Abstract INTRODUCTION Pediatric spinal ependymomas account for approximately 1% of childhood CNS tumors. Most are myxopapillary ependymomas (MPEs). For symptomatic cases, maximal safe surgical resection is the accepted therapeutic standard. However, a role for adjuvant therapy is unclear, underpinned by low incidence rates, inadequate trial data and recent WHO upgrading of the MPE variant. This retrospective national service evaluation aimed to provide safety and outcome data, from which future management guidance could be developed. METHOD Children, teenagers and young adults diagnosed with a spinal ependymoma of any WHO grade since 2000 across 17 UK CCLG centres were evaluated. Patient demographics, therapies, adverse events, and outcomes were captured. RESULTS 102 patients were evaluated. Ten children had NF2 (median age 11 (7.6 – 14) years) with nine located in the cervicomedullary region. All ten patients were alive following surveillance (n=3) or surgical intervention (n=7) with an estimated median PFS of 5.4 (1.7 – 9.1) years. For the remaining 92 patients (median age 12 (0.7 – 19) years), 63% of tumors were lumbosacral, 73% demonstrated MPE morphology and 16% were metastatic. The median symptom interval was 4 (0 - 36) months. Progression or relapse was reported in 30/92 (33%), with a 5-year PFS of 62(+ 6)%, yet only 4 disease-related deaths occurred (mean follow-up 6.8 years; no MPEs). Across this non-NF2 cohort, gross/near total resection and upfront adjuvant radiotherapy independently reduced disease progression risk (p < 0.05). However, improved local control from early irradiation was not statistically proven when localized disease or MPEs were exclusively scrutinized. No radiotherapy-related high-grade toxicity was reported. DISCUSSION Pediatric spinal ependymomas are rare tumors demonstrating excellent survival, particularly MPEs. Maximal safe surgery and early adjuvant radiotherapy can improve local control rates, but European collaboration will be required to evaluate efficacy for certain tumor and clinical subgroups. Conclusions could support future national management guidelines.

Background Dihydropyrimidine dehydrogenase (DPD) deficiency is the main known cause of life-threatening fluoropyrimidine (FP)-induced toxicities. We conducted a meta-analysis on individual patient data to assess the contribution of deleterious DPYD variants *2A/D949V/*13/HapB3 (recommended by EMA) and clinical factors, for predicting G4-5 toxicity. Methods Study eligibility criteria included recruitment of Caucasian patients without DPD-based FP-dose adjustment. Main endpoint was 12-week haematological or digestive G4-5 toxicity. The value of DPYD variants *2A/p.D949V/*13 merged, HapB3, and MIR27A rs895819 was evaluated using multivariable logistic models (AUC). Results Among 25 eligible studies, complete clinical variables and primary endpoint were available in 15 studies (8733 patients). Twelve-week G4-5 toxicity prevalence was 7.3% (641 events). The clinical model included age, sex, body mass index, schedule of FP-administration, concomitant anticancer drugs. Adding *2A/p.D949V/*13 variants (at least one allele, prevalence 2.2%, OR 9.5 [95%CI 6.7–13.5]) significantly improved the model ( p < 0.0001). The addition of HapB3 (prevalence 4.0%, 98.6% heterozygous), in spite of significant association with toxicity (OR 1.8 [95%CI 1.2–2.7]), did not improve the model. MIR27A rs895819 was not associated with toxicity, irrespective of DPYD variants. Conclusions FUSAFE meta-analysis highlights the major relevance of DPYD *2A/p.D949V/*13 combined with clinical variables to identify patients at risk of very severe FP-related toxicity.

BACKGROUND:There is increasing recognition of adverse mental health consequences of preterm birth and the impact on social-emotional development. However, the quality of the developing parent-infant relationship may be protective, with enhanced maternal sensitivity to infants' cues associated with improved outcomes.METHODS:Eighty mothers and their preterm infants born <32 weeks gestation were randomised to intervention and standard care groups. Intervention comprised reflective interview, observation of infant cues and video interaction guidance (VIG). The primary outcome, maternal sensitivity during play, was measured by the Child Adult Relationship Evaluation-Index. Secondary outcomes were infant social-emotional problems measured by the Ages and Stages Questionnaire-Social-Emotional version.RESULTS:There was no statistically significant difference between the intervention and standard care groups in maternal sensitivity during play at 9 months corrected age (CA). In the secondary outcome analysis at 12 months CA, infants in the intervention group had fewer self-regulation problems than infants whose mothers received standard care. Per-protocol analysis revealed that infants whose mothers completed VIG had significantly fewer communication problems.CONCLUSIONS:This early attachment-focussed intervention integrating VIG for mothers and their preterm infants did not enhance maternal sensitivity; however, there were effects on infant social-emotional problems at 12 months CA.IMPACT:Preterm birth can adversely affect infant and parent mental health and the quality of the parent-infant relationship. Early intervention to support parent-infant interaction can have positive effects on infant social-emotional development. There was no statistically significant difference in maternal sensitivity during play at 9 months CA. However, there were fewer infant self-regulation and communication problems reported by mothers at 12 months CA following intervention. Further evaluations of attachment-focussed interventions in the neonatal intensive care unit are needed.

