A document by Abiodun John Ologunowa. Click on the document to view its contents.

Background: Given the limited research on folate and ferritin status in children with cancer undergoing treatment, we investigated the prevalence of abnormalities and their impact on clinical outcomes and treatment complications. Methods: This prospective cohort study enrolled children <18 years diagnosed with cancer between August 2010-February 2014. Data collection occurred at diagnosis, 3, 6, 9, 12 and 18 months. Clinical outcomes were classified as event-free survival or events (relapse, death, the development of new metastasis, becoming palliative), and treatment complications. Micronutrient status was assessed through clinical and nutritional analyses. Binary logistic regression, multilevel model analysis explored relationships between micronutrient status and clinical outcomes. Results: Eighty-two patients [median (IQR) 3.9 (1.9-8.8) years, 56% males] were recruited. Excess ferritin (85%) and folate deficiency (25.5%) were prevalent micronutrient abnormalities throughout the study. Decreased ferritin levels reduced the odds of events by 83.9% (OR=0.161,95% CI=1.000–1.002, p=0.032). Higher ferritin was associated with increased number of treatment-related complications (B=7.3E-5,95% CI=1.5E-5–0.000, p=0.013). Folate status showed significant association with BMI category (χ 2=9.564, p=0.008), indicating that overweight and obese patients were more prone to deficiency. Conclusion: Paediatric cancer patients undergoing treatment exhibit high ferritin and reduced folate levels. Elevated ferritin is linked to increased toxicity and negative clinical outcomes, highlighting the importance of regular assessment and monitoring of both folate and ferritin. Implementing routine monitoring for these biomarkers could help mitigate adverse effects associated with treatment. Large-scale population-based studies and clinical trials are now warranted.

BACKGROUND AND AIMS: There is scarce information about pediatric lymphoblastic lymphoma (LLy) in low and middle-income countries. We describe the clinical characteristics, treatment and outcome of a cohort of children and adolescents with LLy in Latin America (LA). METHODS: Retrospective study analyzing pediatric patients with LLy in 10 institutions of the St. Jude Global Alliance from nine LA countries between 2007 and 2017. RESULTS: One-hundred and twenty-six patients were included. Sixty (47.6%) had T-LLy, 49 (38.9%) B-LLy and in 17 (13.5%) the immunophenotype was unknown. Ninety-seven (77%) presented with stage III/IV disease, and 42 (33.3%) in critical conditions. In 30 cases (23.8%), the results of pathology diagnosis exceeded 15 days from biopsy, and 23 patients (18%) required a review at another institution. The EFS and OS at 5 years were 73% (SE 0.047) and 78% (SE 0.0435), respectively. Five-year abandonment-sensitive EFS and OS were 65% (SE 0.0477) and 70% (SE 0.0459), respectively. Events included relapse/progression (n=22), refractory disease (n =1) abandonment (n=11), induction death (n=4), death in complete remission (n=4), and second malignancies (n=1). CONCLUSIONS: A balanced proportion of LLy-T and B phenotypes was observed. Diagnosis was a challenge. Most of the patients presented with high-risk disease, and many in critical conditions. Toxic deaths and abandonment represented nearly half of the events. Improvements in diagnosis, supportive measures and follow up are imperative to improve the outcomes of pediatric LLy in Latin America.

