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Survival of neuroblastoma patients has improved over recent decades, but chronic health issues and treatment related late effects cause significant morbidity in survivors.We aimed to describe late effects and long-term toxicity in neuroblastoma patients treated at a tertiary, paediatric institution in Australia.Patients with neuroblastoma treated primarily at The Children's hospital at Westmead were eligible for inclusion. Retrospective analysis of 65 (45 with high-risk and 20 with non-high-risk disease) neuroblastoma patients were performed via medical record review. Approximately 60% of patients were5 years from diagnosis and termed the "full effects cohort" who had a range of medical and psychosocial late effects analysed through descriptive means. The remaining 26 patients who had not yet reached 5 years post treatment had audiometry analysis only. Of the 65 patients, 72% were alive at last follow-up. The median length of follow-up was 7 years from diagnosis amongst survivors. Therapy was according to contemporary protocols for neuroblastoma and ranged from standard cytotoxic therapies to intensive multimodal regimens and/or experimental therapy depending on risk group/relapse status. Of the 39 full effects cohort, 85% suffered from at least one late effect. Late effects were common in the endocrine, dental and audiometry domains with 38%, 49% and 72% of patients affected in these areas, respectively. Neuro-cognitive domains were also notably affected with 46% of patients suffering a deficit. Two thirds of survivors were disease free at last follow-up.Survivors of high-risk neuroblastoma suffer from a range of chronic illnesses, which lead to morbidity and affect quality of life of survivors.

Paediatric chronic pancreatitis (CP) is a relatively rare entity, but it can be accompanied by debilitating complications such as pseudocysts, chronic pain and pancreatic duct obstruction. Surgical drainage procedures, such as pancreaticojejunostomy or cystogastrostomy/jejunostomy to address these complications may be required; however, there is a paucity of evidence as to the efficacy and long-term outcomes of these operations in the paediatric population. A scoping review of contemporary (post-2000) studies detailing surgical pancreatic drainage procedures performed in children ( 18 years) was undertaken. After screening, 24 case series detailing a total of 248 patients met the inclusion criteria. Longitudinal pancreaticojejunostomy and cystogastrostomy were the most common surgical procedures performed in children with CP and pseudocysts, respectively. Overall generally favourable outcomes were reported, but all studies were considered to have a high risk of bias. Operative management for paediatric CP is infrequently required; therefore, large prospective studies or trials focusing on this population are infeasible, limiting the best available evidence on the topic to case series, level IV. Recommendations to improve the quality of surgical care in the paediatric CP population could include centralisation and the formation of registries to allow accurate long-term follow-up.

Background The lived experience of children and adolescents diagnosed with cancer differs greatly from that of the adult cancer patient. A diagnosis of cancer disrupts almost every developmental life stage and continues to affect the child, and potentially their whole family, throughout adulthood. Objective While it is important to recognise the potential for post-traumatic growth, a considerable proportion of children and adolescents will experience poorer psychological, social, educational and quality-of-life outcomes. Parents, particularly mothers, have been shown to experience levels of post-traumatic distress even greater than that of survivors. As such, there exists a critical need to provide family-centred support from diagnosis through to long-term survivorship or bereavement. Discussion Ongoing surveillance, proactive management of chronic health conditions, and health behaviour education are critical to survivors' lifelong wellbeing and can be facilitated locally by general practitioners with support from tertiary healthcare teams in a shared-care arrangement.

Com o crescimento dos casos de doenças transmitidas por vetores como o Aedes aegypti, o maior transmissor da dengue no Brasil, os óleos essenciais com propriedades repelentes são considerados uma opção promissora quando associados à nanotecnologia por sua baixa toxicidade e por serem biologicamente amigáveis. A encapsulação do óleo essencial em nanopartículas aumenta a estabilidade da substância promovendo uma liberação controlada no meio em que essas nanopartículas se encontram, aumentando sua durabilidade. Neste trabalho, nanocápsulas de óleos essenciais de cravo-da-índia e melaleuca com propriedades repelentes foram produzidas utilizando a metodologia de nanoprecipitação para o encapsulamento, sendo usado como material base para o revestimento o polímero poli(L-ácido lático), um polímero biodegradável. O processo de síntese das nanocápsulas está em desenvolvimento e, após sua otimização, pretende-se aplicá-las em tecidos de algodão de forma que eles adquiram a propriedade repelente.

Cancer therapy related cardiac dysfunction (CTRCD) is an area of increasing focus, particularly during the survivorship period, for paediatric, adolescent and adult cancer survivors. With the advent of immunotherapy and targeted therapy, there is a new set of mechanisms from which paediatric and young adult patients with cancer may suffer cardiovascular injury. Furthermore, cardiovascular disease is the leading cause of morbidity and mortality in the survivorship period. The recently established Australian Cardio-Oncology Registry is the largest and only population-based cardiotoxicity database of paediatric and adolescent and young adult oncology patients in the world, and the first paediatric registry that will document cardiotoxicity caused by chemotherapy and novel targeted therapies using a prospective approach. The database is designed for comprehensive data collection and evaluation of the Australian practice in terms of diagnosis and management of CTRCD. Using the Australian Cardio-Oncology Registry critical clinical information will be collected regarding predisposing factors for the development of CTRCD, the rate of subclinical left ventricular dysfunction and transition to overt heart failure, further research into protectant molecules against cardiac dysfunction and aid in the discovery of which genetic variants predispose to CTRCD. A health economic arm of the study will assess the cost/benefit of both the registry and cardio-oncology clinical implementation. Finally, an imaging arm will establish if exercise cardiac magnetic resonance imaging and VO2 max testing is a more sensitive predictor of cardiac reserve in paediatric and adolescent and young adult oncology patients exposed to cardiac toxic therapies.