Objectives: Effects of major depressive disorder and early life adversity (ELA) on the maternal HPA axis in the perinatal period were examined. Methods: Four groups of women (n = 127) were recruited, with the perinatal groups being compared during pregnancy (Preg) and at two months postpartum (PP) - [1] Depressed during pregnancy (Depressed-Preg/PP), [2] Prior history of depression but euthymic during pregnancy (History-Preg/PP), [3] Healthy pregnant women (Control-Preg/PP), and [4] Healthy non-pregnant women (Non-pregnant Control). Serial saliva samples were collected over the course of a day and waking and evening cortisol, total cortisol output and the cortisol awakening response were examined. Results: There were no HPA axis differences among the three groups during pregnancy. A history of ELA, regardless of comorbid depression, was associated with higher evening cortisol levels during pregnancy (p = 0.015). Women in the Depressed-PP group had had higher evening cortisol levels compared to the History-PP group (p < 0.017). Conclusions: Evening cortisol measures are a potential marker for both ELA and depression, with higher levels during pregnancy being associated with ELA and higher levels postpartum being associated with antenatal depression.

These disorders are due to abnormalities in the biosynthesis, interconversion and degradation of the purines—adenine and guanine—and of the pyrimidines—cytosine, thymine and uracil. All are heterocyclic bases which exist in tri-, di-, and mono-phosphorylated forms, and as either deoxyribosylated or ribosylated derivatives (deoxyribose and ribose are pentose carbohydrates). The phosphorylated deoxyribosylated and ribosylated derivatives are termed ‘nucleotides’, and the purely ribosylated derivatives, which lack the phosphate group, are ‘nucleosides’....

This study explored the experience of becoming a father following childhood cancer survival. Semi-structured interviews were conducted with five fathers and analysed using interpretative phenomenological analysis. Three superordinate themes emerged: ‘moving away from and revisiting the experience of cancer’, ‘making sense of fortune and loss following a life-threatening illness’ and ‘valuing the opportunity to be a father’. The transition to fatherhood brought unique and specific challenges to fathers. Nevertheless, all appeared to have positively adjusted to this transition. Findings recommended providing information and support to childhood survivors who wish to or who are about to become fathers.

Metastatic breast cancer (mBC) patients with DPYD genetic variants linked to loss of dihydropyrimidine dehydrogenase (DPD) activity are at risk of severe capecitabine-associated toxicities. However, prospective DPYD genotyping has not yet been implemented in routine clinical practice. Following a previous internal review in which two patients underwent lengthy hospitalisations whilst receiving capecitabine, and were subsequently found to be DPD deficient, we initiated routine DPYD genotyping prior to starting capecitabine. This study evaluates the clinical application of routine DPYD screening at a large cancer centre in London. We reviewed medical records for consecutive patients with mBC who underwent DPYD genotyping before commencing capecitabine between December 2014 and December 2017. Patients were tested for four DPYD variants associated with reduced DPD activity. Sixty-six patients underwent DPYD testing. Five (8.4%) patients were found to carry DPYD genetic polymorphisms associated with reduced DPD activity; of these, two received dose-reduced capecitabine. Of the 61 patients with DPYD wild-type, 14 (23%) experienced grade 3 toxicities which involved palmar–plantar erythrodysesthesia (65%), and gastrointestinal toxicities (35%); no patient was hospitalised due to toxicity. Prospective DPYD genotyping can be successfully implemented in routine clinical practice and can reduce the risk of severe fluoropyrimidine toxicities.

