (95% CI, 2.2 to 22.8) and 8.3 (95% CI, 2.8 to 24.4), respectively, with independent contributions from each of procarbazine, ifosfamide, and cyclophosphamide. Other cytotoxics were not associated with bone cancer. CONCLUSION: To our knowledge, we demonstrate-for the first time-that the risk of bone cancer is increased 5- to 10-fold after exposure of bone tissue to cumulative radiation doses of 1-9 Gy. Alkylating agents exceeding 10,000 mg/m2 increase the risk 7- to 8-fold, particularly following procarbazine, ifosfamide, and cyclophosphamide. These substantially elevated risks should be used to develop/update clinical follow-up guidelines and survivorship care plans.

DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome.

BACKGROUND: Constitutional DICER1 mutations were recently reported to cause familial pleuropulmonary blastoma (PPB). AIM: To investigate the contribution and phenotypic spectrum of constitutional and somatic DICER1 mutations to cancer. METHODS AND RESULTS: The authors sequenced DICER1 in constitutional DNA from 823 unrelated patients with a variety of tumours and in 781 cancer cell lines. Constitutional DICER1 mutations were identified in 19 families including 11/14 with PPB, 2/3 with cystic nephroma, 4/7 with ovarian Sertoli-Leydig-type tumours, 1/243 with Wilms tumour (this patient also had a Sertoli-Leydig tumour), 1/1 with intraocular medulloepithelioma (this patient also had PPB), 1/86 with medulloblastoma/infratentorial primitive neuroectodermal tumour, and 1/172 with germ cell tumour. The inheritance was investigated in 17 families. DICER1 mutations were identified in 25 relatives: 17 were unaffected, one mother had ovarian Sertoli-Leydig tumour, one half-sibling had cystic nephroma, and six relatives had non-toxic thyroid cysts/goitre. Analysis of eight tumours from DICER1 mutation-positive patients showed universal retention of the wild-type allele. DICER1 truncating mutations were identified in 4/781 cancer cell lines; all were in microsatellite unstable lines and therefore unlikely to be driver mutations. CONCLUSION: Constitutional DICER1 haploinsufficiency predisposes to a broad range of tumours, making a substantial contribution to PPB, cystic nephroma and ovarian Sertoli-Leydig tumours, but a smaller contribution to other tumours. Most mutation carriers are unaffected, indicating that tumour risk is modest. The authors define the clinical contexts in which DICER1 mutation testing should be considered, the associated tumour risks, and the implications for at-risk individuals. They have termed this condition 'DICER1 syndrome'. ACCESSION NUMBERS: The cDNA Genbank accession number for the DICER1 sequence reported in this paper is NM_030621.2.

Long-term risks of subsequent primary neoplasms among survivors of childhood cancer.

CONTEXT: Survivors of childhood cancer are at excess risk of developing subsequent primary neoplasms but the long-term risks are uncertain. OBJECTIVES: To investigate long-term risks of subsequent primary neoplasms in survivors of childhood cancer, to identify the types that contribute most to long-term excess risk, and to identify subgroups of survivors at substantially increased risk of particular subsequent primary neoplasms that may require specific interventions. DESIGN, SETTING, AND PARTICIPANTS: British Childhood Cancer Survivor Study--a population-based cohort of 17,981 5-year survivors of childhood cancer diagnosed with cancer at younger than 15 years between 1940 and 1991 in Great Britain, followed up through December 2006. MAIN OUTCOME MEASURES: Standardized incidence ratios (SIRs), absolute excess risks (AERs), and cumulative incidence of subsequent primary neoplasms. RESULTS: After a median follow-up time of 24.3 years (mean = 25.6 years), 1354 subsequent primary neoplasms were ascertained; the most frequently observed being central nervous system (n = 344), nonmelanoma skin cancer (n = 278), digestive (n = 105), genitourinary (n = 100), breast (n = 97), and bone (n = 94). The overall SIR was 4 times more than expected (SIR, 3.9; 95% confidence interval [CI], 3.6-4.2; AER, 16.8 per 10,000 person-years). The AER at older than 40 years was highest for digestive and genitourinary subsequent primary neoplasms (AER, 5.9 [95% CI, 2.5-9.3]; and AER, 6.0 [95%CI, 2.3-9.6] per 10,000 person-years, respectively); 36% of the total AER was attributable to these 2 subsequent primary neoplasm sites. The cumulative incidence of colorectal cancer for survivors treated with direct abdominopelvic irradiation was 1.4% (95% CI, 0.7%-2.6%) by age 50 years, comparable with the 1.2% risk in individuals with at least 2 first-degree relatives affected by colorectal cancer. CONCLUSION: Among a cohort of British childhood cancer survivors, the greatest excess risk associated with subsequent primary neoplasms at older than 40 years was for digestive and genitourinary neoplasms.