Com o aumento da proliferação do mosquito Aedes aegypti, transmissor de doenças como a dengue, a febre amarela, a febre Chikungunya e o vírus da Zika, faz-se necessária a busca por métodos de combate ao mosquito. O uso intensivo de inseticidas comumente utilizados pelas organizações de vigilância sanitária tem provocado uma resistência e um problema no controle desses vetores. O presente projeto visa extrair o óleo essencial de botões florais do cravo-da-índia para sua utilização como agente larvicida, por se tratar de um controle sobre a fase larval do mosquito e já eliminá-la antes da fase adulta. Primeiramente, ocorreu a preparação dos botões e a extração do óleo essencial pelo processo de hidrodestilação. Foram realizadas análises para definir as propriedades físico-químicas do óleo, com isso foi possível classificar sua pureza e qualidade. Além disso, foi realizada a cromatografia gasosa, método utilizado para identificar os componentes do óleo essencial do cravo-da-índia, em que foram identificados dois constituintes. Após essas análises, seguiu-se com o teste de toxicidade que foi aplicado nas larvas do Aedes aegypti, utilizando concentrações mais altas do que às encontradas na literatura. A partir dos resultados coletados, foi estabelecida a concentração letal do óleo essencial em torno de 1,92 mg.mL-1, evidenciando a resistência criada por esses vetores ao longo dos anos. O óleo essencial de cravo-da-índia não apresentou nocividade frente ao meio ambiente e aos seres vivos, sendo muito viável o seu uso.

PURPOSE Few studies have investigated the health-related quality of life (HRQoL) of young childhood cancer survivors and their parents. This study describes parent and child cancer survivor HRQoL compared to population norms and identifies factors influencing child and parent HRQoL. METHODS We recruited parents of survivors who were currently 5 years postdiagnosis. Parents reported on their child's HRQoL (Kidscreen-10), and their own HRQoL (EQ-5D-5L). Parents rated their resilience and fear of cancer recurrence and listed their child's cancer-related late effects. RESULTS One hundred eighty-two parents of survivors (mean age = 12.4 years old and 9.7 years postdiagnosis) participated. Parent-reported child HRQoL was significantly lower than population norms (48.4 vs. 50.7, p

Urosepsis is a significant risk associated with prostate biopsy. Resistance of microorganisms to antibiotics is a challenging issue for clinicians in everyday practice. In the current study, we investigated the rates of sepsis and hospital admissions following transperineal (TP) prostate biopsies using a single dose of gentamicin.Data for consecutive patients who underwent TP prostate biopsies (March 2019-March 2020) were included. Patients received a single-dose of prophylactic gentamicin 120 mg IV and had skin preparation with antiseptic povidone-iodine or chlorhexidine solution prior to the procedure. Patient's electronic records were reviewed for rates of sepsis and readmission to hospital within 7 days following TP prostate biopsy.A total of 365 consecutive patients were included in the study. After exclusion of non-eligible patients, 280 patients were included in final analysis. The median age was 67 years (32-83), the median prostate-specific antigen (PSA) level was 8.5 ng/ml (0.2-58), and the median prostate size was 44 cc (10-188). Approximately 58% of patients had one or more comorbidities in the form of diabetes mellitus (DM), hypertension, asthma, chronic kidney disease, or ischemic heart disease. Adenocarcinoma was found in 71.7% of patients. None of the 280 patients developed sepsis. Urinary tract infection (UTI) occurred in 2.8% of patients with E.coli, none of them required hospital readmission.Our single centre experience showed a 0% sepsis rate after TP prostate biopsy with single prophylactic dose of gentamicin. Future randomized controlled trials (RCTs) should explore the possibility of performing these procedures without antibiotic prophylaxis in order to reduce the unnecessary use of antibiotics.

Background Symptoms of anxiety may arise from fear of cancer recurrence and memories of traumatic experiences during treatment. This study aimed to identify changes in mental health and cortisol, a biological marker of stress, associated with oncology surveillance clinic attendance. Methods Adolescent and young adult (AYA) survivors of childhood cancer (aged 12–30 years, N = 46) attending a survivorship clinic were recruited. The State-Trait Anxiety Inventory, an anxiety self-rating and open answer question, and salivary cortisol collections were completed two weeks before and one day before clinic, on clinic day and two weeks after. Results Trait anxiety scores were consistent with the normal population. State anxiety scores two weeks after clinic were significantly lower than baseline (p = 0.02). Cortisol diurnal slopes were flatter than baseline after clinic (p = 0.02). Evening cortisol levels were significantly higher than baseline two weeks post clinic (p = 0.02). Limitations Combined results from biological and psychometric assessments can be difficult to interpret. Larger cohorts will further delineate cortisol pathway activity and distress in AYA cancer survivors. Conclusions Psychometric evidence indicates that AYA survivors of childhood cancer perceive themselves to be less anxious after a survivorship clinic visit. Biological evidence, however, indicates a dysregulation of the hypothalamic-pituitary-adrenal axis which may be linked to clinic attendance. Weak correlations suggest that cortisol may not be a reliable indicator of self-perceived anxiety. This may be due to confounding lifestyle factors influencing the stress response or potential ‘coping strategies’ developed during past treatment experience which may, hypothetically, have masked self-perceived anxiety.

