Genetic Susceptibility in Endothelial Injury Syndromes after Hematopoietic Cell Transplantation and Other Cellular Therapies: Climbing a Steep Hill.

Hematopoietic stem cell transplantation (HSCT) remains a cornerstone in the management of patients with hematological malignancies. Endothelial injury syndromes, such as HSCT-associated thrombotic microangiopathy (HSCT-TMA), veno-occlusive disease/sinusoidal obstruction syndrome (SOS/VOD), and capillary leak syndrome (CLS), constitute complications after HSCT. Moreover, endothelial damage is prevalent after immunotherapy with chimeric antigen receptor-T (CAR-T) and can be manifested with cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Our literature review aims to investigate the genetic susceptibility in endothelial injury syndromes after HSCT and CAR-T cell therapy. Variations in complement pathway- and endothelial function-related genes have been associated with the development of HSCT-TMA. In these genes, CFHR5, CFHR1, CFHR3, CFI, ADAMTS13, CFB, C3, C4, C5, and MASP1 are included. Thus, patients with these variations might have a predisposition to complement activation, which is also exaggerated by other factors (such as acute graft-versus-host disease, infections, and calcineurin inhibitors). Few studies have examined the genetic susceptibility to SOS/VOD syndrome, and the implicated genes include CFH, methylenetetrahydrofolate reductase, and heparinase. Finally, specific mutations have been associated with the onset of CRS (PFKFB4, CX3CR1) and ICANS (PPM1D, DNMT3A, TE2, ASXL1). More research is essential in this field to achieve better outcomes for our patients.

Hodgkin Lymphoma in Children and Adolescents of Northern Greece: 25-Year Results and Long-term Follow-up.

Aim of this study was to evaluate the long-term therapeutic outcome and treatment-related complications in Hodgkin disease. We reviewed the medical records of 93 patients diagnosed with classic Hodgkin lymphoma, treated, and followed-up during the last 25 years. The cohort study included 49 males and 44 females with median age 11.8 years old (range: 3.95 to 17.42 y). The most common subtype was nodular sclerosis in 47/93 (50.5%). B symptoms were present in 15/93 (16.1%). From January 2009 until December 2020, 55 (59%) patients diagnosed with Hodgkin lymphoma were treated according to European Network for Pediatric Hodgkin Lymphoma (EURONET)-PHL-C1 protocol. Concerning outcome, a total of 89/93 patients are alive. Relapse occurred in 7/93. Second malignancies are reported in a total of 5 patients, 3 solid tumors (thyroid cancer, breast cancer, and osteosarcoma), and 2 acute myeloid leukemias. The overall survival and event-free survival for the whole cohort were 95.7% and 83.9%, respectively. Disease-free survival was 92.5%. Although a considerable high fraction of patients with Hodgkin disease can achieve continuous complete remission, they are at a high risk of developing long-term treatment-related complications. High curative rates as well as prevention of late effects can be achieved by implementation of individualized treatment strategies and innovative treatments.

Voriconazole plasma concentrations and dosing in paediatric patients below 24 months of age.

Voriconazole (VCZ) is an important first-line option for management of invasive fungal diseases and approved in paediatric patients ≥24 months at distinct dosing schedules that consider different developmental stages. Information on dosing and exposures in children <24 months of age is scarce. Here we report our experience in children <24 months who received VCZ due to the lack of alternative treatment options. This retrospective analysis includes 50 distinct treatment episodes in 17 immunocompromised children aged between 3 and <24 months, who received VCZ between 2004 and 2022 as prophylaxis (14 patients; 47 episodes) or as empirical treatment (3 patients; 3 episodes) by mouth (46 episodes) or intravenously (4 episodes) based on contraindications, intolerance or lack of alternative options. Trough concentrations were measured as clinically indicated, and tolerability was assessed based on hepatic function parameters and discontinuations due to adverse events (AEs). VCZ was administered for a median duration of 10 days (range: 1-138). Intravenous doses ranged from 4.9 to 7.0 mg/kg (median: 6.5) twice daily, and oral doses from 3.8 to 29 mg/kg (median: 9.5) twice daily, respectively. The median trough concentration was 0.63 mg/L (range: 0.01-16.2; 38 samples). Only 34.2% of samples were in the recommended target range of 1-6 mg/L; 57.9% had lower and 7.9% higher trough concentrations. Hepatic function parameters analysed at baseline, during treatment and at end of treatment did not show significant changes during VCZ treatment. There was no correlation between dose and exposure or hepatic function parameters. In three episodes, VCZ was discontinued due to an AE (6%; three patients). In conclusion, this retrospective analysis reveals no signal for increased toxicity in paediatric patients <24 months of age. Empirical dosing resulted in mostly subtherapeutic exposures which emphasises the need for more systematic study of the pharmacokinetics of VCZ in this age group.

