ATM germline pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematological malignancies.

Ataxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene. Children with A-T are predisposed to hematological malignancies. We aimed to investigate their characteristics and outcomes in order to generate data-based treatment recommendations. In this multinational, observational study we report 202 patients aged ≤25 years with A-T and hematological malignancies from 25 countries. Ninety-one patients (45%) presented with mature B-cell lymphomas, 82 (41%) with acute lymphoblastic leukemia/lymphoma, 21(10%) with Hodgkin lymphoma and eight (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% CI 43.6-59.1) and 47.9% (95% CI 40.8-56.2), respectively. Cure rates have not significantly improved over the last four decades (p=.76). The major cause of treatment failure was treatment-related mortality (TRM) with a four-year cumulative incidence of 25.9% (95% CI 19.5-32.4). Germline ATM PVs were categorized as null or hypomorphic and patients with available genetic data (n=110) were classified as having absent (n=81) or residual (n=29) ATM kinase activity. Four-year EFS was 39.4% (95% CI 29-53.3) vs 78.7% (95% CI 63.7-97.2), (p<.001), and TRM rates were 37.6% (95% CI 26.4-48.7) vs 4.0% (95% CI 0-11.8), (p=.017), for those with absent and residual ATM kinase activity, respectively. Absence of ATM kinase activity was independently associated with decreased EFS (HR=0.362, 95% CI 0.16-0.82; p=.009) and increased TRM (HR=14.11, 95% CI 1.36-146.31; p=.029). Patients with A-T and leukemia/lymphoma may benefit from de-escalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity.

PAX5 Alterations in a Consecutive Childhood B-Cell Acute Lymphoblastic Leukemia Cohort Treated Using the ALL IC-BFM 2009 Protocol.

In this study, we aimed to identify patients within our B-ALL cohort with altered PAX5. Our objective was to use a comprehensive analysis approach to characterize the types of genetic changes, determine their origin (somatic/germline), and analyze the clinical outcomes associated with them. A consecutive cohort of 99 patients with B-ALL treated at the Children's Hospital of the UMC Ljubljana according to the ALL IC-BFM 2009 protocol was included in our study. We used RNA sequencing data for gene expression analysis, fusion gene detection and single nucleotide variant identification, multiplex-ligation dependent probe amplification for copy number variation assessment, and Sanger sequencing for germline variant detection. PAX5 was impacted in 33.3% of our patients, with the genetic alterations ranging from CNVs and rearrangements to SNVs. The most common were CNVs, which were found in more than a third of patients, followed by point mutations in 5.2%, and gene rearrangements in 4.1%. We identified eight patients with a PAX5-associated genetic subtype that were previously classified as "B-other", and they showed intermediate outcomes. We showed higher minimal residual disease values at the end of induction and poorer event-free survival in hyperdiploid cases carrying duplications in PAX5 compared to other hyperdiploid cases. We also report an interesting case of a patient with PAX5::FKBP15 and a pathogenic variant in PTPN11 who underwent an early relapse with a monocytic switch. In conclusion, this study provides valuable insights into the presence, frequency, and prognostic significance of diverse PAX5 alterations in B-ALL patients, highlighting the complexity of genetic factors and their impact on patient outcomes.

Integrative Transcriptomic Profiling of the Wilms Tumor.

Our study aimed to identify relevant transcriptomic biomarkers for the Wilms tumor, the most common pediatric kidney cancer, independent of the histological type and stage. Using next-generation sequencing, we analyzed the miRNA profiles of 74 kidney samples, which were divided into two independent groups: fresh frozen tissue and formalin-fixed paraffin-embedded tissue samples. Subsequent mRNA expression profiling and pathway analysis were performed to establish the interplay and potential involvement of miRNAs and mRNA in the Wilms tumor. Comparative analysis, irrespective of post-dissection tissue processing, revealed 41 differentially expressed miRNAs, with 27 miRNAs having decreased expression and 14 miRNAs having increased expression in the Wilms tumor tissue compared to healthy kidney tissue. Among global mRNA transcriptomic profile differences, cross-sectional analysis suggested a limited list of genes potentially regulated by differentially expressed miRNAs in the Wilms tumor. This study identified the comprehensive miRNA and mRNA profile of the Wilms tumor using next-generation sequencing and bioinformatics approach, providing better insights into the pathogenesis of the Wilms tumor. The identified Wilms tumor miRNAs have potential as biomarkers for the diagnosis and treatment of the Wilms tumor, regardless of histological subtype and disease stage.