Background: Autosomal recessive severe congenital neutropenia (SCN) has been associated with homozygous variants in the HAX1(HCLS1 Associated Protein X-1) gene. In this rare disease, ovarian insufficiency has been reported only in nine female patients in the literature. There is insufficient data on the gonadal function of patients with SCN due to HAX1 gene variant ( HAX1-SCN ) in childhood and the age of onset of premature ovarian insufficiency (POI) is unknown. The aim of this cross-sectional study was to evaluate the gonadal functions and pubertal development in pediatric patients with HAX1-SCN. Methods: Forty-five patients, including 24 females (median age 11.3 years, 1.5–31 years, 13 pubertal and 11 prepubertal), and 21 males (median age 9.5 years, 3–18.8 years, 7 pubertal and 14 prepubertal), followed in 7 centers, were included. POI is defined as a menstrual disturbance with increased follicle stimulating hormone (FSH) and low anti-Mullerian hormone (AMH). We classified prepubertal female patients as impending POI when they had low AMH and high FSH values, indicating impaired ovarian function. Results: A homozygous single nucleotide insertion (position 130-131insA) leading to a premature stop codon; p.Trp44*(c.132G>A) variant in HAX1 gene was detected in 42 (93.3%) affected individuals. Other homozygous variants were p.Arg86*(c.256C>T) and p.Glu60Aspfs*25(c.180delA). We detected elevated serum FSH levels in 10/11 (90.9%) of prepubertal female patients, supporting the diagnosis of impending POI, and in 12/13 (92.3%) of pubertal female patients, classifying them as POI. All female patients had low AMH levels. Male patients did not exhibit gonadal insufficiency. Conclusions: This is the first and largest case series covering early childhood to evaluate patients with HAX1-SCN for gonadal functions. It has been observed that pubertal girls develop POI, prepubertal girls are at increased risk for gonadal failure and male patients are not affected. Our results suggest that HAX1 has an important role in ovarian maturation and/or function. The genotype-phenotype relationship of these patients and the effect of clinical features of SCN on gonadal function should be further investigated.

Background: Paediatric palliative care (PPC) is considered an essential component of the management of children and adolescents with cancer. The International Society of Paediatric Oncology Global Mapping Programme surveyed hospital-based paediatric oncology facilities across Africa from 2018-2020 to document PPC and provision of PPC services. Procedure: An electronic and paper survey were widely distributed to elicit the presence of components of PPC: PPC teams, bereavement counselling services, patient support groups, and spiritual and religious support. Results were correlated with the countries’ Gini coefficient, World Bank income status indicators and Human Development Index. Results: Hospital-based paediatric oncology facilities in 16/54 African countries reported having all four PPC services while those in 11 countries reported having none of the four PPC services. No clear correlations were found between provision of such services and selected economic factors. Conclusions: This study demonstrates that hospital-based paediatric oncology facilities with limited resources caring for children and adolescents can provide PPC. Adoption of the World Health Organisation’s conceptual framework for palliative care and knowledge transfer between African facilities on the integration of PPC into paediatric oncology care, would benefit the increasing numbers of children and adolescents with cancer across the continent.

Introduction: Academic achievement is crucial for advancing learning goals. For disease-related and possibly additional reasons, children with sickle cell anaemia (SCA) in Sub-Saharan Africa (SSA) may be at risk of disease-associated school difficulties. Limited data exist on academic achievement of school-age children with SCA in the region. We aimed to assess academic achievement of children with SCA in Uganda. Methods: This cross-sectional study was conducted in Kampala, Uganda. Participants were school-going children with SCA, aged 6-12 years, attending Mulago Hospital SCA Clinic, and age-matched sibling controls without SCA. Academic achievement was assessed using the Wide Range Achievement Test, Fourth Edition (WRAT4) using outcome measures of spelling, mathematical computation, word reading, and sentence comprehension by age-normalized Z-scores. Results: Among 68 SCA and 69 controls tested, mean age was 9.4 (SD2.0) years; with males 55.9% and 46.4%, respectively. Mean haemoglobin was 7.9 (0.)g/dL in the SCA group versus 12.8 (0.)g/dL in the controls, (p<0.001). Children with SCA scored lower in spelling, (mean difference [95% confidence interval] -0.36 [-0.02 to -0.69], p=0.04) and mathematical computation, (mean difference [95% confidence interval] -0.51 [-0.17 to -0.85], p=0.003) than the controls. No differences by group were found in word reading or sentence comprehension. In the SCA group, lower scores in spelling correlated with age, and males performed better than females in mathematical computation. Discussion: School-aged children with SCA were at risk of poor performance in spelling and mathematical computation. Our findings suggest their need for educational evaluation and support, especially in these two areas, in SSA.

