Vol 23, No 4 (2024)

Myeloid neoplasms associated with Down syndrome (DS) are represented by transient abnormal myelopoiesis, acute myeloid leukemia (AML) and myelodysplastic syndrome. Transient abnormal myelopoiesis is a clonal myeloproliferative syndrome characterized by an increased number of blast cells in the peripheral blood, morphologically and immunophenotypically most commonly related to megakaryoblasts, and the presence of an acquired mutation in the GATA1 gene. This syndrome occurs in infants up to 6 months of age. Children with DS have an abnormally high risk of developing hematological malignancies. The incidence of AML in these patients is 150–400 times higher than in children without DS. Survival rates and prognosis in children with AML and DS (AML-DS) treated with reduced-intensity chemotherapy are significantly higher than in children without DS: the overall survival ranges from 84% to 90% and the event-free survival is up to 89%. At the same time, standard intensive chemotherapy (with high-dose anthracyclines and intensive timing of induction) is associated in these patients with high toxicity and significant mortality due to infectious complications. Treatment outcomes in patients with AML-DS in Russia do not exceed 66%, which is significantly lower than those achieved by international cancer research groups. There is a need for standardization of therapy for AML-DS in Russia and introduction of a uniform treatment protocol with reduced chemotherapy doses and common standards of supportive care as well as prophylaxis and treatment of infectious complications. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of Russia.

Monitoring of viral “load” in intraocular fluid and intravitreal injections (IVIs) of antiviral drugs along with systemic antiviral therapy is an effective measure of control of cytomegalovirus retinitis in hematopoietic stem cell (HSC) recipients, but the safety of this method in children has not been studied. Complications of serial intraocular fluid sampling and IVIs of antiviral drugs (pain, hemorrhage, corneal erosion) were evaluated after 585 IVIs in 48 pediatric HSC recipients. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. Pain was assessed using the visual analog pain scale, and ophthalmoscopy was performed before the IVI and the day after it to detect other complications (1174 exams). Pain developing immediately after the IVI was shown to be an almost inevitable consequence of the procedure (43 (96%) of 45 patients; after 92% of injections) and was independent of the drug administered (ganciclovir vs foscarnet) or its concentration. The most common complication was subconjunctival hemorrhage of varying severity (16%), with rare complications represented by hyphema (0.3%) and corneal erosion. Serial IVIs of antiviral drugs with intraocular fluid sampling is an effective and safe method of treatment of cytomegalovirus retinitis in pediatric recipients of allogeneic HSC, but it inevitably causes post-manipulation pain requiring analgesia.

Hemophilia is the second most common inherited bleeding disorder after von Willebrand disease. Delayed clotting is usually observed in all main types of hemophilia caused by deficiencies in blood coagulation factors. Primary prophylaxis is considered the gold standard to prevent acute hemarthrosis and chronic arthropathy in patients with severe hemophilia A. However, some low-income countries, like Iran, have to prioritize access to preventive care to balance the financial resources and per capita access to coagulation factors. In order to compare the cost-effectiveness of on-demand and preventive treatment, we conducted a retrospective study on 55 patients with hemophilia A. We collected data from two groups of patients: those who had received routine prophylactic treatment and those who had received on-demand (episodic) treatment. The results of our study revealed a significant difference in the annualized bleeding rates (ABRs) between the two groups: ABR in the prophylactic treatment group was lower than in the on-demand treatment group (2.19 vs 7.25). In addition, we found substantial differences between the prophylactic and on-demand treatment groups in the number of hospital visits per year (9.8 vs 14.41), the annual number of infusions (107.35 vs 229.58), and in the mean cost of treatment (30.96€ vs 63€). In conclusion, prophylactic therapy seems to be more effective than on-demand treatment. This study was conducted in accordance with the principles of the Declaration of Helsinki. The study was approved by the Ethics Committee of the Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran (IR.AJUMS.REC.1398.456). Written informed consent was obtained from the patients’ parents.

