Preoperative word-finding difficulties in children with posterior fossa tumours: a European cross-sectional study.

PURPOSE: Posterior fossa tumour surgery in children entails a high risk for severe speech and language impairments, but few studies have investigated the effect of the tumour on language prior to surgery. The current crosslinguistic study addresses this gap. We investigated the prevalence of preoperative word-finding difficulties, examined associations with medical and demographic characteristics, and analysed lexical errors. METHODS: We included 148 children aged 5-17 years with a posterior fossa tumour. Word-finding ability was assessed by means of a picture-naming test, Wordrace, and difficulties in accuracy and speed were identified by cut-off values. A norm-based subanalysis evaluated performance in a Swedish subsample. We compared the demographic and medical characteristics of children with slow, inaccurate, or combined slow and inaccurate word finding to the characteristics of children without word-finding difficulties and conducted a lexical error analysis. RESULTS: Thirty-seven percent (n = 55) presented with slow word finding, 24% (n = 35) with inaccurate word finding, and 16% (n = 23) with both slow and inaccurate word finding. Children with posterior fossa tumours were twice as slow as children in the norming sample. Right-hemisphere and brainstem location posed a higher risk for preoperative word-finding difficulties, relative to left-hemisphere location, and difficulties were more prevalent in boys than in girls. The most frequent errors were lack of response and semantically related sideordinated words. CONCLUSION: Word-finding difficulties are frequent in children with posterior fossa tumours, especially in boys and in children with right-hemisphere and brainstem tumours. Errors resemble those observed in typical development and children with word-finding difficulties.

Postoperative speech impairment and cranial nerve deficits after secondary surgery of posterior fossa tumours in childhood: a prospective European multicentre study.

PURPOSE: Brain tumours constitute 25% of childhood neoplasms, and half of them are in the posterior fossa. Surgery is a fundamental component of therapy, because gross total resection is associated with a higher progression-free survival. Patients with residual tumour, progression of residual tumour or disease recurrence commonly require secondary surgery. We prospectively investigated the risk of postoperative speech impairment (POSI) and cranial nerve dysfunction (CND) following primary and secondary resection for posterior cranial fossa tumours. METHODS: In the Nordic-European study of the cerebellar mutism syndrome, we prospectively included children undergoing posterior fossa tumour resection or open biopsy in one of the 26 participating European centres. Neurological status was assessed preoperatively, and surgical details were noted post-operatively. Patients were followed up 2 weeks, 2 months and 1 year postoperatively. Here, we analyse the risk of postoperative speech impairment (POSI), defined as either mutism or reduced speech, and cranial nerve dysfunction (CND) following secondary, as compared to primary, surgery. RESULTS: We analysed 426 children undergoing primary and 78 undergoing secondary surgery between 2014 and 2020. The incidence of POSI was significantly lower after secondary (12%) compared with primary (28%, p = 0.0084) surgery. In a multivariate analysis adjusting for tumour histology, the odds ratio for developing POSI after secondary surgery was 0.23, compared with primary surgery (95% confidence interval: 0.08-0.65, p = 0.006). The frequency of postoperative CND did not differ significantly after primary vs. secondary surgery (p = 0.21). CONCLUSION: Children have a lower risk of POSI after secondary than after primary surgery for posterior fossa tumours but remain at significant risk of both POSI and CND. The present findings should be taken in account when weighing risks and benefits of secondary surgery for posterior fossa tumours.

Ataxia and mobility in children following surgical resection of posterior fossa tumour: A longitudinal cohort study.

PURPOSE: To report the course of ataxia in children up to 2 years post-operatively, following surgical resection of a posterior fossa tumour (PFT). METHODS: Thirty-five children, (median age 9 years, range 4-15) having resection of PFT, were assessed using the Scale for the Assessment and Rating of Ataxia (SARA), Brief Ataxia Rating Scale (BARS) and the mobility domain of the Paediatric Evaluation of Disability Index (PEDI-m) at initial post-operative period (baseline), 3 months, 1 year and 2 years post-operatively. RESULTS: Baseline median scores of the SARA and BARS were 8.5 (range 0-35.5), and 7 (0-25) respectively. Ataxia improved at 3 months (median SARA and BARS reduction 3.5 and 4, respectively). Additional gradual improvements in SARA were recorded at 1 (median reduction 2) and 2 years post-operatively (median reduction 0.5). Median baseline PEDI-m was 54.75 (range 15.2-100) with improvement at 3 months (median increase 36.95) and small improvement at 1 year (median increase 2.5) and 2 years (median increase 5.8). Children with medulloblastoma and midline tumours (median baseline SARA 10 and 11, respectively) demonstrated more severe ataxia than children with low-grade gliomas and unilateral tumours (median baseline SARA 7.5 and 6.5, respectively). CONCLUSION: The largest improvement in ataxia scores and functional mobility scores is demonstrated within the first 3 months post-operatively, but ongoing gradual improvement is observed at 2 years. Children with medulloblastoma and midline tumour demonstrated higher ataxia scores long term.

