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.

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.

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.

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.

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.).

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.

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.

Constitutional translocation breakpoint mapping by genome-wide paired-end sequencing identifies HACE1 as a putative Wilms tumour susceptibility gene.

BACKGROUND: Localisation of the breakpoints of chromosomal translocations has aided the discovery of several disease genes but has traditionally required laborious investigation of chromosomes by fluorescent in situ hybridisation approaches. Here, a strategy that utilises genome-wide paired-end massively parallel DNA sequencing to rapidly map translocation breakpoints is reported. This method was used to fine map a de novo t(5;6)(q21;q21) translocation in a child with bilateral, young-onset Wilms tumour. METHODS AND RESULTS: Genome-wide paired-end sequencing was performed for approximately 6 million randomly generated approximately 3 kb fragments from constitutional DNA containing the translocation, and six fragments in which one end mapped to chromosome 5 and the other to chromosome 6 were identified. This mapped the translocation breakpoints to within 1.7 kb. Then, PCR assays that amplified across the rearrangement junction were designed to characterise the breakpoints at sequence-level resolution. The 6q21 breakpoint transects and truncates HACE1, an E3 ubiquitin-protein ligase that has been implicated as a somatically inactivated target in Wilms tumourigenesis. To evaluate the contribution of HACE1 to Wilms tumour predisposition, the gene was mutationally screened in 450 individuals with Wilms tumour. One child with unilateral Wilms tumour and a truncating HACE1 mutation was identified. CONCLUSIONS: These data indicate that constitutional disruption of HACE1 likely predisposes to Wilms tumour. However, HACE1 mutations are rare and therefore can only make a small contribution to Wilms tumour incidence. More broadly, this study demonstrates the utility of genome-wide paired-end sequencing in the delineation of apparently balanced chromosomal translocations, for which it is likely to become the method of choice.

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.

Management strategies for recurrent ependymoma in the paediatric population.

INTRODUCTION: The management of recurrent ependymoma within the paediatric population remains a therapeutic challenge. The options available are varied and patients may have already received prior radio- or chemotherapy. As yet, no consensus exists regarding their optimal treatment. We review the literature and present our contemporary management strategies for this interesting group of patients. RESULTS AND DISCUSSION: Survival following recurrence is poor and those prognostic factors that predispose to recurrence include extent of surgical resection and the timing of administration of adjuvant therapy. The extent of resection at re-operation can confer a survival advantage, without a necessary increase in morbidity. Strategies aimed at improving surgical resection at first diagnosis include improving and centralising post-surgical radiological review, defining what are true residuals, and centralising surgical review of incompletely resected tumours. Re-irradiation can improve survival, and with the use of conformal radiation fields need not necessarily lead to neuropsychological damage. Cisplatin and etoposide remain the most effective chemotherapeutic agents to date and with an increase in the understanding of tumour biology this may improve further. Because of the complex nature of this group of patients, decisions regarding their management require the involvement of a paediatric neurosurgeon, paediatric neuro-oncologist and paediatric radiation oncologist.

Molecular diagnosis of vascular access device-associated infection in children being treated for cancer or leukaemia.

Blood samples were collected for quantitative 16S rDNA analysis from the vascular access device (VAD) of patients presenting with fever at participating centres of the UK Children's Cancer and Leukaemia Group. In total, 260 of 301 episodes of fever were evaluable and were classified as probable, possible, unlikely or unclassifiable VAD-associated infection. The sensitivity of the 16S rDNA assay declined concomitantly with delays from time of presentation to sampling. The sensitivity with >0.125 pg of bacterial DNA/microL of whole blood was 80% for the 20 probable VAD-associated infections diagnosed with samples collected on the day of or day following presentation. The specificity rose with increasing amounts of bacterial DNA, from 93% with >0.125 pg, to 98% with 0.25-0.5 pg, and to 100% with >0.5 pg/microL blood. The positive predictive value (for probable or possible) was 88% (95% CI 70-98%) with 0.25 pg/microL, and 100% (95% CI 83-100%) with >0.5 pg/microL. All 18 (6.8%) episodes with >0.5 pg of bacterial DNA/microL blood were associated with positive blood cultures. Identifications derived from the DNA sequence were consistent with the blood culture identifications for 15 of the 17 episodes with a DNA sequence identification. The VAD was removed because of suspected infection in six (2.8%) of 216 episodes with <0.125 pg of bacterial DNA/microL, in one (5%) of 20 episodes with 0.125-0.25 pg/microL, in one (16.7%) of six episodes with 0.25-0.5 pg/microL, and in nine (50%) of 18 episodes with >0.5 pg/microL. A bacterial DNA concentration of >0.5 pg/microL in blood drawn through a central venous catheter at the time of fever presentation had a high positive predictive value for VAD-associated infection and predicted an increased risk of VAD removal because of suspected infection.

