Vol 19, No 1 (2020)

The prognostic role of HL in AML in children is a matter of a discussion. 185 patients were treated for AML in our center, 36 of 185 had HL (19.5%). The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. Median Le was 97 × 109 /l (50–428 ± 109 /l). Standard risk group were 4 pts, intermediate – 8, hight – 24. The most common variants were M4/M5 in FAB classification – 30 pts and genetic rearrangement – MLL in 15 of 36 pts. Thirty-five patients with HL received cytoreduction course and ADE. After that, all patients received ADE and 21 pts second part of induction – course HAM. Remission was achieved in 27 (75%) out of 36 pts. HSCT was performed in 23 pts. Thirteen out of 36 patients with HL died: 4 (30%) – due to leukostasis complications. OS for HL group was 0.56 ± 0.09, for non-HL group was 0.75 ± 0.04, p = 0.005; EFS (HL) 0.42 ± 0.09, EFS (non-HL) 0.49 ± 0.04, p = 0.026. Also, differences in I CR achievement, median of remission length and death before remission between two groups were statistically significant (p = 0.036; p = 0.028; p = 0.021 respectively). OS and EFS in patients with M4/M5 with HL > 50 ± 109 /l were better than in patients all FAB with HL > 100 ± 109 /l, OS 0.71 ± 0.1 vs OS 0.43 ± 0.1 (p = 0.012); EFS 0.54 ± 0.1 vs EFS 0.29 ± 0.1 (p = 0.038) respectively. HL significantly worsens OS and EFS in children with AML.

Immune thrombocytopenia (ITP) is a disease with a heterogeneous clinical manifestation. In the majority of children newly diagnosed ITP is a self-limited benign disorder, while chronic ITP develops rarely. The clinical onset of ITP can occur in very different ways: from nearly invisible skin hemorrhage to severe life-threatening bleeding. Conventional treatments promote a response in most patients, but in a small number of children thrombocytopenia is unresponsive. In this article, we describe our experience of the clinical use of romiplostim in children with severe unresponsive newly diagnosed ITP. 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. The severity of bleeding decreased significantly after the start of romiplostim therapy in all cases. Durable complete (platelets > 100 × 109 /l) response was achieved in five out of six patients 4 to 8 weeks after starting therapy. Three children have remained in lasting remission for 1 to 3 years after the discontinuation of romiplostim. There were no adverse events associated with romiplostim.

L-asparaginase is widely distributed among microorganisms, animals and plants. L-asparaginase has been utilized as a drug in the treatment of lymphoid malignancies and plays a crucial role in asparagine metabolism in plant stress response mechanisms. Multiple sequence alignment of Neighbor–Joining phylogenetic tree was executed utilizing Mega 4.0. Two plants asparaginase were identified whose three dimensional structures compared well with two bacterial samples of L-asparaginase used in humans as a therapeutic drug. Prediction of antigen cites, B-cell epitope identification and prediction of epitopes by use of Cytotoxic T-lymphocyte was performed using various in silico server resources. The survey showed that between the 40 plants, 2 identified items of human, 12 bacteria and 6 algae of asparaginase genes, generally two main branches created that samples of green algae is in the neighborhood of to the bacterial samples. Interestingly the data showed that the two bacterial samples of L-asparaginase used in medicine, when compared to plant asparaginase genes, have less similarity to asparaginase genes of human, while the two human asparaginase genes are located perfectly between the plant groups with their sequence revealing high similarity with plant species. Although there was some allergen epitope found in plant asparaginase, these are different from the allergen epitopes of microbial asparaginase that are used as a drug in humans with no common sequence being found between them. This manuscript provides evidence suggesting the potential utilization of Phaseolus vulgaris asparaginase, which has less epitopes, better predicting tool scores and high similarity, in drug design as an enzymetherapy in leukemia and other cancers.