The conserved oligomeric Golgi (COG) complex is involved in intracellular vesicular transport, and is composed of eight subunits distributed in two lobes, lobe A (COG1-4) and lobe B (COG5-8). We describe fourteen individuals with Saul-Wilson syndrome, a rare form of primordial dwarfism with characteristic facial and radiographic features. All affected subjects harbored heterozygous de novo variants in COG4, giving rise to the same recurrent amino acid substitution (p.Gly516Arg). Affected individuals' fibroblasts, whose COG4 mRNA and protein were not decreased, exhibited delayed anterograde vesicular trafficking from the ER to the Golgi and accelerated retrograde vesicular recycling from the Golgi to the ER. This altered steady-state equilibrium led to a decrease in Golgi volume, as well as morphologic abnormalities with collapse of the Golgi stacks. Despite these abnormalities of the Golgi apparatus, protein glycosylation in sera and fibroblasts from affected subjects was not notably altered, but decorin, a proteoglycan secreted into the extracellular matrix, showed altered Golgi-dependent glycosylation. In summary, we define a specific heterozygous COG4 substitution as the molecular basis of Saul-Wilson syndrome, a rare skeletal dysplasia distinct from biallelic COG4-CDG.

Hematopoietic cell transplantation (HCT) is a potentially curative treatment for children and adults with malignant and nonmalignant diseases. Despite increasing survival rates, long-term morbidity after HCT is substantial. Neurocognitive dysfunction is a serious cause of morbidity, yet little is known about neurocognitive dysfunction after HCT. To address this gap, collaborative efforts of the Center for International Blood and Marrow Transplant Research and the European Society for Blood and Marrow Transplantation undertook an expert review of neurocognitive dysfunction after HCT. In this review we define what constitutes neurocognitive dysfunction, characterize its risk factors and sequelae, describe tools and methods to assess neurocognitive function in HCT recipients, and discuss possible interventions for HCT patients with this condition. This review aims to help clinicians understand the scope of this health-related problem, highlight its impact on well-being of survivors, and help determine factors that may improve identification of patients at risk for declines in cognitive functioning after HCT. In particular, we review strategies for preventing and treating neurocognitive dysfunction in HCT patients. Finally, we highlight the need for well-designed studies to develop and test interventions aimed at preventing and improving neurocognitive dysfunction and its sequelae after HCT.

Hematopoietic cell transplantation (HCT) is a potentially curative treatment for children and adults with malignant and non-malignant diseases. Despite increasing survival rates, long-term morbidity following HCT is substantial. Neurocognitive dysfunction is a serious cause of morbidity, yet little is known about neurocognitive dysfunction following HCT. To address this gap, collaborative efforts of the Center for International Blood and Marrow Transplant Research and the European Society for Blood and Marrow Transplantation undertook an expert review of neurocognitive dysfunction following HCT. In this review, we define what constitutes neurocognitive dysfunction, characterize its risk factors and sequelae, describe tools and methods to assess neurocognitive function in HCT recipients, and discuss possible interventions for HCT patients with this condition. This review aims to help clinicians understand the scope of this health-related problem, highlight its impact on well-being of survivors, and to help determine factors that may improve identification of patients at risk for declines in cognitive functioning after HCT. In particular, we review strategies for preventing and treating neurocognitive dysfunction in HCT patients. Lastly, we highlight the need for well-designed studies to develop and test interventions aimed at preventing and improving neurocognitive dysfunction and its sequelae following HCT.

Pain and fatigue are under-researched late effects of childhood cancer and its treatment, and may be interpreted by survivors as indicating cancer recurrence. Moreover, unmet information needs for managing pain and fatigue may be related to fear of cancer recurrence. We investigated the complex relationships between perceived cancer-related pain and fatigue, unmet information needs for managing pain and fatigue, and fear of cancer recurrence.We surveyed 404 adult survivors of any form of childhood cancer (M = 16.82 years since treatment completion).Many survivors reported perceived cancer-related pain (28.7%) and fatigue (40.3%), and anticipated future pain (19.3%) and fatigue (26.2%). These symptomologies were all related to unmet information needs for managing pain (18.8%) and fatigue (32.2%; all p's.001). Survivors reporting unmet information needs for managing pain (B = .48, 95% CI = 0.19-0.76, p = .001) and fatigue (B = .32, 95% CI = 0.06-0.52, p = .015) reported higher fear of cancer recurrence than survivors reporting no information needs.Survivors often have unmet information needs for managing pain and fatigue, and these unmet needs are related to fear of cancer recurrence.Long-term follow-up clinics should assess pain and fatigue. Information provision about pain and fatigue may be an important tool to help manage fear of cancer recurrence.