The Impact of Cell-Free DNA Analysis on the Management of Retinoblastoma.

Retinoblastoma is a childhood eye cancer, mainly caused by mutations in the RB1 gene, which can be somatic or constitutional. Unlike many other cancers, tumour biopsies are not performed due to the risk of tumour dissemination. As a result, until recently, somatic genetic analysis was only possible if an affected eye was removed as part of a treatment. Several recent proof of principle studies have demonstrated that the analysis of tumour-derived cell-free DNA, either obtained from ocular fluid or blood plasma, has the potential to advance the diagnosis and influence the prognosis of retinoblastoma patients. It has been shown that a confirmed diagnosis is possible in retinoblastoma patients undergoing conservative treatment. In vivo genetic analysis of retinoblastoma tumours is also now possible, allowing the potential identification of secondary genetic events as prognostic biomarkers. In addition, noninvasive prenatal diagnosis in children at risk of inheriting retinoblastoma has been developed. Here, we review the current literature and discuss the potential impact of cell-free DNA analysis on both the diagnosis and treatment of retinoblastoma patients and their families.

Adjuvant use of laser in eyes with macular retinoblastoma treated with primary intravenous chemotherapy.

BACKGROUND: Adjuvant use of laser with systemic chemotherapy for treatment of retinoblastoma may reduce recurrence rates while also causing local side effects. Information is lacking on the effect of laser on visual outcomes. METHODS: A retrospective review of two retinoblastoma centres in the United Kingdom was conducted. Patients were included if there was a macular tumour in at least one eye. Eyes that received chemotherapy alone were compared with eyes that received chemotherapy plus adjuvant laser. RESULTS: A total of 76 patients and 91 eyes were included in the study. Systemic chemotherapy alone was used in 71 eyes while chemotherapy plus laser was used in 20 eyes. Demographic characteristics of both groups were similar. Macular relapse rates were similar between groups: 22/71 (31%) eyes in chemotherapy group and 9/20 (45%) eyes in laser group (p=0.29). There was no increase in vitreous relapses in the laser group (2/20 eyes), compared with the chemotherapy group 10/71 eyes (p=0.99). Survival analysis demonstrated similar time to first relapse between groups. Final visual acuity was equal between groups with 6/15 or better present in 31.1% of eyes in the chemotherapy group and 37.5% of eyes in the laser group (p=0.76). Presence of tumour at the fovea was predictive of final visual acuity, regardless of treatment group. CONCLUSION: Adjuvant laser in the treatment of retinoblastoma is safe and does not lead to increased rate of vitreous recurrence. Final visual acuity is determined by the presence of tumour at the fovea and not the use of laser.

Current Indications of Secondary Enucleation in Retinoblastoma Management: A Position Paper on Behalf of the European Retinoblastoma Group (EURbG).

Secondary enucleation (SE) puts an irreversible end to eye-preserving therapies, whenever their prolongation is expected to violate the presumed state of metastatic grace. At present, it must be acknowledged that clear criteria for SE are missing, leading to empiric and subjective indications commonly related to disease progression or relapse, disease persistence masking the optic nerve head or treatment-related complications obscuring the fundus view. This absence of evidence-based consensus regarding SE is explained by the continuously moving frontiers of the conservative management as a result of diagnostic and therapeutic advances, as well as by the lack of studies sufficiently powered to accurately stratify the risk of metastasis in conservatively treated patients. In this position paper of the European Retinoblastoma Group (EURbG), we give an overview of the progressive shift in the indications for SE over the past decades and propose guidelines to assist decision-making with respect to when SE becomes imperative or recommended, with corresponding absolute and relative SE indications. Further studies and validation of biologic markers correlated with the risk of metastasis are expected to set more precisely the frontiers of conservative management and thus consensual criteria for SE in the future.