Targeted Genotyping of MIS-C Patients Reveals a Potential Alternative Pathway Mediated Complement Dysregulation during COVID-19 Infection.

Complement dysregulation has been documented in adults with COVID-19 and implicated in relevant pediatric inflammatory responses against SARS-CoV-2. We propose that signatures of complement missense coding SNPs associated with dysregulation could also be identified in children with multisystem inflammatory syndrome (MIS-C). We investigated 71 pediatric patients with RT-PCR validated SARS-CoV-2 hospitalized in pediatric COVID-19 care units (November 2020-March 2021) in three major groups. Seven (7) patients suffered from MIS-C (MIS-C group), 32 suffered from COVID-19 and were hospitalized (admitted group), whereas 32 suffered from COVID-19, but were sent home. All patients survived and were genotyped for variations in the C3, C5, CFB, CFD, CFH, CFHR1, CFI, CD46, CD55, MASP1, MASP2, MBL2, COLEC11, FCN1, and FCN3 genes. Upon evaluation of the missense coding SNP distribution patterns along the three study groups, we noticed similarities, but also considerably increased frequencies of the alternative pathway (AP) associated with SNPs rs12614 CFB, rs1061170, and rs1065489 CFH in the MIS-C patients. Our analysis suggests that the corresponding substitutions potentially reduce the C3b-inactivation efficiency and promote slower and weaker AP C3bBb pre-convertase assembly on virions. Under these circumstances, the complement AP opsonization capacity may be impaired, leading to compromised immune clearance and systemic inflammation in the MIS-C syndrome.

Invasive Mucormycosis in Children With Malignancies: Report From the Infection Working Group of the Hellenic Society of Pediatric Hematology-Oncology.

Mucormycosis is an invasive, life-threatening fungal infection that mainly affects immunocompromised hosts. We collected data of pediatric mucormycosis cases from all 7 Greek Hematology-Oncology Departments for the years 2008-2017. Six cases of invasive mucormycosis diagnosed during treatment for malignancies were included in the study. In 4 children (66%) mucormycosis occurred within the first 20 days after diagnosis of the underlying disease. Two cases were classified as proven mucormycosis and 4 as probable. The most frequently recorded species was Rhizopus arrhizus (2 patients), followed by Mucor spp (1), and Lichtheimia spp (1). All patients received liposomal amphotericin B. Combined antifungal treatment was used in 5 cases. Surgical excision was performed in 4 cases (66%). Two patients died at 6 and 12 months after the diagnosis, respectively, 1 (17%) because of mucormycosis. Our data suggest that mucormycosis may occur early after the initiation of intensive chemotherapy in children with malignancies.

Plasma exposures following posaconazole delayed-release tablets in immunocompromised children and adolescents.

BACKGROUND: Posaconazole is a recommended option for antifungal prophylaxis in paediatric patients >12 years of age. However, little is known about plasma exposures and safety following administration of the delayed-release tablets (DRTs) in children and adolescents. METHODS: In a retrospective observational study, we analysed steady-state trough concentrations of posaconazole in all paediatric patients who had received the DRT formulation between May 2015 and December 2018 for antifungal prophylaxis. Dosing was guided by a published population pharmacokinetic model with weight-based dosing. Drug concentrations in plasma were measured by a validated tandem MS method. Liver function and drug discontinuations due to adverse effects were also assessed. RESULTS: A total of 34 patients (21 male, 13 female; median age 12 years, range 5-17 years; median body weight 43.5 kg, range 16-84 kg) undergoing treatment for haemato-oncological disorders (n=23) or immunosuppression for polyarthritis (n=1) or post-allogeneic HSCT (n=11) received posaconazole DRTs for a median of 70 days (range 9-391 days). The median first steady-state trough plasma concentration following model-derived dosing was 1607 ng/mL (range 501-8485 ng/mL) with trough concentrations being above the dosing target of ≥700 ng/mL in 32/34 patients (94%). Considering all (first and subsequent) trough concentrations, target attainment was 90% (63/70 samples). Posaconazole was well tolerated without adverse event-related discontinuations or breakthrough infections. CONCLUSIONS: Administration of posaconazole DRTs to paediatric patients guided by a population pharmacokinetic-derived dosing algorithm resulted in predictable and potentially effective exposures and was well tolerated over prolonged time periods.