Introduction Pulmonary graft versus host disease is a pathological process arising in peripheral airways causing significant morbidity and mortality post-Bone Marrow Transplantation (BMT). Current screening and diagnosis focuses on spirometry change from baseline to identify Bronchiolitis Obliterans Syndrome (BOS), and an at-risk pre-BOS stage BOS0p (≥10% fall FEV1). Sensitive peripheral airway function tools exist but remain under-utilized and utility is unclear. Aim To investigate longitudinal peripheral airway function change, detected by Multiple Breath Washout (MBW) and Forced Oscillation Technique (FOT), in pediatric BMT subjects with/without BOS and BOS0p. Methods Children aged ≥3 years were recruited. Testing occurred at baseline, monthly during 1st year and 6-monthly to 3yrs: MBW (LCI, Scond and Sacin, ExhalyserD®, Ecomedics), FOT (Rrs and Xrs at 5Hz, AX, Fres, tremoFlo®, Thorasys) and, if feasible, spirometry, plethysmography and DLCO. Groups (BOS, BOS0p, unaffected) compared at baseline, 12, 24 and 36 months. Results Of 24 recruited subjects (mean±SD (range) age 10.2±4.2 (3.3-18.1) years at BMT, 54% AML/ALL diagnosis, 71% male), 1 withdrew and 6 died (5 within 12 months). BOS and BOS0p alone were detected in 3 (12.5%) and 8 (33.3%), respectively. BOS was associated with pattern of marked abnormality, significant increases from baseline were observed in LCI, Scond, Sacin, Xrs, AX and Fres. One subject developed BOS3 at 105 days (1st feasible post-BMT test). MBW/FOT abnormality was detected 26 and 207 days prior to BOS≥1 in other cases. LCI trajectory increased with increasing BOS severity. At 3 years, statistically significant differences between BOS0p vs unaffected were observed for LCI (p=0.009), Sacin(p=0.03), Xrs (p=0.004) and approached significance for AX (p=0.09) and Fres (p=0.09). Conclusion BOS and its earlier at-risk stage BOS0p were associated with significant peripheral airway abnormality detectable on MBW and FOT. MBW and FOT abnormality predated BOS≥1 in 2/3 BOS cases.

Survivors of hematopoietic cell transplantation (HCT) are at risk of subsequent solid tumors, including central nervous system (CNS) tumors. The risk of CNS tumors after HCT in pediatric HCT recipients is not known. We evaluated the incidence and risk factors for CNS tumors in pediatric recipients of allogeneic HCT reported to the Center for International Blood and Marrow Transplant Research between 1976 and 2008. A case control design was used. There were no CNS tumors in the nonmalignant cohort (n = 4543) or in those undergoing HCT for solid tumors (n = 26). There were 59 CNS tumors in 8720 patients transplanted for hematologic malignancies. In comparison with the general population, pediatric HCT recipients with hematologic malignancies had a 33 times higher than expected rate of CNS tumors (95% confidence interval, 22.98 to 45.77; P .0001). The cumulative incidence of subsequent CNS tumors was 1.29% (95% confidence interval .87 to 1.87) at 20 years after HCT. Significant risk factors in the entire cohort were having an unrelated donor (HR, 3.35; P = .0002) and CNS disease before HCT for both acute lymphoblastic leukemia (HR, 8.21; P = .0003) and acute myeloid leukemia (HR, 6.21; P = .0174). Analysis of the matched cohort showed having an unrelated donor transplant (HR, 4.79; P = .0037), CNS disease before HCT (HR, 7.67; P = .0064), and radiotherapy exposure before conditioning (HR, 3.7; P = .0234) to be significant risk factors. Chronic graft-versus-host disease was associated with a lower risk (HR, .29; P = .0143). Survivors of HCT for nonmalignant diseases did not show an increased incidence of CNS tumors, whereas survivors of hematologic malignancies have a markedly increased incidence of CNS tumors that warrants lifelong surveillance.

Background Over the last 25 years, donor source, conditioning, graft-versus-host disease prevention and supportive care for children undergoing hematopoeitic stem cell transplantation (HSCT) have changed dramatically. HSCT indications for acute lymphoblastic leukemia (ALL) now include high-risk patients in first and subsequent remission. There is a large burden of infectious and pre-HSCT morbidities, due to myelosuppressive therapy required for remission induction. We hypothesized that, despite these trends, overall survival (OS) had increased. Procedure A retrospective audit of allogeneic pediatric HSCT for ALL was performed in our institution over 25 years. Outcomes for 136 HSCTs were analyzed in three consecutive 8-year periods (Period 1: 1/1/1984–31/8/1992, Period 2: 1/9/1992–30/4/2001, Period 3: 1/5/2001–31/12/2009). Results Despite a significant increase in unrelated donor HSCT, event-free and OS over 25 years improved significantly. (EFS 31.6–64.8%, P = 0.0027; OS 41.8–78.9%, P

