ОНКОГЕМАТОЛОГИЯ АКТУАЛЬНОСТЬОпухоли средостения (тимомы, карциномы тимуса, нейроэндокринные, герминогенные опухоли и др.) составляют менее 1% всех опухолей человека. Большая часть из них -лимфопролиферативные заболевания, поддающиеся системному лечению. Лимфомы средосте-ния могут быть первичными для данной локализации или вторичными при генерализации процесса, источником роста могут являться лимфатические узлы средостения или тимус. Манифестация болезни происходит в виде появления медиастинальной массы, локализованной в переднем, верхнем или среднем средостении. Существуют объективные трудности клинической и морфологической диагностики опухолей средостения, особенно лимфоид-ной природы. Получить диагностический материал слож-но, для этого используют различные виды биопсий, но полученный материал зачастую небольшого объема и деформирован. Помимо малого количества и деформа-ции материала, что само по себе затрудняет морфологи-ческую диагностику, лимфомы средостения демонстриру-ют значительную вариабельность гистологических и цито-логических изменений, что влечет за собой необходи-мость выполнения иммуногистохимического исследова-ния во всех случаях [1,2].У большинства пациентов наблюдаются симптомы, вызванные наличием медиастинального образования: одышка, общая слабость, боль в груди, кашель, синдром компрессии верхней полой вены. Симптомы интоксика-ции -B-симптомы (лихорадка выше 38 °С, профузные ночные поты и потеря массы тела более 10% в течение 6 месяцев) наблюдаются менее чем у половины пациентов. Лимфома распространяется на окружающие органы и структуры, такие как плевра, перикард, легкие, сосуды, и может вовлекать мягкие ткани грудной стенки и даже грудину. Лимфома, поражающая легкие, может проникать в бронхи и образовывать эндобронхиальные массы. Также описаны случаи распространения лимфомы через диафрагму в печень. Инвазивный тип роста данного типа опухоли зачастую приводит к развитию синдрома верх-

About 20% of initially high-risk patients with neuroblastoma (NB) develop primary resistant to chemotherapy and more than 50% of them subsequently have a relapse. There is currently no uniform approach to therapy in this group and long-term outcomes are dismal. The study was approved by the Independent Ethics Committee and the Scientific Council of the I.P. Pavlov First Saint Petersburg State Medical University. A total of 78 patients with a median age of 5 (1–20) years with primary resistant (n = 33) or (n = 45) relapsed NB receiving treatment in R.M. Gorbacheva Memorial Center were included in this study. In 20 cases the 2nd-line therapy including topotecan (n = 10) or irinotecan (n = 10) was used, 58 patients received combined chemo- and targeted therapy (RIST regimen: rapamycin, irinotecan, sirolimus, temozolomide). Nineteen patients with primary resistant disease (n = 4) or systemic relapse (n = 15) subsequently underwent an allogeneic hemopoietic stem cell transplantation from haploidentical donor (haplo-HSCT). In all cases fludarabin-based reduced intensity conditioning (RIC) regimens were used. Ten patents received modified graft (immunomagnetic selection or depletion), in 9 unmodified graft with subsequent post-transplant cyclophosphamide (PTCM) was used. Also, 16 of 19 haplo-HSCT recipients had post-transplant therapy. The clinical effect was seen in 79% of patients. The median event-free survival (EFS) in 2nd-line therapy and RIST recipients was 2.5 (1–11) and 8 (1–76) months, accordingly. The complete of good partial response in 2nd-line therapy or RIST recipients was seen in 5% and 15%, 14% and 31% of cases accordingly. The therapy toxicity was comparable in both groups. The median EFS for haplo-HSCT recipients was 15 months with 2-year OS and EFS in this group bring 44% and 21% accordingly. Seven of 19 (37%) patients are currently alive and 4 (21%) of 19 maintain response. All long-term responders have history of posttransplant therapy. There was no statistically significant difference based on graft-versus-host disease prophylaxis used (graft modification or PTCM) or KIR compatibility. Combined chemo- and targeted therapy (RIST) is characterized by acceptable toxicity and effective even in some previously resistant cases. In 20% of responders a long-term effect may be achieved by subsequent haplo-HSCT and post-transplant therapy.