The molecular landscape and associated clinical experience in infant medulloblastoma: prognostic significance of second-generation subtypes.

AIMS: Biomarker-driven therapies have not been developed for infant medulloblastoma (iMB). We sought to robustly sub-classify iMB, and proffer strategies for personalized, risk-adapted therapies. METHODS: We characterized the iMB molecular landscape, including second-generation subtyping, and the associated retrospective clinical experience, using large independent discovery/validation cohorts (n = 387). RESULTS: iMBGrp3 (42%) and iMBSHH (40%) subgroups predominated. iMBGrp3 harboured second-generation subtypes II/III/IV. Subtype II strongly associated with large-cell/anaplastic pathology (LCA; 23%) and MYC amplification (19%), defining a very-high-risk group (0% 10yr overall survival (OS)), which progressed rapidly on all therapies; novel approaches are urgently required. Subtype VII (predominant within iMBGrp4 ) and subtype IV tumours were standard risk (80% OS) using upfront CSI-based therapies; randomized-controlled trials of upfront radiation-sparing and/or second-line radiotherapy should be considered. Seventy-five per cent of iMBSHH showed DN/MBEN histopathology in discovery and validation cohorts (P < 0.0001); central pathology review determined diagnosis of histological variants to WHO standards. In multivariable models, non-DN/MBEN pathology was associated significantly with worse outcomes within iMBSHH . iMBSHH harboured two distinct subtypes (iMBSHH-I/II ). Within the discriminated favourable-risk iMBSHH DN/MBEN patient group, iMBSHH-II had significantly better progression-free survival than iMBSHH-I , offering opportunities for risk-adapted stratification of upfront therapies. Both iMBSHH-I and iMBSHH-II showed notable rescue rates (56% combined post-relapse survival), further supporting delay of irradiation. Survival models and risk factors described were reproducible in independent cohorts, strongly supporting their further investigation and development. CONCLUSIONS: Investigations of large, retrospective cohorts have enabled the comprehensive and robust characterization of molecular heterogeneity within iMB. Novel subtypes are clinically significant and subgroup-dependent survival models highlight opportunities for biomarker-directed therapies.

Neutrophil function is impaired in paediatric patients with malignancy and may be a useful clinical marker.

PURPOSE: Patients treated with cytotoxic chemotherapy are at risk of neutropenia, neutropenic fever and neutropenic sepsis. We hypothesised that pre-existing neutrophil function dysfunction may increase susceptibility to neutropenic fever in paediatric patients receiving cytotoxic chemotherapy. METHODS: Prospective cohort study recruited patients at Alder Hey Children's NHS Foundation Trust, United Kingdom. We measured neutrophil phagocytic function using a validated flow cytometric whole blood phagocytosis assay in paediatric patients (n = 16) with oncological disease before and after chemotherapy in a prospective cohort study. We recruited healthy children as a control comparator (n = 10). RESULTS: We found significantly decreased phagocytic function in oncology patients compared to healthy participants. In five patients who developed neutropenic fever, we observed increased pre-dose neutrophil respiratory burst. CONCLUSION: With further validation, measurement of neutrophil function could potentially be used to personalise appropriate prophylactic antimicrobial administration for patients receiving cytotoxic chemotherapy.

Detection of rotavirus in paediatric oncology patients with diarrhoea: the impact of rotavirus vaccine.

Seven years' data were reviewed to examine stool-testing for rotavirus in patents treated in a regional paediatric oncology unit before and after the introduction of UK-wide rotavirus immunization in July 2013. The prevalence of rotavirus positivity has diminished since the introduction of rotavirus immunization, with 21 of 416 positive samples between 2010 and 2012, but only one positive test out of 122 samples in 2015 and 2016. Based on these results, there seems to be little use for routine rotavirus-testing in children and young people with cancer presenting with diarrhoea.