Introduction: Peripheral airway abnormalities are common in children post Bone Marrow Transplantation (BMT). Lung Clearance Index (LCI) was abnormal in 50% of a paediatric post BMT cohort at our institution.(1) Little is known about the progression of peripheral airway function in children post BMT. Adult data has reported increasing LCI values over time post BMT.(2) Aim: To evaluate the change in lung function (including peripheral airway function) over time in our paediatric post BMT cohort. Methods: Follow up assessment of the previously studied cohort, performed 12-24 months after initial testing. Protocol included Multiple Breath Washout (SF 6 based), conventional lung function and Liverpool respiratory questionnaire (LRQ). Lung function data presented as median (range) for z scores or raw values. SF6 LCI ULN – 7.38. Maximum score for LRQ 128. Statistical analysis: Wilcoxon signed rank test. Results: 17 tested to date: 76% males; age 15.3(5.6-20.0) years, 6.3 (1.6- 12.8) years post BMT and 1.2(0.9-1.8) years since last assessment. Proportion with abnormal LCI was similar at baseline and on follow up testing (47%vs 35%, p=0.3) as were FEV1 z-scores (18% vs 18%). No significant change in LCI over time: 0.18 (-3.93 to 2.05). No significant change in spirometry z-score change over time; FEV1 0.16 (-0.77 to 0.71); FVC -0.08 (-0.80 to 0.81); FEV1/FVC 0.20 (-0.45 to 0.43); FEF25-75; -0.03 (-0.69 to 0.53). No significant change in LRQ score over time; 0(-28 to 30). Conclusion: Across the overall cohort respiratory symptoms, peripheral airway function and spirometry did not worsen. However within individual subjects considerable variation was observed.

Childhood cancer survivors (CCS) are at increased risk of primary gonadal insufficiency (PGI). This study evaluated the prevalence and clinical characteristics of PGI in CCS.In this single-center, retrospective, observational, longitudinal study, we characterized CCS with PGI attending the oncology Long-Term Follow-Up (LTFU) Clinic at an Australian university hospital (January 2012-August 2014). From a cohort of 276 CCS, 54 (32 males) met criteria for PGI: elevated gonadotropins plus low estradiol/amenorrhoea (females) or low testosterone/small testicles for age (males).Median age at primary diagnosis was 4.8 years (inter-quartile range [IQR] 3.0-9.7 years) and at LTFU, it was 22.3 years (IQR 18.2-25.7 years). Fifty-three participants (98.1%) were treated with known highly gonadotoxic therapies: alkylating chemotherapy (96.3%), radiotherapy (70.3%), total body irradiation (29.6%), bone marrow transplantation (51.9%), or multimodal protocols (68.5%). At primary diagnosis, 86.7% participants were Tanner stage I and at LTFU, 89.1% participants were Tanner stage V. More females (95.5%; n = 21) than males (40.6%; n = 13) were treated with hormone development therapy (HDT) (p 0.01). Of these, more than half (n = 18; 7 males) required pubertal induction. There was no significant difference in serum luteinizing hormone/follicle stimulating hormone (LH/FSH), testosterone/estradiol between those untreated and those treated with HDT. Among those on HDT, 60.7% had persistently elevated FSH±LH and 33.3% had low testosterone or estradiol. Six males had semen analysis (five azoospermic, one oligospermic). Psychological assessment was documented in 61.1% of participants, and two-thirds reported fertility concerns.PGI is an evolving phenotype that is common in CCS. Suboptimal treatment and non-adherence occur frequently. Ongoing assessment is essential to ensure prompt diagnosis, adequate intervention and to promote HDT adherence.

Childhood cancer survivors (CCS) are at increased risk of metabolic dysfunction as a late effect of cancer treatment. However, pediatric metabolic syndrome (MetS) lacks a unified definition, limiting the diagnosis of MetS in CCS. This study evaluated individual metabolic health risk factors and potential areas for intervention in this at-risk population.This single center, retrospective observational longitudinal study evaluated the metabolic health of all CCS attending an oncology long-term follow-up clinic at a university hospital in Sydney, Australia (January 2012-August 2014). Participants were 276 CCS (52.2% male; mean age 18.0 years; range 6.8-37.9 years), at least 5 years disease free with a broad spectrum of oncological diagnoses. Primary metabolic health risk factors included raised body mass index, hypertension, and hypertransaminasemia. Participants treated with cranial radiotherapy (n = 47; 17.0% of cohort) had additional biochemical variables analyzed: fasting glucose/insulin, HDL/LDL cholesterol, and triglycerides.Hypertension was common (19.0%), with male sex (p0.01) and being aged 18 years or above (p0.01) identified as risk factors. Cranial irradiation was a risk factor for overweight/obesity (47.8% in cranial radiotherapy-treated participants vs. 30.4%; p = 0.02). Hypertransaminasemia was more prevalent among participants treated with radiotherapy (15.6% vs. 7.3%; p = 0.03), and overweight/obese participants (17.6% vs. 8.2%; p = 0.04).Metabolic health risk factors comprising MetS are common in CCS, placing this population at risk of premature adverse cardiovascular consequences. Proactive surveillance and targeted interventions are required to minimize these metabolic complications, and a unified definition for pediatric MetS would improve identification and monitoring.

