139 results on '"Galina Novichkova"'
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2. Blinatumomab as postremission therapy replaces consolidation and substantial parts of maintenance chemotherapy and results in stable MRD negativity in children with newly diagnosed B-lineage ALL
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Guenter Henze, Ekaterina Mikhailova, Alexander Popov, Julia Roumiantseva, Oleg Budanov, Svetlana Lagoyko, Liudmila Zharikova, Natalia Miakova, Dmitry Litvinov, Lili Khachatryan, Alexey Pshonkin, Natalia Ponomareva, Elmira Boichenko, Svetlana Varfolomeeva, Julia Dinikina, Galina Novichkova, and Alexander Karachunskiy
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
The bispecific T cell-binding antibody blinatumomab (CD19/CD3) is widely and successfully used for the treatment of children with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Here, we report the efficacy of a single course of blinatumomab instead of consolidation chemotherapy to eliminate minimal residual disease (MRD) and maintain stable MRD-negativity in children with primary BCP-ALL.Between February 2020 and November 2022, 177 children with non-high-risk BCP-ALL were enrolled in the ALL-MB 2019 pilot study (NCT04723342). Patients received the usual risk-adapted induction therapy according to the ALL-MB 2015 protocol. Those who achieved a complete remission at the end of induction (EOI) received treatment with blinatumomab immediately after induction at a dose of 5 μg/m2/day for 7 days and 21 days at a dose of 15 μg/m2/day, followed by 12 months of maintenance therapy. MRD was measured using multicolor flow cytometry (MFC) at the EOI, then immediately after blinatumomab treatment, and then four times during maintenance therapy at 3-month intervals.All 177 patients successfully completed induction therapy and achieved a complete hematological remission. In 174 of these, MFC-MRD was measured at the EOI. 143 patients (82.2%) were MFC-MRD negative and the remaining 31 patients had varying degrees of MFC-MRD positivity.MFC-MRD was assessed in all 176 patients who completed the blinatumomab course. With one exception, all patients achieved MFC-MRD negativity after blinatumomab, regardless of the MFC-MRD score at EOI. One adolescent girl with high MFC-MRD positivity at EOI remained MFC-MRD positive. Of 175 patients who had completed 6 months of maintenance therapy, MFC-MRD data were available for 156 children. Of these, 155 (99.4%) were MFC-MRD negative. Only one boy with t(12;21) (p13;q22)/ETV6::RUNX1 became MFC-MRD positive again. The remaining 174 children had completed the entire therapy. MFC-MRD was examined in 154 of them, and 153 were MFC-MRD negative. A girl with hypodiploid BCP-ALL showed a reappearance of MFC-MRD with subsequent relapse.In summary, a single 28-day course of blinatumomab immediately after induction, followed by 12 months of maintenance therapy, is highly effective in achieving MRD-negativity in children with newly diagnosed non-high risk BCP-ALL and maintaining MRD-negative remission at least during the treatment period.
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- 2024
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3. Flow cytometric minimal residual disease measurement accounting for cytogenetics in children with non‐high‐risk acute lymphoblastic leukemia treated according to the ALL‐MB 2008 protocol
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Alexander Popov, Guenter Henze, Grigory Tsaur, Oleg Budanov, Julia Roumiantseva, Mikhail Belevtsev, Tatiana Verzhbitskaya, Liudmila Movchan, Svetlana Lagoyko, Liudmila Zharikova, Yulia Olshanskaya, Tatiana Riger, Alena Valochnik, Natalia Miakova, Dmitry Litvinov, Olga Khlebnikova, Olga Streneva, Elena Stolyarova, Natalia Ponomareva, Galina Novichkova, Olga Aleinikova, Larisa Fechina, and Alexander Karachunskiy
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acute lymphoblastic leukemia ,flow cytometry ,genetic risk groups ,minimal residual disease ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Quantitative measurement of minimal residual disease (MRD) is the “gold standard” for estimating the response to therapy in childhood B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL). Nevertheless, the speed of the MRD response differs for different cytogenetic subgroups. Here we present results of MRD measurement in children with BCP‐ALL, in terms of genetic subgroups with relation to clinically defined risk groups. Methods A total of 485 children with non‐high‐risk BCP‐ALL with available cytogenetic data and MRD studied at the end‐of‐induction (EOI) by multicolor flow cytometry (MFC) were included. All patients were treated with standard‐risk (SR) of intermediate‐risk (ImR) regimens of “ALL‐MB 2008” reduced‐intensity protocol. Results and Discussion Among all study group patients, 203 were found to have low‐risk cytogenetics (ETV6::RUNX1 or high hyperdiploidy), while remaining 282 children were classified in intermediate cytogenetic risk group. For the patients with favorable and intermediate risk cytogenetics, the most significant thresholds for MFC‐MRD values were different: 0.03% and 0.04% respectively. Nevertheless, the most meaningful thresholds were different for clinically defined SR and ImR groups. For the SR group, irrespective to presence/absence of favorable genetic lesions, MFC‐MRD threshold of 0.1% was the most clinically valuable, although for ImR group the most informative thresholds were different in patients from low‐(0.03%) and intermediate (0.01%) cytogenetic risk groups. Conclusion Our data show that combining clinical risk factors with MFC‐MRD measurement is the most useful tool for risk group stratification of children with BCP‐ALL in the reduced‐intensity protocols. However, this algorithm can be supplemented with cytogenetic data for part of the ImR group.
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- 2024
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4. Novel hemizygous CORO1A variant leads to combined immunodeficiency with defective platelet calcium signaling and cell mobility
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Anna Khoreva, MD, Kirill R. Butov, MD, Elena I. Nikolaeva, MD, Alexey Martyanov, PhD, Elena Kulakovskaya, MD, Dmitry Pershin, MD, Maxim Alexenko, MD, Maria Kurnikova, MD, Ruslan Abasov, MD, Elena Raykina, PhD, Dmitry Abramov, MD, Kristina Arnaudova, PhD, Yulia Rodina, PhD, Natalia Trubina, MD, Yulia Skvortsova, PhD, Dmitry Balashov, PhD, Anastasia Sveshnikova, PhD, Alexey Maschan, PhD, Galina Novichkova, PhD, Mikhail Panteleev, PhD, and Anna Shcherbina, PhD
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CORO1A ,combined immunodeficiency ,cytoskeleton ,actin ,granulomatous dermatitis ,platelet ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Background: To date, fewer than 20 patients have been identified as having germline biallelic mutations in the coronin-1A gene (CORO1A) and its protein with clinical features of combined immunodeficiency characterized by T-cell lymphopenia ranging from the severe phenotype to the mild phenotype, recurrent infections, and lymphoproliferative disorders. However, the effects of CORO1A protein disruption on actin-dependent functions in primary cells have not been fully delineated. Objective: We sought to characterize the underlying defects of actin-dependent cellular functions in a female patient with combined immunodeficiency caused by a novel missense variant in the CORO1A gene in combination with a de novo heterozygous microdeletion of chromosome 16p11.2 and also to provide evidence of the pathogenicity of this gene mutation. Methods: To identify the genetic defect, next-generation sequencing followed by Sanger confirmation and array comparative genomic hybridization were performed. Western blot and quantitative PCR tests were used to assess the effects on the protein. Flow cytometry and live microscopy were performed to investigate cellular motility and immune cell counts and function. Results: We demonstrated that the CORO1A hemizygous variant c.19C>T, p. A7C induces significant decreases in cellular levels of the CORO1A protein while leaving mRNA concentrations unaffected. The observed mutation resulted in impaired natural killer cell cytotoxicity and platelet calcium signaling. In addition, primary granulocytes and mesenchymal cells showed significant defects in motility. Conclusion: Collectively, we added new data about the CORO1A gene as a key player in actin cytoskeleton dynamics and cell signaling. Our findings expand the clinical spectrum regarding CORO1A protein deficiency and confirm the importance of a personalized therapeutic approach for each patient.
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- 2024
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5. Immunophenotypic but Not Genetic Changes Reclassify the Majority of Relapsed/Refractory Pediatric Cases of Early T-Cell Precursor Acute Lymphoblastic Leukemia
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Irina Demina, Aya Dagestani, Aleksandra Borkovskaia, Alexandra Semchenkova, Olga Soldatkina, Svetlana Kashpor, Yulia Olshanskaya, Julia Roumiantseva, Alexander Karachunskiy, Galina Novichkova, Michael Maschan, Elena Zerkalenkova, and Alexander Popov
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ETP-ALL ,immunophenotype ,relapse ,lineage switch ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) develops from very early cells with the potential for both T-cell and myeloid differentiation. The ambiguous nature of leukemic blasts in ETP-ALL may lead to immunophenotypic alterations at relapse. Here, we address immunophenotypic alterations and related classification issues, as well as genetic features of relapsed pediatric ETP-ALL. Between 2017 and 2022, 7518 patients were diagnosed with acute leukemia (AL). In addition to conventional immunophenotyping, karyotyping, and FISH studies, we performed next-generation sequencing of the T-cell receptor clonal repertoire and reverse transcription PCR and RNA sequencing for patients with ETP-ALL at both initial diagnosis and relapse. Among a total of 534 patients diagnosed with T-cell ALL (7.1%), 60 had ETP-ALL (11.2%). Ten patients with ETP-ALL experienced relapse or progression on therapy (16.7%), with a median time to event of 5 months (ranging from two weeks to 5 years). Most relapses were classified as AL of ambiguous lineage (n = 5) and acute myeloid leukemia (AML) (n = 4). Major genetic markers of leukemic cells remained unchanged at relapse. Of the patients with relapse, four had polyclonal leukemic populations and a relapse with AML or bilineal mixed-phenotype AL (MPAL). Three patients had clonal TRD rearrangements and relapse with AML, undifferentiated AL, or retention of the ETP-ALL phenotype. ETP-ALL relapse requires careful clinical and laboratory diagnosis. Treatment decisions should rely mainly on initial examination data, taking into account both immunophenotypic and molecular/genetic characteristics.
