Breakthrough in pediatric hematology-oncology in Russia and Eurasia, or why autumn 2018 will go down in history?

Introduction. Neuroblastoma (NB) is the most common extracranial pediatric solid tumor. The high-risk group patients are characterized by adverse prognosis and require intensive complex therapy including high-dose chemotherapy (HDCT) with hematopoietic stem cell transplantation (auto-HSCT). The current study presents a single center experience of HSCT with auto-HSCT for high-risk NB performed in Raisa Gorbacheva Memorial Research Institute of Children Oncology, Hematology and Transplantation, First Pavlov State Medical University of St. Petersburg, Ministry of Health of Russia.

Patients and methods. A cohort of 72 consecutive high-risk NB patients was included in the study. Among them 69 patients received Bu-Mel conditioning regimen (busulfan 16 mg/kg, melphalan 140 mg/m2 ), in 3 patients the 5D/5D regimen was used (carboplatin 1000 mg/m2 , irinotecan 150 mg/m2 , temozolomide 750 mg/m2 , etoposide 400 mg/m2 , cyclophosphamide 140 mg/kg). In most cases the autologous hematopoietic stem cells source was bone marrow (BM) (n = 59; 82 %), peripheral blood stem cells (PBSC) (n = 11; 15 %), or BM and PBSC (n = 2; 3 %). In 52/66 (79 %) patients with initial bone marrow involvement the potential transplant contamination was assessed by flow cytometry.

Results. The 2-year and 5-year overall (OS) and event-free (EFS) survival was 61 % and 48 %, 41 % and 35 % accordingly. The main adverse factors for OS and EFS were age of more than 18 months at diagnosis, combined bone marrow and bones involvement, MYCN amplification, initial neuron-specific enolase level of more than 100 ng/ml, primary resistance or relapse, and metaiodobenzylguanidinepositive lesions persistence prior to or after HSCT with auto-HSCT.

Conclusions. The results achieved are comparable to those described for similar cohorts. Some patient subgroups are unlikely to achieve response after HSCT with auto-HSCT. Therefore, additional stratification methods and treatment modalities are needed.

Conflict of interest. The authors declare no conflict of interest.

Funding. The study was performed without external funding.

Introduction. Neuroblastoma (NB) is the most common extracranial solid tumor in children. As a rule, NB is localized in the adrenal gland, retroperitoneal space and posterior mediastinum. The head and neck area belongs to the rare localization of NB, which accounts for 2.6 % of cases, and is most common in children aged 0–3 years. Localization of NB in the neck in most cases has a favorable prognosis.

Materials and methods. For the period from September 2013 to September 2017 (48 months) in the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology received treatment for 8 patients with NB in the neck. Examination, assessment of the prevalence of the process and stratification into risk groups in all patients were carried out according to the recommendations of the protocol of the German group for the treatment of NB NB-2004. For the purpose of histological verification of the diagnosis and detection of unfavorable molecular genetic markers, patients underwent surgical intervention, performed risk-adapted therapy according to the NB-2004 protocol.

Results. The median age of diagnosis was 8.7 (1.2–34.1) months. In our cohort of patients in 87.5 % of cases, the diagnosis was made in the first year of life. In most cases, there was not only the identification of tumor masses, but also other symptoms of the disease. In 3 (37.5 %) patients the 2nd stage was established, in 1 (12.5 %) patient – the 3rd stage, in 3 (37.5 %) patients – the 4th stage and in 1 (12.5 %) patient – 4S stage of the disease. When stratifying patients into risk groups, in the observation group and the high-risk group was stratified by 3 (37.5 %) children and 2 (25 %) patients were classified as high-risk group. 3 (37.5 %) patients showed unfavorable cytogenetic abnormalities. When evaluating the response to therapy in most patients, a complete and very good partial response was stated. Overall (OS) and event-free (EFS) survival rates were 75 ± 15 % and 50 ± 17 %, respectively. The median of observation is 43 (26–61) months.

Discussion. NB with the localization of the primary tumor in the head and neck area is a favorable form in terms of the stage of the disease and the risk group, however, it should be noted that in our patient cohort half of the subjects showed the development of certain adverse events, which was also reflected in the OS and EFS. Moreover, this localization dictates its risks from the point of view of the surgical stage of treatment. The main danger is complications after surgical treatment associated with the anatomical proximity of the central arteriovenous trunks, cranial nerves, and their involvement in the tumor process. In the case of the development of life threatening conditions (LTC), it is possible to use low-intensity chemotherapy courses.

Conclusion. Experience Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology shows the need for timely diagnosis and the start of treatment of NB with localization in the neck. The choice of management tactics in favor of carrying out only surgical treatment is possible in patients of the observation group without the development of LTC. Not always the localization of NB in the neck region correlates with a favorable prognosis.

Conflict of interest. The authors declare no conflict of interest.

Funding. The study was performed without external funding.