Unrelated umbilical cord blood (UCB) is an alternative stem cell source for paediatric patients lacking a matched related or unrelated marrow donor. We report the results of all paediatric unrelated UCB transplants performed in Australia and New Zealand over a 10-year period. A total of 135 patients were transplanted, 100 for malignant disease (74%) and 35 for non-malignant disorders. The majority (88%) of patients received an HLA-mismatched graft. The median infused total nucleated cell dose was 4.7 x 10(7)/kg and CD34+ count 1.9 x 10(5)/kg. Neutrophil engraftment occurred in 83% of patients by day 42 (median 23 days) and platelet engraftment in 55% by day 60 (median 56 days). Grades II-IV and III-IV acute GVHD occurred in 41 and 18% of patients, respectively. TRM and overall survival 1-year post transplant were 32 and 61%, respectively. A higher probability of neutrophil recovery (P=0.004) and faster time to recovery (median 18 days vs 26 days, P=0.008) were observed in recipients of a cord unit with a CD34 cell dose >or=1.7 x 10(5)/kg. Our results support selection of cord units with CD34 cell doses >or=1.7 x 10(5)/kg to promote faster engraftment, improve survival and lower TRM.

Aim: Pulmonary complications are common following Bone Marrow Transplantation (BMT) but peripheral airway involvement may be underestimated by conventional lung function measures, such as spirometry. This study aimed to characterize peripheral airway function in children post BMT using Multiple Breath Washout (MBW) in comparison to standard lung function. Methods: Cross sectional study of children following BMT at a single tertiary centre. Inclusion criteria included age ≥3 years, allogenoeic BMT, similar conditioning regimens and stability at the time of testing. Assessment included MBW (performed using simultaneous inert gas washout with SF 6 and Helium) and conventional lung function. Non-parametric data displayed as median (range). Results: 24 subjects have been recruited to date: 16 (67%) male, age 14.3 (4.3-18.6) years, tested at 4.8 (0.7-12.1) years post BMT. Spirometry was feasible in 15/24 (63%) of the cohort, with abnormal values present in 5/24 (21%) for FEV 1 and 4/15 (17%) for FEF 25-75 . MBW was feasible in all subjects. Abnormal MBW parameters were observed in a greater proportion (18/24, 75%) vs. either FEV 1 or FEF 25-75 (p 6 MBW indices was greatest with S cond (0.034 (0.004-0.089), Upper limit of normal (ULN) 0.023, abnormal in 18/24, (75%) followed by LCI (7.52 (5.03-23.59), ULN 7.35, abnormal in 14/24, 58%) and S acin (0.105 (0.056-0.463), ULN 0.121, abnormal in 8/24, 33%). Conclusion: MBW offered improved feasibility, compared to spirometry, for lung function assessment. Peripheral airway involvement was present in the majority of the cohort, and was underappreciated by spirometry.

Background: Patients with severe combined immunodeficiency disease who have matched sibling donors (MSDs) can proceed to hematopoietic cell transplantation (HCT) without conditioning chemotherapy. Objective: We sought to determine whether the results of HCT without chemotherapy-based conditioning from matched unrelated donors (URDs), either from volunteer adults or umbilical cord blood, are comparable with those from MSDs. Methods: We performed a multicenter survey of severe combined immunodeficiency transplantation centers in North America, Europe, and Australia to compile retrospective data on patients who have undergone unconditioned HCT from either URDs (n= 37) or MSDs (n= 66). Results: Most patients undergoing URD HCT (92%) achieved donor T-cell engraftment compared with 97% for those with MSDs; however, estimated 5-year overall and event-free survival were worse for URD recipients (71% and 60%, respectively) compared with MSD recipients (92% and 89%, respectively; P< .01 for both). URD recipients who received pre-HCT serotherapy had similar 5-year overall survival (100%) to MSD recipients. The incidences of grade II to IV acute and chronic graft-versus-host disease were higher in URD (50% and 39%, respectively) compared with MSD (22% and 5%, respectively) recipients ( P< .01 for both). In the surviving patients there was no difference in T-cell reconstitution at the last follow-up between the URD and MSD recipients; however, MSD recipients were more likely to achieve B-cell reconstitution (72% vs 17%, P< .001). Conclusion: Unconditioned URD HCT achieves excellent rates of donor T-cell engraftment similar to that seen in MSD recipients, and reconstitution rates are adequate. However, only a minority will have myeloid and B-cell reconstitution, and attention must be paid to graft-versus-host disease prophylaxis. This approach might be safer in children ineligible for intense regimens to spare the potential complications of chemotherapy. © 2014 American Academy of Allergy, Asthma & Immunology.

To measure and compare the percentage of surface and luminal thickness of encrustation in Allium and conventional double J ureteric stents after exposure for 6 weeks to an accelerated encrustation model. An artificial urine solution was prepared and three stents were immersed into each of six containers allocated to each stent type, representing each week of encrustation. Slight agitation was accomplished by placing a magnetic stirrer at the bottom of each container. Images were obtained by examination under a stereomicroscope and analyzed with the aid of specialized image analysis software (Image J). By week 2, nearly 100 % of the stent surface was covered by a thin layer of encrustation, gradually increasing in thickness through weeks 3–6. On completion of 6 weeks of encrustation, the 10 mm length double J stent specimens did not show visible encrustation, while the 60 mm long Allium stents showed 100 % surface coverage. This was most evident in the mid-section of the stents compared to the ends, suggesting a correlation between stent length and encrustation formation. There was also no blockage of the lumen of either stents between weeks 1–6. The designed accelerated encrustation model was successful and showed 80 % surface coverage after 6 weeks. In our study, there appears to be a slightly reduced level of surface encrustation to that of earlier reports. A correlation between stent length and geometry was suggested. This model may be used to compare encrustation for a variety of polymeric stent materials.