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- 2024
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6. Novel SLFN14 mutation associated with macrothrombocytopenia in a patient with severe haemorrhagic syndrome
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Dmitrii Polokhov, Daria Fedorova, Anastasiya Ignatova, Evgeniya Ponomarenko, Elena Rashevskaya, Alexey Martyanov, Nadezhda Podoplelova, Maxim Aleksenko, Irina Mersiyanova, Elena Seregina, Aleksandr Poletaev, Ekaterina Truchina, Elena Raykina, Svetlana Plyasunova, Galina Novichkova, Pavel Zharkov, and Mikhail Panteleev
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SLFN14 ,Inherited thrombocytopenia ,macrothrombocytopenia ,Platelet dysfunction ,Bleeding ,Platelet function tests ,Medicine - Abstract
Abstract Background Platelet-type bleeding disorder 20 (BDPLT20), as known as SLFN14-related thrombocytopenia, is a rare inherited thrombocytopenia (IT). Previously, only 5 heterozygous missense mutations in the SLFN14 gene have been reported. Methods A comprehensive clinical and laboratory examination of a 17-year-old female patient with macrothrombocytopenia and severe mucocutaneous bleeding was performed. Examination was carried out using standardized questionnaires to assess bleeding, high-throughput sequencing (Next Generation Sequencing), optical and fluorescence microscopy, flow cytometry with activation and analysis of intracellular calcium signaling of platelets, light transmission aggregometry and thrombus growth in the flow chamber. Results Analysis of the patient’s genotype revealed a previously undescribed c.655 A > G (p.K219E) variant in the hotspot of the SLFN14 gene. Immunofluorescence and brightfield examination of platelets in the smear showed heterogeneity in cells size, including giant forms over 10 μm (normal size 1–5) in diameter, with vacuolization and diffuse distribution of β1-tubulin and CD63. Activated platelets showed impaired contraction and shedding/internalization of GPIb. GP IIb/IIIa clustering was increased at rest and attenuated upon activation. Intracellular signalling study revealed impaired calcium mobilization upon TRAP 35.97 nM (reference range 180 ± 44) and CRP-XL 10.08 nM (56 ± 30) stimulation. Aggregation with ADP, collagen, TRAP, arachidonic acid and epinephrine was impaired in light transmission aggregometry; agglutination with ristocetin persisted. In the flow chamber with a shear rate of 400 s-1 platelet adhesion to collagen and clot growth were impaired. Conclusion The revealed disorders of phenotype, cytoskeleton and intracellular signaling explain the nature of SLFN14 platelet dysfunction and the patient’s severe hemorrhagic syndrome.
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- 2023
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7. A Single Dose of PEG-Asparaginase at the Beginning of Induction Not Only Accelerates MRD Clearance but Also Improves Long-Term Outcome in Children with B-Lineage ALL
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Alexander Popov, Günter Henze, Julia Roumiantseva, Oleh Bydanov, Mikhail Belevtsev, Tatiana Verzhbitskaya, Liudmila Movchan, Grigory Tsaur, Svetlana Lagoyko, Liudmila Zharikova, Natalia Myakova, Dmitry Litvinov, Olga Khlebnikova, Olga Streneva, Elena Stolyarova, Natalia Ponomareva, Galina Novichkova, Larisa Fechina, Olga Aleinikova, and Alexander Karachunskiy
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acute lymphoblastic leukemia ,PEG-asparaginase ,minimal residual disease ,flow cytometry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
This report presents the results of the assessment of MRD response by multicolor flow cytometry (MFC) with regard to the randomized use of pegylated asparaginase (PEG). In this study, PEG was randomly administered at a dose of 1000 U/m2 on day 3 of induction therapy in children with B-lineage ALL. Methods. Conventional induction therapy consisted of dexamethasone, vincristine, and daunorubicin. MRD data was available in 502 patients who were randomized at the start of induction therapy, standard-risk (SR) patients into three (conventional induction without PEG, induction with additional PEG and with PEG but without daunorubicin) and intermediate-risk (ImR) patients into two groups (with additional PEG and without PEG). Results. The single administration of PEG resulted in a significantly higher proportion of rapid responders, in SR patients even when no anthracyclines were used for induction. In the SR group, the event-free survival of the MFC-MRD fast responders was similar in the PEG− and PEG+ arms (92.0 ± 3.1% vs. 96.2 ± 1.5%, respectively), and the same unfavorable trend was observed for MFC-MRD slow responders (57.5 ± 12.3% vs. 66.7 ± 15.7%, respectively). Results were similar in ImR patients: (94.3 ± 3.2% vs. 95.1 ± 2.4%, for fast responders and 63.3 ± 7.6% vs. 78.1 ± 7.9%, for slow responders in PEG− and PEG+ arms, respectively). However, there is a large difference between the proportion of MFC-MRD slow responders in the PEG− and PEG+ groups (18.3% vs. 5.2% for the SR group and 44.2% vs. 25.0% for the ImR group). Conclusions. Therefore, early use of PEG-ASP not only leads to an accelerated reduction of blasts, but also to an excellent outcome in a significantly larger proportion of patients in both risk groups.
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- 2023
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8. Unusual Presentation of SET::NUP214-Associated Concomitant Hematological Neoplasm in a Child—Diagnostic and Treatment Struggle
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Yaroslav Menchits, Tatiana Salimova, Alexander Komkov, Dmitry Abramov, Tatiana Konyukhova, Ruslan Abasov, Elena Raykina, Albert Itov, Marina Gaskova, Aleksandra Borkovskaia, Anna Kazakova, Olga Soldatkina, Svetlana Kashpor, Alexandra Semchenkova, Alexander Popov, Galina Novichkova, Yulia Olshanskaya, Alexey Maschan, and Elena Zerkalenkova
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pediatric leukemia and lymphoma ,NUP214 ,fusion genes ,HSCT ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Simultaneous multilineage hematologic malignancies are uncommon and associated with poorer prognosis than single-lineage leukemia or lymphoma. Here, we describe a concomitant malignant neoplasm in a 4-year-old boy. The child presented with massive lymphoproliferative syndrome, nasal breathing difficulties, and snoring. Morphological, immunocytochemical, and flow cytometry diagnostics showed coexistence of acute myeloid leukemia (AML) and peripheral T-cell lymphoma (PTCL). Molecular examination revealed a rare t(9;9)(q34;q34)/SET::NUP214 translocation as well as common TCR clonal rearrangements in both the bone marrow and lymph nodes. The disease showed primary refractoriness to both lymphoid and myeloid high-dose chemotherapy as well as combined targeted therapy (trametinib + ruxolitinib). Hence, HSCT was performed, and the patient has since been in complete remission for over a year. This observation highlights the importance of molecular techniques for determining the united nature of complex SET::NUP214-positive malignant neoplasms arising from precursor cells with high lineage plasticity.
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- 2023
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9. Case report: First case of undifferentiated embryonal sarcoma of the liver in a child with neurofibromatosis type 1, treated by hepatic chemoperfusion with transcatheter arterial chemoembolization
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Ksenia Sinichenkova, Ludmila Yasko, Dmitry Akhaladze, Anton Petrushin, Dmitry Konovalov, Ruslan Abasov, Yulia Mareeva, Olga Melekhina, Natalia Usman, Alexander Karachunsky, Galina Novichkova, Dmitry Litvinov, and Alexander Druy
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undifferentiated embryonal sarcoma of the liver ,malignant peripheral nerve sheath tumor ,transarterial chemoembolization ,chemoperfusion ,neurofibromatosis type 1 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
IntroductionIn this report we firstly describe undifferentiated embryonal sarcoma of the liver (UESL) in a patient with neurofibromatosis type 1 (NF1), fatally complicated by synchronous malignant peripheral nerve sheath tumor (MPNST) with a highly aggressive metastatic course. The case also represents our first experience of chemoperfusion involving the transcatheter arterial chemoembolization (TACE) in a pediatric patient, applied as a treatment for UESL.Case presentationA 13-year-old girl was diagnosed with NF1 and presented with a liver tumor identified as UESL by histological assessment. The tumor was refractive to the conventional first-line chemotherapy. The patient received hepatic chemoperfusion with TACE, which was efficacious; however, the overall curative outcome was unsatisfactory due to synchronous unresectable retroperitoneal MPNST with mesenteric metastases and ultimate progression of the UESL.ConclusionThis is the first reported case of UESL in a patient with NF1. The results demonstrate the efficacy of hepatic chemoperfusion with TACE in pediatric UESL.
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- 2022
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10. Methodological Challenges of Digital PCR Detection of the Histone H3 K27M Somatic Variant in Cerebrospinal Fluid
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Margarita Zaytseva, Natalia Usman, Ekaterina Salnikova, Agunda Sanakoeva, Andge Valiakhmetova, Almira Chervova, Ludmila Papusha, Galina Novichkova, and Alexander Druy
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cerebrospinal fluid ,liquid biopsy ,dPCR ,cell-free DNA ,CNS tumor ,diffuse midline glioma ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Pathology ,RB1-214 - Abstract
Cell-free DNA (cfDNA) in body fluids is invaluable for cancer diagnostics. Despite the impressive potential of liquid biopsies for the diagnostics of central nervous system (CNS) tumors, a number of challenges prevent introducing this approach into routine laboratory practice. In this study, we adopt a protocol for sensitive detection of the H3 K27M somatic variant in cerebrospinal fluid (CSF) by using digital polymerase chain reaction (dPCR). Optimization of the protocol was carried out stepwise, including preamplification of the H3 target region and adjustment of dPCR conditions. The optimized protocol allowed detection of the mutant allele starting from DNA quantities as low as 9 picograms. Analytical specificity was tested using a representative group of tumor tissue samples with known H3 K27M status, and no false-positive cases were detected. The protocol was applied to a series of CSF samples collected from patients with CNS tumors (n = 18) using two alternative dPCR platforms, QX200 Droplet Digital PCR system (Bio-Rad) and QIAcuity Digital PCR System (Qiagen). In three out of four CSF specimens collected from patients with H3 K27M-positive diffuse midline glioma, both platforms allowed detection of the mutant allele. The use of ventricular access for CSF collection appears preferential, as lumbar CSF samples may produce ambiguous results. All CSF samples collected from patients with H3 wild-type tumors were qualified as H3 K27M-negative. High agreement of the quantitative data obtained with the two platforms demonstrates universality of the approach.
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- 2022
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11. Molecular Heterogeneity of Pediatric AML with Atypical Promyelocytes Accumulation in Children—A Single Center Experience
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Aleksandra Borkovskaia, Sofia Bogacheva, Tatiana Konyukhova, Elina Dadakhanova, Marina Gaskova, Olga Soldatkina, Maria Dubrovina, Alexander Popov, Ekaterina Mikhailova, Evgenia Inushkina, Marat Kazanov, Evgeniy Matveev, Galina Novichkova, Michael Maschan, Alexey Maschan, Yulia Olshanskaya, and Elena Zerkalenkova
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AML ,atypical promyelocytes ,fusion genes ,RAR gene family ,KMT2A ,Genetics ,QH426-470 - Abstract
Acute promyelocytic leukemia (APL) pathogenesis is based on RARA gene translocations, which are of high importance in the diagnosis of and proper therapy selection for APL. However, in some cases acute myeloid leukemia (AML) demonstrates APL-like morphological features such as atypical promyelocytes accumulation. This type of AML is characterized by the involvement of other RAR family members or completely different genes. In the present study, we used conventional karyotyping, FISH and high-throughput sequencing in a group of 271 de novo AML with atypical promyelocytes accumulation. Of those, 255 cases were shown to carry a typical chromosomal translocation t(15;17)(q24;q21) with PML::RARA chimeric gene formation (94.1%). Other RARA-positive cases exhibited cryptic PML::RARA fusion without t(15;17)(q24;q21) (1.8%, n = 5) and variant t(5;17)(q35;q21) translocation with NPM1::RARA chimeric gene formation (1.5%, n = 4). However, 7 RARA-negative AMLs with atypical promyelocytes accumulation were also discovered. These cases exhibited TBL1XR1::RARB and KMT2A::SEPT6 fusions as well as mutations, e.g., NPM1 insertion and non-recurrent chromosomal aberrations. Our findings demonstrate the genetic diversity of AML with APL-like morphological features, which is of high importance for successful therapy implementation.