Minimal residual disease (MRD) monitoring by flow cytometry at the end of induction therapy is one of the key ways of a prognosis assessment in patients with acute lymphoblastic leukemia (ALL). In B-cell precursor ALL (BCP–ALL), this method of MRD detection is complicated due to the immunophenotypic similarity between leukemic cells and normal B-cell precursors (BCPs). A decrease in intensity of induction therapy can lead to a more frequent appearance of normal BCPs in the bone marrow, which significantly complicates the MRD monitoring. Aim: to assess the incidence of normal BCPs in bone marrow on the 36th day of induction therapy with two different regimens of glucocorticoid (GC) administration according to ALL-MB 2015 protocol. This study was approved by the Independent Ethical Committee and the Academic Council of Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology, Immunology Ministry of Healthcare of Russian Federation. The study included 220 patients with BCP-ALL who were randomized to two types of GC-based induction therapy: a continuous administration of dexamethasone (n = 139) and an intermittent regimen with a 1-week dexamethasone therapy stop (n = 81). On the 36th day of induction therapy, MRD and normal BCPs were quantified in bone marrow samples by flow cytometry. On the 36th day of treatment, 43.2% of BCP(+) samples were established in the intermittent-therapy group, and 27.3% in the continuous-therapy group (p = 0.016). Comparison of the BCP level in BCP(+) samples revealed the more equitable distribution of BCPs at different developmental stages in the intermittent-therapy group, meanwhile mainly the immature BCPs in a quantity of less than 0.01% were found in the continuous-therapy group. Reduced-intensity induction therapy for patients with BCP-ALL leads to a noticeable increase of normal BCPs in bone marrow at the end of this treatment stage. A higher rate of BCP(+) bone marrow samples hinder the MRD detection due to the immunophenotypic similarity of BCPs and leukemic cells.

¹²³I-metaiodobenzylguanidine (¹²³I-MIBG) scintigraphy is widely used for the detection and staging of neuroblastoma. Risk-adapted treatment in patients with neuroblastic tumors is based on many clinical and genetic factors including histopathology. Purpose: non-invasive prediction of an unfavorable histological variant in patients with neuroblastic tumors using quantitative assessment of ¹²³I-MIBG uptake. This study was approved by the Independent Ethical Committee and the Academic Council of Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology, Immunology Ministry of Healthcare of Russian Federation. 96 patients were included in this retrospective study. ¹²³I-MIBG-scintigraphy including whole body planner images and SPECT/CT were performed for all patients before any type of treatment. Semiquantitative and quantitative assessment of ¹²³I-MIBG uptake were calculated and analyzed. Out of 96 patients: 54 with neuroblastoma (NB), 28 with ganglioneuroblastoma (GNB) and 14 with ganglioneuroma (GN). The average values of TLCRR and SUV_max for NB were 5.67 and 7.5, for GNB – 2.58 and 3.1 and for GN – 1.48 and 1.85, respectively. A centile analysis was carried out for all groups. SPECT/CT in combination with modern software allows semiquantitative and quantitative assessment of ¹²³I-MIBG uptake in neuroblastic tumor. The TLCRR and SUV_max can be used separately as well as in combination with NSE for prediction of histological variant. 

Birkitt lymphoma (BL) is one of the most studied and curable type of lymphoma in children. But inspite of lymphomagenesis deep understanding on immunologic, molecular and genetic levels, diagnosis of some rare clinical presentations of disease become challenging task for well-qualified clinicians. In the current issue we present rare case of skin involvement in pediatric 4 year old patient with disseminated BL. It is presented clinical and morphologic characteristic of specific skin presentation. Used multiagent chemotherapy with rituximab deliver the result of complete response. Skin site regression was found on 2d day of treatment. Parents give their agreement to use personal data, including fotos, in research and publications.

A 6-year-old patient was admitted to the Petrovsky National Research Center of Surgery in Moscow, diagnosed with hepatoblastoma (HB) of the right lobe of the liver and after undergoing 4 cycles of SIOPEL (super PLADO) pre-operative chemotherapy. An immunohistochemistry test, performed after liver resection, revealed a rare combination of mixed epithelial and mesenchymal hepatoblastoma and yolk sac tumor. The epithelial component of HB consisted of highly differentiated fetal cells, while the mesenchymal component consisted of osteoid. The morphological structure of the second lesion corresponded to yolk sac tumor. Both tumors had regressive changes conditioned by chemotherapy: these changes were most pronounced in HB. In the highly differentiated fetal component of HB it was possible to detect a weak focal perinuclear alpha-fetoprotein expression, HepPar expression, membranous expression of beta-catenin and diffuse glutamine synthetase expression. Mitotic figures were not determined. The node of the yolk sac tumor had the characteristic histological structure of an endodermal sinus tumor with a hepatoid component. In the main tumor node and its nodular elements in the fibrovascular stroma it was possible to identify alpha-fetoprotein expression, CD34, nuclear and cytoplasmic expression of beta-catenin, CDX2, as well as a rare expression of PLAP and multi-cytokeratin, and mitotic activity was high (21 in 10 high power fields, 400x magnification). In the existing literature available to us, there is only one observation of combined hepatoblastoma and yolk sac tumor. Parents patients agreed to use personal data, including the fotos, in research and publications.