BACKGROUNDRejuvenation of stored red blood cells (RBCs) increases levels of adenosine 5′‐triphosphate (ATP) and 2,3‐diphosphoglycerate (2,3‐DPG) to those of fresh cells. This study aimed to optimize and validate the US‐approved process to a UK setting for manufacture and issue of rejuvenated RBCs for a multicenter randomized controlled clinical trial in cardiac surgery.STUDY DESIGN AND METHODSRejuvenation of leukoreduced RBC units involved adding a solution containing pyruvate, inosine, phosphate, and adenine (Rejuvesol, Zimmer Biomet), warming at 37°C for 60 minutes, then “manual” washing with saline adenine glucose mannitol solution. A laboratory study was conducted on six pools of ABO/D‐matched units made the day after donation. On Days 7, 21, and 28 of 4 ± 2°C storage, one unit per pool was rejuvenated and measured over 96 hours for volume, hematocrit, hemolysis, ATP, 2,3‐DPG, supernatant potassium, lactate, and purines added (inosine) or produced (hypoxanthine) by rejuvenation. Subsequently, an operational validation (two phases of 32 units each) was undertaken, with results from the first informing a trial component specification applied to the second. Rejuvenation effects were also tested on crossmatch reactivity and RBC antigen profiles.RESULTSRejuvenation raised 2,3‐DPG to, and ATP above, levels of fresh cells. The final component had potassium and hemolysis values below those of standard storage Days 7 and 21, respectively, containing 1.2% exogenous inosine and 500 to 1900 μmoles/unit of hypoxanthine. The second operational validation met compliance to the trial component specification. Rejuvenation did not adversely affect crossmatch reactivity or RBC antigen profiles.CONCLUSIONThe validated rejuvenation process operates within defined quality limits, preserving RBC immunophenotypes, enabling manufacture for clinical trials.

BackgroundAcute lymphoblastic leukaemia (ALL) is the commonest childhood malignancy in Europe. The survival rate has dramatically increased due to advances in treatment and it is of extreme importance to optimise and individualise treatment for each child. A crucial drug in this treatment is methotrexate. This can be given through the oral, intravenous and intrathecal route. However, methotrexate has various side effects, particularly neurotoxicity. MRI typically shows white matter changes known as leukoencephalopathy. The aim of this study was to look at the MRI changes in these patients and to determine persistence of neurological effects.MethodA retrospective study looking at patients, treated for ALL, on UK ALL 2003 and 2011 trials in a single centre who developed Methotrexate Neurotoxicity were selected. Parameters including type of symptoms, length of symptoms, and timing from last Methotrexate dose were correlated with MRI findings.ResultsThere were 6 patients out of 138 enrolled on study who were diagnosed with neurotoxicity following MTX treatment. The age ranged from 4–11 years old with a mean age of 7. All 6 patients had MRIs. 2 patients had changes on their scans. White matter changes were displayed consistent with leukoencephalopathy. Both patients have been followed up in clinic and have no further neurological deficit. There have been no reports of further neurological deficit in the other 4 patients. Novel findings in this study found that patients with MRI changes also showed generalised changes on their EEG.ConclusionsThis study describes the clinical course and radiological findings of patients with Methotrexate-induced Leukoencephalopathy. This appears to be a reversible entity without any apparent long-term effects. Long term follow-up and evaluation will be necessary to confirm this. Prospective add-on studies are warranted to evaluate this issue in a more robust manner.

Objective To evaluate the effects of a range of modifying factors on an early attachment focused intervention for parents of very preterm infants in the NICU on maternal sensitivity and infant social-emotional development. Methods Design and setting: A pragmatic randomised controlled trial in a level III NICU including infants born at 32 weeks gestation and their parents. Exclusion criteria were infant major congenital abnormality and maternal low level of fluency in English. Intervention: comprised reflective interview, observation of infant cues and Video Interaction Guidance (VIG). The primary outcome, maternal sensitivity during playful interaction with her infant was measured by the Child Adult Relationship Evaluation (CARE-Index). Secondary outcomes were infant social-emotional problems measured by the Ages and Stages Questionnaire-Social-Emotional version (ASQ-SE) and self-reported parental mental health. Modification of the effect of the programme on the primary outcome, maternal sensitivity, was explored using general linear model univariate analysis of sociodemographic, maternal and infant characteristics. Significant interactions are presented. Results Eighty mothers and their preterm infants were randomized to the intervention and standard care groups. The groups were similar in baseline sociodemographic and perinatal characteristics, although more mothers in the intervention group had completed higher-level education and subsequent analyses were adjusted accordingly. At 12 months corrected age (CA) infants in the intervention group had fewer self-regulation problems at 12 months of age (Chi-Square 3.84, df=1, p=0.05, partial eta squared=0.07) and infants whose mothers had received VIG had significantly fewer communication problems (Chi square=20.41, df=6, p=0.002, phi=0.61), however there was no statistically significant difference between the intervention and standard care groups in maternal sensitivity during play at 9 months CA or measures of maternalmentalhealth. Fathers in the intervention group had lower depression scores at folllow up.There was modifying effect of maternal ethnicity (B=4.179, CI=0.921–7.437, p=0.013); there was a significant difference in mean sensitivity of mothers of infants with IVH, (1. 85 points) (CI=0.083–3.614, p=0.041) but there was no significant interaction with group assignment. Conclusion This early attachment focused intervention integrating VIG for mothers and their very preterm infants had significant positive effects on infant social-emotional problems at 12 months CA.Maternal ethnicity modified the intervention effect