The majority of children with NHL can be cured with first-line therapy but 10–25% of affected patients develop relapsed or refractory disease (R-R). The prognosis in these cases is unfavorable, no matter what form of modern treatment is adopted. New approaches to the treatment of this small, yet important, group of patients need to be introduced, including, first and foremost, targeted therapy and immunotherapy. As is known, PD-L1 is frequently expressed in non-Hodgkin lymphomas (NHL), which means that the use of checkpoint inhibitors (CPI) is theoretically justified. Objectives: to analyze the results of treatment with checkpoint inhibitors Nivolumab and Pembrolizumab in children with R-R NHL. The study was approved by the Independent Ethics Committee of the I.P. Pavlov First Saint-Petersburg State Medical University. We used CPIs in 8 children with R-R NHL undergoing treatment at the R.M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation. The median age was 12 (2–17) years. The distribution of the patients by diagnosis was as follows: primary mediastinal large B-cell lymphoma (PMBCL, n = 3), peripheral T-cell lymphoma (PTCL, n = 2), diffuse large B-cell lymphoma (n = 1), lymphoblastic lymphoma (n = 2). The median number of prior lines of therapy was 3 (1–5), and all patients had received at least 1 line of standard treatment. Refractory NHL was observed in 5 cases, and 3 patients had had multiple relapses (≥ 3). All patients had progression of their primary disease at the time of prescription of the CPI therapy. Nivolumab was administered at a dose of either 1 mg/kg (n = 4) or 3 mg/kg (n = 3) every 2 weeks, Pembrolizumab - at a dose of 2 mg/kg once every 3 weeks (n = 1). The median number of CPI doses received by the patients was 5.5 (2–12). In 5 patients, CPIs were administered as monotherapy, in 3 – in combination with cytostatic agents: FLAG, Gemcitabine and intrathecal triples (n = 1), Brentuximab vedotin (n = 1) and Bendamustine (n = 1). The efficacy of the treatment was evaluated in accordance with the LYRIC criteria. Once remission was achieved, we used hematopoietic stem cell transplantation and/or radiotherapy for consolidation. Response to the CPI therapy was observed in 4 out of 8 patients (complete response – in 2 patients). Interestingly, only patients with PMBCL and PTCL responded to the treatment. At the median follow-up of 368 (36–879) days, 5 patients were alive, with three of them remaining in long-term remission. During the follow-up period, there was only 1 clinically significant complication (cytopenia) that resolved after treatment with glucocorticosteroids. Finally, we would like to point out that this paper is one of the first reports on the successful use of CPIs in children with R-R NHL. PMBCL and PTCL turned out to be responsive to the treatment. This therapy can be used to achieve remission or possibly even cure in children whose only option would be palliative care if they were treated with standard approaches.

Hodgkin’s lymphoma, being a highly malignant disease, has now acquired the property of a curative one. The article describes the basic principles of therapy of children with Hodgkin’s lymphoma, slow fixation of risk-adapted treatment positions. The possibility of complete cure of most patients appeared, which made this tumor a unique model for studying the remote consequences of cancer treatment. After the antitumor treatment of Hodgkin’s lymphoma, boys may suffer from testicular insufficiency (due to cytostatics), obstructive azoospermia (as a consequence of radiation therapy in the pelvic area), hypogonadism (secondary - after exposure of the pituitary gland to radiation, primary - after exposure of the pelvis due to the toxic effects of cytostatics). In order to reduce the gonadotoxicity of treatment, studies are being conducted to modify chemotherapy in the direction of lowering the doses of alkylating cytostatics, reducing the doses of radiation therapy without losing the effectiveness of treatment. Regardless of the cause of male infertility diagnosis includes the collection of reproductive history, external examination of the genitals, analysis of ejaculate, ultrasound examination of the scrotum, assessment of hormone levels (follicle stimulating hormone, total testosterone, serum testosterone, luteinizing hormone, prolactin, inhibin B, thyroid stimulating hormone).