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- 2023
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12. Recognizing Minor Leukemic Populations with Monocytic Features in Mixed-Phenotype Acute Leukemia by Flow Cell Sorting Followed by Cytogenetic and Molecular Studies: Report of Five Exemplary Cases
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Alexandra Semchenkova, Elena Zerkalenkova, Irina Demina, Svetlana Kashpor, Egor Volchkov, Elena Zakharova, Sergey Larin, Yulia Olshanskaya, Galina Novichkova, Alexey Maschan, Michael Maschan, and Alexander Popov
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flow cell sorting ,mixed-phenotype acute leukemia ,fluorescence in situ hybridization ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Mixed-phenotype acute leukemia (MPAL), a rare and heterogeneous category of acute leukemia, is characterized by cross-lineage antigen expression. Leukemic blasts in MPAL can be represented either by one population with multiple markers of different lineages or by several single-lineage populations. In some cases, a major blast population may coexist with a smaller population that has minor immunophenotypic abnormalities and may be missed even by an experienced pathologist. To avoid misdiagnosis, we suggest sorting doubtful populations and leukemic blasts and searching for similar genetic aberrations. Using this approach, we examined questionable monocytic populations in five patients with dominant leukemic populations of B-lymphoblastic origin. Cell populations were isolated either for fluorescence in situ hybridization or for clonality assessment by multiplex PCR or next-generation sequencing. In all cases, monocytic cells shared the same gene rearrangements with dominant leukemic populations, unequivocally confirming the same leukemic origin. This approach is able to identify implicit cases of MPAL and therefore leads to the necessary clinical management for patients.
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- 2023
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13. Immunophenotypic changes in leukemic blasts in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia after treatment with CD19-directed chimeric antigen receptor (CAR)- expressing T cells
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Ekaterina Mikhailova, Olga Illarionova, Larisa Shelikhova, Elena Zerkalenkova, Olga Molostova, Yulia Olshanskaya, Galina Novichkova, Alexey Maschan, Michael Maschan, and Alexander Popov
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2021
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14. Reliable Flow-Cytometric Approach for Minimal Residual Disease Monitoring in Patients with B-Cell Precursor Acute Lymphoblastic Leukemia after CD19-Targeted Therapy
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Ekaterina Mikhailova, Olga Illarionova, Alexander Komkov, Elena Zerkalenkova, Ilgar Mamedov, Larisa Shelikhova, Yulia Olshanskaya, Natalia Miakova, Galina Novichkova, Alexander Karachunskiy, Michael Maschan, and Alexander Popov
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minimal residual disease ,flow cytometry ,blinatumomab ,CAR-T cells ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
We aimed to develop an antibody panel and data analysis algorithm for multicolor flow cytometry (MFC), which is a reliable method for minimal residual disease (MRD) detection in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) treated with CD19-directed therapy. The development of the approach, which was adapted for the case of possible CD19 loss, was based on the additional B-lineage marker expression data obtained from a study of primary BCP-ALL patients, an analysis of the immunophenotypic changes that occur during blinatumomab or CAR-T therapy, and an analysis of very early CD19-negative normal BCPs. We have developed a single-tube 11-color panel for MFC-MRD detection. CD22- and iCD79a-based primary B-lineage gating (preferably consecutive) was recommended. Based on patterns of antigen expression changes and the relative expansion of normal CD19-negative BCPs, guidelines for MFC data analysis and interpretation were established. The suggested approach was tested in comparison with the molecular techniques: IG/TR gene rearrangement detection by next-generation sequencing (NGS) and RQ-PCR for fusion-gene transcripts (FGTs). Qualitative concordance rates of 82.8% and 89.8% were obtained for NGS-MRD and FGT-MRD results, respectively. We have developed a sensitive and reliable approach that allows MFC-MRD monitoring after CD19-directed treatment, even in the case of possible CD19 loss.
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- 2022
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15. Hematopoietic stem cell transplantation in a patient with type 1 mosaic variegated aneuploidy syndrome
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Alexandra Laberko, Dmitry Balashov, Elena Deripapa, Olga Soldatkina, Elena Raikina, Alexei Maschan, Galina Novichkova, and Anna Shcherbina
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Mosaic variegated aneuploidy syndrome ,BUB1B gene. ,Hematopoietic stem cell transplantation. ,TCRαβ+/CD19+ graft depletion. ,Medicine - Abstract
Abstract Background Mosaic variegated aneuploidy (MVA) syndrome is a chromosomal instability disorder that leads to aneuploidies of different chromosomes in various tissues. Type 1 MVA (MVA1) is caused by mutations in the budding uninhibited by benzimidazoles 1 homolog beta (BUB1B) gene. The main clinical features of MVA1 syndrome are growth and mental retardation, central nervous system anomalies, microcephaly, and predisposition to cancers. There have been no reports of hematopoietic stem cell transplantation (HSCT) in MVA patients. Results We report an 11-year old boy diagnosed with MVA1 syndrome. The BUB1B gene mutations c.498_505delAAACTTTA and c.1288 + 5G > A were detected using the next generation sequencing (NGS) method. The patient presented with cytopenia soon after birth, but remained stable until 9 years of age, when he developed myelodysplastic syndrome associated with monosomy of chromosome 7. Due to severe dependence on blood transfusions, a TCRαβ+/CD19+ depleted HSCT was performed from a matched unrelated donor (MUD) using a treosulfan-based reduced intensity conditioning (RIC) regimen. The engraftment occurred, and no severe toxicity was observed soon after the HSCT, but on day + 47, graft rejection was detected. It was followed by prolonged pancytopenia and sepsis with multi-organ Enterococcus faecium infection, which led to the patient’s death on day + 156 after HSCT. Conclusions In conclusion, we demonstrate that RIC HSCT with TCRαβ+/CD19+ depletion was well tolerated and resulted in complete hematologic recovery in our MVA1 patient, but, unfortunately, it was followed by rapid graft rejection. This fact needs to be taken into consideration for HSCT in other MVA patients.
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- 2019
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16. Lineage Conversion in Pediatric B-Cell Precursor Acute Leukemia under Blinatumomab Therapy
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Alexandra Semchenkova, Ekaterina Mikhailova, Alexander Komkov, Marina Gaskova, Ruslan Abasov, Evgenii Matveev, Marat Kazanov, Ilgar Mamedov, Anna Shmitko, Vera Belova, Anna Miroshnichenkova, Olga Illarionova, Yulia Olshanskaya, Grigory Tsaur, Tatiana Verzhbitskaya, Natalia Ponomareva, Gleb Bronin, Konstantin Kondratchik, Larisa Fechina, Yulia Diakonova, Liudmila Vavilova, Natalia Myakova, Galina Novichkova, Alexey Maschan, Michael Maschan, Elena Zerkalenkova, and Alexander Popov
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acute lymphoblastic leukemia ,lineage switch ,blinatumomab ,minimal residual disease ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
We report incidence and deep molecular characteristics of lineage switch in 182 pediatric patients affected by B-cell precursor acute lymphoblastic leukemia (BCP-ALL), who were treated with blinatumomab. We documented six cases of lineage switch that occurred after or during blinatumomab exposure. Therefore, lineage conversion was found in 17.4% of all resistance cases (4/27) and 3.2% of relapses (2/63). Half of patients switched completely from BCP-ALL to CD19-negative acute myeloid leukemia, others retained CD19-positive B-blasts and acquired an additional CD19-negative blast population: myeloid or unclassifiable. Five patients had KMT2A gene rearrangements; one had TCF3::ZNF384 translocation. The presented cases showed consistency of gene rearrangements and fusion transcripts across initially diagnosed leukemia and lineage switch. In two of six patients, the clonal architecture assessed by IG/TR gene rearrangements was stable, while in others, loss of clones or gain of new clones was noted. KMT2A-r patients demonstrated very few additional mutations, while in the TCF3::ZNF384 case, lineage switch was accompanied by a large set of additional mutations. The immunophenotype of an existing leukemia sometimes changes via different mechanisms and with different additional molecular changes. Careful investigation of all BM compartments together with all molecular –minimal residual disease studies can lead to reliable identification of lineage switch.
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- 2022
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17. Immunophenotypic changes of leukemic blasts in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia who have been treated with blinatumomab
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Ekaterina Mikhailova, Evgeny Gluhanyuk, Olga Illarionova, Elena Zerkalenkova, Svetlana Kashpor, Natalia Miakova, Yulia Diakonova, Yulia Olshanskaya, Larisa Shelikhova, Galina Novichkova, Michael Maschan, Alexey Maschan, and Alexander Popov
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2020
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18. Complex Multisystem Phenotype With Immunodeficiency Associated With NBAS Mutations: Reports of Three Patients and Review of the Literature
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Anna Khoreva, Ekaterina Pomerantseva, Natalia Belova, Inna Povolotskaya, Fedor Konovalov, Vladimir Kaimonov, Alena Gavrina, Sergey Zimin, Dmitrii Pershin, Nataliia Davydova, Vasilii Burlakov, Ekaterina Viktorova, Anna Roppelt, Ekaterina Kalinina, Galina Novichkova, and Anna Shcherbina
- Subjects
SOPH syndrome ,primary immunodeficiency ,osteogenesis imperfecta ,liver failure ,optic atrophy ,Pediatrics ,RJ1-570 - Abstract
Objectives: Mutations in the neuroblastoma-amplified sequence (NBAS) gene were originally described in patients with skeletal dysplasia or isolated liver disease of variable severity. Subsequent publications reported a more complex phenotype. Among multisystemic clinical symptoms, we were particularly interested in the immunological consequences of the NBAS deficiency.Methods: Clinical and laboratory data of 3 patients ages 13, 6, and 5 in whom bi-allelic NBAS mutations had been detected via next-generation sequencing were characterized. Literature review of 23 publications describing 74 patients was performed.Results: We report three Russian patients with compound heterozygous mutations of the NBAS gene who had combined immunodeficiency characterized by hypogammaglobulinemia, low T-cells, and near-absent B-cells, along with liver disease, skeletal dysplasia, optic-nerve atrophy, and dysmorphic features. Analysis of the data of 74 previously reported patients who carried various NBAS mutations demonstrated that although the most severe form of liver disease seems to require disruption of the N-terminal or middle part of NBAS, mutations of variable localizations in the gene have been associated with some form of liver disease, as well as immunological disorders.Conclusions:NBAS deficiency has a broad phenotype, and referral to an immunologist should be made in order to screen for immunodeficiency.
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- 2020
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19. Molecular Stratification of Childhood Ependymomas as a Basis for Personalized Diagnostics and Treatment
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Margarita Zaytseva, Ludmila Papusha, Galina Novichkova, and Alexander Druy
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ependymoma ,risk stratification ,molecular group ,prognosis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Ependymomas are among the most enigmatic tumors of the central nervous system, posing enormous challenges for pathologists and clinicians. Despite the efforts made, the treatment options are still limited to surgical resection and radiation therapy, while none of conventional chemotherapies is beneficial. While being histologically similar, ependymomas show considerable clinical and molecular diversity. Their histopathological evaluation alone is not sufficient for reliable diagnostics, prognosis, and choice of treatment strategy. The importance of integrated diagnosis for ependymomas is underscored in the recommendations of Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy. These updated recommendations were adopted and implemented by WHO experts. This minireview highlights recent advances in comprehensive molecular-genetic characterization of ependymomas. Strong emphasis is made on the use of molecular approaches for verification and specification of histological diagnoses, as well as identification of prognostic markers for ependymomas in children.