The importance of the research lies in the fact that it aims to study the genetic polymorphisms of the haptoglobin (Hp) gene in patients with sickle cell anemia, hepatitis C, and sickle cell anemia with hepatitis C, as well as to study the relationship between the polymorphisms of the gene and the liver enzymes (alkaline phosphatase, aspartate aminotransferase, and alanine transaminase). Hp is a type of alpha-2 globulin found in human plasma. Its primary function is to bind to the globin portion of free hemoglobin in the bloodstream. Objectives: Determining the genotypes of the Hp gene in patients with sickle cell anemia and hepatitis C using allele-specific polymerase chain reaction and studying the relationship between genetic polymorphisms and increased liver enzymes (alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase). This study included 130 participants. They were classified to 4 groups: patients with sickle cell anemia (n = 40), patients with hepatitis C (n = 40), sickle cell patients with hepatitis C (n = 10), and a control group (n = 40). DNA was isolated and polymerase chain reaction was performed using genotype-specific primers for the three regions of the Hp gene. The genotypes were determined after electrophoresis on agarose gel and determination of the amplified fraction of each allele. Alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase levels were measured by colorimetric methods. The results showed that the Hp2-2 genotype was more frequent in all three patient groups than the Hp1-1 or Hp2-1 genotypes. The liver enzyme levels were also significantly higher in the Hp2-2 genotype group than in the other two groups. Hp2-2 was the most prevalent Hp phenotype among the patient groups and it may play a role in the pathogenesis of sickle cell anemia and hepatitis C. The study was approved by the Research Committee of the Thi-Qar Institutional Health Department in 2022.

The objective of our study was to establish characteristic values of the main hematological parameters (platelet, red blood cell (RBC), and white blood cell (WBC) counts, and hemoglobin level) in preterm infants in early childhood, taking into account their birth weight. The study was approved by the independent Ethics Committee and the Scientific Council of the Siberian State Medical University of Ministry of Healthcare of the Russian Federation (Tomsk). The study included data from 302 children born between 2014 and 2020 in Tomsk. The inclusion criteria for the main study group were premature infants with a birth weight of less than 2500 grams. The main group (n = 226) was stratified by birth weight: low birth weight (n = 78), very low birth weight (n = 76), and extremely low birth weight (n = 72). The inclusion criteria for the control group (n = 76) were healthy full-term infants with a birth weight of more than 2500 grams. During follow-up care for the first three years of life, the following complete blood count parameters were measured in the early neonatal period (initial examination within the first 24 hours of birth), and at the age of one, two, and three years: hemoglobin level (g/L), RBC count (× 10¹²/L), WBC count (× 10⁹/L) and platelet count (× 10⁹/L). Our study showed a correlation of complete blood count parameters with birth weight in children from birth to three years. In the neonatal period, there was a direct correlation between birth weight and RBC count (r = 0.428; p < 0.001), hemoglobin levels (r = 0.137; p = 0.029), and platelet counts (r = 0.453; p < 0.001). In the first days of life, children with extremely low birth weight had statistically significantly lower RBC counts (3.92 (3.51–4.27) × 10¹²/L), platelet counts (171.5 (133–229) × 10⁹/L) and hemoglobin levels (156 (142–172) g/L) than children in other groups. We observed an inverse correlation between hemoglobin level and birth weight and a direct correlation between platelet count and birth weight in early childhood. The study revealed the dependence of some hematological parameters in premature infants on their birth weight, which requires further investigation. 