Childhood Acute Lymphoblastic Leukemia: Results of the Randomized Acute Lymphoblastic Leukemia Intercontinental-Berlin-Frankfurt-Münster 2009 Trial.

PURPOSE: The International Berlin-Frankfurt-Münster (BFM) study group conducted a study on pediatric acute lymphoblastic leukemia (ALL). Minimal residual disease (MRD) was assessed using flow cytometry (FCM), and the impact of early intensification and methotrexate (MTX) dose on survival was evaluated. PATIENTS AND METHODS: We included 6,187 patients younger than 19 years. MRD by FCM refined the risk group definition previously used in the ALL intercontinental-BFM 2002 study on the basis of age, WBC count, unfavorable genetic aberrations, and treatment response measured morphologically. Patients at intermediate risk (IR) and high risk (HR) were randomly assigned to protocol augmented protocol I phase B (IB) versus IB regimen. MTX doses of 2 versus 5 g/m2 every 2 weeks, four times, were evaluated in precursor B-cell-ALL (pcB-ALL) IR. RESULTS: The 5-year event-free survival (EFS ± SE) and overall survival (OS ± SE) rates were 75.2% ± 0.6% and 82.6% ± 0.5%, respectively. Their values in risk groups were standard risk (n = 624), 90.7% ± 1.4% and 94.7% ± 1.1%; IR (n = 4,111), 77.9% ± 0.7% and 85.7% ± 0.6%; and HR (n = 1,452), 60.8% ± 1.5% and 68.4% ± 1.4%, respectively. MRD by FCM was available in 82.6% of cases. The 5-year EFS rates in patients randomly assigned to protocol IB (n = 1,669) and augmented IB (n = 1,620) were 73.6% ± 1.2% and 72.8% ± 1.2%, respectively (P = .55), while those in patients receiving MTX doses of 2 g/m2 (n = 1,056) and MTX 5 g/m2 (n = 1,027) were 78.8% ± 1.4% and 78.9% ± 1.4%, respectively (P = .84). CONCLUSION: The MRDs were successfully assessed using FCM. An MTX dose of 2 g/m2 was effective in preventing relapse in non-HR pcB-ALL. Augmented IB showed no advantages over the standard IB.[Media: see text].

Excellent results of screening for subsequent breast cancers in long-term survivors of childhood Hodgkin's lymphoma-Results of a population-based study.

Introduction: Subsequent breast cancer (SBC) represents a major complication in childhood cancer survivors and screening for SBC in survivors after incidental irradiation of breasts is recommended. In this article, we report the results and discuss benefits of SBC screening in female pts treated for Hodgkin's lymphoma (HL) in Slovenia in a period of 45 years. Methods: Between 1966 and 2010, 117 females were treated for HL under the age of 19 in Slovenia. One hundred five of them survived for 5 years and were included in our study. They were 3-18 (med. 15) years old at diagnosis and followed for 6-52 (med. 28) years. Eighty-three percent of them had chest RT with a median dose of 30 Gy. Ninety-seven (92%) of 105 pts were regularly followed according to the international guidelines including yearly screening mammography/breast MRI in those who received chest RT. Results: We diagnosed 10 SBCs in eight pts 14-39 (med. 24) years after diagnosis at the age of 28-52 (med. 42) years. At 40 years of follow-up, cumulative incidence of SBCs in females who got chest RT was 15.2%. Seven of eight patients (with 9 SBCs) got chest RT with 24-80 (med. 36) Gy at the age of 12 to 18 (median 17) years. Two patients in this group got bilateral SBC. One patient got invasive SBC after being treated with ChT containing high-dose of anthracyclines without chest RT at the age of 13. All eight invasive SBCs were invasive ductal cancers, HER2 receptors negative, all but one with positive hormonal receptors. Six invasive cancers were of stage T1N0, one T1N1mi, only one, diagnosed before era of screening, was of T2N1. None of 8 pts died of SBC. Conclusion: After introduction of regular breast screening in our female patients, who received chest RT in childhood, all SBCs were of early stage and no patients died of SBC. Survivors of pediatric HL should be informed about the risk of late sequelae of treatment for HL, including SBC. Regular follow-up with breast cancer screening and breast self-examination is of vital importance in those treated with chest RT.

Photobiomodulation for Chemotherapy-Induced Oral Mucositis in Pediatric Patients.