Disseminated Bartonella henselae disease mimicking Langerhans' cell histiocytosis.

Bartonella henselae, the causative agent of cat-scratch disease, has been recognized to be responsible for a broad range of clinical syndromes. We report the case of a patient with disseminated B. henselae infection mimicking Langerhans cell histiocytosis at presentation and its successful management with neurosurgery, prolonged antibacterial therapy, and observation.

Epidemiology and management burden of invasive fungal infections after autologous hematopoietic stem cell transplantation: 10-year experience at a European Pediatric Cancer Center.

BACKGROUND: Autologous hematopoietic stem cell transplantation (HSCT) carries risks of infectious morbidity. We analysed epidemiology and management burden associated with invasive fungal diseases (IFDs) in children and adolescents undergoing autologous HSCT. METHODS: In a retrospective, single-centre observational study, epidemiology and management burden associated with IFDs were analysed in all paediatric cancer patients who underwent autologous HSCT between 2005 and 2014. Clinical, radiographic and microbiological data were assessed up to 100 days post-transplant. The primary endpoint was the incidence of proven, probable and possible IFDs. Further endpoints included the use of systemic antifungal agents for prevention and management of IFDs; infectious and non-infectious comorbidities; and survival until day + 100. RESULTS: Of 95 patients (median age: 8 years; r, 0.75-20) underwent 103 HSCT procedures for solid tumours (92) or lymphoma (11). Primary antifungal prophylaxis was administered in 49 procedures (47.5%). No single case of proven/probable IFD was diagnosed. Nine cases (8.7%) fulfilled criteria of possible pulmonary mould infection and received treatment for a median of 14 days (r, 7-35). In an additional 12 procedures, empiric antifungal therapy with mould active agents was given for a median of 8 days (r, 3-105). Microbiologically documented non-fungal infections were observed in 17 procedures, and five patients were transferred to the ICU. There was one death from biopsy documented toxic endothelial damage at day 83 post-transplant. CONCLUSIONS: Autologous HSCT for solid tumours or lymphoma was associated with low morbidity from IFDs. However, utilisation of systemic antifungal agents for prevention and management of suspected IFDs was considerable.

Invasive fungal infections in pediatric patients treated with tumor necrosis alpha (TNF-α) inhibitors.

Macromolecular immunosuppressive monoclonal antibodies and fusion proteins directed against molecules or cells involved in inflammation and immunity represent a recent and important addition to our therapeutic armamentarium. Tumor necrosis alpha (TNFα) is a cytokine involved in systemic inflammation and clinical utilization of its antagonists has revolutionized treatment of juvenile rheumatoid and psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, and plaque psoriasis. Clinical utility has also been demonstrated for use against steroid-refractory graft-vs-host disease and other immune-mediated conditions. Currently, five anti-TNFα agents are approved by the European Medicines Agency (EMA), including the monoclonal anti-TNF antibodies infliximab, adalimumab, golimumab and certolizumab pegol along with etanercept, a TNFα-receptor/IgG-Fc fusion protein. Theoretical considerations related to their mode of action and clinical observations suggest that opportunistic infectious complications should be seriously considered as possible adverse events of macromolecular immunosuppressants. The purpose of this review is to critically analyze the literature on invasive fungal infections (IFIs) occurring in association with TNFα inhibitors alone or in combination with other immunosuppressive agents, with a focus on pediatric patients, and to provide a framework of evaluating the risk for IFIs in this population.

Invasive fungal infections in paediatric patients treated with macromolecular immunomodulators other than tumour necrosis alpha inhibitors.