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- 2021
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20. BTK, NUTM2A, and PRPF19 Are Novel KMT2A Partner Genes in Childhood Acute Leukemia
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Elena Zerkalenkova, Svetlana Lebedeva, Aleksandra Borkovskaia, Olga Soldatkina, Olga Plekhanova, Grigory Tsaur, Michael Maschan, Aleksey Maschan, Galina Novichkova, and Yulia Olshanskaya
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pediatric acute leukemia ,fusion genes ,KMT2A ,cytogenetics ,NGS ,Biology (General) ,QH301-705.5 - Abstract
Chromosomal rearrangements of the human KMT2A/MLL gene are associated with acute leukemias, especially in infants. KMT2A is rearranged with a big variety of partner genes and in multiple breakpoint locations. Detection of all types of KMT2A rearrangements is an essential part of acute leukemia initial diagnostics and follow-up, as it has a strong impact on the patients’ outcome. Due to their high heterogeneity, KMT2A rearrangements are most effectively uncovered by next-generation sequencing (NGS), which, however, requires a thorough prescreening by cytogenetics. Here, we aimed to characterize uncommon KMT2A rearrangements in childhood acute leukemia by conventional karyotyping, FISH, and targeted NGS on both DNA and RNA level with subsequent validation. As a result of this comprehensive approach, three novel KMT2A rearrangements were discovered: ins(X;11)(q26;q13q25)/KMT2A-BTK, t(10;11)(q22;q23.3)/KMT2A-NUTM2A, and inv(11)(q12.2q23.3)/KMT2A-PRPF19. These novel KMT2A-chimeric genes expand our knowledge of the mechanisms of KMT2A-associated leukemogenesis and allow tracing the dynamics of minimal residual disease in the given patients.
- Published
- 2021
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21. Efficacy of combined immunosuppression with or without eltrombopag in children with newly diagnosed aplastic anemia
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Olga Goronkova, Galina Novichkova, Tatiana Salimova, Irina Kalinina, Dina Baidildina, Ulyana Petrova, Kristina Antonova, Maria Sadovskaya, Elena Suntsova, Dmitry Evseev, Victor Matveev, Dmitry Venyov, Lili Khachatryan, Dmitry Litvinov, Alexey Pshonkin, Galina Ovsyannikova, Natalia Kotskaya, Darina Gobadze, Yulia Olshanskaya, Alexander Popov, Elena Raykina, Olga Mironenko, Kirill Voronin, Bazarma Purbueva, Elmira Boichenko, Yulia Dinikina, Evgeniya Guseynova, Dmitry Sherstnev, Elena Kalinina, Sergey Mezentsev, Olga Streneva, Natalia Yudina, Olga Plaksina, Elena Erega, Michael Maschan, and Alexey Maschan
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Hematology - Abstract
We compared the efficacy and safety of eltrombopag (ELTR) combined with immunosuppressive therapy (IST) and IST alone in treatment-naïve children with severe (SAA) and very severe (vSAA) aplastic anemia. Ninety-eight pediatric patients were randomized to receive horse antithymocyte globulin (hATG) and cyclosporin A (CsA) with (n = 49) or without (n = 49) ELTR. The primary endpoint was the overall response rate (ORR) at 4 months. After 4 months, nonresponders were crossed over to the alternative group. In all patients, the ORR in ELTR + IST and IST groups was similar (65% vs 53%; P = .218); however, the complete response (CR) rate was significantly higher in the ELTR + IST group (31% vs 12%; P = .027). In severity subgroups, the ORR was 89% vs 57% (P = .028) in favor of IST + ELTR in SAA, but it did not differ in patients with vSAA (52% vs 50%; P = .902). At 6 months after the crossover, 61% of initial ELTR(−) patients achieved a response compared with 17% of initial ELTR(+) patients (P = .016). No significant difference in ELTR + IST and IST groups was observed in the 3-year overall survival (OS) (89% vs 91%; P = .673) or the 3-year event-free survival (EFS) (53% vs 41%; P = .326). There was no unexpected toxicity related to ELTR. Adding ELTR to standard IST was well tolerated and increased the CR rate. The greatest benefit from ELTR combined with IST was observed in patients with SAA but not in those with vSAA. The second course of IST resulted in a high ORR in initial ELTR(−) patients who added ELTR and had limited efficacy among patients who received ELTR upfront. This trial was registered at Clinicaltrials.gov as #NCT03413306.
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- 2023
22. Correlation of the surface expression of thymic stromal lymphopoietin receptor with the presence of <scp> CRLF2 </scp> gene rearrangements in children with B‐lineage acute lymphoblastic leukemia
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Irina Demina, Elena Zerkalenkova, Olga Soldatkina, Anna Kazakova, Alexandra Semchenkova, Maria Goncharova, Galina Novichkova, Michael Maschan, Alexander Karachunskiy, Yulia Olshanskaya, and Alexander Popov
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Biochemistry (medical) ,Clinical Biochemistry ,Hematology ,General Medicine - Published
- 2023
23. Vemurafenib combined with cladribine and cytarabine results in durable remission of pediatric BRAF V600E-positive LCH
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Dmitry Evseev, Daria Osipova, Irina Kalinina, Elena Raykina, Anna Ignatova, Evelina Lyudovskikh, Dina Baidildina, Alexander Popov, Vladimir Zhogov, Alexandra Semchenkova, Eugeny Alexandrovich Litvin, Natalia Kotskaya, Ekaterina Cherniak, Kirill Voronin, Eugeny Burtsev, Gleb Bronin, Irina Vlasova, Bazarma Purbueva, Olesya Fink, Ekaterina Pristanskova, Irina Dzhukaeva, Elena Erega, Galina Novichkova, Alexey Maschan, and Mikhail Maschan
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Hematology - Abstract
Langerhans cell histiocytosis (LCH) is a disorder with a variety of clinical signs. The most severe forms affect "risk organs" (RO). The established role of BRAF V600E mutation in LCH led to a targeted approach. However, the targeted therapy can't cure the disease and the cessation leads to quick relapses. In our study, we combined cytarabine (Ara-C) and 2'-chlorodeoxyadenosine (2-CdA) with targeted therapy to achieve stable remission. Nineteen children were enrolled in the study: 13 RO+ and 6 RO-. Five patients received the therapy upfront, while the other 14 - as the second or third line. The protocol starts with 28 days of vemurafenib (20 mg/kg) which is followed by 3 courses of Ara-C and 2-CdA (100 mg/m2/every 12 h, 6 mg/m2/day, Days 1-5) with concomitant vemurafenib therapy. After that, vemurafenib therapy was stopped, and 3 courses of mono 2-CdA followed. All patients rapidly responded to vemurafenib: the median DAS decreased from 13 to 2 points in the RO+ group and from 4.5 to 0 points in the RO- group on Day 28. All patients except one received complete protocol treatment, and 15 of them didn't have disease progression. The 2-year relapse-free survival (RFS) for RO+ was 76.9% with a median follow-up of 21 months and 83.3% with a median follow-up of 29 months for RO-. Overall survival is 100%. Importantly, 1 patient experienced secondary MDS (sMDS) after 14 months from vemurafenib cessation. Our study demonstrates that combined vemurafenib plus 2-CdA and Ara-C is effective in a cohort of children with LCH, and the toxicity is manageable. This trial is registered at www.clinicaltrials.gov as NCT03585686.
- Published
- 2023
24. BENCHMARKING AS AN IMPORTANT METHOD FOR THE DEVELOPMENT OF THE HEALTH CARE SYSTEM ON THE «CHILDREN’S ONCOLOGY AND HEMATOLOGY» PROFILE MODEL
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Aleinikova Olga, Elena Zavaleva, Galina Novichkova, and Aleksei Slinin
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Pediatrics, Perinatology and Child Health - Abstract
The national medical research centers (NMRCs) play an important role in managing the quality of healthcare system and evaluating its resources within the supervised profiles in Russia. The lack of controlling resources within NMRCs limit the possibility for improving the efficiency of healthcare in supervised profiles. The electronic benchmarking system could’ve become such a tool for the controlling over medical organizations (MO). It would allow evaluating the activities of MO (for example, comparing the activities of the analyzed MO with the reference MO, or dynamics of changes in MO - historical benchmarking), finding and implementing the most effective methods for organization of work of MO and improving the quality of medical care provided to patients. The authors of the article describe the experience of development and implementation of benchmarking system in MO of the “Children's Oncology and Hematology” profile. Based on the initial results of the analysis, the following issues were identified: 1) absence of nutritive support algorithms (in 90 % of MO analyzed); 2) absence of children patient register for oncology and hematology (61 % of MO analyzed); 3) inability to organize radiation therapy service (55 % of MO analyzed); 4) deficit of surgeon operators in the field of “pediatric oncology” (42 % of MO analyzed); 5) absence of capacity for isolation of immunocompromised patients within intensive care units (39 % of MO analyzed). Thus, after analyzing with the use of electronic benchmarking tools, the primary problematics can be shown therefore the key problems requiring corrective measures by the MO management can be distinguished. The further dynamic assessment also allows evaluating of the effectiveness of the ‘work on bugs’ done.