Oral mucositis (OM) is a common side effect in patients undergoing chemotherapy (CT), especially in children due to their rapid epithelial mitotic rate. It has been associated with a significant reduction in life quality since it leads to pain, an inadequate intake of nutrients, an increased risk of opportunistic infections, and interruptions of CT. Photobiomodulation (PMB) with low-level laser therapy (LLLT) has shown faster healing, reduction in pain, and the reduced use of analgesic compared to placebo groups. The purpose of this review is to analyze and compare the existing clinical trials and identify their shortcomings in hope to make future research easier. Using MeSH terms and keywords, the Embase, Medline, and PubMed databases we searched for the period of the last 5 years. We identified a total of 15 clinical trials, with a total of 929 pediatric patients analyzed in this review. We compared different light sources and other laser technique characteristics used in clinical trials such as wavelength, energy and power density, spot size, irradiation time, PBM protocol, and OM evaluation. The main findings show inconsistent laser parameter quotations, differences in the PBM protocol along with a laser application technique, and a lack of clinical trials. Based on that, more studies with a high methodological quality should be conducted in order to provide a unified PBM protocol suitable for the pediatric population.

Pediatric Precursor B-Cell Lymphoblastic Malignancies: From Extramedullary to Medullary Involvement.

B-cell lymphoblastic lymphoma (BCP-LBL) and B-cell acute lymphoblastic leukemia (BCP-ALL) are the malignant counterparts of immature B-cells. BCP-ALL is the most common hematological malignancy in childhood, while BCP-LBL accounts for only 1% of all hematological malignancies in children. Therefore, BCP-ALL has been well studied and treatment protocols have changed over the last decades, whereas treatment for BCP-LBL has stayed roughly the same. Clinical characteristics of 364 pediatric patients with precursor B-cell malignancies were studied, consisting of BCP-LBL (n = 210) and BCP-ALL (n = 154) patients. Our results indicate that based on the clinical presentation of disease, B-cell malignancies probably represent a spectrum ranging from complete isolated medullary disease to apparent complete extramedullary disease. Hepatosplenomegaly and peripheral blood involvement are the most important discriminators, as both seen in 80% and 95% of the BCP-ALL patients and in 2% of the BCP-LBL patients, respectively. In addition, we show that the overall survival rates in this cohort differ significantly between BCP-LBL and BCP-ALL patients aged 1−18 years (p = 0.0080), and that the outcome for infants (0−1 years) with BCP-LBL is significantly decreased compared to BCP-LBL patients of all other pediatric ages (p < 0.0001).

Trends in treatment of childhood cancer and subsequent primary neoplasm risk.

BACKGROUND: The aim of the study was to investigate long-term risk and spectrum of subsequent neoplasm (SN) in childhood cancer survivors and to identify how trends in therapy influenced cumulative incidence of SN. PATIENTS AND METHODS: The population-based cohort comprises 3271 childhood cancer patients diagnosed in Slovenia aged ≤ 18 years between 1st January 1961 and 31st December 2013 with a follow-up through 31st December 2018. Main outcome measures are standardised incidence ratios (SIRs), absolute excess risks (AERs), and cumulative incidence of SN. RESULTS: After median follow-up time of 21.5 years for 5-year survivors, 230 patients experienced 273 SN, including 183 subsequent malignant neoplasm (SMN), 34 meningiomas and 56 nonmelanoma skin cancers. 10.5% patients received radiotherapy only, 31% chemotherapy only, 26.9% a combination of chemotherapy and radiotherapy and 16.1% surgery only. The overall SIR was almost 3 times more than expected (SIR 2.9), with survivors still at 2-fold increased risk after attained age 50 years. The observed cumulative incidence of SMN at 30-year after diagnosis was significantly lower for those diagnosed in 1960s, compared with the 1970s and the 1980s (P heterogeneity < 0.001). Despite reduced use of radiotherapy over time, the difference in cumulative incidence for the first 15 years after diagnosis was not significant for patients treated before or after 1995 (p = 0.11). CONCLUSIONS: Risks of developing a SMN in this study are similar to other European population-based cohorts. The intensity of treatment peaked later and use of radiotherapy declined slower compared to high income countries, making continuous surveillance even more important in the future.

High BMP4 expression in low/intermediate risk BCP-ALL identifies children with poor outcomes.

Pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) outcome has improved in the last decades, but leukemic relapses are still one of the main problems of this disease. Bone morphogenetic protein 4 (BMP4) was investigated as a new candidate biomarker with potential prognostic relevance, and its pathogenic role was assessed in the development of disease. A retrospective study was performed with 115 pediatric patients with BCP-ALL, and BMP4 expression was analyzed by quantitative reverse transcription polymerase chain reaction in leukemic blasts at the time of diagnosis. BMP4 mRNA expression levels in the third (upper) quartile were associated with a higher cumulative incidence of relapse as well as a worse 5-year event-free survival and central nervous system (CNS) involvement. Importantly, this association was also evident among children classified as having a nonhigh risk of relapse. A validation cohort of 236 patients with BCP-ALL supported these data. Furthermore, high BMP4 expression promoted engraftment and rapid disease progression in an NSG mouse xenograft model with CNS involvement. Pharmacological blockade of the canonical BMP signaling pathway significantly decreased CNS infiltration and consistently resulted in amelioration of clinical parameters, including neurological score. Mechanistically, BMP4 favored chemoresistance, enhanced adhesion and migration through brain vascular endothelial cells, and promoted a proinflammatory microenvironment and CNS angiogenesis. These data provide evidence that BMP4 expression levels in leukemic cells could be a useful biomarker to identify children with poor outcomes in the low-/intermediate-risk groups of BCP-ALL and that BMP4 could be a new therapeutic target to blockade leukemic CNS disease.

Clinical impacts of copy number variations in B-cell differentiation and cell cycle control genes in pediatric B-cell acute lymphoblastic leukemia: a single centre experience.

BACKGROUND: IKZF1 gene deletions have been identified as a poor prognostic factor in pediatric B-cell acute lymphoblastic leukemia (B-ALL), especially in the presence of co-occurring deletions (IKZF1plus profile). This study aimed to determine the frequency of IKZF1 deletions and deletions in other B-cell differentiation and cell cycle control genes, and their prognostic impact in Slovenian pediatric B-ALL patients. PATIENTS AND METHODS: We studied a cohort of 99 patients diagnosed with B-ALL from January 2012 to December 2020 and treated according to the ALL IC-BFM 2009 protocol. Eighty-eight bone marrow or peripheral blood samples were analysed for copy number variations (CNVs) using the SALSA MLPA P335 ALL-IKZF1 probemix. RESULTS: At least one CNV was detected in more than 65% of analysed samples. The most frequently altered genes were PAX5 and CDKN2A/B (30.7%, 26.1%, and 25.0%, respectively). Deletions in IKZF1 were present in 18.2% of analysed samples and were associated with an inferior 5-year event-free survival (EFS; 54.8% vs. 85.9%, p = 0.016). The IKZF1plus profile was identified in 12.5% of the analysed samples, and these patients had an inferior 5-year EFS than those with deletions in IKZF1 only and those without deletions (50.8% vs. 75.0% vs. 85.9%, respectively, p = 0.049). Overall survival (OS) was also worse in patients with the IKZF1plus profile than those with deletions in IKZF1 only and those without deletions (5-year OS 76.2% vs. 100% vs. 93.0%, respectively). However, the difference between the groups was not statistically significant. CONCLUSIONS: Our results are in concordance with the results obtained in larger cooperative clinical trials. Copy number variations analysis using the SALSA MLPA kit is a reliable tool for initial diagnostic approach in children with B-ALL, even in smaller institutions in low- and middle-income countries.

Micafungin for Candida infections in Slovenia and Romania: A multicenter, observational, prospective study.

INTRODUCTION: An echinocandin, such as micafungin, is recommended as first-line treatment for invasive Candida infections in immunocompromised patients. This multicenter, observational, prospective, non- interventional study evaluated the real-world use of micafungin in clinical practice in Slovenia and Romania, as this remains unexplored. METHODOLOGY: The primary endpoint was evaluation of micafungin use, including rationale for prescription, treatment duration, and daily dose. Secondary endpoints included recordings of patient baseline characteristics and evaluations of efficacy and safety. Across 11 centers in two countries, 118 patients (18 children [< 16 years] and 100 adults [≥ 16 years]) received micafungin for the first time according to their clinic's standard practice. RESULTS: Micafungin was prescribed for treatment in 57.6% of patients and for prophylaxis in 40.7% of patients. The median (range) treatment duration was 9.0 (0 - 54) days and 13.0 (2 - 6)] days, respectively. The median dose of micafungin was higher than recommended for children receiving prophylaxis or treatment for invasive candidiasis and for adults receiving prophylaxis. Fever was the most commonly observed clinical sign at baseline (16 children [88.9%] and 31 adults [31%]) and hematologic malignancy was the most frequent primary diagnosis at admission (11 children [61.1%] and 40 adults [40%]). Candida species were the most commonly identified causal agents of invasive fungal infections (2 children [11.1%] and 48 adults [48%]). CONCLUSIONS: The efficacy and safety profiles of micafungin use in Slovenia and Romania based on clinician's own experiences in local clinical practice were consistent with those reported in other real-world studies.