Clinical value of stool culture in paediatric oncology patients: hospital evaluation and UK survey of practice.

Diarrhoea is a frequently occurring symptom in paediatric oncology patients. The role of routine testing for enteric bacteria in hospitalized patients with diarrhoea is considered limited, but the diagnostic value of testing in children with oncological conditions has not been reported. Therefore, we conducted a five-year retrospective service evaluation in our tertiary paediatric oncology unit together with a national survey of 21 centres to estimate the utility of stool cultures in oncology patients with diarrhoea and the national approach to testing. Our local survey demonstrated very low diagnostic yield using routine enteric stool cultures with only one sample out of 842 (0.1%) testing positive. The national survey demonstrated considerable variation in practice. There is little evidence to support the use of conventional stool culture for enteric bacteria in children with cancer in our centre. These findings should inform national testing policies.

Inter-rater reliability and validity of two ataxia rating scales in children with brain tumours.

OBJECTIVES: This study aimed to investigate the inter-rater reliability and construct validity of the Scale for the Assessment and Rating of Ataxia (SARA) and Brief Ataxia Rating Scale (BARS) in children with posterior fossa tumours. These scales have been developed for adults with genetic ataxias, and the performance of these scales in children with brain tumours has not previously been described. METHODS: The participants, who had undergone surgical resection for a posterior fossa tumour (inclusion criteria age 4-18 years), were recruited from the neuro-oncology service at a tertiary children's hospital. Children were assessed using the SARA, BARS and Paediatric Evaluation of Disability Index (PEDI) mobility domain, a measure of function. Children were independently rated by two therapists to determine the inter-rater reliability of the SARA and BARS. The construct validity was determined by assessing the correlation between the two scales with the PEDI. RESULTS: Forty-four children were recruited. Inter-rater reliability was good for both scales, demonstrating the strong correlations (SARA, r = 0.94; BARS, r = 0.91) and the good consistency (93 % of SARA and 90 % of BARS paired scores differing by less than 2 points) between two raters. Both ataxia scales demonstrated a strong negative correlation with the mobility domain of the PEDI (SARA, r = -0.77; BARS, r = -0.76), indicating that more severe ataxia was associated with worse mobility. The mean time for completion of the SARA was 4.5 and 2.7 min for the BARS. CONCLUSIONS: The SARA and BARS are reliable and valid measures and appear to be of equal value in determining the severity of ataxia in children with posterior fossa tumours.

Cellular memory of hypoxia elicits neuroblastoma metastasis and enables invasion by non-aggressive neighbouring cells.

Therapies targeting cancer metastasis are challenging owing to the complexity of the metastatic process and the high number of effectors involved. Although tumour hypoxia has previously been associated with increased aggressiveness as well as resistance to radio- and chemotherapy, the understanding of a direct link between the level and duration of hypoxia and the individual steps involved in metastasis is still missing. Using live imaging in a chick embryo model, we have demonstrated that the exposure of neuroblastoma cells to 1% oxygen for 3 days was capable of (1) enabling cell migration towards blood vessels, (2) slowing down their velocity within blood vessels to facilitate extravasation and (3) promoting cell proliferation in primary and secondary sites. We have shown that cells do not have to be hypoxic anymore to exhibit these acquired capabilities as a long-term memory of prior hypoxic exposure is kept. Furthermore, non-hypoxic cells can be influenced by neighbouring hypoxic preconditioned cells and be entrained in the metastatic progression. The acquired aggressive phenotype relies on hypoxia-inducible factor (HIF)-dependent transcription of a number of genes involved in metastasis and can be impaired by HIF inhibition. Altogether, our results demonstrate the need to consider both temporal and spatial tumour heterogeneity because cells can 'remember' an earlier environment and share their acquired phenotype with their close neighbours. As a consequence, it is necessary to monitor the correct hypoxic markers to be able to predict the consequences of the cells' history on their behaviour and their potential response to therapies.

Population pharmacokinetics of teicoplanin in children.