Donor lymphocyte infusion (DLI) for prophylactic purposes enhances the immunoadoptive antitumor effect, thereby reducing the risk of relapse after allogeneic hematopoietic stem cell transplantation (HSCT) in patients with acute leukemia. One of the main limiting factors for the use of DLI is the risk of developing graft-versus-host disease (GVHD). According to studies, the incidence of this complication of DLI ranges from 15% to 45% for acute GVHD (aGVHD) and from 10% to 50% for the chronic form. The development of GVHD after DLI also leads to enhancement of the antitumor effect and reduces the risk of relapse. At the same time, an increased risk of relapse is associated with the loss of HLA heterozygosity after haploidentical HSCT, and the role of GVHD in this process has not been investigated yet. In this single-center retrospective study, we performed a comparative analysis of the risk of bone marrow and extramedullary relapses in pediatric patients with acute lymphoblastic leukemia and acute myeloid leukemia who had received prophylactic DLI after allogeneic HSCT. We also assessed the severity of DLI-induced aGVHD and the incidence and severity of chronic GVHD, and investigated the relationship between aGVHD and the loss of HLA heterozygosity. We identified two groups of patients: those who had received prophylactic DLI (an intervention group; n = 41) and those who had not (a comparison group; n = 46). Informed consent to the inclusion in the study was obtained from all the patients/legal representatives. Protocol (No. 249 dated 31.05.2021) was registered in the Ethics Committee of the I.P. Pavlov First Saint Petersburg State Medical University of Ministry of Healthcare of the Russian Federation. All the patients were divided into four subgroups according the use of IDL and the development of aGVHD: +DLI – patients with DLI and without aGVHD (n = 34); +DLIGVHD – patients with DLI-induced aGVHD (n = 7); –DLI – patients without DLI and aGVHD (n = 34); –DLIGVHD – patients without DLI and with a history of aGVHD (n = 12). A total of 7 (17%) cases of DLI-induced aGVHD were recorded. There were no statistically significant differences in the incidence and severity of gastrointestinal tract involvement (p = 1) and liver involvement (p = 0.75) between the 2 groups. The incidence of grade III–IV skin GVHD (p = 0.06) was higher in the non-DLI group. No deaths associated with DLI-induced GVHD were recorded. The median number of aGVHD treatment lines (2 (1–4) and 1 (1–2); p = 0.2) and the duration of treatment (63 (23–1455) days and 70 (44–111) days; p = 0.72) were similar in the 2 groups. The incidence of chronic GVHD in the DLI group (n = 7; 17%) and in the comparison group (n = 12; 26%) did not differ significantly (p = 0.45). The cumulative incidence of bone marrow relapses was significantly lower in those patients who developed aGVHD, after DLI or without DLI (–DLI 63% (95% confidence interval (CI) 43–77), +DLI 41% (95% CI 24–57), –DLIGVHD 21% (95% CI 5–46), +DLIGVHD 14% (1–50%) (p = 0.003)). There were no significant differences between the study groups in terms of the cumulative incidence of extramedullary relapses that ranged from 16% to 29% (p = 0.8). The overall survival of the patients with aGVHD (from the –DLIGVHD and +DLIGVHD groups) was 86% (95% CI 33–98) and 84% (95% CI 50–96), respectively, and it was statistically significantly different from the overall survival of the patients without aGVHD: 54% (95% CI 35–70) and 38% (95% CI 20–56) in the +DLI and –DLI subgroups, respectively (p = 0.012). The loss of HLA heterozygosity was evaluated in 22 (40%) out of 55 patients with a post-transplant relapse. In total, HLA haplotype loss was detected in 7 (32%) patients, 3 of whom were from the +DLI group (42.9%), 2 from the –DLI group (28.6%), and another 2 from the –DLIGVHD group (28.6%). Out of 15 individuals without HLA loss, one patient (6.7%) had a history aGVHD and did not receive DLI (p = 0.57). Thus, prophylactic DLI in children with acute lymphoblastic leukemia and acute myeloid leukemia is shown to be effective in preventing bone marrow relapses after allogeneic HSCT. The development of aGVHD has a potentiating effect resulting in increased immunoadoptive activity of donor lymphocytes. The severity and clinical manifestations of DLI-induced aGVHD in pediatric patients do not differ significantly from those patients who develop classical aGVHD early after transplantation.

Accurate and timely laboratory diagnosis plays a key role in specifying the causes of hemorrhagic events both in children and adults. However, due to the rarity and diversity of some bleeding disorders, a full spectrum of laboratory testing may not be available in certain regions or hospitals. Taking into account these limitations, a programme of remote diagnosis of von Willebrand disease (VWD) was initiated in 2019. The aim of our study was to assess the results of the programme. In accordance with the study protocol, peripheral blood samples from patients suspected of VWD were collected at local healthcare facilities and, after initial sample preparation, were transferred to the Laboratory of Clinical Hemostasis of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. Ethical approval was not required since the study only involved the use of anonymized and generalized retrospective data obtained during routine clinical practice. Coagulation analysis included tests for von Willebrand factor antigen (vWF:Ag), von Willebrand factor ristocetin cofactor activity (vWF:RCo), and factor VIII (FVIII) clotting activity. From 04 November 2019 to 31 December 2023, we received a total of 512 frozen samples from 375 children aged under 18 years (the mean age was 10 years (1 month – 17 years)) and 139 adult patients (the mean age was 35 (18–72) years) from 21 regions of the Russian Federation. Pre-analytical errors were identified in 42 (8.2%) cases. Decreased vWF activity (< 50%) was found in 125 (26.6%) patients. VWF activity < 30% was registered in 52 (11.1%) patients, while vWF:RCo < 50% and > 30% – in 73 (15.5%) cases. In 68 (54.4%) patients, laboratory findings were consistent with vWD type 1, in 50 (40%) cases testing results were indicative of vWD type 2, and 7 (5.6%) patients had vWD type 3. Thirty (6.4%) patients had decreased FVIII/vWF:Ag ratio. Type 2N VWD was found in one woman with low FVIII activity (the FVIII binding activity of VWF was 2%, normal range: 70–130%). The implementation of this programme has allowed us to specify a diagnosis in 125 patients without their in-person presence and regardless of their place of residence. This expands our possibilities of detecting VWD in patients living in regions with limited diagnostic capacity.