Micronized, Microencapsulated Ferric Iron Supplementation in the Form of >Your< Iron Syrup Improves Hemoglobin and Ferritin Levels in Iron-Deficient Children: Double-Blind, Randomized Clinical Study of Efficacy and Safety.

A major problem of oral iron supplementation efficacy in children is its tolerability and compliance. We aimed to determine the safety and efficacy of a novel food supplement >Your< Iron Syrup in the replenishment of iron stores and improvement of hematological parameters in iron-deficient children aged nine months to six years. We randomized 94 healthy children with iron deficiency in a ratio of 3:1 to either receive >Your< Iron Syrup or placebo. A 12-week supplementation with >Your< Iron Syrup resulted in a significant increase in ferritin and hemoglobin levels as compared to placebo (p = 0.04 and p = 0.02). Adverse events were reported with similar frequencies across both study arms. >Your< Iron Syrup represents an effective, well-tolerated, and safe option for the management of nutritional iron deficiency in children.

Second malignant neoplasms after treatment of non-Hodgkin's lymphoma-a retrospective multinational study of 189 children and adolescents.

Data on the spectrum of second malignant neoplasms (SMNs) after primary childhood non-Hodgkin's lymphoma (NHL) are scarce. One-hundred-and-eighty-nine NHL patients diagnosed in a 30 years period of 1980-2010 developing an SMN were retrieved from 19 members of the European Intergroup for Childhood NHL and/or the international Berlin-Frankfurt-Münster Study Group. Five subgroups of SMNs were identified: (1) myeloid neoplasms (n = 43; 23%), (2) lymphoid neoplasms (n = 51; 27%), (3) carcinomas (n = 48; 25%), (4) central nervous system (CNS) tumors (n = 19; 10%), and (5) "other" SMNs (n = 28; 15%). In 37 patients (20%) preexisting disorders were reported with 90% having any kind of cancer predisposition syndrome (CPS). For the 189 primary NHL patients, 5-year overall survival (OS) after diagnosis of an SMN was 56 ± 4%, being worst for patients with preexisting disorders at 28 ± 8%. Five-year OS rates were 38 ± 8%, 59 ± 7%, 79 ± 8%, 34 ± 12%, and 62 ± 11%, respectively, for patients with myeloid and lymphoid neoplasms, carcinomas, CNS tumors, and "other" SMNs (p < 0.0001). Patients with SMNs after childhood NHL having a reported CPS, mostly mismatch repair disorders, carried a very poor prognosis. Moreover, although outcome was favorable in some subtypes of SMNs after childhood NHL (carcinomas, lymphoid neoplasms), other SMNs such as myeloid neoplasms and CNS tumors had a dismal prognosis.

Platelet lumiaggregation testing: Reference intervals and the effect of acetylsalicylic acid in healthy adults.

BACKGROUND: Light transmission aggregometry with lumiaggregometry are methods commonly recommended as a first-line test in platelet dysfunction diagnostic work-up. They are poorly standardized and usually performed in specialized laboratories. For proper interpretation, each laboratory should establish its own diagnostic approach in order to recognize abnormal aggregation patterns. The aim of this study was to measure plasma lumiaggregometry with basic agonists to establish the analyzer-reagent reference intervals (RI) for adults and to test the method response to aspirin. METHODS: The Chrono-Log Model 700 lumiaggregometer using Chrono-Par and Chrono-lume reagents (Chrono-Log Corp., Havertown, PA, USA) was used to measure the maximal aggregation and adenosine triphosphate release using adenosine diphosphate (2 µmol/L), collagen (2 µg/mL), arachidonic acid (1 µmol/L), epinephrine (5.5 µmol/L) and ristocetin (1.25 mg/mL), and thrombin (1 U/mL). The effect of aspirin on platelet aggregation and granule release was inspected. RESULTS: RIs derived from 40 healthy adults were calculated using the non-parametric approach. Wider intervals and low lower limits were determined for weak agonist as well as absence or impaired aggregation in up to one of 7 healthy controls. The response of platelets to aspirin shows response comparable to previously reported study. CONCLUSIONS: Locally established RI in our study enable us to investigate platelet function in patients with a high probability of bleeding disorders. Values are agonist and equipment specific. The variability of the method can be reduced by considering standardized preanalytical and analytical variables. Pathological results must be interpreted in the context of other hemostasis test results and clinical findings.