Updated Breast Cancer Surveillance Recommendations for Female Survivors of Childhood, Adolescent, and Young Adult Cancer From the International Guideline Harmonization Group.

PURPOSE: As new evidence is available, the International Late Effects of Childhood Cancer Guideline Harmonization Group has updated breast cancer surveillance recommendations for female survivors of childhood, adolescent, and young adult cancer. METHODS: We used evidence-based methods to apply new knowledge in refining the international harmonized recommendations developed in 2013. The guideline panel updated the systematic literature review, developed evidence summaries, appraised the evidence, and updated recommendations on the basis of evidence, clinical judgement, and consideration of benefits versus the harms of the surveillance interventions while attaining flexibility in implementation across different health care systems. The GRADE Evidence-to-Decision framework was used to translate evidence to recommendations. A survivor information form was developed to counsel survivors about the potential harms and benefits of surveillance. RESULTS: The literature update identified new study findings related to the effects of prescribed moderate-dose chest radiation (10 to 19 Gy), radiation dose-volume, anthracyclines and alkylating agents in non-chest irradiated survivors, and the effects of ovarian function on breast cancer risk. Moreover, new data from prospective investigations were available regarding the performance metrics of mammography and magnetic resonance imaging among survivors of Hodgkin lymphoma. Modified recommendations include the performance of mammography and breast magnetic resonance imaging for survivors treated with 10 Gy or greater chest radiation (strong recommendation) and upper abdominal radiation exposing breast tissue at a young age (moderate recommendation) at least annually up to age 60 years. As a result of inconsistent evidence, no recommendation could be formulated for routine breast cancer surveillance for survivors treated with any type of anthracyclines in the absence of chest radiation. CONCLUSION: The newly identified evidence prompted significant change to the recommendations formulated in 2013 related to moderate-dose chest radiation and anthracycline exposure as well as breast cancer surveillance modality.

Non-invasive diagnosis of retinoblastoma using cell-free DNA from aqueous humour.

Retinoblastoma is the most common eye malignancy in childhood caused by mutations in the RB1 gene. Both alleles of the RB1 gene must be mutated for tumour development. The initial RB1 mutation may be constitutional germline or somatic (originating in one retinal cell only). Distinguishing between these alternative mechanisms is crucial, with wider implications for management of the patient and family members. Bilateral retinoblastoma is nearly always due to a constitutional mutation; however, approximately 15% of unilateral cases also carry a germline mutation, and identifying these cases is important. This can be achieved by identifying both mutation types in tumour tissue and excluding their presence in blood. Modern eye-saving chemotherapy treatment (systemic, intra-arterial and intravitreal) has resulted in fewer enucleations. As a result, tumour tissue required to identify sporadic RB1 mutation(s) is not always available. Modern intravitreal chemotherapeutic techniques for retinoblastoma involve aspiration of aqueous humour (AH), providing a novel sample source for analysis. By analysing cell-free DNA present in the AH fluid of eyes affected with retinoblastoma, we have developed a screening test capable of detecting somatic RB1 mutations that is comparable to current tests on enucleated tumour tissue. The results obtained with fluid from enucleated eyes were concordant with tumour tissue in all 10 cases analysed. In addition, AH analysis from two patients undergoing intravitreal chemotherapy successfully identified somatic variants in both cases. Our findings suggest that AH fluid is a promising source of tumour-derived DNA in retinoblastoma for analysis.

Is infection in the community a real threat? The example of CAUTI.

Targeting health care associated infections (HCAIs) is a key priority of current health policy. This applies as much to the community as to hospitals, although the latter receive far more media attention. One of the commonest HCAIs in the community is catheter-associated urinary tract infection (CAUTI). Cutting infection rates is a challenge. Many CAUTIs are the result of inappropriate catheterization, often combined with reduced sensitivity of bacteria to antibiotics given prophylactically. The government's rapid reaction task force has recommended use of a silver-alloy coated catheter, but closer surveillance is needed to persuade budget-holders of the cost and clinical benefits of this intervention.

Prevention and control of infection in non-acute healthcare settings.