Background: Adherence to follow-up visits is crucial for optimizing clinical outcomes in paediatric patients with sickle cell disease (SCD). This study aimed to evaluate compliance with follow-up visits among paediatric SCD patients over a five-year period. Methodology: A retrospective analysis was conducted using data from the sickle cell disease clinic of Nnamdi Azikiwe University Teaching Hospital, spanning from January 2015 to December 2019. A total of 271 unique paediatric patients with SCD and 1117 follow-up visits were included. Compliance with follow-up visits, defined as attendance within 100 days of the previous visit, was assessed using Kaplan-Meier curves and Cox regression analysis. Results: During the study period, a total of 1117 follow-up visits were documented among 271 children diagnosed with sickle cell anaemia. The median age of the study cohort was 8 years (IQR: 4 to 12 years). Male patients constituted 57% of the study population. Fifty percent of subjects remained compliant with follow-up visits at 14.2 months (95% CI = 8.9-24.1 months) and this compliance decreased to 40% at 24 months (95% CI = 31-49 months). Males showed a lower likelihood to be compliant to follow-up visits than females (HR: 0.83; CI: 0.56-1.23). Following adjustments, patients who were sicker and young adolescents (10 to 14 years) had an increased likelihood of complying to follow up visits (HR: 1.05; CI: 0.71-1.57 vs HR: 1.15; CI: 0.682-1.940 respectively) but this was not statistically significant. Conclusion: The overall poor compliance rate to follow up visits underscores the urgent need for interventions aimed at improving adherence to follow-up visits in this vulnerable population. Counselling interventions and further exploration of factors influencing compliance are warranted to enhance the management and outcomes of children living with sickle cell anaemia.

Juvenile xanthogranuloma (JXG) is a clonal non-Langerhans cell histiocytic disorder characterized by a variety of cutaneous and non-cutaneous manifestations, predominantly in children. The mitogen-activated protein kinase pathway (MAPK) is a key driver in many histiocytic disorders, including JXG. We report a rare presentation of JXG in the mastoid bone of a which recurred after surgery and was refractory to two lines of chemotherapy before responding to the MEK inhibitor trametinib, even in the absence of an identifiable MAPK pathway mutation. MEK inhibitors may be a therapeutic option for this sometimes difficult to treat disease.

A document by Gail Budhu. Click on the document to view its contents.

Practical Challenges Associated with Efanesoctocog Alfa (ALTUVIIIO) Prophylaxis in a 19-month-oldwith Severe Hemophilia AJessica N. Mistretta1, Maria G. Español1,2, Michael D. Tarantino1,2, Dane C. Christ1, Maureen D. Jones1,Jonathan C. Roberts1,21Bleeding & Clotting Disorders Institute, Peoria IL USA2Departments of Pediatrics and Medicine, University of Illinois College of Medicine at Peoria, Peoria, IL USA

Objective: To delineate the natural history of splenic complications other than the loss of splenic function in children with sickle cell disease (SCD), we performed a retrospective chart review of patients with SCD treated at the Texas Children’s Hospital. Methods: We determined the dates of diagnoses of splenic complications, the number of ASSC events, and hydroxyurea treatment in patients with SCD. We also examined the association of hydroxyurea therapy with the onset and severity of ASSC. Results: The cumulative prevalence of splenic complications was 24.7% for splenomegaly, 24.2% for ASSC, 9.6% for hypersplenism, and 5.6% for splenectomy. The cumulative prevalence of all splenic complications was highest in patients with hemoglobin Sβ 0 (69.2%), intermediate in hemoglobin SS (33.3%), low in hemoglobin SC (9.0%), and non-existent in hemoglobin Sβ +. The overall event-rate of ASSC was 8.3 per hundred patient-years. The event-rate was 28.4 in the hemoglobin Sβ 0, 10.9 in hemoglobin SS, and 3.5 in hemoglobin SC Patients with hemoglobin SS and hemoglobin Sβ 0 on hydroxyurea therapy had a significantly higher occurrence of ASSC than those who were not, with event-rates of 14.2 and 3.1, respectively. The event-rate was also higher for children who started hydroxyurea before age 2 years than for those who started after this age (19.8 and 9.2 respectively). Conclusions: The prevalence and severity of splenic problems vary widely between different sickle cell genotypes, with hemoglobin Sβ 0 having the most severe complications. Hydroxyurea therapy is strongly associated with incidence of ASSC, particularly when initiated before two years of age.