The choice of the optimal donor in the absence of an HLA-compatible relative, as well as the analysis of the risks of hematopoietic stem cell transplantation (HSCT), is extremely important, especially in patients with non-cancerous diseases. The article analyzes 99 allogeneic HSCTs from unrelated donors in the bone marrow transplantation department of the Russian Children’s Clinical Hospital. The analysis included patients with acquired and congenital forms of non-malignant diseases. The choice of an optimal unrelated donor in the absence of a compatible relative donor, as well as an analysis of the risks of treatment, requires studying the factors that influence the outcome of treatment in this group of patients. It was shown that the level of 2-year overall survival (OS) was 74 % (standard deviation ± 4.7 %). At the same time, clinical manifestations of the acute graft versus host disease of grade I–IV were recorded in 67 % (n = 66) of patients, and severe forms of grade III–IV in 13 % (n = 13) of children. Chronic graft versus host disease (chGVHD) was observed in 29 % (n = 29) patients. When studying the factors associated with the donor, it was found that the differences in the HLA system have a negative effect on the incidence of chGVHD; in a (9/10) HLA-incompatible donor, it was 29 % higher (p = 0.019). Increasing the age of the donor for every 10 years consistently reduces the OS by 9–11 % (p = 0.117), however, the OS with a donor over 46 years old was 100 % (n = 7). No effect on the agents with respect to the following factors with respect to the recipient was found: by sex, blood group, serostatus for cytomegalovirus (CMV). It was noted that the combination of CMV-positive serostatus of the donor and the negative status of the recipient increases the risk of transplant rejection up to 50 % in comparison with other variants of CMV serostatus (p = 0.001). In general, the possibility of performing HSCT from an unrelated donor for patients with non-malignant diseases and possible ways of selecting the optimal donor was noted. 

Conflict of interest. The authors declare no conflict of interest.

Funding. The study was performed without external funding.

Introduction. This study focuses on topical issues of etiopathogenesis, clinic and treatment of radiation injuries of hard dental tissues in patients who completed antitumor therapy.

Review of literature data. In the course of reviewing both domestic and foreign sources of literature covering certain aspects of the problem, the authors formulate the principles of the differential diagnosis of radiation caries, prevention and treatment specificity.

Results. The studies were performed at the TRSC “Russkoe Pole” from January 2017 to August 2018 (the median is 20 months). A group of 2005 patients who received radiation therapy for the treatment of hemoblastosis, solid tumors, including for the purpose of consolidation before the hematopoietic stem cell transplantation, was selected. The most severe lesions of the dentition were detected in 74 (3.2 %) patients during the rehabilitation period, mainly with tumors of the central nervous system: radiation caries, trisism, adentia. Radiation caries is a common complication of radiation therapy in the treatment of malignant neoplasms in children and adolescents.

Conclusion. The severity of radial caries is determined by the local dose and age of the patients at the time of exposure.

Conflict of interest. The authors declare no conflict of interest.

Funding. The study was performed without external funding.

Insomnia is a common symptom in children with malignant diseases and especially in children with tumors of the central nervous system (CNS). However, little attention is paid this complication during the therapy of malignant neoplasms. Insomnia violates the quality of life of children and their immediate surroundings. In this article, the etiology, pathogenesis, and diagnostics are discussed in detail, and methods for treating this pathology are presented with two clinical cases confirming the diverse nature of insomnia in CNS tumors. Thus, the importance of an individual approach to the therapy of insomnia is emphasized.

Conflict of interest. The authors declare no conflict of interest.

Funding. The study was performed without external funding

Atypical teratoid/rhabdoid tumors (AT/RT) are a group of rare highly aggressive malignant tumors in young patients. Among all the malignant tumors of the central nervous system (CNS) in children, they are 1–2 %, which, due to the small number of groups, makes it difficult to develop uniform recommendations for antitumor therapy. The molecular genetic profile of AT/RT, which largely determines the characteristics of the disease, has been studied sufficiently. Despite the large number of ongoing clinical studies, the results of treatment of AT/RT CNS in the world today remain unsatisfactory. The early age of patients limits the use of radiation therapy, which leads to the need to intensify chemotherapy regimens and to choose the optimal strategy in the toxicity – benefit ratio. The article describes modern approaches to the treatment of central nervous system disorders in children, presents the results of studies with the largest number of included patients, using the multimodal treatment strategy, identifies current trends in targeted therapy.

Conflict of interest. The authors declare no conflict of interest.

Funding. The study was performed without external funding.

Patients with oncohematological diseases, both children and adults, face high risks of thrombotic and hemorrhagic complications.

About 40 % of pediatric patients with acute lymphoblastic leukemia develop bleedings, and the incidence of thrombosis in this disease ranges from 1 to 36 %. Most thromboses are associated with the use of central venous catheters and the use of L-asparaginase, which leads to a significant reduction in the synthesis of coagulation proteins.