Treatment of rhabdomyosarcoma in children and adolescent from four low health expenditures average rates countries.

Background Survival of children with cancer in Eastern and Central Europe is 10-20% lower than in high income European countries. We evaluated outcome of children and adolescents with rhabdomyosarcoma (RMS) in Slovenia, Croatia, Slovakia and in Romania. Patients and methods We retrospectively analysed event-free survival (EFS) and overall survival (OS) for all patients treated in Slovenia and Croatia. Slovakia included patients from two centers, representing half of expected cases. Romania included patients from single institution, representing only 10% of expected patients. Joint database for analysis was established. Results One hundred seventy-eight children and adolescent with RMS diagnosed from January 2000 to December 2015 were included. Mean patient age at diagnosis was 7.7 years, one third was older than 10 years. Twenty-five percent had alveolar histology and 72% unfavorable location. Higher than expected proportion of patients had nodal involvement (24%) or metastatic disease (27%). All patients received systemic chemotherapy, 57% had radiotherapy and 63% surgery as local control. Kaplan- Meier estimates for 5-year EFS and OS were 50.7% and 59.6%, respectively. Five-year OS for patients with localised disease was 72% compared to 24% for metastatic disease. Conclusions Children with RMS treated in Eastern and Central Europe have inferior outcome compared to their counterparts treated in high income European countries. Active participation of low health expenditures average rates (LHEAR) countries in international clinical trials may improve outcome of paediatric oncology patients.

Association of CEP72 rs924607 TT Genotype with Vincristine-induced Peripheral Neuropathy Measured by Motor Nerve Conduction Studies.

Vincristine is at the core of many treatment protocols for childhood malignancies. The major dose-limiting side effect is vincristine-induced peripheral neuropathy (VIPN) which may cause morbidity and disrupt curative treatment. Several studies have tried to identify pharmacogenetic biomarkers for susceptibility to vincristine-induced toxicity (Egbelakin A et al., Pediatr Blood Cancer 2011; 56: 361-367. Aplenc R et al., Br J Haematol 2003; 122: 240-244. Diouf B et al., JAMA 2015; 313: 815-823. Zgheib NK et al., Pharmacogenet Genomics, 2018; 28: 189-195. Gutierrez-Camino A et al., Pharmacogenet Genomics 2016; 26: 100-102. Wright GE et al., Clin Pharmacol Ther 2019; 105: 402-410. Kayilioglu H et al., J Pediatr Hematol Oncol 2017; 39(6): 458-462). A major limitation of these studies is that VIPN is difficult to measure objectively using only clinical examination and clinical scales. This is especially true for children, who are often unable to report or grade symptoms such as paresthesia, numbness, and pain. Furthermore, some studies are questioning the validity of currently available neuropathy grading scales (Postma TJ et al., Ann Oncol 1998; 9: 739-744). Our group recently showed that electrophysiological studies can be used with great accuracy for early detection of VIPN (Kavcic M et al., J Pediatr Hematol Oncol 2017; 39: 266-271). In the previous study, we found that VIPN presents with primary axonal involvement and is more pronounced on motor neurons (Kavcic M et al., J Pediatr Hematol Oncol 2017; 39: 266-271).

Centrosomal protein72 rs924607 and vincristine-induced neuropathy in pediatric acute lymphocytic leukemia: meta-analysis.

AIM: We examined the utility of the rs924607 TT genotype of the centrosomal protein 72 (CEP72) as a potential biomarker for predilection toward vincristine-induced peripheral neuropathy in children treated for acute lymphoblastic leukemia. MATERIALS & METHODS: We conducted a random-effects meta-analysis of data from four studies comprising 817 patients. We tested for an association using a recessive model where a one-sided p-value < 0.05 was considered statistically significant. RESULTS & CONCLUSION: We were unable to confirm the association between the rs924607 TT genotype and neurotoxicity (odds ratio: 1.99; p = 0.16; 95% CI: 0.76-5.25) in our global meta-analysis. Analysis of the continuation phase (following induction) studies showed significantly higher odds for neuropathy in CEP72 rs924607 TT homozygotes (odds ratio: 2.28; p = 0.02; 95% CI: 1.16-6.87).