- Published
- 2022
25. A simple procedure to identify children with B‐lineage acute lymphoblastic leukemia who can be successfully treated with low or moderate intensity: Sequential versus single‐point minimal residual disease measurement
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Alexander Popov, Guenter Henze, Julia Roumiantseva, Oleg Budanov, Mikhail Belevtsev, Tatiana Verzhbitskaya, Elena Boyakova, Liudmila Movchan, Grigory Tsaur, Maria Fadeeva, Svetlana Lagoyko, Liudmila Zharikova, Natalia Miakova, Dmitry Litvinov, Olga Khlebnikova, Olga Streneva, Elena Stolyarova, Natalia Ponomareva, Galina Novichkova, Larisa Fechina, Olga Aleinikova, and Alexander Karachunskiy
- Subjects
Oncology ,Pediatrics, Perinatology and Child Health ,Hematology - Published
- 2023
26. Flow cell sorting followed by <scp>PCR</scp> ‐based clonality testing may assist in questionable diagnosis and monitoring of acute lymphoblastic leukemia
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Alexandra Semchenkova, Vladimir Zhogov, Elena Zakharova, Ekaterina Mikhailova, Olga Illarionova, Sergey Larin, Galina Novichkova, Alexander Karachunskiy, Michael Maschan, and Alexander Popov
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Biochemistry (medical) ,Clinical Biochemistry ,Hematology ,General Medicine - Published
- 2023
27. Genetic characteristics and treatment outcome in infants with KMT2A germline B‐cell precursor acute lymphoblastic leukemia: Results of MLL‐Baby protocol
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Alexander Popov, Grigory Tsaur, Zhan Permikin, Guenter Henze, Tatiana Verzhbitskaya, Olga Plekhanova, Ekaterina Nokhrina, Alena Valochnik, Petr Sibiryakov, Elena Zerkalenkova, Yulia Olshanskaya, Tatiana Gindina, Liudmila Movchan, Egor Shorikov, Olga Streneva, Olga Khlebnikova, Olga Makarova, Oleg Arakaev, Elmira Boichenko, Konstantin Kondratchik, Natalia Ponomareva, Elena Lapotentova, Olga Aleinikova, Natalia Miakova, Galina Novichkova, Alexander Karachunskiy, and Larisa Fechina
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Oncology ,Pediatrics, Perinatology and Child Health ,Hematology - Published
- 2023
28. Supratentorial tumor resembling anaplastic ependymoma in an adolescent
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Margarita Zaytseva, Ludmila Papusha, Agnesa Panferova, Andge Valiakhmetova, Anastasia Shekhtman, Sergey Obydennyi, Igor Kireev, Galina Novichkova, and Alexander Druy
- Subjects
General Neuroscience ,Neurology (clinical) ,Pathology and Forensic Medicine - Published
- 2023
29. Acute myeloid leukemia with t(X;6)9p11;q23);MYB-GATA1 and female sex: GATA1 insufficiency may be insufficient for pathogenesis
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Alexandra E. Kovach, Elena Zerkalenkova, Ludmila Zemtsova, Aleksandra Borkovskaya, Marina Gaskova, Marat Kazanov, Alexander Popov, Liudmila Baidun, Michael Maschan, Alexey Maschan, Paul S. Gaynon, Deepa Bhojwani, Galina Novichkova, Yulia Olshanskaya, and Gordana Raca
- Subjects
Chromosomes, Human, X ,Cancer Research ,Oncogene Proteins, Fusion ,Sequence Analysis, RNA ,Infant ,Translocation, Genetic ,Leukemia, Myeloid, Acute ,Proto-Oncogene Proteins c-myb ,Genetics ,Humans ,Chromosomes, Human, Pair 6 ,Female ,GATA1 Transcription Factor ,Chromosomes, Human, Pair 9 ,Molecular Biology - Abstract
Pediatric acute myeloid leukemia (AML) is genetically heterogenous (Olsson et al., 2016). t(X;6)(p11;q23) is a rare but recurrent chromosomal translocation in infant AML thought to be associated with male sex and basophilic differentiation (Dastugue et al., 1997). Here we report molecular characterization of AML with t(X;6)(p11;q23);MYB-GATA1 in two female infants and demonstrate preserved GATA1 expression in the sample tested. These findings further debunk a concept that this fusion was restricted to males, in whom it disrupts the only copy of the X-linked GATA1 gene, causing presumable complete loss of GATA1 function. Our data also demonstrate the power and efficiency of RNA sequencing for subclassification of leukemia on a clinically relevant timeline.
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- 2022
30. Thrombopoietin receptor agonists for the treatment of severe persistent and chronic immune trombocytopenia in children: clinical data of Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, Immunology
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Z. A. Kuzminova, M. N. Korsantya, U. N. Petrova, D. V. Fedorova, M. N. Sadovskaya, A. V. Pshonkin, N. M. Trubina, N. N. Kotskaya, O. N. Mironenko, T.Yu. Salimova, Elena V. Suntsova, Alexey Maschan, I.I. Kalinina, G. S. Ovsyannikova, D.D. Baydildina, and Galina Novichkova
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Romiplostim ,Thrombocytosis ,business.industry ,medicine.medical_treatment ,Immunology ,Splenectomy ,Pediatric Hematology/Oncology ,Eltrombopag ,Retrospective cohort study ,Hematology ,medicine.disease ,Discontinuation ,chemistry.chemical_compound ,Oncology ,chemistry ,Pediatrics, Perinatology and Child Health ,Immunology and Allergy ,Medicine ,business ,Adverse effect ,medicine.drug - Abstract
Thrombopoietin receptor agonists (TPO-RA) – romiplostim and eltrombopag – changed considerably the therapeutic options for severe persistent and chronic immune thrombocytopenia (ITP). The article presents the results of a retrospective study of TPO-RA efficacy and safety in patients under 18 years of age. The study was approved by the Independent Ethics Committee and Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. Sixty-eight children had a total of 89 courses of TPO-RA (44 romiplostim and 45 eltrombopag). Their median age was 6.5 years. The median ITP duration was 15.8 months. All patients received previous ITP therapy (1–6 lines). Before the initiation of TPO-RA, the majority of patients had thrombocytopenia with bleeding. In most cases, the platelet response was achieved within the first 2 months of treatment. The average effective doses of romiplostim and eltrombopag were 10 mg/kg per week and 75 mg per day, respectively. Half of patients in romiplostim group and 62% of patients in eltrombopag group did not require extra therapy. The majority of patients (75.6–81.8%) achieved an overall response, but only near 50% achieved a durable (more than 24 weeks) platelet response. Six patients sustained the response after TPO-RA discontinuation. The most common adverse events (AE) of TPO-RA therapy were transient elevation in hepatic enzymes in eltrombopag group (28.9%) and thrombocytosis (18.2–22.2%) in both groups. In 6 cases the therapy was discontinued due to AEs. Two AEs were serious. Our results demonstrate that TPO-RA could safely increase platelet counts and decrease the risk of spontaneous life-threatening bleeding in nearly half of children with severe persistent and chronic ITP. TPO-RA could help to avoid long-term immunosuppressive therapy and splenectomy or delay them and the ITP remission is possible in some cases.
- Published
- 2021
31. Flow cytometric MRD at the end of consolidation in childhood B-lineage acute lymphoblastic leukemia has significant prognostic value but limited clinical implications: Results of study ALL-MB 2008
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Alexander Popov, Guenter Henze, Julia Roumiantseva, Oleg Budanov, Tatiana Verzhbitskaya, Elena Boyakova, Grigory Tsaur, Maria Fadeeva, Svetlana Lagoyko, Liudmila Zharikova, Natalia Miakova, Dmitry Litvinov, Olga Khlebnikova, Olga Streneva, Natalia Ponomareva, Galina Novichkova, Larisa Fechina, and Alexander Karachunskiy
- Subjects
Cancer Research ,Oncology ,Hematology - Published
- 2022
32. Vemurafenib provides a rapid and robust clinical response in pediatric Langerhans cell histiocytosis with the BRAF V600E mutation but does not eliminate low-level minimal residual disease per ddPCR using cell-free circulating DNA
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Zalina Abashidze, Anna Mitrofanova, Elena Raykina, Daria Osipova, Irina Kalinina, Michael Maschan, Anna Ignatova, Dmitry Evseev, Galina Novichkova, and Alexey Maschan
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Male ,Proto-Oncogene Proteins B-raf ,Oncology ,medicine.medical_specialty ,Neoplasm, Residual ,Antineoplastic Agents ,Disease ,Polymerase Chain Reaction ,Sepsis ,Langerhans cell histiocytosis ,Internal medicine ,medicine ,Humans ,Vemurafenib ,Protein Kinase Inhibitors ,Alleles ,Hematology ,business.industry ,Infant ,medicine.disease ,Minimal residual disease ,Histiocytosis, Langerhans-Cell ,Histiocytosis ,Treatment Outcome ,Amino Acid Substitution ,Child, Preschool ,Mutation ,Toxicity ,Female ,business ,medicine.drug - Abstract
Langerhans cell histiocytosis (LCH) is a disease that arises from myeloid cells that phenotypically resemble Langerhans cells (LC), which is typically driven by the BRAF V600E mutation. High-risk LCH has a poor prognosis. Fifteen children with BRAF V600E + LCH received vemurafenib between March 2016 and February 2020. The median age at LCH onset was 2 months and the median age at the start of vemurafenib treatment was 22 months. The median disease activity score (DAS) at the start of vemurafenib treatment was 12 points. The median duration of vemurafenib treatment was 29 months. All patients responded to treatment, with median DAS of 4 points at week 4 and 1 point at 6 months. Two patients died: 1 of hepatic failure after NSAID overdose and 1 of neutropenic sepsis. Cessation of vemurafenib resulted in relapse in 5 patients and was only possible for 1 patient. Serial measurements of BRAF V600E using cell-free circulating DNA revealed that 7 patients had persistently high mutant allele levels. Vemurafenib is effective in children with BRAF V600E + LCH. However, treatment with vemurafenib does not eradicate the disease and its long-term toxicity has not been established.
- Published
- 2021
33. Molecular heterogeneity of pediatric choroid plexus carcinomas determines the distinctions in clinical course and prognosis
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Margarita Zaytseva, Andge Valiakhmetova, Ludmila Yasko, Alexey Samarin, Ludmila Papusha, Anastasia Shekhtman, Natalia Usman, Kirill Voronin, Alexander Karachunskiy, Galina Novichkova, and Alexander Druy
- Subjects
Cancer Research ,Oncology ,Neurology (clinical) - Abstract
Background Choroid plexus carcinomas (CPCs) are rare aggressive pediatric tumors of the brain with no treatment standards. Genetic profiling of CPCs is often confined to possible association with Li–Fraumeni syndrome, though only about a half of CPCs develop from syndromic predispositions. Whole-chromosome gains and losses typical of CPCs reflect genomic instability of these tumors, but only partially explain the aggressive clinical course. Methods This retrospective study enrolled 25 pediatric patients with CPC, receiving treatment between January 2009 and June 2022. Molecular-genetic testing was performed for 20 cases with available tumor tissue and encompassed mutational status, chromosomal aberrations, and gene expression profiles. We analyzed several factors presumably influencing the outcomes, including molecular profiles and clinical parameters. The median follow-up constituted 5.2 years (absolute range 2.8–12.6 years). Results All studied CPCs had smooth mutational profiles with the only recurrent event being TP53 variants, either germline or somatic, encountered in 13 cases. Unbalanced whole-chromosome aberrations, notably multiple monosomies, were highly typical. In 7 tumors, chromosome losses were combined with complex genomic rearrangements: segmental gains and losses or signs of chromothripsis. This phenomenon was associated with extremely low 5-year survival: 20.0 ± 17.9% vs 85.7 ± 13.2%; P = .009. Transcriptomically, the cohort split into 2 polar clusters Ped_CPC1 and Ped_CPC2 differing by survival: 31.3 ± 17.8% vs 100%; P = .012. Conclusion CPCs split into at least 2 molecular subtypes distinguished both genomically and transcriptomically. Clusterization of the tumors into Ped_CPC1 and Ped_CPC2 significantly correlates with survival. The distinction may prove relevant in clinical trials for dedicated and patient-oriented optimization of clinical protocols for these rare tumors.