An expanding list of immunomodulatory or immunosuppressive monoclonal antibodies (mAbs) and biologic therapeutics is currently entering clinical practice, particularly in the areas of oncology, transplantation and autoimmune disorders. These agents are directed against molecules or cells involved in inflammation and immunity and may therefore be associated with serious and opportunistic infections. The purpose of this review was to critically analyse the literature on invasive fungal infections (IFIs) occurring in association with mAbs and fusion proteins other than tumour necrosis alpha (TNF-α) inhibitors, including therapeutics modulating T-cell-mediated pathologies (muromonab, abatacept, belatacept, ipilimumab, basiliximab, daclizumab), inducing lymphopenia (alemtuzumab), depleting CD20+ B cells (rituximab) and interfering with various targets (anakinra, natalizumab, blodalumab, ixekizumab and others) with a focus on children, and to provide a framework of evaluating the risk for IFIs in this population.

Invasive candidiasis and candidaemia in neonates and children: update on current guidelines.

Invasive candidiasis (IC) and candidaemia are leading causes of infectious morbidity and mortality among immunocompromised paediatric patients and those admitted to intensive care units. Despite improvements in diagnosis, prevention and treatment, both mortality rates and the economic burden of disease still remain high. To address this issue, several international societies and organisations have proposed guidelines for the management of IC/candidaemia in both neonates and children. In this article, we review current recommendations of the Infectious Diseases Society of America, the European Conference on Infection in Leukaemia, the European Society of Clinical Microbiology and Infectious Diseases and the German Speaking Mycological Society/Paul-Ehrlich Society for Chemotherapy for the management and prevention of IC/candidaemia in children and neonates.

The Challenge for a Correct Diagnosis of Refractory Thrombocytopenia: ITP or MDS with Isolated Thrombocytopenia?

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by isolated thrombocytopenia. It is diagnosed in patients with a platelet count below 100,000 per cubic millimeter in whom other causes of thrombocytopenia have been ruled out, and its diagnosis is generally one of exclusion. Clinical manifestations of patients may vary from asymptomatic disease to mild mucocutaneous or life-threatening bleeding. Glucocorticoids are used as first-line treatment for ITP, while other second-line medications, mainly thrombopoietin-receptor agonists (TPO-RA) and rituximab, are given to patients in whom ITP does not remit, or relapses soon after glucocorticoid treatment. Refractoriness of ITP strongly questions its diagnosis and necessitates a thorough clinical and laboratory work-up to decide whether that is the case of refractory ITP or a misdiagnosis. The aim of this review is to summarize the conditions associated with isolated thrombocytopenia and highlight the characteristics of confusing cases. Even though the case of a myelodysplastic syndrome presented with isolated thrombocytopenia (MDS-IT) is relatively rare and not well-established in the literature, it constitutes one of the most predominant misdiagnoses of refractory ITP. MDS-IT patients are thought to present with multilineage dysplasia, normal karyotype and low risk prognostic score, based on IPSS-R. It has been shown that a significant proportion of MDS-IT patients are misdiagnosed as having the more common ITP. Therefore, it is crucial that in confusing cases of persistent thrombocytopenia a detailed diagnostic work-up is applied-including evaluation of peripheral-blood smear, bone marrow examination and cytogenetic testing-to avoid unnecessary therapy delay.

Impact of Tyrosine Kinase Inhibitors (TKIs) on Growth in Children and Adolescents with Chronic Myeloid Leukemia: A Systematic Review.

BACKGROUND: Chronic Myeloid Leukemia (CML) is a rare myeloproliferative disease in childhood. Treatment in CML includes Tyrosine Kinase Inhibitors (TKI's), which inhibit the cytoplasmic kinase BCR/ABL. Tyrosine kinases play a key role in the secretion of growth hormone and insulin-like growth factor1 (IGF-1). OBJECTIVE: The aim of this systematic review was to study the effect of TKIs on the growth of children and adolescents with CML. METHODS: English-language publications were searched in the PubMed/Cochrane library/Google Scholar databases (2002-2023), and retrieved studies were assessed according to PRISMA-Statement and Newcastle- Ottawa-scale. RESULTS: The search strategy yielded 1066 articles. After applying the inclusion/exclusion criteria, 941 were excluded based on title screening and 111 on abstract review. The systematic review included 14 articles (11 retrospective observational studies/3 clinical trials). Twelve studies reported data on the prevalence of growth disorders after the administration of 1st generation TKIs (imatinib). Two studies reported a negative effect of 2nd generation TKIs (dasatinib/nilotinib) on physical growth. Four studies recorded a decrease in height z-score after treatment compared to baseline. Two 1st-generation TKIs studies reported data on children's final height; one reported restoration of final height to normal after the onset of puberty, despite initial slowing, and the final height was lower than mid-parental target height. Serum IGF-1 levels were reported in 2 studies to be within normal range, while in 3 studies, a significant decrease was documented. Considerable study heterogeneity was observed related to dosage/duration of treatment/disease phase/stage of puberty/ethnicity. CONCLUSION: A negative effect of TKIs on the growth and final height of children was noted.