To date, about 500 genetic defects are known to cause clinical manifestations of immunodeficiency. Genetic diagnosis is necessary to guide the management of patients with inborn errors of immunity (IEI) and plays an important role in genetic counselling of families. To find the genetic cause of IEI, 2395 probands were tested, in 1507 (65.7%) of them we identified 164 forms of IEI with defects in 143 single genes and abnormalities in 8 chromosomes. The majority of IEIs (89.1%) were monogenic, with 98.6% of them being of germline origin. Only 10.6% of IEIs were due to large chromosomal breaks. The most common monogenic forms of IEI with a confirmed genetic defect are Wiskott–Aldrich syndrome, X-linked chronic granulomatous disease, X-linked agammaglobulinemia, Nijmegen syndrome, hereditary angioedema types 1 and 2, ataxia-telangiectasia, Schwachman–Diamond syndrome, severe congenital neutropenia, X-linked severe combined immunodeficiency. Among IEIs associated with chromosomal abnormalities, del22.q11.2 syndrome (DiGeorge syndrome) predominates. These 10 forms of IEI were detected in 51% (775/1507) of all the probands with a confirmed genetic diagnosis. In our study, 6.4% (96/1507) of the probands had unique IEIs: a total of 80 different IEI entities associated with defects in 73 genes and 6 chromosomes (each entity affecting 1 or 2 patients). The majority of them were autosomal recessive IEIs (65%), 30% were autosomal dominant, and only 5% of the cases were X-linked. In addition, polygenic IEIs were identified in 0.3% of the probands and somatic mutations in wellknown genes (NRAS, KRAS, FAS, NLRP3) led to IEI in 0.9% of the probands. The frequency of familial cases among the probands with a confirmed genetic diagnosis was 9.6% (145/1507). Understanding the mechanisms of occurrence and inheritance of IEI in the heterogeneous Russian population will play an important role in the development of diagnostic and therapeutic strategies for patients and their families. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. Informed consent for genetic testing and for the publication of its results was obtained from the patients and/or from at least one parent of a child under the age of consent.

Malignant liver tumors are a rare type of pediatric cancer, accounting for 1–2% of all malignant neoplasms in children. Hepatoblastoma is the most common malignant liver tumor, occurring in 80% of cases in children aged 6 months to 3 years. Hepatocellular carcinoma (HCC) usually affects older children, and in adolescents it is more common than hepatoblastoma. Unlike adults, etiological factors for HCC have not been identified in most children. When discussing the histological classification (the 5th edition of the World Health Organization), special attention was drawn to one of the subtypes of HCC – the steatohepatitic variant, which, according to the literature, had never been encountered in children. Here, we present a clinical case of an 11-yearold girl, who was diagnosed with malignant tumor of the right liver lobe. The patient's parents gave consent to the use of their child's data, including photographs, for research purposes and in publications. The diagnosis was made based on the results of a comprehensive diagnostic evaluation, including imaging studies and blood testing for tumor markers. The initial alphafetoprotein level was increased to more than 8000 ng/mL. After successful neoadjuvant multi-agent chemotherapy, the patient underwent surgery involving the resection of hepatic segments V and VI containing the tumor. Histological examination and immunohistochemistry revealed the steatohepatitic variant of HCC. The radicality of the surgery (R0 resection) was confirmed. In some published studies, an association of steatohepatitic HCC (SH-HCC) with obesity and metabolic syndrome is discussed. In others, however, it is suggested that there may be no connection between the development of SH-HCC and obesity or nonalcoholic fatty liver disease. This clinical case report is the first description of SH-HCC in a child. Despite the uniqueness of this case, pediatric oncologists should be aware that the steatohepatitic variant of HCC not associated with obesity or metabolic syndrome can also occur in children. SH-HCC is more likely to result from alterations of common genes or metabolic pathways within the tumor and is an ideal subtype for future genetic studies.

Vitamin K-dependent coagulopathy caused by vitamin K deficiency holds an important place among bleeding disorders in newborns and infants. The late type of this disease is considered to be the most dangerous one because up to 50% of children develop intracranial hemorrhage which often leads to disability or even death if diagnosis is delayed. Here, we report on the prevalence, treatment and prevention of vitamin K-dependent coagulopathy in neonates and infants.

Local and generalized thrombotic events can affect patient outcomes and quality of life. The purpose of our scoping review was to investigate the influence of thrombotic events in pediatric maxillofacial pathology on the results of surgical treatment. The search for publications was carried out in December 2023 in the PubMed information system. Two authors independently reviewed the studies and extracted data for analysis. The study included 8 publications out of 654 found. The pediatric cohort in the selected studies was mixed with adult patients. Insufficient information was obtained to carry out a meta-analysis and definitively answer the research question. It seems likely that the anatomical and pathophysiological features of maxillofacial pathology, pharmacological effects of therapy and methods of surgical correction may influence the development and progression of local intravascular coagulopathy. There are no recommendations on the choice of standard or integral hemostasis tests for the diagnosis and monitoring of coagulopathy in this pathology. The use of low-molecular-weight heparins can reduce the clinical manifestations of local intravascular coagulopathy.