Teicoplanin is frequently administered to treat Gram-positive infections in pediatric patients. However, not enough is known about the pharmacokinetics (PK) of teicoplanin in children to justify the optimal dosing regimen. The aim of this study was to determine the population PK of teicoplanin in children and evaluate the current dosage regimens. A PK hospital-based study was conducted. Current dosage recommendations were used for children up to 16 years of age. Thirty-nine children were recruited. Serum samples were collected at the first dose interval (1, 3, 6, and 24 h) and at steady state. A standard 2-compartment PK model was developed, followed by structural models that incorporated weight. Weight was allowed to affect clearance (CL) using linear and allometric scaling terms. The linear model best accounted for the observed data and was subsequently chosen for Monte Carlo simulations. The PK parameter medians/means (standard deviation [SD]) were as follows: CL, [0.019/0.023 (0.01)] × weight liters/h/kg of body weight; volume, 2.282/4.138 liters (4.14 liters); first-order rate constant from the central to peripheral compartment (Kcp), 0.474/3.876 h(-1) (8.16 h(-1)); and first-order rate constant from peripheral to central compartment (Kpc), 0.292/3.994 h(-1) (8.93 h(-1)). The percentage of patients with a minimum concentration of drug in serum (Cmin) of <10 mg/liter was 53.85%. The median/mean (SD) total population area under the concentration-time curve (AUC) was 619/527.05 mg · h/liter (166.03 mg · h/liter). Based on Monte Carlo simulations, only 30.04% (median AUC, 507.04 mg · h/liter), 44.88% (494.1 mg · h/liter), and 60.54% (452.03 mg · h/liter) of patients weighing 50, 25, and 10 kg, respectively, attained trough concentrations of >10 mg/liter by day 4 of treatment. The teicoplanin population PK is highly variable in children, with a wider AUC distribution spread than for adults. Therapeutic drug monitoring should be a routine requirement to minimize suboptimal concentrations. (This trial has been registered in the European Clinical Trials Database Registry [EudraCT] under registration number 2012-005738-12.).

Burkitt lymphoma of thyroid gland in an adolescent.

Burkitt Lymphoma is a highly aggressive form of non-Hodgkin's lymphoma that in nonendemic areas has abdominal primary sites. We report a very rare case of Burkitt lymphoma of the thyroid gland presenting as a rapidly growing thyroid swelling in a 14-year-old white Caucasian British male with no preexisting thyroid or medical problems. The diagnosis was confirmed by an open wedge biopsy following a fine needle aspiration. The patient was treated according to the Children's Cancer and Leukaemia Group guidelines for BL-Group B protocol and currently is in remission.

Galectin-3 is a marker of favorable prognosis and a biologically relevant molecule in neuroblastic tumors.

Childhood neuroblastic tumors are characterized by heterogeneous clinical courses, ranging from benign ganglioneuroma (GN) to highly lethal neuroblastoma (NB). Although a refined prognostic evaluation and risk stratification of each tumor patient is becoming increasingly essential to personalize treatment options, currently only few biomolecular markers (essentially MYCN amplification, chromosome 11q status and DNA ploidy) are validated for this purpose in neuroblastic tumors. Here we report that Galectin-3 (Gal-3), a ß-galactoside-binding lectin involved in multiple biological functions that has already acquired diagnostic relevance in specific clinical settings, is variably expressed in most differentiated and less aggressive neuroblastic tumors, such as GN and ganglioneuroblastoma, as well as in a subset of NB cases. Gal-3 expression is associated with the INPC histopathological categorization (P<0.001) and Shimada favorable phenotype (P=0.001), but not with other prognostically relevant features. Importantly, Gal-3 expression was associated with a better 5-year overall survival (P=0.003), and with improved cumulative survival in patient subsets at worse prognosis, such as older age at diagnosis, advanced stages or NB histopathological classification. In vitro, Gal-3 expression and nuclear accumulation accompanied retinoic acid-induced cell differentiation in NB cell lines. Forced Gal-3 overexpression increased phenotypic differentiation and substrate adherence, while inhibiting proliferation. Altogether, these findings suggest that Gal-3 is a biologically relevant player for neuroblastic tumors, whose determination by conventional immunohistochemistry might be used for outcome assessment and patient's risk stratification in the clinical setting.

The management of bifocal intracranial germinoma in children.