Epidemiology of Invasive Fungal Diseases: A 10-Year Experience in a Tertiary Pediatric Hematology-Oncology Department in Greece.

Although advances in the management of pediatric neoplasms have profoundly improved infectious disease outcomes, invasive fungal diseases (IFDs) remain a major cause of morbidity and mortality in children and adolescents with high-risk hematological malignancies. A retrospective study was conducted in the Pediatric Hematology-Oncology Department of the University General Hospital of Heraklion for 2013-2022 to estimate the prevalence and describe the clinical and epidemiological characteristics of IFDs for pediatric and adolescent patients with neoplasia. Demographic, clinical, and laboratory parameters were analyzed to identify risk factors for the development of IFD. The overall prevalence of IFDs was estimated to be 7.8% (12/154 patients) throughout the study. The mean age at IFD diagnosis was 9.8 years (SD 6.4 years). The most common IFD was possible/probable invasive pulmonary aspergillosis (IPA; in ≈50%), followed by candidemia/invasive candidiasis (in 44%). Candida parapsilosis was the most prevalent Candida species (4/6 events). Of interest, the majority (75%) of IFDs were breakthrough infections. Patients with increased risk for IFDs were those who were colonized by fungi in sites other than the oral cavity, hospitalized in the intensive care unit for >7 days, received >7 different antimicrobials in the last 3 months, or had severe neutropenia for >44 days. Two children out of a total of 12 with IFD died due to refractory disease or relapse (16.7%). More detailed and prospective epidemiological studies on fungal infections in pediatric patients with hematological or solid neoplasms can contribute to the optimization of prevention and treatment.

Effect of apolipoprotein E (APOE) gene polymorphisms on the lipid profile of children being treated for acute lymphoblastic leukemia.

BACKGROUND: Medications used to treat acute lymphoblastic leukemia (ALL), such as L-asparaginase, can cause blood lipid disturbances. These can also be associated with polymorphisms of the lipoprotein lipase (LpL) and apolipoprotein E (APOE) genes. PROCEDURE: We aimed to investigate the association between lipid profile, certain LpL and APOE gene polymorphisms (rs268, rs328, rs1801177 and rs7412, rs429358 respectively) as well as the risk subgroup in 30 pediatric patients being treated for ALL, compared with 30 pediatric ALL survivors and 30 healthy controls. RESULTS: The only APOE gene polymorphism with significant allelic and genotypic heterogeneity was rs429358. Further analysis of this polymorphism showed that genotype (CC, CT, or TT) was significantly associated with (1) changes in the lipid profile at the end of consolidation (total cholesterol, LDL, apo-B100, and lipoprotein a) and during re-induction (total cholesterol and apo-B100), and (2) classification in the high risk-ALL subgroup (for CC genotype/C allele presence). CONCLUSIONS: Lipid abnormalities in children being treated for ALL may be associated with the APOE genotype, which is also possibly associated with risk stratification. Further research is needed to confirm the potential prognostic value of these findings.

miRNAs as predictive biomarkers of response to treatment in pediatric patients with acute lymphoblastic leukemia.