- Published
- 2022
34. One-point flow cytometric MRD measurement to identify children with excellent outcome after intermediate-risk BCP-ALL: results of the ALL-MB 2008 study
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Alexander Popov, Guenter Henze, Julia Roumiantseva, Oleg Budanov, Mikhail Belevtsev, Tatiana Verzhbitskaya, Elena Boyakova, Liudmila Movchan, Grigory Tsaur, Maria Fadeeva, Svetlana Lagoyko, Liudmila Zharikova, Natalia Miakova, Dmitry Litvinov, Olga Khlebnikova, Olga Streneva, Elena Stolyarova, Natalia Ponomareva, Galina Novichkova, Larisa Fechina, Olga Aleinikova, and Alexander Karachunskiy
- Subjects
Cancer Research ,Oncology ,General Medicine - Abstract
Measurement of minimal residual disease (MRD) with multicolor flow cytometry (MFC) has become an important tool in childhood acute lymphoblastic leukemia (ALL), mainly to identify rapid responders and reduce their therapy intensity. Protocols of the Moscow-Berlin (MB) group use a comparatively low (for standard risk; SR) or moderate (for intermediate risk; ImR) treatment intensity from the onset, based on initial patient characteristics. Recently, we reported that 90% of SR patients-50% B cell precursor (BCP-ALL)-MFC-MRD negative at end of induction (EOI)-had 95% event-free survival (EFS). METHODS: In the present study, we applied this method to children with initial ImR features. In study MB 2008, 1105 children-32% of BCP-ALL patients-were assigned to the ImR group. Of these, 227 were treated in clinics affiliated with MFC laboratories of the MB group network, and included in this MFC-MRD pilot study. A single-point MFC-MRD measurement at the EOI with the threshold of 0.01% identified 65% of patients-20% of all BCP-ALL patients-with EFS of 93.5%. Taking both studies together, the combination of clinical parameters and a one-point MRD measurement identifies 70% of BCP-ALL patients with an excellent outcome after low- or moderate-intensity therapy and avoids overtreatment of a significant proportion of patients.
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- 2022
35. A single flow cytometric MRD measurement in children with B-lineage acute lymphocytic leukemia and hyperleukocytosis redefines the requirements of high-risk treatment: Results of the study ALL-MB 2008
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Alexander Popov, Guenter Henze, Julia Roumiantseva, Oleg Budanov, Mikhail Belevtsev, Tatiana Verzhbitskaya, Elena Boyakova, Liudmila Movchan, Grigory Tsaur, Maria Fadeeva, Svetlana Lagoyko, Liudmila Zharikova, Natalia Miakova, Dmitry Litvinov, Olga Khlebnikova, Olga Streneva, Elena Stolyarova, Natalia Ponomareva, Galina Novichkova, Larisa Fechina, Olga Aleinikova, and Alexander Karachunskiy
- Subjects
Cancer Research ,Neoplasm, Residual ,Oncology ,Humans ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Child ,Flow Cytometry - Published
- 2022
36. Quantitative Bone Marrow MRI in Children with Acute Lymphoblastic Leukemia
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Dmitry A. Kupriyanov, Nataliia A. Kriventsova, Galina V. Tereshchenko, Peter E. Menshchikov, Dmitry Litvinov, and Galina Novichkova
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Pathology ,medicine.medical_specialty ,bone marrow ,General Immunology and Microbiology ,pediatrics ,business.industry ,hematology ,General Neuroscience ,Lymphoblastic Leukemia ,quantitative magnetic resonance imaging ,General Biochemistry, Genetics and Molecular Biology ,medicine.anatomical_structure ,fat fraction ,Medicine ,Bone marrow ,fat cells ,business - Abstract
The aim of this study was to evaluate, using MRI, the changes in bone marrow fat fraction (BMFF) of patients with acute lymphoblastic leukemia (ALL), in comparison with children without hematological disorders. Methods and Results: The cohort of the study subjects included 20 patients aged between 5 and 17 years (mean age of 11.2±3.6 years; 10 boys and 10 girls) with clinically and morphologically confirmed diagnosis of ALL All patients underwent MRI scanning in the acute phase of the disease before the start of specific therapy. Then, the study was repeated in 10 patients (mean age of 12.2±2.3 years; 8 boys and 2 girls) during treatment, according to the ALL-MB 2015 protocol for patients with primary ALL and according to the ALL-REZ-MB 2016 protocol for patients with relapsed ALL. The control group consisted of 24 healthy controls of the same age group (mean age of 12±2.8; 17 boys and 7 girls) with no prior hematologic diseases. MRI scanning was carried out using a Philips Achieva dStream 3T scanner with a 32-channel FlexCoverage abdominal receiving coil. The MRI protocol included images obtained with the mDIXON Quant technique in the coronal plane, completely covering the pelvic bones and lumbar spine. Fat fraction (FF) maps were generated automatically on the MRI console using the 7-peak fat model and were corrected for T2* effects. Regions of interest (ROI) measuring 150 mm2 were placed in the bodies of the left and right iliac bones (Ilium L, Ilium R) as well as in the L4 and L5 vertebral bodies, taking care to avoid blood vessels, cortical bones and areas that could potentially contain artifacts. In the group of healthy controls, BMFF value was 51%±11% in the bodies of the iliac bones and 32%±10% in the lumbar vertebrae. In the group of patients with the acute phase of the disease, BMFF was as low as 3.1%±2.6% in all the bone structures. In patients who had undergone chemotherapy, the mean BMFF increased up to 77%±7% in the iliac bones and up to 65%±13% in the vertebrae. Student's t-test for dependent samples revealed a statistically significant increase in the mean BMFF values in all the bone structures after chemotherapy (P
- Published
- 2021
37. Blinatumomab following haematopoietic stem cell transplantation – a novel approach for the treatment of acute lymphoblastic leukaemia in infants
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Alexander Popov, Grigory Tsaur, Yulia Abugova, Galina Novichkova, Natalia Miakova, Dmitry Balashov, Veronika Fominikh, Larisa Shelikhova, Alexey Maschan, Elena Zerkalenkova, Ekaterina Mikhailova, and Yulia Olshanskaya
- Subjects
Male ,Oncology ,medicine.medical_specialty ,Neoplasm, Residual ,medicine.medical_treatment ,Kaplan-Meier Estimate ,Disease-Free Survival ,03 medical and health sciences ,Antineoplastic Agents, Immunological ,0302 clinical medicine ,Refractory ,Recurrence ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,hemic and lymphatic diseases ,Internal medicine ,Antibodies, Bispecific ,medicine ,Humans ,Salvage Therapy ,business.industry ,Hematopoietic Stem Cell Transplantation ,Infant ,Histone-Lysine N-Methyltransferase ,Hematology ,Immunotherapy ,Minimal residual disease ,body regions ,Transplantation ,Haematopoiesis ,Child, Preschool ,030220 oncology & carcinogenesis ,Lymphoblastic leukaemia ,Female ,Blinatumomab ,Stem cell ,business ,Myeloid-Lymphoid Leukemia Protein ,030215 immunology ,medicine.drug - Abstract
Blinatumomab with subsequent haematopoietic stem cell transplantation was applied in 13 infants with acute lymphoblastic leukaemia (ALL). Eight patients were treated in first remission due to slow clearance of minimal residual disease (MRD); one for MRD-reappearance after long MRD negativity, one for primary refractory disease and three during relapse treatment. In slow MRD responders, complete MRD response was achieved prior to transplantation, with an 18-month event-free survival of 75%. In contrast, only one of five patients with relapsed/refractory ALL is still in complete remission. These data provide a basis for future studies of immunotherapy in very high-risk infant ALL.
- Published
- 2021
38. Platelet function and bleeding at different phases of childhood immune thrombocytopenia
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Anastasia N. Sveshnikova, Irina V. Serkova, Aleksey Maschan, Viktor E. Matveev, Elena V. Suntsova, Maya N. Korsantiya, Maria N. Sadovskaya, Anastasia A. Ignatova, A.V. Pshonkin, Galina S. Ovsyannikova, Selima Sh. Uzueva, N. S. Smetanina, Irina Kalinina, Pavel A Zharkov, A.L. Khoreva, Kristina S. Antonova, Kirill Voronin, Natalia N. Kotskaya, Galina Novichkova, Dmitry M. Polokhov, Marina V. Krasilnikova, Anna Shcherbina, Lili A. Hachatryan, Alexey A. Martyanov, Mikhail A. Panteleev, Evgeniya A Ponomarenko, Ksenia I. Romanova, Natalia M. Trubina, Daria V Fedorova, and Dmitry Evseev
- Subjects
Blood Platelets ,Male ,medicine.medical_specialty ,Adolescent ,Platelet Function Tests ,Recombinant Fusion Proteins ,Science ,chemistry.chemical_element ,Hemorrhage ,Disease ,Receptors, Fc ,030204 cardiovascular system & hematology ,Calcium ,Paediatric research ,Predictive markers ,Gastroenterology ,Article ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,Internal medicine ,hemic and lymphatic diseases ,medicine ,Humans ,Platelet ,Calcium Signaling ,Aplastic anemia ,Child ,Immunological disorders ,Whole blood ,Purpura, Thrombocytopenic, Idiopathic ,Multidisciplinary ,Romiplostim ,business.industry ,Infant ,medicine.disease ,Leukemia ,chemistry ,Thrombopoietin ,Case-Control Studies ,Child, Preschool ,Cohort ,Medicine ,Female ,business ,030215 immunology ,medicine.drug - Abstract
Immune thrombocytopenia (ITP) is believed to be associated with platelet function defects. However, their mechanisms are poorly understood, in particular with regard to differences between ITP phases, patient age, and therapy. We investigated platelet function and bleeding in children with either persistent or chronic ITP, with or without romiplostim therapy. The study included 151 children with ITP, of whom 56 had disease duration less than 12 months (grouped together as acute/persistent) and 95 were chronic. Samples of 57 healthy children were used as controls, while 5 patients with leukemia, 5 with aplastic anemia, 4 with MYH9-associated thrombocytopenia, and 7 with Wiskott-Aldrich syndrome were used as non-ITP thrombocytopenia controls. Whole blood flow cytometry revealed that platelets in both acute/persistent and chronic ITP were increased in size compared with healthy donors. They were also pre-activated as assessed by PAC1, CD62p, cytosolic calcium, and procoagulant platelet levels. This pattern was not observed in other childhood thrombocytopenias. Pre-activation by CD62p was higher in the bleeding group in the chronic ITP cohort only. Romiplostim treatment decreased size and pre-activation of the patient platelets, but not calcium. Our data suggest that increased size, pre-activation, and cytosolic calcium are common for all ITP platelets, but their association with bleeding could depend on the disease phase.