This article discusses the main principles of infection prevention and control in non-acute healthcare settings. It explores the use of a set of ten tools developed by the Infection Control Nurses Association (ICNA) to audit infection prevention and control, using the standard statements and criteria within the tools as a checklist. The results of the audit of facilities, commodities and practice using the ICNA audit tools will help staff to identify areas of best practice and areas where improvements are needed to enhance patient care.

Long term cause specific mortality among 34 489 five year survivors of childhood cancer in Great Britain: population based cohort study.

OBJECTIVE:  To determine whether modern treatments for cancer are associated with a net increased or decreased risk of death from neoplastic and non-neoplastic causes among survivors of childhood cancer. DESIGN:  Population based cohort study. SETTING:  British Childhood Cancer Survivor Study. PARTICIPANTS:  Nationwide population based cohort of 34 489 five year survivors of childhood cancer with a diagnosis from 1940 to 2006 and followed up until 28 February 2014. MAIN OUTCOME MEASURES:  Cause specific standardised mortality ratios and absolute excess risks are reported. Multivariable Poisson regression models were utilised to evaluate the simultaneous effect of risk factors. Likelihood ratio tests were used to test for heterogeneity or trend. RESULTS:  Overall, 4475 deaths were observed, which was 9.1 (95% confidence interval 8.9 to 9.4) times that expected in the general population, corresponding to 64.2 (95% confidence interval 62.1 to 66.3) excess deaths per 10 000 person years. The number of excess deaths from all causes declined among those treated more recently; those treated during 1990-2006 experienced 30% of the excess number of deaths experienced by those treated before 1970. The corresponding percentages for the decline in excess deaths from recurrence or progression and non-neoplastic causes were 30% and 60%, respectively. Among survivors aged 50-59 years, 41% and 22% of excess deaths were attributable to subsequent primary neoplasms and circulatory conditions, respectively, whereas the corresponding percentages among those aged 60 years or more were 31% and 37%. CONCLUSIONS:  The net effects of changes in cancer treatments, and surveillance and management for late effects, over the period 1940 to 2006 was to reduce the excess number of deaths from both recurrence or progression and non-neoplastic causes among those treated more recently. Among survivors aged 60 years or more, the excess number of deaths from circulatory causes exceeds the excess number of deaths from subsequent primary neoplasms. The important message for the evidence based surveillance aimed at preventing excess mortality and morbidity in survivors aged 60 years or more is that circulatory disease overtakes subsequent primary neoplasms as the leading cause of excess mortality.

Risk of Adverse Health and Social Outcomes Up to 50 Years After Wilms Tumor: The British Childhood Cancer Survivor Study.

PURPOSE: Survivors of Wilms tumor (WT) are at risk for adverse health and social outcomes but risks beyond 30 years from diagnosis remain uncertain. We investigated the risks of adverse outcomes among 5-year survivors of WT, in particular, those between 30 and 50 years from diagnosis. PATIENTS AND METHODS: The British Childhood Cancer Survivor Study includes 1,441 5-year survivors of WT. We investigated cause-specific mortality, risk of subsequent primary neoplasms (SPNs), and, for those who completed a questionnaire, the extent of smoking and drinking, educational achievement, health status, and health service use compared with the general population. RESULTS: Cumulative risk of death from all causes, excluding recurrence, increased substantially from 5.4% to 22.7% at 30 years and 50 years, respectively, after WT diagnosis-75% of excess deaths beyond 30 years from diagnosis were attributable to SPNs (50%) and cardiac diseases (25%). Digestive cancer, most frequently bowel, accounted for 41% of excess cancers beyond 30 years. CONCLUSION: Between 30 and 50 years from diagnosis, survivors of WT are at a substantially increased risk of premature mortality, and 75% of excess deaths were accounted for by SPNs and cardiac diseases. Radiotherapy exposure was a risk factor for both outcomes. The proportion of patients with WT who are exposed to radiotherapy has reduced substantially in recent decades because of initiatives such as the SIOP WT 2001 clinical trial, which sought to reduce late effects; however, the majority of current survivors, who are at least 30 years from diagnosis, received radiotherapy. Surveillance of this group should focus on SPNs, in particular, bowel and breast cancers, and cardiac conditions.