Purpose Evaluate the potential risk for long-term complications related to cancer therapy among childhood cancer survivors who completed treatment in Tanzania at Bugando Medical Centre (BMC), and compare the relative risk assessment of BMC survivor cohort and British Childhood Cancer Survivor Study (BCCSS) cohort. Methods Files of all patients age <18 yo with an oncologic diagnosis who received and completed their treatment at BMC from 2016 to 2022 were retrospectively reviewed. Extracted data included patient demographics, primary disease diagnosis and site, treatment received, and cumulative treatment doses. BCCSS risk assessment was assigned. Predicted long term follow up surveillance needs were extrapolated from published Children’s Oncology Group Long-Term Follow-Up Guidelines. Results A total of 173 patients were included in the survivor cohort (47% female, average age =7). The most common diagnoses were Burkitt lymphoma (26%, n=45) and Wilms (30%, n=52). Within the cohort, 98% received chemotherapy (n=170), 49% (n=73) underwent tumor resection, and 18% (n=32) received radiation. Distribution of BCCSS late effect risk assessment included 6% low risk (n=10), 80% moderate risk (n=139) and 14% (n=24) high risk. Based on treatment received, the late effects with highest potential risk were cardiomyopathy (57% of patients, n=98), bladder and urinary tract toxicity (50%, n=87), and ototoxicity (22%, n=38). Conclusion Childhood cancer survivors at BMC have a higher risk of late effects as compared to published survivor cohorts in high-income countries. There is a need to develop and improve long-term follow-up care for survivors by enhancing patient and provider education to promote early detection of late effects.[1](#fn-0002)

Langerhans cell histiocytosis (LCH) is a rare hematologic neoplasm characterized by the clonal proliferation of Langerhans-like cells. Colony-stimulating Factor 1 receptor (CSF1R) is a membrane-bound receptor that is highly expressed in LCH cells and tumor-associated macrophages. In this study, a soluble form of CSF1R protein (sCSF1R) was identified by plasma proteome profiling, and its role in evaluating LCH prognosis was explored. We prospectively measured plasma sCSF1R levels in 104 LCH patients and 10 healthy children using ELISA. Plasma sCSF1R levels were greater in LCH patients than in healthy controls ( P < 0.001) and significantly differed among the three disease extents, with the highest level in MS RO+ LCH patients ( P < 0.001). Accordingly, immunofluorescence showed the highest level of membrane-bound CSF1R in MS RO+ patients. Furthermore, the plasma sCSF1R concentration at diagnosis could efficiently predict the prognosis of LCH patients treated with standard first-line treatment (AUC =0.782, P < 0.001). Notably, dynamic monitoring of sCSF1R levels could predict relapse early in patients receiving BRAF inhibitor treatment. In vitro drug sensitivity data showed that sCSF1R increased resistance to Ara-C in THP-1 cells expressing ectopic BRAF-V600E. Overall, the plasma sCSF1R level at diagnosis and during follow-up is of great clinical importance in pediatric LCH patients.

Background: Thrombin is a critical protease modulating thrombosis as well as inflammation which are one of the main pathophysiological mechanisms in sickle vasculopathy, and its levels were reported to be high in sickle cell disease (SCD). The thrombin-thrombomodulin complex activates an inhibitor of fibrinolysis called TAFI acting by reducing plasmin affinity for its substrate hindering fibrinolysis. Objective: We aimed to determine the influence of the Thr325Ile single nucleotide polymorphism on TAFI antigen levels and potential effects on the severity of SCD in a cohort of Egyptian patients. Methods: Genotyping of Thr325lle polymorphism using Taq-Man SNP genotyping assay and TAFI level measurement using an Enzyme-Linked Immunosorbent Assay (ELISA) were performed for 80 SCD patients and 80 health control subjects. Results: Plasma TAFI levels were higher in SCD patients with Thr325Ile polymorphism, yet the difference was not statistically significant (p=0.204). SCD patients with polymorphic genotypes had a greater number of hospital admissions (p=0.03), Ten patients with acute chest syndrome had the homozygous polymorphic genotype (GG), and all patients with pulmonary hypertension had the polymorphic genotype (6 were homozygous [GG] and 5 were heterozygous [GA]). SCD patients complicated with pulmonary hypertension showed significantly higher plasma TAFI levels (p= 0.044). Conclusion: The analysis of Thr325Ile polymorphism combined with plasma TAFI level possibly suggests that the analyzed SNP could influence plasma levels and subsequently disease severity and hospitalization rate, which might be regarded as predictors for complex disease.