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- 2021
39. Allogeneic Donor-Derived Myeloid Antigen Directed CAR-T Cells - for Relapsed/Refractory Acute Myeloid Leukemia in Children after Allogeneic Hematopoietic Stem Cell Transplantation: Report of Three Cases
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Larisa Shelikhova, Arina Rakhteenko, Olga Molostova, Elena Kurnikova, V. Ukrainskaya, Yakov Muzalevsky, Dmitry Pershin, Alexander Popov, Elena Kulakovskaya, Dina Baidildina, Alexey Stepanov, Elena Osipova, Galina Novichkova, Alexey Maschan, and Michael Maschan
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
40. Incidence and prognostic value of central nervous system involvement in infants with B‐cell precursor acute lymphoblastic leukemia treated according to the MLL‐Baby protocol
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Alexander Popov, Grigory Tsaur, Zhan Permikin, Veronika Fominikh, Tatiana Verzhbitskaya, Tatiana Riger, Anna Demina, Egor Shorikov, Anatoly Kustanovich, Liudmila Movchan, Olga Streneva, Olga Khlebnikova, Olga Makarova, Oleg Arakaev, Alexander Solodovnikov, Elmira Boichenko, Konstantin Kondratchik, Natalia Ponomareva, Elena Lapotentova, Olga Aleinikova, Natalia Miakova, Galina Novichkova, Alexander Karachunskiy, and Larisa Fechina
- Subjects
Central Nervous System ,Neoplasm, Residual ,Oncology ,Incidence ,Pediatrics, Perinatology and Child Health ,Humans ,Infant ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,Burkitt Lymphoma - Abstract
The aim of the study was to evaluate the incidence and prognostic impact of central nervous system (CNS) involvement in infants with B-cell precursor acute lymphoblastic leukemia (BCP-ALL), as well as its relation with minimal residual disease (MRD) data.A total of 139 consecutive infants with BCP-ALL from the MLL-Baby trial were studied. Cerebrospinal fluid (CSF) samples were investigated by microscopy of cytospin slides. MRD was evaluated according to the protocol schedule by flow cytometry and PCR for fusion gene transcripts (FGT).Involvement of the CNS at any level was found in 50 infants (36.0%). The incidence of CNS involvement was higher in patients with KMT2A gene rearrangements (44.0% for KMT2A-r vs. 15.4% for KMT2A-g, p = .003). The outcome of CNS-positive infants was significantly worse than that of CNS-negative infants, although this prognostic impact was limited to the KMT2A-r group (event-free survival 0.21 for CNS-positive vs. 0.48 for CNS-negative infants, p = .044). CNS-positive infants could not be treated successfully by conventional chemotherapy alone, irrespective of the rapidity of MRD response. In contrast, the combination of initial CNS negativity and FGT-MRD negativity identified a group comprising up to one-third of infants with KMT2A-r ALL who can be treated with chemotherapy and achieve very good outcomes (disease-free survival above 95%), and remaining patients should be allocated to receive other types of treatment.We can conclude that this combination of initial CNS involvement and MRD data can significantly improve risk-group allocation in future clinical trials enrolling infants with ALL.
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- 2022
41. B-lineage antigens that are useful to substitute CD19 for minimal residual disease monitoring in B cell precursor acute lymphoblastic leukemia after CD19 targeting
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Ekaterina Mikhailova, Albert Itov, Elena Zerkalenkova, Julia Roumiantseva, Yulia Olshanskaya, Alexander Karachunskiy, Galina Novichkova, Michael Maschan, and Alexander Popov
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Histology ,Neoplasm, Residual ,Antigens, CD19 ,Cell Biology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Flow Cytometry ,Burkitt Lymphoma ,Pathology and Forensic Medicine ,Immunophenotyping ,Antigens, CD ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,Acute Disease ,Humans ,Neprilysin ,Child - Abstract
The potential loss of CD19 during targeted treatment of B cell precursor acute lymphoblastic leukemia (BCP-ALL) can hamper flow cytometric minimal residual disease (MRD) monitoring. In the current study, we present expression data for antigens that are candidates for CD19 substitution: surface CD22, CD24, CD10, and intracellular (i) CD79a.Bone marrow samples from 519 consecutive children (below 18 y.o.) with primary BCP-ALL were studied with a focus on expression of CD19, CD10, CD22, CD24, and iCD79a. As these antigens are planned to be used as substitutions for CD19 for primary B cell gating, only total expression on the leukemic population (≥95% cells) was considered appropriate.It was found that each of these antigens is totally expressed in nearly 90% of patients. For each single marker, a subgroup of patients without complete positivity presented with BCP-ALL harboring diverse cytogenetic and molecular genetic aberrations. Based on expression data, we have developed algorithm of simultaneous application of these antigens for initial B-lineage compartment gating, that is applicable for nearly all patients after CD19 targeting.We conclude that the addition of CD22, CD24, and iCD79a to the conventional antibody panel and their application together with CD10 allow for the identification of B-lineage compartment including residual tumor blasts, for MFC-MRD searching in virtually all patients with BCP-ALL after CD19-directed treatment.
- Published
- 2022
42. Plerixafor added to <scp>G‐CSF</scp> allows mobilization of a sufficient number of hematopoietic progenitors without impacting the efficacy of <scp>TCR</scp> ‐alpha/beta depletion in pediatric haploidentical and genoidentical donors failing to mobilize with <scp>G‐CSF</scp> alone
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Elena Kurnikova, Pavel Trakhtman, Dmitry Pershin, Mariya Ilyushina, Alexey Maschan, Rimma Khismatullina, Michael Maschan, and Galina Novichkova
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Mobilization ,business.industry ,Plerixafor ,CD34 ,Hematology ,General Medicine ,030204 cardiovascular system & hematology ,Filgrastim ,Pharmacology ,03 medical and health sciences ,Haematopoiesis ,0302 clinical medicine ,Apheresis ,Vomiting ,Medicine ,Progenitor cell ,medicine.symptom ,business ,030215 immunology ,medicine.drug - Abstract
BACKGROUND Collection of a large number of early hematopoietic progenitors is essential for allogeneic apheresis products intended for TCR-alpha/beta depletion. MATERIALS AND METHODS We added plerixafor 0.24 mg/kg body weight (bw) on day 4 of high-dose filgrastim mobilization 10 hours prior to apheresis in 16 (30.5%) pediatric allogeneic donors who failed to recover a sufficient number of CD34+ cells. RESULTS On day 4 of G-CSF, the median CD34+ cell count in peripheral blood was 6 per μL (range 4-9 per μL) in 6 poor mobilizers and 16 per μL (range 12-19 per μL) in insufficient mobilizers. In all donors, the threshold of 50 CD34+ cells/μL was achieved, and the median increase was 14.8-fold in poor mobilizers and 6.5-fold in insufficient mobilizers, whereas it was 3.45-fold increase in those mobilized with G-CSF alone. DISCUSSION In all donors, a predefined number of >10 × 106 CD34+ cells/kg of recipient bw before depletion was reached in the apheresis product. The use of plerixafor did not affect the purity of further TCR-alpha/beta depletion. Side effects were mild to moderate and consisted of nausea and vomiting. CONCLUSION Thus, the safety and high efficacy of plerixafor was proven in healthy pediatric allogeneic hematopoietic cell donors.
- Published
- 2021
43. GATA1 mutation analysis and molecular landscape characterization in acute myeloid leukemia with trisomy 21 in pediatric patients
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Ekaterina Mikhailova, Anna Kazakova, Yulia Olshanskaya, Michael Maschan, Aleksey Maschan, Natalia Timofeeva, Marina Gaskova, Irina Kalinina, Galina Novichkova, Lili Hachatrian, Agnesa Panferova, Eugenyi Nikitin, Alexander Popov, Viktor E. Matveev, and Pavel Baryshev
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Male ,Cohesin complex ,medicine.medical_treatment ,Clinical Biochemistry ,030204 cardiovascular system & hematology ,Biology ,Targeted therapy ,03 medical and health sciences ,Exon ,symbols.namesake ,0302 clinical medicine ,medicine ,Humans ,GATA1 Transcription Factor ,Child ,Sanger sequencing ,Biochemistry (medical) ,Myeloid leukemia ,GATA1 ,Exons ,Hematology ,General Medicine ,Amplicon ,medicine.disease ,Leukemia, Myeloid, Acute ,Mutation ,Cancer research ,symbols ,Female ,Down Syndrome ,Trisomy ,030215 immunology - Abstract
Introduction Accurate detection of GATA1 mutation is highly significant in patients with acute myeloid leukemia (AML) and trisomy 21 as it allows optimization of clinical protocol. This study was aimed at (a) enhanced search for GATA1 mutations; and (b) characterization of molecular landscapes for such conditions. Methods The DNA samples from 44 patients with newly diagnosed de novo AML with trisomy 21 were examined by fragment analysis and Sanger sequencing of the GATA1 exon 2, complemented by targeted high-throughput sequencing (HTS). Results Acquired GATA1 mutations were identified in 43 cases (98%). Additional mutations in the genes of JAK/STAT signaling, cohesin complex, and RAS pathway activation were revealed by HTS in 48%, 36%, and 16% of the cases, respectively. Conclusions The GATA1 mutations were reliably determined by fragment analysis and/or Sanger sequencing in a single PCR amplicon manner. For patients with extremely low blast counts and/or rare variants, the rapid screening with simple molecular approaches must be complemented with HTS. The JAK/STAT and RAS pathway-activating mutations may represent an extra option of targeted therapy with kinase inhibitors.
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- 2021
44. Rare case of pediatric trilineal mixed-phenotype acute leukemia with t(11;19)(q23.3;p13)/KMT2A::ELL
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Irina Demina, Elena Zerkalenkova, Alexandra Semchenkova, Egor Volchkov, Elmira Boychenko, Maria Prudnikova, Galina Novichkova, Michael Maschan, Alexey Maschan, Yulia Olshanskaya, and Alexander Popov
- Subjects
Cancer Research ,Oncology ,Hematology - Published
- 2023
45. Quantification of <scp>NG2</scp> ‐positivity for the precise prediction of <scp> KMT2A </scp> gene rearrangements in childhood acute leukemia
- Author
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Olga Illarionova, Svetlana Lebedeva, Liudmila Baidun, Michael Maschan, Alexander Popov, Elena Osipova, Svetlana Kashpor, Galina Novichkova, Ekaterina Mikhaylova, Yulia Olshanskaya, Elena Zerkalenkova, and Alexey Maschan
- Subjects
Male ,Cancer Research ,medicine.medical_specialty ,Myeloid ,Adolescent ,Chromosomal translocation ,Gastroenterology ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Internal medicine ,Biomarkers, Tumor ,Genetics ,medicine ,Humans ,Genetic Testing ,Antigens ,Child ,Gene Rearrangement ,Acute leukemia ,biology ,medicine.diagnostic_test ,Infant ,Histone-Lysine N-Methyltransferase ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Leukemia ,medicine.anatomical_structure ,KMT2A ,nervous system ,Child, Preschool ,030220 oncology & carcinogenesis ,Cohort ,biology.protein ,Female ,Proteoglycans ,Myeloid-Lymphoid Leukemia Protein - Abstract
It has long been known that there is a link between neuron glial antigen 2 (NG2) surface expression and KMT2A gene rearrangements in acute leukemia (AL). However, the exact levels of NG2 positivity that predict the presence of KMT2A rearrangement are not known. The current study focuses on a cohort of 505 pediatric AL patients who showed any level of positive NG2 expression (greater than 1% of cells) for whom comprehensive genetic data were available. NG2 expression was measured as either the percentage of positive cells or the number of molecules on the cell surface. KMT2A gene rearrangements were identified by FISH. The fusion partner was detected with RT-PCR, LDI-PCR or anchored multiplex PCR followed by high-throughput sequencing. KMT2A-positive samples comprised a substantial proportion of the NG2-positive cohort (180 of 505, 36%), with a total of 19 different types of translocation. Despite its occurrence in other AL genetic subgroups, NG2 expression was significantly increased in AL patients with KMT2A rearrangements in terms of both the cell percentage and number of molecules per cell. The threshold levels (TL) for NG2-positivity were established by ROC analysis of the whole cohort and separately for children less than 1 years old and older with lymphoblastic (ALL) and myeloid (AML) leukemia. The lowest TL was defined in infants with ALL (7%), while in older children, the threshold was higher (12%). In AML patients, the situation was reversed, with 28% NG2-positivity in infants and 14% in patients >1 year old. The defined TLs resulted in improved diagnostic performance compared to the conventional thresholds of 10% and 20% for all patient groups.