OBJECTIVES: Bifocal intracranial germinoma (BFG) is a tumour of the pineal and suprasellar regions, which is known to be highly radiosensitive. The definitive treatment and outcomes are not well defined, particularly in the paediatric population. We review our series of purely paediatric cases from a single institution and combine them with the limited reports in the literature to determine the results of different management strategies. METHODS: Four patients were treated at our institution with a median age of 15.3 years. A literature search identified a further 38 paediatric cases with a median age of 12.9 years. RESULTS: All four patients had normal serum and CSF tumour markers. One patient had a diagnosis made based on imaging findings of bifocal pineal and suprasellar lesions presenting with diabetes insipidus. Three others underwent biopsy. All had craniospinal radiotherapy, which has led to complete cure with no cases of progression at a mean follow-up of 3 years. The most common treatment modality in published cases is craniospinal irradiation. In the cases reviewed, limited radiation treatments (whole ventricle or focal) combined with chemotherapy regimens yield comparable outcomes where there is no spinal dissemination. Outcomes do not appear to be altered by biopsy in cases with negative tumour markers and characteristic imaging appearances. CONCLUSION: Patients who present with a classic appearance of germinoma, negative tumour markers and diabetes insipidus probably do not require a biopsy to confirm the diagnosis. No evidence of dissemination may obviate the need for craniospinal irradiation, but good quality long-term follow-up data are required to demonstrate the benefits of combined focal radiotherapy and chemotherapy regimes.

Diffuse intrinsic pontine glioma treated with prolonged temozolomide and radiotherapy--results of a United Kingdom phase II trial (CNS 2007 04).

Diffuse intrinsic pontine glioma (DIPG) has a dismal prognosis with no chemotherapy regimen so far resulting in any significant improvement over standard radiotherapy. In this trial, a prolonged regimen (21/28d) of temozolomide was studied with the aim of overcoming O(6)-methylguanine methyltransferase (MGMT) mediated resistance. Forty-three patients with a defined clinico-radiological diagnosis of DIPG received radiotherapy and concomitant temozolomide (75 mg/m(2)) after which up to 12 courses of 21d of adjuvant temozolomide (75-100mg/m(2)) were given 4 weekly. The trial used a 2-stage design and passed interim analysis. At diagnosis median age was 8 years (2-20 years), 81% had cranial nerve abnormalities, 76% ataxia and 57% long tract signs. Median Karnofsky/Lansky score was 80 (10-100). Patients received a median of three courses of adjuvant temozolomide, five received all 12 courses and seven did not start adjuvant treatment. Three patients were withdrawn from study treatment due to haematological toxicity and 10 had a dose reduction. No other significant toxicity related to temozolomide was noted. Overall survival (OS) (95% confidence interval (CI)) was 56% (40%, 69%) at 9 months, 35% (21%, 49%) at 1 year and 17% (7%, 30%) at 2 years. Median survival was 9.5 months (range 7.5-11.4 months). There were five 2-year survivors with a median age of 13.6 years at diagnosis. This trial demonstrated no survival benefit of the addition of dose dense temozolomide, to standard radiotherapy in children with classical DIPG. However, a subgroup of adolescent DIPG patients did have a prolonged survival, which needs further exploration.

Use of a tissue expander as a radio-protective spacer with a latissimus dorsi flap in the management of a peripheral primitive neuroectodermal tumour (pPNET).

Peripheral primitive neuroectodermal tumours (pPNET) are aggressive neoplasms that require radical surgical resection with adjuvant chemotherapy and radiotherapy. A pPNET of the posterior chest wall was resected with wide soft tissue margins in a 14 year old male. Following tumour excision a spacer device was positioned in the retroperitoneum adjacent to the ipsilateral left kidney displacing it from the planned radiotherapy field. A pedicled latissimus dorsi myocutaneous flap was used to achieve robust soft tissue cover. Ultrasound demonstrated anteromedial displacement of the left kidney with no hydronephrosis and renal function remained normal during subsequent radiotherapy. This report highlights the usefulness of a tissue expander in providing protection for vital structures during radiotherapy.

Prolonged survival associated with the use of intraoperative carmustine (Gliadel) in a paediatric patient with recurrent grade III astrocytoma.

A 15-year-old female presented with a middle cranial fossa anaplastic astrocytoma that was completely excised. She received local radiotherapy (54 Gy) and oral temozolomide. Five months after therapy, MRI showed local relapse. She underwent resection of the tumour with implantation of seven carmustine-impregnated wafers (Gliadel). She then received six cycles of procarbazine and lomustine therapy. Three years later, she is well and disease free. This case supports the further investigation of Gliadel in children and young people with relapsed high-grade glioma, particularly in the setting of a second complete resection.

Exploitation of chick embryo environments to reprogram MYCN-amplified neuroblastoma cells to a benign phenotype, lacking detectable MYCN expression.