Infantile myofibromatosis of the craniovertebral junction.

Infantile myofibromatosis (IM) is a rare pathological entity characterized by solitary or multiple nodular skin, soft tissues or bony lesions. Craniovertebral (CV) junction lesions are rare. We report the successful management of a solitary IM involving the posterior elements of the CV junction in a 6-month-old child.

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.

Cardiac troponin T following anthracycline chemotherapy in children and adolescents.

Cardiac troponin T (CTT) is elevated acutely in animal models of anthracycline cardiotoxicity. We assessed CTT release in children receiving anthracylines using a third generation assay. We measured CTT in 30 children receiving anthracycline chemotherapy. A total of 3 samples were taken from each child: 1) prior to, 2) immediately after and 3) between 24-48 hours after the infusion. The dose range given during the measurements of cardiac troponin T was 15-60 (median 25) mg/m(2) and the previous exposure ranged from 0-300 (median 150) mg/m(2). Not one child had a detectable CTT level at any time. This study shows a lack of acute elevation CTT following anthracycline administration. In this respect it is unlikely that early estimation of CTT using this modern assay will be useful for screening for anthracycline cadiomyopathy. Further studies using a third generation assay, are, however, indicated to determine whether delayed elevation of CTT occurs.

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.

Pet ownership in immunocompromised children--a review of the literature and survey of existing guidelines.

Pet ownership has been associated with both emotional and physical health benefits. However, owning pets may also pose health risks to immunocompromised patients through zoonotic transmission of disease. Our initial impression was that there is a lack of any evidence base in information given by health care professionals regarding these risks. We therefore aimed to produce evidence-based guidelines addressing this issue. A Pubmed search was undertaken and a variety of literature on zoonoses reviewed. Existing guidelines were evaluated and a survey of all Paediatric Oncology Centres in the UK performed. There is a paucity of level 1 and 2 data addressing this issue and clearly more studies, particularly Randomised Controlled Trials (RCTs), are required. Nevertheless, general themes emerged and certain specific guidance was produced based on that produced by the Centres for Disease Control and Prevention in the US. Animal-associated pathogens of concern include Toxoplasma gondii, Cryptosporidium spp., Salmonella spp., Campylobacter spp., Giardia lamblia, Rhodococcus equi, Bartonella spp., Bordetella bronchiseptica, Chlamydia psittaci and dermatophytes. Despite this, the literature would suggest that with the exception of Bartonella henselae and dermatophytes only a relatively small number of infections in people are likely to be associated with pet contact. The majority of pet species do not appear to pose a major risk to immunocompromised children. Some animals, particularly reptiles, should be avoided because of the high risk of salmonellosis. Guidelines include general advice on good hygiene practices, veterinary care, pet foods, purchasing of new pets and age restrictions. Health care professionals should actively enquire about household pets and provide accurate information and practical advice on how to minimise the risk of infection. However, the overall benefits of the human-animal bond must be considered and with proper handling and husbandry immunocompromised patients should be able to continue to enjoy the significant benefits of pet ownership.

A prospective study of septicaemia on a paediatric oncology unit: a three-year experience at The Royal Liverpool Children's Hospital, Alder Hey, UK.

Septicaemia in neutropaenic patients is predominantly due to gut translocation [endogenous septicaemia] and contamination of the central venous catheter by microorganisms not carried by the patient [exogenous septicaemia]. To control both types of infection, a protocol was implemented based on pre 1990's parenteral and enteral antimicrobials together with strict hygiene. Surveillance cultures of throat/rectum were taken to distinguish exogenous from endogenous septicaemia and enteral non-absorbable antibiotics are administered as part of selective decontamination of the digestive tract (SDD). This protocol was evaluated in a 14-bedded paediatric oncology unit over a period of 3 years. 313 Septicaemia episodes were recorded in 131 children. 28.4% of the septicaemias were caused by microorganisms associated with the unit, equivalent to 0.82 episodes per 100 patient days. Low-level pathogens such as coagulase-negative staphylococci caused more than 70% of infections. Amongst the potential pathogens, Pseudomonas species (7.8%) and Staphylococcus aureus (5.5%) were predominant. Antibiotic resistance was rare with no superinfections or outbreaks. Four patients (3%) died, two due to Candida species and two due to Pseudomonas aeruginosa. We believe that the addition of enteral non-absorbable antibiotics to systemic antibiotics maintained a low level of resistance and mortality but a randomised controlled trial is indicated to confirm these observations.