The thiopurine drugs azathioprine and mercaptopurine are effective in the treatment of disorders of immune regulation and acute lymphoblastic leukaemia. Although developed in the 1950s, thiopurines remained relevant in the anti-tumour necrosis factor biologic era, finding widespread use as a co-immunomodulator. Step changes in the management of patients treated with thiopurines have reduced the incidence of severe, sometimes life-threatening toxicity. Testing for thiopurine methyltransferase (TPMT) deficiency directs a safe initial dose for therapy. The introduction of red cell thioguanine nucleotide (TGN) monitoring provides a basis for dose adjustment and the identification of patients with high levels of red cell methylmercaptopurine (MMP) and an increase in the MMP:TGN ratio. These patients are at risk for hepatotoxicity and where TGN levels are sub-therapeutic, non-response to therapy. Switching thiopurine hypermethylators to low-dose thiopurine and allopurinol combination therapy resolves hepatoxicity and increases sub-therapeutic TGN levels to regain clinical response. NUDT15 variants are a common cause of severe myelotoxicity in Asian populations where the frequency of TPMT deficiency is low. There is increasing evidence that testing for NUDT15 and TPMT deficiency in all populations prior to the start of thiopurine therapy is clinically useful and should be the first step in personalising thiopurine therapy.

Modern Management of Perinatal Psychiatric Disorders. Edited by Carol Henshaw, John Cox and Joanne Barton. 2nd edn. (330 pp; ISBN 9781909726772). RCPsych Publications, London, UK, 2017 - Volume 36 Issue 3

Ireland has the second-highest birth rate in Europe and poorly developed perinatal psychiatry services. There are no screening services for antenatal depression and no data available on prevalence rates of depression among women attending the Irish obstetric services. The aim of this study was to assess the prevalence rates of depression during pregnancy in a population sample in Ireland using the Edinburgh Postnatal Depression Scale (EPDS) as a screening tool. Pregnant women during all stages of pregnancy were recruited from five maternity hospitals throughout the Republic of Ireland. Approximately 5000 EPDS questionnaires were collected. Information on the participant’s age, gestational week, gravidity, parity, and level of education attained was also collected. A score of > 12 was used as a measure of probable depression. Overall, 15.8% of pregnant women scored > 12 in the EPDS. There was a significant association between gestational week and rates of depression, with increasing rates occurring with advancing pregnancy (p < 0.001). Overall, higher socioeconomic groups were over-represented in the sample although we replicated the well-established findings of higher EPDS scores in women with lower educational attainment (p < 0.005). This study demonstrates that prevalence rates of probable antenatal depression are high among women attending the obstetric services in Ireland and highlight the importance of increasing awareness of antenatal depression. These high rates of antenatal depression may be related to certain conditions that are specific to an Irish setting: the absence of screening for depression in the context of grossly under-resourced perinatal psychiatry services. These findings provide indirect confirmatory evidence for the need for streamlined mental health services within reproductive health services.

Tanev, Dobromir MD, PhD; Peteva, Parvoleta MD; Fairbanks, Lynette PhD; Marinaki, Anthony PhD; Ivanova, Milena PhD; Alaikov, Tzvetan MD; Shivarov, Velizar MD, PhD, MSc Author Information

Thiopurines, available as azathioprine, mercaptopurine, and thioguanine, are immunomodulating agents primarily used to maintain corticosteroid-free remission in patients with inflammatory bowel disease. To provide a state-of-the-art overview of thiopurine treatment in inflammatory bowel disease, this clinical review critically summarises the available literature, as assessed by several experts in the field of thiopurine treatment and research in inflammatory bowel disease.