There is no doubt that autologous hematopoietic stem cell transplantation (auto-HSCT) with high-dose polychemotherapy (PCT) is a standard method for the second remission consolidation in case of relapse or for the fist remission consolidation in refractory disease in adult patients with non-Hodgkin lymphomas (NHL) (with the exception of lymphoblastic lymphoma in which allogeneic transplantation is preferable). Similar to patients older than 18 years of age, an identical algorithm is applied in pediatric patients, however in the absence of randomized clinical trials and due to a small number of patients, the evidence base in children is weaker compared to adults, which complicates the analysis. Due to a signifiant number of nonrandomized studies confiming the benefis of transplantation, it is impossible to plan and make a direct comparison of auto-HSCT and standard chemotherapy in pediatric patients within a randomized study primarily because of ethical reasons. Although transplantation is not able to fundamentally change the prognosis in all children with relapsed or refractory (R/R) NHL, a cure cannot be achieved without this method. Taking into account that most of the works devoted to auto-HSCT in children with R/R NHL were published more than 10 years ago, current data on this issue are of great interest due to the large-scale implementation of the effective methods of targeted and immunotherapy over the past decade. This study was approved by the Independent Ethics Committee and the Scientifi Council of the I.P. Pavlov First Saint-Petersburg State Medical University, Ministry of Healthcare of the Russian Federation. At the R.M. Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, 31 children with R/R NHL underwent auto-HSCT from 2008 to 2020. The median age at the time of transplantation was 14 (2–18) years. At the onset of the disease, most patients were diagnosed with stage III or IV cancer (n = 30, 97%), the CNS involvement was registered in 4 patients (13%), the bone marrow involvement was registered in 2 patients (6%). The histological variants were as follows: primary mediastinal large B-cell lymphoma (n = 11, 35%), anaplastic large cell lymphoma (n = 6, 9%), Burkitt's lymphoma (n = 5, 16%), diffse large B-cell lymphoma (n = 5, 16%), peripheral T-cell lymphoma (n = 2, 7%), unspecifid B-NHL (n = 1, 3%) and lymphoblastic lymphoma (n = 1, 3%). The Karnofsky performance status prior to transplantation was ≥ 90% in all patients. The median time from diagnosis to auto-HSCT was 304 (122–3888) days. The median number of prior lines of therapy was 2 (1–4). In the majority of the patients (n = 27, 87%), a fist-line treatment was carried out according to the principles developed by the BFM group and in 4 older children (13%), we used regimens based on CHOP. As a second-line treatment, 18 (58%) patients received R-ICE (rituximab, ifosfamide, carboplatin, etoposide); the rest of the patients were treated with other regimens. NHL was relapsed (n = 14, 45%) or refractory (n = 17, 55%). A histological confimation of R/R NHL was carried out in 11 (35%) patients; in the rest of the cases, the diagnosis was made based on the imaging results and their correlation with the clinical presentation. Remission prior to auto-HSCT was achieved in 90% (n = 28) of cases: complete remission was observed in 39% (n = 8) of cases, and partial remission was observed in 51% (n = 16) of cases. In addition, transplantation was carried out in three patients (10%) who did not achieve remission. The graft sources were peripheral hematopoietic stem cells (n = 19, 61%) and bone marrow (n = 12, 39%). The median CD34+cells/kg was 3.85 (2–7.6). As conditioning regimens we used BEAM (n = 13, 42%) and BeEAM (n = 18, 58%). Both regimens consisted of etoposide 200 mg/m2/day from D5 to D2, cytarabine 400 mg/m2/day from D5 to D2, melphalan 140 mg/m2/day on D1. The regimens diffred in the following: we used carmustine 300 mg/m2/day on D6 in BEAM or bendamustine 160 mg/m2/day on D7 and D6 in BeEAM. Immunotherapy or targeted therapy prior to auto-HSCT was carried out in the majority of the patients (n = 25, 80%). The following medications were used: rituximab (n = 20, 65%), brentuximab vedotin (n = 6, 19%), nivolumab (n = 3, 10%), crizotinib (n = 2, 6%). Temporary three-lineage grade IV cytopenia was observed in all patients after auto-HSCT. Grade III–IV mucositis was registered in 10 (30%) patients, and 3 (10%) children developed grade III–IV infectious complications. Transplant-related mortality was not registered. During the follow-up period, six (19%) patients died due to the underlying disease progression. At the median follow-up of 888 (66–3375) days, the 5-year overall (OS) and event-free (EFS) survival rates were 70% (95% CI: 43–86) and 62% (95% CI: 41–80), respectively. The cumulative incidence of relapse was 38% (95% CI: 20–58). Based on the data obtained in our work, we can conclude that the use of targeted or immunotherapy provides a statistically signifiant improvement in overall survival (OS) (p = 0.013). This is associated with both factors: a more sustained remission prior to auto-HSCT and the availability of effctive treatment for some patients (mainly for the patients with anaplastic large cell lymphoma) in case of relapse after auto-HSCT. The achieved long-term survival rate is comparable or even slightly superior to the data previously obtained by other researchers. Almost one third of the patients suffred from primary mediastinal large B-cell lymphoma, and this is one of the possible reasons for higher long-term OS and EFS rates compared to the previously published results. Moreover, the presence of 6 patients with R/R anaplastic large cell lymphoma with a more favorable prognosis, and, probably, the absence of the morphological confimation of R/R NHL (“second look”) in some patients (n = 20, 65%) could have inflenced the survival rates, which does not exclude the possible inclusion of a number of cured patients in the work. The importance of our work lies in the fact that a signifiant part of the patients (n = 25, 80%) underwent targeted or immunotherapy. This allowed us to show the effctiveness of transplantation in different types of NHL in children in the so-called era of immunotherapy. Auto-HSCT is an effctive and relatively safe treatment strategy for children with R/R NHL which makes it possible to achieve a cure in a signifiant number of patients. The use of targeted and immunotherapy improves the prognosis in transplanted patients. A second biopsy is recommended to confim R/R NHL.