Neuroblastoma is a paediatric cancer that arises from the sympathetic ganglia (SG) or adrenal gland. Tumours that occur in patients under 18 months of age have a particularly good prognosis and frequently undergo spontaneous regression. This led to the hypothesis that developmental cues in the youngest patients may prompt belated differentiation and/or apoptosis of the tumour cells. To test our hypothesis, we have injected MYCN-amplified neuroblastoma cells into the extra embryonic veins of chick embryos at embryonic day 3 (E3) and E6 and analysed the response of these Kelly cells at E10 and E14. Amplification of the MYCN gene occurs in up to 30% of tumours and is normally associated with a very poor prognosis. Kelly cells injected at E3 follow neural crest pathways and integrate into neural locations such as SG and the enteric nervous system although never into the adrenal gland. Additionally they migrate to non-neural locations such as the heart, meninges, jaw regions and tail. The cells respond to their respective microenvironments and in SG, some cells differentiate, they show reduced cell division and crucially all cells have undetectable MYCN expression by E10. In non-neural locations, cells form more rapidly dividing clumps and continue to express MYCN. The downregulation of MYCN is dependent on continuous and direct interaction with the sympathetic ganglion environment. We propose that the MYCN-amplicon in the Kelly cells retains the ability to correctly interpret the environmental cues leading to downregulation of MYCN.

Accuracy of bacterial DNA testing for central venous catheter-associated bloodstream infection in children with cancer.

BACKGROUND: Central venous catheters (CVCs) are widely used for children with cancer and are a major risk factor for bloodstream infection. Early and specific diagnosis of CVC-associated bloodstream infection allows early targeted treatment, reducing the risk of CVC removal and avoiding the operative risks and trauma of reinsertion, but peripheral vein sampling, as used in adults, improves specificity but is not usually acceptable in children. OBJECTIVE: To improve the detection and treatment of CVC-associated bloodstream infection in children (aged 0-18 years) with cancer admitted with fever. METHODS: There were four main studies: (1) evaluation of the diagnostic accuracy of a quantitative molecular method for the detection of bacterial deoxyribonucleic acid (DNA), based solely on blood samples drawn through the CVC; (2) analysis of the prognostic risk of CVC removal and duration of intravenous (i.v.) antibiotic treatment days in relation to presenting clinical features, blood culture results and bacterial DNA test results; (3) systematic reviews of treatment options for CVC-associated infection and a questionnaire survey of current practice in paediatric oncology centres; (4) evaluation of the clinical effectiveness of different test-treatment strategies to reduce i.v. antibiotic treatment days and unnecessary CVC removals. RESULTS: (1) The bacterial DNA test detected two-thirds [95% confidence interval (CI) 44% to 83%] of children classified with probable CVC-associated infection - specificity was 88% (95% CI 84% to 92%). Although high bacterial DNA concentrations were associated with subsequent CVC removal and long duration of i.v. antibiotic treatment, the test did not improve the prediction of these outcomes over and above clinical signs of CVC-associated infection combined with blood culture results. (2) High DNA load was predictive of CVC removal and i.v. treatment duration, before blood culture results became available at 48 hours after sampling. (3) There was limited evidence that antibiotic lock treatment reduces the risk of recurrent CVC-associated infection or CVC removal (pooled relative risk 0.7, 95% CI 0.47 to 1.05), but prophylactic use of antimicrobial locks halved the risk of bloodstream infection (pooled incidence rate ratio 0.43, 95% CI 0.36 to 0.51). Contrary to this, the national survey of paediatric oncology centres found that locks are being used for treatment rather than prevention and that problems related to the formulation of lock solutions currently impede a shift to their prophylactic use in children. (4) Most i.v. treatment days would be saved by early stopping of treatment for children at low risk of infection. LIMITATIONS: The accuracy study was limited primarily by the lack of an adequate reference standard, and the main limitation of the series of systematic reviews was the poor quality of included studies and lack of randomised controlled trials of CVC removal or antimicrobial locks for treatment of infection. CONCLUSIONS: There is strong evidence to support the use of antimicrobial locks for prevention of CVC-associated infection; however, few of these studies involved children with cancer. The analysis does not support routine bacterial DNA testing on admission to detect CVC-associated infection, but repeated testing (as a marker of microbial load) should be evaluated in high-risk groups. Further research should determine the effectiveness of antibiotic locks for treating CVC-associated infection. TRIAL REGISTRATION: Current Controlled Trials ISRCTN68138140. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 15, No. 7. See the HTA programme website for further project information.