Introduction Telomeres are specialized DNA structures found at the end of linear chromosomes. In humans, they contain the repetitive sequence (TTAGGG)nalong with its complementary strand and associated proteins. With each cell division, the telomere shortens due to incomplete replication of the lagging strand, a phenomenon known as the end replication problem. Oxidative damage, as well as the action of nucleases also leads to telomere attrition. Once the telomere reaches a critically short length, cells enter senescence or apoptosis. In the general population, telomere length (TL) varies greatly, and is seen to decline with age. Patients with Dyskeratosis Congenita (DC) have inherently short telomeres, which leads to multiple organ dysfunction. These patients suffer increased organ toxicity when given standard myeloablative conditioning regimens during hematopoietic stem cell transplantation (HSCT). This is most likely due to the reduced ability of their cells to replicate and recover following cytotoxic treatment. It is not known whether patients without DC, who have telomere lengths at the lower end of the normal spectrum also suffer increased rates of toxicity. Thus we undertook a retrospective analysis to determine if there was an association between short TL and increased transplant-related mortality (TRM) following HSCT in children. Method Medical records of patients who underwent allogeneic HSCT at the Children's Hospital at Westmead (Sydney, Australia) between 2002 to 2013 were examined and demographic, prior treatment, transplant, toxicity and transplant information was extracted. The primary outcome measured was TRM, while overall survival, relapse and graft versus host disease (GVHD) being secondary outcomes of interest. Stored DNA, extracted from bone marrow, taken within 3 months prior to HSCT was used for telomere length testing, as a surrogate marker for TL in other tissues in the body. Quantitative PCR was carried out to determine relative telomere length, which was converted to an age adjusted TL (AATL) by subtracting the expected relative TL (i.e. 50th percentile for age of the patient) from the measured relative TL, so that patients of all ages could be analyzed together. Results Between 2002 and 2013, there were 121 patients who underwent allogeneic HSCT at our institution. Of these, 78 had DNA stored, with appropriate consent and ethics approval to be used in our study. Most children were undergoing HSCT for hematological malignancies (acute lymphoblastic leukemia 52%, acute myeloid leukemia 39%), with 55% having relapse or refractory disease. Matched sibling donors made up 46% of cases. At a median follow up of 3.2 years, 64% of patients remained alive. The single leading cause of death was relapse (48%) with 52% of deaths attributable to transplant-related causes. The median AATL for the entire cohort was -0.21 (range -0.61-0.28). Telomere length was not associated with relapse or refractory disease. There was no correlation between AATL and specific organ toxicity, relapse or overall survival. When the cohort was divided into 2 groups based on AATL, there was a trend (p=0.055) towards increased TRM in patients who had AATL below the median for the cohort (Figure 1). Multivariate analysis adjusting for age at transplant, CMV status, disease status and HLA matching showed a reduced risk (HR 0.33; p value 0.072) of TRM in patients with AATL above the median for the cohort. Conclusion AATL was shorter in patients pre-HSCT compared with age matched controls. There was a trend towards increased TRM in patients with shorter telomere length, however most likely due to small sample size, this did not achieve significance. If extended to a larger cohort of patients, TL may prove to be a significant marker for children at increased risk of TRM prior to HSCT. This could influence the choice to use less myeloablative conditioning in these patients. Support: NHMRC GNT1056667 Disclosures No relevant conflicts of interest to declare.

The authors investigated implicit memory in 21 adult children of alcoholics (ACAs) and 24 control individuals (all college undergraduates) who performed a serial reaction time task (SRT) to evaluate their implicit memory performance and their formation of new associations. Each group was presented with 5 blocks of 100 trials per block in which Blocks 1-4 contained a 10-item repeating sequence; Block 5 was a pseudo-random sequence. The latency difference between Block 4 and Block 5 presumably measure implicit memory. The amount of implicit memory did not differ (in ms) between the ACAs (M = 55 ms) and the controls (M = 67 ms). Implicit memory (at least as measured by the SRT task) appears to be preserved in ACAs.

Despite significant advances in the treatment of childhood acute lymphoblastic (ALL) and acute myeloid (AML) leukemias, the prognosis of those with primary refractory, secondary and early relapsed disease remains extremely poor with survival reported in most studies at less than 20%. Salvage rates are particularly poor in children with ALL who relapse on therapy and in children with AML who relapse post autologous bone marrow transplant. Encouraging results using the re-induction combination regimen of Fludarabine, high dose Cytarabine and Idarubicin (FLAG-IDA) have been reported, however the majority of data is in adult patients. Here we report the largest series of pediatric patients with high risk acute leukemias receiving this regimen in combination with allogeneic hematopoietic cell transplantation as salvage therapy. Between 1999–2005 a toal of 32 patients at 2 Australian Pediatric Cancer Centers were given Fludarabine (30mg/m2 IV over 1 hour for 5 days); Idarubicin (8mg/m2 IV over 1 hour for 3 days); Cytarabine (2000mg/m2 IV over 4 hours for 5 days) and GCSF (5mcg/kg/day). There were 21 males and 11 females, with a median age of 10.4 years (range 1.7 to 15.5 years). All patients had high risk leukemias; relapsed ALL (n=13), primary refractory ALL (n=3), relapsed AML (n=13), primary refractory AML (n=1) and secondary AML (n=2). For the overall cohort median duration of first complete remission (CR1) was 16 months (range 2–34 months). Relapsed ALL patients were all considered extremely high risk with a CR1 duration of 22 of the 23 patients (10 AML and 12 ALL) who achieved remission proceeded to an allogeneic bone marrow transplant, following a further 2–3 courses of FLAG (without IDA) for consolidation. 70% of patients received an unrelated donor transplant. Stem cell source was MUD BM (n=9), unrelated UCB (n=6) and HLA-ID sibling donor (n=7). Overall 17 of the 22 (77.3%) remain alive and leukaemia free (9 AML and 8 ALL patients) with a median duration of 36.5 months (9–84 months). Cause of death in the transplanted patients was progressive disease (n=4) and Pneumocystis Carinii pneumonitis (n=1). In summary, for this group of high risk, early relapsed and heavily pretreated pediatiric patients, re-induction chemotherapy with FLAG-IDA followed by allogeneic transplantation has provided an excellent strategy in the achievement of long term cure.