- Published
- 2020
46. T-cell tracking, safety, and effect of low-dose donor memory T-cell infusions after αβ T cell-depleted hematopoietic stem cell transplantation
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Rimma Khismatullina, Galina Novichkova, Alexei Maschan, Elena Kurnikova, Dmitriy M. Chudakov, Yakov Muzalevskii, Dmitriy Balashov, Julia Starichkova, Dmitriy Pershin, Alexei Kazachenok, Ivan V. Zvyagin, Viktoria Fomchenkova, Mikhail Shugay, Sergey Blagov, Michael Maschan, Elena Osipova, Ekaterina A. Komech, Maria Efimenko, Svetlana Glushkova, Larisa Shelikhova, and Maria Fadeeva
- Subjects
Transplantation ,business.industry ,medicine.medical_treatment ,Lymphocyte ,T cell ,T-cell receptor ,Hematology ,Hematopoietic stem cell transplantation ,Acquired immune system ,03 medical and health sciences ,surgical procedures, operative ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,medicine ,Cumulative incidence ,business ,Receptor ,Memory T cell ,030215 immunology - Abstract
The delayed recovery of adaptive immunity underlies transplant-related mortality (TRM) after αβ T cell-depleted hematopoietic stem cell transplantation (HSCT). We tested the use of low-dose memory donor lymphocyte infusions (mDLIs) after engraftment of αβ T cell-depleted grafts. A cohort of 131 pediatric patients (median age 9 years) were grafted with αβ T cell-depleted products from either haplo (n = 79) or unrelated donors (n = 52). After engraftment, patients received mDLIs prepared by CD45RA depletion. Cell dose was escalated monthly from 25 × 103 to 100 × 103/kg (haplo) and from 100 × 103 to 300 × 103 /kg (MUD). In a subcohort of 16 patients, T-cell receptor (TCR) repertoire profiling with deep sequencing was used to track T-cell clones and to evaluate the contribution of mDLI to the immune repertoire. In total, 343 mDLIs were administered. The cumulative incidence (CI) of grades II and III de novo acute graft-versus-host disease (aGVHD) was 5% and 2%, respectively, and the CI of chronic graft-versus-host disease was 7%. Half of the patients with undetectable CMV-specific T cells before mDLI recovered CMV-specific T cells. TCR repertoire profiling confirmed that mDLI-derived T cells significantly contribute to the TCR repertoire up to 1 year after HSCT and include persistent, CMV-specific T-cell clones.
- Published
- 2020
47. Two clinically distinct cases of infant hemispheric glioma carrying ZCCHC8:ROS1 fusion and responding to entrectinib
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Ludmila Papusha, Margarita Zaytseva, Agnesa Panferova, Alexander Druy, Andge Valiakhmetova, Anton Artemov, Ekaterina Salnikova, Alexey Kislyakov, Evgeny Imyanitov, Alexander Karachunsky, Alexey Maschan, Eugene I Hwang, Galina Novichkova, and Roger J Packer
- Subjects
Cancer Research ,Indazoles ,Lung Neoplasms ,Oncology ,Proto-Oncogene Proteins ,Benzamides ,Humans ,Infant ,Nuclear Proteins ,Neurology (clinical) ,Glioma ,Protein-Tyrosine Kinases ,Carrier Proteins - Published
- 2022
48. Efficacy and safety of a reduced dose of plerixafor in combination with granulocyte colony-stimulating factor in healthy haploidentical stem cell donors
- Author
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Elena Kurnikova, Pavel Trakhtman, Dmitry Balashov, Juliya Garloeva, Irina Kumukova, Rimma Khismatullina, Dmitriy Pershin, Larisa Shelikhova, Galina Novichkova, and Alexey Maschan
- Subjects
Adult ,Benzylamines ,Stem Cells ,Body Weight ,Hematopoietic Stem Cell Transplantation ,Antigens, CD34 ,Hematology ,General Medicine ,Cyclams ,Hematopoietic Stem Cell Mobilization ,Heterocyclic Compounds ,Granulocyte Colony-Stimulating Factor ,Humans ,Prospective Studies - Abstract
Implementation of the technique of immunomagnetic selection requires the procurement of a large number of CD34+ cells from haploidentical donors within a single apheresis procedure. The release of stem cells with granulocyte colony-stimulating factor (G-CSF) alone is unsatisfactory in a number of donors, and plerixafor, a CXCR4 chemokine receptor antagonist, could be used as an additional mobilization agent. The aim of our study was to examine whether a lower dose of plerixafor (0.12 mg/kg) can provide sufficient increase in CD34+ cells in the peripheral blood of allogeneic healthy donors in comparison with a historical control group. In addition, we assessed the risk of inability to provide the recipient with a transplant containing the optimal dose of 8-10 × 10In a prospective, single-arm study, we examined the results of 105 mobilizations in healthy adult haploidentical donors with G-CSF and plerixafor at a dose of 0.12 mg/kg. The historical control group consisted of 106 mobilizations with G-CSF and plerixafor at 0.24 mg/kg.The median increase in the number of CD34+ cells from day 4 to day 5 of mobilization was 69 cells/μl (range, 28-240) versus 77 cells/μl (24-217) in the groups of 0.12 and 0.24 mg/kg of plerixafor, respectively (p-value 0.255). The apheresis products contained a median of 14.4 × 10The obtained differences in collection were not significant, and thus the application of a decreased dose of plerixafor did not affect the results of mobilization.
- Published
- 2022
49. FLAER‐negative CD15+ neutrophils can be used for the simplified screening of suspected PNH cases
- Author
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Alexander Popov, Svetlana Kashpor, Vyacheslav Borisov, Olga Illarionova, Tatiana Verzhbitskaya, Galina Novichkova, Larisa Fechina, Alexey Maschan, and Alexandra Semchenkova
- Subjects
Adult ,Male ,medicine.medical_specialty ,Pathology ,Adolescent ,Neutrophils ,Clinical Biochemistry ,Hemoglobinuria, Paroxysmal ,Lewis X Antigen ,Diagnostic Specificity ,CD15 ,030204 cardiovascular system & hematology ,GPI-Linked Proteins ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Screening method ,Humans ,Aplastic anemia ,Child ,Aged ,Aged, 80 and over ,Hematology ,business.industry ,Biochemistry (medical) ,Bone marrow failure ,General Medicine ,Middle Aged ,Flow Cytometry ,medicine.disease ,Peripheral blood ,Child, Preschool ,embryonic structures ,Paroxysmal nocturnal hemoglobinuria ,Female ,business ,Biomarkers ,030215 immunology - Abstract
Background The flow cytometry analysis of GPI-linked proteins on red blood cells and leukocytes is crucial for paroxysmal nocturnal hemoglobinuria (PNH) diagnostics. However, the commonly used multicolor panels cannot be implemented in low-resourced hematology laboratories. In order to develop a simple prediagnostic test for PNH screening, we analyzed the diagnostic accuracy of the two-color (FLAER/CD15) detection of GPI-deficient neutrophils. Methods We reanalyzed multicolor data set of 1594 peripheral blood samples of patients screened for PNH applying only two markers (FLAER/CD15). The quantitative positivity/negativity was reported. Then, these results were compared in a blinded manner with previously obtained multicolor data from the same samples. Results Among the 1594 samples included in the study, 507 samples were PNH-positive by the multicolor assay. The two-color method revealed 510 PNH-positive samples. The detailed examination of this discrepancy revealed 12 false-positives and 9 false-negatives. Therefore, FLAER/CD15 screening method displayed 98.90% of the diagnostic specificity and 98.22% of the sensitivity. Conclusion This simple two-color evaluation of FLAER-negative neutrophils is a highly effective screening test for PNH. Although this approach is not intended to replace the multicolor diagnostic procedure, it could minimize the number of patients requiring a conventional multicolor flow cytometric assay.
- Published
- 2020
50. EPIDEMIOLOGY OF PRIMARY IMMUNODEFICIENCIES IN THE RUSSIAN FEDERATION
- Author
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M.A. Grakhova, Omsk City Polyclinic No. , Omsk, Russia, I.V. Sazonova, L.Yu. Barycheva, N.B. Yudina, T.V. Shilova, Marina N. Guseva, L.I. Pyatkina, V.V. Lebedev, Irina Kondratenko, A.M. Milichkina, V.M. Shinkareva, Immunology named after Dmitry Rogachev, Moscow, Russia, N.A. Parfenova, E.G. Chernyshova, N.I. Ilyina, N.B. Kuzmenko, T.B. Pavlova, N.B. Migacheva, T.V. Samofalova, G.A. Davletbaeva, M.V. Gurkina, E.A. Goltsman, A.Yu. Shcherbina, N.V. Zinovieva, L.R. Kalmetieva, Daria Fomina, S.Yu. Starikova, O.P. Ukhanova, N.V. Shakhova, Irina A. Tuzankina, Microbiology, Saint Petersburg, Russia, Diagnostic Polyclinic No. , Volgograd, Russia, O.A. Rychkova, R.M. Khayrullina, S.B. Zimin, D.D. Prolygina, T.P. Alexandrova, L.S. Khachirova, E.V. Averina, T.V. Bukina, D.V. Mashkovskaya, Alexander Rumyantsev, Mother, S.S. Vakhlyarskaya, E.I. Kleshchenko, A.Yu. Kutlyantseva, Galina Novichkova, L.T. Kubanova, Z.I. Kruglaya Scientific, O.S. Selezneva, V.A. Alekseenko, F.I. Sibgatulina, I.A. Mirsayapova, K.A. Voronin, A.A. Totolyan, V.A. Kalinkina, S.N. Isakova, A.V. Gorenkova, O.M. Laba, M.M. Vasilyeva, Tatiana V. Latysheva, E.V. Efremenkov, Murmansk City Children's Polyclinic No. , Murmansk, Russia, K.P. Kuzmicheva, A.P. Prodeus, Consultative, A.A. Bologov, O.E. Pashchenko, I.V. Yarovaya, A.M. Kostinova, E.V. Vlasova, E.V. Timofeeva, A.V. Zhestkov, E.V. Troitskaya, A.L. Khoreva, Anna Mukhina, A.N. Pampura, A.S. Ermakova, G.V. Molokova, E.M. Kamaltynova, M.A. Bolkov, Z.V. Bambaeva, M.G. Ipatova, R.N. Suprun, E.V. Demikhova, T.V. Asekretova, D.N. Balashov, E.V. Volodina, E.A. Orlova, E.M. Gracheva, O.A. Shvets, Bryansk Clinical, G.I. Tsyvkina, Ekaterina A. Deordieva, Yu.A. Rodina, E.I. Sulima, I.V. Fisyun, S.N. Duryagina, V.G. Demikhov, I.V. Smoleva, E.A. Latysheva, Immunology, Vladivostok, Primorsky Krai, Russia, A.A. Moiseeva, E.V. Barmina, M.A. Filippova, and R.N. Kuznetsova
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medicine.medical_specialty ,business.industry ,Family medicine ,Pediatrics, Perinatology and Child Health ,Epidemiology ,Medicine ,Russian federation ,business - Published
- 2020
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