Wiskott–Aldrich syndrome (WAS) is a rare X-linked immunodeficient disease accompanied by microthrombocytopenia, which leads to spontaneous/post-traumatic haemorrhages. It has been demonstrated that WAS is caused by gene mutation of WASP protein, which is participating in the processes of actin polarization and actin cytoskeleton re-organisation. It is yet unknown how this mutation affects intracellular signalling and functional responses of platelets of patients with WAS. Assessment of the intracellular calcium signalling, shape change and fibrinogen binging by the platelets of WAS patients. The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. Three patients with WAS and three healthy volunteers were included in the study. Intracellular signaling and platelet functional responses were observed on a BD Facs Canto II flow cytometer. To measure the calcium concentration in the platelet cytosol, the Fura-Red fluorophore was used, platelet shape change upon activation was evaluated by side scattering of cells at a wavelength of 488 nm, platelet integrin activation was evaluated by binding of fluorescently-labeled fibrinogen. During activation, the platelet concentration was 1000 cells per ul to avoid the effects of secondary activation. In quescent state of platelets, an increased concentration of calcium in the cytosol of platelets of patients was observed compared with platelets of healthy donors. In response to stimulation, the highest achievable calcium concentrations were comparable in both cases. The binding of fibrinogen to platelets in patients was not significantly changed compared to healthy donors. On the other hand, the change in the shape of the cells in response to activation, expressed as a percentage, was more significant in patients than the change in the shape of the platelets of healthy donors. With similar maximum responses to stimulation by all agonists, the concentration of calcium in resting platelets, as well as the change in the platelet shape of patients with WAS is significantly higher than that of healthy platelet donors. These results can be explained by the increased ratio of the platelet membrane area to their volume.

Wiskott–Aldrich Syndrome (WAS) is a primary immunodeficiency (PID), characterized by varying severity of typical symptoms: thrombocytopenia, infections, immune dysregulation and cancer predisposition. Therefore any lymphoproliferative complications in WAS patients require lymph node biopsy. However, the interpretation of the histological picture is often complicated and requires the knowledge of the lymph node pathomorphology in patients with immunodeficiency. This article describes a rare combination of late diagnosis of WAS complicated by lymphadenopathy, which clinically and morphologically resembles Rosai–Dorfman disease (RDD). Parents gave their consent to use information about the child, including the fotos, in the article.

This article presents analysis of recent publications on hyperleukocytosis in children with AML. The mechanisms of the development of life-threatening complications accompanying hyperleukocytosis are analyzed in detail. In this review of the literature, the authors focus on the adequacy and timing of therapy for such life-threatening complications of hyperleukocytosis as leukostasis, DIC, and acute tumor lysis syndrome. The authors emphasize that in the treatment of hyperleukocytosis an important place, in addition to specific therapy, is taken by the accompanying therapy in the intensive care unit. The place of replacement blood transfusions and leukopheresis as part of the accompanying therapy is discussed.

Complement system is a part of the immune system that provides organism cells with protection against foreign pathogens. Various kinds of defects in the complement system can induce development of serious diseases. This review summarizes different malfunctions of the complement system and also shows how these defects can result in development of severe diseases.

Invasive aspergillosis (IA) is a major cause of morbidity in immunocompromised children. Patients with acute myeloid leukemia, relapsed acute luekemia and stem cells recipients are at high-risk for IA. Despite improving of diagnosis, prevention and treatment of IA mortality remains high. The main factors for favorable outcome of IA are early diagnosis and prompt appropriate treatment. Currently, few different international guidelines for IA have been developed but there are no Russian recommendations. An additional problem typical for Russia is poor level of microbiological diagnostic leading to underestimated frequency of IA or non-appropriate usage of antifungal drugs. This article presents an algorithm for diagnosis and treatment of IA in immunocompromised patient taking into account the characteristics of children with hematologic malignancy.