Purpose: Four patients with Saul-Wilson syndrome were reported between 1982 and 1994, but no additional individuals were described until 2018, when the molecular etiology of the disease was elucidated. Hence, the clinical phenotype of the disease remains poorly defined. We address this shortcoming by providing a detailed characterization of its phenotype. Methods: Retrospective chart reviews were performed and primary radiographs assessed for all 14 individuals. Four individuals underwent detailed ophthalmologic examination by the same physician. Two individuals underwent gynecologic evaluation. Z-scores for height, weight, head circumference and BMI were calculated at different ages. Results: All patients exhibited short stature, with sharp decline from the mean within the first months of life, and a final height Z-score between −4 and −8.5 standard deviations. The facial and radiographic features evolved over time. Intermittent neutropenia was frequently observed. Novel findings included elevation of liver transaminases, skeletal fragility, rod-cone dystrophy, and cystic macular changes. Conclusion: Saul-Wilson syndrome presents a remarkably uniform phenotype, and the comprehensive description of our cohort allows for improved understanding of the long-term morbidity of the condition, establishment of follow-up recommendations for affected individuals, and documentation of the natural history into adulthood for comparison with treated patients, when therapeutics become available.

Introduction: Fludarabine phosphate is commonly used as part of conditioning regimens in children undergoing allogeneic haematopoietic stem cell transplantation (HSCT) for both malignant (n = 47) and non-malignant (n = 39) diseases, but its use has been associated with engraftment failure or mixed chimerism1. The aim of this study was to examine whether suboptimal engraftment is associated with fludarabine pharmacokinetics. Material (or patients) and methods: The clinical pharmacokinetics of fludarabine phosphate was evaluated by studying the free concentrations of the active metabolite, (9B-D-arabinosyl-2 fludarabine, F-Ara-A). Eighty-six HSCTs were studied in 84 children 0.1 to 19 years. Glomerular filtration rate (GFR) was determined by measuring the plasma clearance of diethylenetriaminepentacetic acid (DTPA). The children in this study were treated according to specific HSCT conditioning protocols which varied with respect to the total administered fludarabine dose and the number of days over which it was administered (range: 3 to 6). A weight-based dose of 1 to 2 mg/kg was used in 13 transplants where the patient weighed Results: Mixed chimerism or graft rejection occurred following 10 (of 86) transplants and, of these, 8 were being treated for malignant diseases. First dose free F-Ara-A AUC was significantly lower for these transplants compared with the remainder: median 3.0 (2.4 - 3.8) mg/L.h versus 4.1 (3.3 - 5.2) mg/L.h, p = 0.038, but the difference in clearance was not significant: 6.3 (5.2 - 11.0) L/h versus 4.6 (2.7 - 8.1) L/h, p = 0.06. The recovery of neutrophils also correlated significantly with first dose free AUC (r = -0.22, p= 0.044) but not with clearance (r=0.193, p = 0.075). Recovery of platelets was not significantly associated with any estimate of free F-Ara-A exposure. Within the fludarabine dose range of 25 to 40 mg/m2, there was a linear association with median free F-Ara-A AUC (r 2= 0.977), which was represented by the equation median F-Ara-A AUC (mg/l.h) = 0.1306 x fludarabine dose (mg/m2). There was a significant negative correlation between clearance and GFR (r = -0.31, p < 0.005) and GFR was significantly higher in patients with suboptimal engraftment: median 126 (116 - 152) versus and 111 (92 - 133) ml/min/1.73 m2 (p = 0.015). Suboptimal engraftment was significantly associated with poorer overall survival using Kaplan Meier survival analysis (p = 0.002 using log rank test). Conclusions: The data suggests that patients with good renal function are at greater risk of suboptimal engraftment since they have lower exposure to free F-Ara-A. These children may therefore require higher doses of fludarabine. We found that mg/m2 fludarabine dose was linear with free F-Ara-A AUC between the 25 and 40 mg/m2 dose range. 1.Lee JH, Joo YD, Kim H, Ryoo HM, Kim MK, Lee GW, et al. Randomized trial of myeloablative conditioning regimens: busulfan plus cyclophosphamide versus busulfan plus fludarabine. J Clin Oncol 2013 Feb 20; 31(6): 701-709. Disclosures No relevant conflicts of interest to declare.