MicroRNAs (miRNAs/miRs) are promising prognostic biomarkers in pediatric acute lymphoblastic leukemia (ALL). The present study aimed to identify miRNAs that could serve as prognostic biomarkers or as novel therapeutic targets in ALL. The expression levels of 84 miRNAs were assessed in the bone marrow aspirates of 10 pediatric patients with newly diagnosed ALL at diagnosis and on day 33 of induction of the ALL Intercontinental Berlin-Frankfurt-Münster 2009 protocol, and associations with established prognostic factors were evaluated. The levels at diagnosis of 25 miRNAs were associated with ≥2 prognostic factors. Higher expression levels of let-7c-5p, miR-106b-5p, miR-26a-5p, miR-155-5p, miR-191-5p, miR-30b-5p and miR-31-5p were significantly associated with a good prednisone response. The expression levels of miR-125b-5p, miR-150-5p and miR-99a-5p were significantly higher in standard- or intermediate-risk patients compared with those in high-risk patients (P=0.017, P=0.033 and P=0.017, respectively), as well as in those with a complete response at the end of induction (P=0.044 for all three miRNAs). The change in expression levels between diagnosis and the end of induction differed significantly between risk groups for three miRNAs: miR-206, miR-210 and miR-99a (P=0.033, P=0.047 and P=0.008, respectively), with the post induction levels of miR-206 increased in high-risk patients, whilst miR-210 and miR-99a levels were increased in intermediate/standard risk patients. Therefore, miRNAs that could be integrated into the risk stratification of pediatric ALL after further evaluation in larger patient cohorts were identified.

Metabolic Fingerprint in Childhood Acute Lymphoblastic Leukemia.

INTRODUCTION: Acute lymphoblastic leukemia (ALL) is the most prevalent childhood malignancy. Despite high cure rates, several questions remain regarding predisposition, response to treatment, and prognosis of the disease. The role of intermediary metabolism in the individualized mechanistic pathways of the disease is unclear. We have hypothesized that children with any (sub)type of ALL have a distinct metabolomic fingerprint at diagnosis when compared: (i) to a control group; (ii) to children with a different (sub)type of ALL; (iii) to the end of the induction treatment. MATERIALS AND METHODS: In this prospective case-control study (NCT03035344), plasma and urinary metabolites were analyzed in 34 children with ALL before the beginning (D0) and at the end of the induction treatment (D33). Their metabolic fingerprint was defined by targeted analysis of 106 metabolites and compared to that of an equal number of matched controls. Multivariate and univariate statistical analyses were performed using SIMCAP and scripts under the R programming language. RESULTS: Metabolomic analysis showed distinct changes in patients with ALL compared to controls on both D0 and D33. The metabolomic fingerprint within the patient group differed significantly between common B-ALL and pre-B ALL and between D0 and D33, reflecting the effect of treatment. We have further identified the major components of this metabolic dysregulation, indicating shifts in fatty acid synthesis, transfer and oxidation, in amino acid and glycerophospholipid metabolism, and in the glutaminolysis/TCA cycle. CONCLUSIONS: The disease type and time point-specific metabolic alterations observed in pediatric ALL are of particular interest as they may offer potential for the discovery of new prognostic biomarkers and therapeutic targets.

Inside the "fragile" infant: pathophysiology, molecular background, risk factors and investigation of neonatal osteopenia.

Current research in bone mineral metabolism reveals many aspects of osteopenia occurred in premature infants. This review examines not only the pathophysiological and molecular mechanisms of newborn osteopenia but also the risk factors and investigation. Osteopenia of premature infants has increased incidence among other diseases of prematurity. Identification of risk factors is essential for monitoring of osteopenia. Some of the risk factors include low birth weight, prematurity, long term administration of drugs such as corticosteroids, methyloxanthines, furosemide, abnormalities in vitamin D metabolism, poor maternal nutritional and mineral uptake etc. Neonatologists, pediatricians and endocrinologists should investigate premature, low birth weight infants that have high serum alkaline phosphatase and have at least one risk factor.

Cardiotoxicity of Targeted Therapies in Children with Haematological Malignancies and Solid Tumors.

Cardiotoxicity represents an important acute or chronic adverse event of treatment modalities for childhood cancer. In the last two decades the emergence of novel cancer therapies has aimed to increase unaided or mostly in combination with conventional chemotherapy for the survival rates of pediatric cancer especially for those patients with relapsed and/or refractory disease. The use of emerging targeted therapies in combination with conventional chemotherapy is related to cardiovascular adverse events mostly reported in adults. The aim of our short review was to investigate the cardiotoxic side effects of targeted chemotherapeutic agents as monoclonal antibodies and small molecules in pediatric cancer patients.