Massive hemorrhages account for two-thirds of all causes of early death in pediatric patients with acute myelogenous leukemia (AML). Absolute risks of death due to bleeding and leukostasis range from 1.8 % in the total population of children with AML to 14.3 % in a population with hyperleukocytosis more than 200 × 109 /l. The risk of thrombotic complications in children with AML varies between 3.4–11 %. In patients with AML, complex systemic coagulopathies may occur, such as disseminated intravascular coagulation (DIC), excessive fibrinolysis, or nonspecific proteolysis. This scale is not yet applicable due to the lack of research on its effectiveness in the pediatric population. The laboratory diagnostics of hemostasis is difficult due to the combined nature of thrombotic and hemorrhagic complications: bleeding, thrombosis and even DIC syndrome (combining both hyper- and hypocoagulation phases) can be expected in each specific patient with hemoblastosis. Because of the long-term nature of the treatment and the varying intensity of the various treatment units, the patient’s hemostasis during disease manifestation does not allow one to predict with any certainty the complications on induction or consolidation therapy. Involving all the components of the hemostasis system – vascular, platelet and plasma – into the pathological process makes prediction and diagnosis of thrombohemorrhagic complications impossible with the help of standard hemostatic tests and a general blood test, since these tests are designed to assess the concentrations of individual proteins and the functioning of individual components of the hemostatic system, and does not assess the balance between its procoagulant and anticoagulant components. Global hemostatic tests such as thromboelastography, thrombodynamics and thrombin generation test adequately reflect hypercoagulable conditions and can serve as a basis for the development of a new set of laboratory hemostasis tests.

Conflict of interest. F.I. Ataullakhanov is co-founder of HemaCore LLC, which holds several patents and patent applications that are related to the diagnostic use of Thrombodynamics® (Ataullakhanov F.I., international patent applications: PCT/CH2007/000543 filing date 02.11.2007 and РСТ/RU2012/000570 filing date 16.07.2012). None of the other authors has any competing interests to declare.

The article describes a clinical case of a patient aged 15 years with a sequential transformation of the ameloblastoma of the upper jaw into ameloblastic fibrosarcoma and undifferentiated round-cell sarcoma as a result of frequent relapses against the background of standard anticancer treatment. This clinical example is of interest not only because of the preservation of the mutation in the BRAF gene at all stages of transformation, which made it possible to conduct successful therapy with BRAF and MEK inhibitors after the exhaustion of all standard therapeutic possibilities.

Conflict of interest. The authors declare no conflict of interest.

Funding. The study was performed without external funding

Neuroblastoma (NB) is one of the most common childhood solid tumors. Current problem of children’s oncology is treatment of patients from high-risk NB. Now the standard of treatment of these patients is application of the stage-by-stage therapy including induction, consolidation, and post-consolidation. During induction the maximum reduction of the primary tumor and the metastasis for a possibility of optimum local control is reached. Consolidation consists in high-dose chemotherapy which purpose is to consolidate the reached remission. After the completions of treatment patients receive the maintenance therapy, the standard is use of the differentiating therapy in combination with monoclonal anti-GD2-antibody (dinutuximab). Certainly, this tactics allowed achieving considerable progress in treatment of primary patients with unfavorable prognosis. Options of treatment for high-risk NB depend on some factors. Certainly, the tumor dissemination is characterized by extremely adverse forecast for life and recovery of the patient. However a local recurrence can be successfully cured. The purpose of this study is to demonstrate a rare clinical case of therapy from isolated central nervous system NB recurrence.

Conflict of interest. The authors declare no conflict of interest.

Funding. The study was performed without external funding.

Malignant kidney tumors make up 6 % of all childhood tumors and require careful differential diagnosis with other diseases. This article discusses the differential diagnosis of nephroblastoma and kidney tuberculosis.

Conflict of interest. The authors declare no conflict of interest.

Funding. The study was performed without external funding.

VII International Symposium on Solid Tumors in Children.

Secretory diarrhea (SD) due to increased production of vasoactive intestinal peptide (VIP) in neuroblastoma (NB) is a rare paraneoplastic syndrome (PNS). Depending on the time of development of SD in relation to the diagnosis of NB, primary and secondary hypersecretion of VIP is distinguished. It is difficult to diagnose NB in the debut of a disease in a child with diarrhea as the main symptom, given that diarrhea is one of the most common syndromes found in pediatric practice and characteristic of acute intestinal infections, especially in young children. However, long-term SD in a child is an indication for screening for a neurogenic tumor. This article describes 2 clinical cases of PNS in patients with NB in the form of SD, which developed before the diagnosis of a malignant neoplasm, and at the stage of special treatment, as well as a review of the literature.

Conflict of interest. The authors declare no conflict of interest.

Funding. The study was performed without external funding.

This article is devoted to the analysis of problems associated with the state of the genitourinary system (GUS) in patients who have undergone a malignant neoplasm in childhood. The main diseases and pathological conditions that can develop in this population are considered. The risks of the development of pathological changes in the kidneys, treatment and prevention are described. Separately, the effects of various types of anticancer therapy (chemoradiotherapy) on GUS were analyzed. Recommendations are given on the definition of risk groups, physical activity and recommended actions.