We conducted a feasibility study to evaluate micronutrients and body mass index. Fat soluble vitamins A, D, E and trace elements copper (Cu), selenium (Se) and zinc (Zn) levels were evaluated. Weight, height, body mass index (BMI) and Z-scores were recorded. Side effects or specific adverse events were documented. No patients had a Z score for height, weight, or BMI of <2SD or >2SD. Ninety percent of patients had one or more micronutrient levels below normal. These results suggest that micro-nutrient abnormalities are common despite no obvious evidence of malnutrition. Side effects of chemotherapy may be exacerbated by micronutrient depletion.

Objective: Childhood spinal tumors often present with musculoskeletal symptoms, potentially causing a misdiagnosis and delays in diagnosis and treatment. This study aims to identify, characterize, and compare children with spinal tumors who had prior musculoskeletal misdiagnoses to those without, analyzing clinical presentation, diagnostic interval, and outcome. Study design: This retrospective cohort study evaluated all children aged 0-14 years diagnosed with a spinal tumor in Denmark from 1996 to 2018. The cohort was identified through the Danish Childhood Cancer Registry, and the registry data were supplemented with data from medical records. The survival was compared using the Kaplan-Meier method. Results: Among 58 patients, 57% (33/58) recieved musculoskeletal misdiagnoses before the spinal tumor diagnosis. Misdiagnoses were mostly non-specific (64%, 21/33), involving pain and accidental lesions, while 36% (12/33) were rheumatic diagnoses. The patients with prior misdiagnosis had less aggressive tumors, fewer neurological/general symptoms, and 5.5 months median diagnostic interval versus 3 months for those without a misdiagnosis. Those with prior misdiagnoses tended to have a higher 5-year survival of 83% (95% CI 63-92%) compared to 66% (95% CI 44-82%) for those without (p=0.15) Conclusion: Less aggressive spinal tumors may manifest as gradual skeletal abnormalities and musculoskeletal symptoms without neurological/general symptoms, leading to misdiagnoses and delays.

In utero tumor development and identification ofCTNNB1 mutation in a newborn case of ossifying renal tumor of infancy Shin Kasai1, Minori Tamai1, Eiji Sugihara2, Naoki Oishi3, Kyoko Hinata1, Koshi Akahane1, Kumiko Goi1, Yuko Hata2, Tetsuo Kondo3, Takahiko Mitsui4, Mio Tanaka5, and Takeshi Inukai1*1) Departments of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan2) Division of Gene Regulation, Cancer Center and Open Facility Center, Research Promotion Headquarters, Fujita Health University School of Medicine, Toyoake, Aichi, Japan3) Department of Pathology, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan4) Department of Urology, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan5) Department of Pathology, Kanagawa Children’s Medical Center, Yokohama, Japan.*Corresponding authorTakeshi Inukai, Department of Pediatrics, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409–3898, Japan. Email: tinukai@yamanashi.ac.jpWord count: 849/850 wordsFigures: 2Supplemental Tables: 2Supplemental Figures: 5Running title: CTNNB1 mutation in ossifying renal tumor of infancy (44/50 characters)Key words: CTNNB1, Ossifying renal tumor of infancy, β-catenin, hematuria, calcification, renal tumorAn abbreviations keyORTI: Ossifying renal tumor of infancyWES: Whole exome sequencingEMA: Epithelial membrane antigenPBMC: Peripheral blood mononuclear cellsCNV: Copy number variationILNR: Intralobar nephrogenic restCNSET: Calcifying nested stromal-epithelial tumor

Air-leak syndrome (ALS) is an independent poor prognosis factor among adult patients who have received hematopoietic stem cell transplantation (HSCT), which 5-year overall survival (OS) is less than 30%. However, the clinical features of ALS among post-transplant pediatric patients have rarely been explored.We retrospectively reviewed 2,206 pediatric patients who received an allo-HSCT between January 2013 and December 2019 at the Hebei Yanda Lu Daopei Hospital and analyzed the role of ALS in their prognosis following HSCT.We divided ALS into two categories: 15 cases of bronchiolitis obliterans syndrome (BOS) and 13 cases of idiopathic pneumonia syndrome (IPS).Following treatment of the ALS, 18 patients survived (18/28, 64.3%) and 10 patients died of respiratory failure or infection (10/28, 35.7%). The OS of ALS in our hospital is significantly higher than that cited in previous reports which may be related to early diagnosis and timely FAM treatment.