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Introduction. Аngioimmunoblastic T-cell lymphoma (AITL) is a T-cell lymphoma, characterized by abundant polymorphocellular infiltrate of lymph nodes with the small number of tumor CD4 + T-cells. AITL could often be misdiagnosed as reactive processes and other lymphomas, including Hodgkin’s lymphoma. Molecular methods of determining clonality are used to confirm the diagnosis. TCR gene rearrangements detected in the lymph nodes may not coincide with those detected in the bone marrow (BM), blood or skin, that makes their interpretation difficult. Recently discovered point somatic RHOA (Ras homolog gene family, member A) Gly17Val mutation is present in 53–71 % of angioimmunoblastic T-cell lymphomas. The aim of the study was to evaluate the number of RHOA Gly17Val mutated cells in different tissues of AITL patients and to correlate it with corresponding T-cell clonality results. Materials and methods . TCRG and TCRB gene rearrangements were PCR-amplified according to BIOMED-2 standardized protocol and analyzed by capillary electrophoresis on ABI Prism 3130. Gly17Val mutation was analyzed by quantitative allele-specific (qAS) TaqMan Real-Time PCR assay. Lymph nodes (LN) and skin biopsies, blood and BM samples were studied for 40 patients with AITL. Results. The clonal TCR gene rearrangements were found in 37 (92 %) of 40 patients in LN and in 26 (96 %) of 28 patients in BM, but they were not matched in length in LN and BM in 12 (46 %) of 26 patients. RHOA (Gly17Val) mutation in LN was revealed in 60 % (24 of 40) patients. Number of cells with RHOA mutation was highest in the LN (in average 26.7 % of the total cells), while in the BM RHOA mutation were undetectable (in 7 patients), or detected in 10 patients in a low quantity (in average 2 % of the total cells). Skin, blood and BM samples with the T-cell clonality peaks that differ from those found in the LN were also negative for the presence of cells having RHOA Gly17Val mutation. Also, in four patients we showed that clonal products in BM and blood that do not coincide with LN refer to CD8+ lymphocytes. Conclusions. The results of the study demonstrate that the quantitative determination of cells with the mutation of RHOA Gly17Val must be taken into account in staging the disease and interpreting the results of T-cell clonality assay. Clonal cells with rearrangements not matching those identified for the LN should be considered reactive.

Hydroxycarbamide is an antitumor agent mainly used for treatment of Ph-negative myeloproliferative disorders and sickle cell disease. The development of skin ulcers is a rare but serious adverse event in long-term antitumor therapy. Hydroxycarbamide-induced ulcers are often multiple and bilateral, and usually occur in the lower legs, although they can occur in other regions of the body. The ulcers are smallsized and shallow with sharp margins and yellow fibrine-covered base. They cause constant severe, difficult to treat pain which is a characteristic sign. The drug withdrawal usually leads to spontaneous healing of ulcers. Regular dermatologic screening must be obligatory for all the patients receiving hydroxycarbamide. The present paper provides a literature review on dermatological toxicity of hydroxycarbamide and a clinical case description.

Background: Follicular lymphoma (FL) is characterized by clinical and morphological heterogeneity. It is based on the pathogenetic mechanisms of the development of tumor cells. The identification and assessment of risk factors associated with the course of the disease and treatment outcome in FL is an important task, as it allows to evaluate and predict the effectiveness of therapy. Objective: Identify and estimate risk factors for overall survival (OS) and progression free survival (PFS) in FL. Patients and Methods: The prospective exploratory study conducted at National Research Center for Hematology (Moscow) from 01/2017 to 04/2021 included patients (pts)(in total, 80) with FL. Morpho-immunohistochemical, cytogenetic and molecular studies were performed on biopsies of lymph nodes taken before the start of therapy. The mutational status of exon 16 and intron polymorphism rs_2072407 of the EZH2 gene were investigated by Sanger sequencing. 18q21/BCL-2 rearrangements were determined by conventional cytogenetic analysis and/or FISH study. The results obtained in a blind study were compared with the effect of the therapy. Results: Of the 80 pts 34 were male: Me (median) age 50 years (range 30-72) and 46 were female: Me 56 (range 21-81). The median follow-up (FU) time was 53 months. As a result of the study in the multivariate Cox regression model (likelihood-ratio test, p=0.01) of significant factors, selected in the previously univariate analysis, the following statistically significant (Wald test) risk factors for OS and PFS (the events: progression, relapse, or death) were obtained: • BCL-2 gene rearrangements (no vs yes) • EZH2 gene genotypes (AA/AG vs GG) • proliferation index Ki-67 (>35%) • morphological grade (3А vs 1/2) • tumor size (>6 cm /bulky/) (Tab. 1, Fig. 1) The BCL-2 rearrangements were found in 45 from 80 pts (56%; 95 % CI 45-66). The probability of BCL-2 rearrangements is estimated to be about 0.5 (50%). According to the results of Cox-regression analysis (by OS) in the absence of BCL-2 rearrangements, the risk of death in FL was generally significantly (p = 0.01) higher than in the group with its presence: HR = 4.3 (95 % CI 1.5-13.0) (Fig. 2) Mutations in the 16th exon of the EZH2 gene (mutEZH2) were found in 10/80 (13%) pts. Analysis of EZH2 gene mutations with BCL-2 rearrangements revealed that in the mutEZH2 group with the presence of BCL-2 rearrangements, the number of deaths associated with progression is significantly less than in the control initial groups (mutEZH2 with BCL-2 rearrangements - 0/6, mutEZH2 without BCL-2 rearrangements - 2/4, wEZH2 with BCL-2 rearrangements - 3/39 (8%), wEZH2 without BCL-2 rearrangements - 11/31 (35%)) . The prognostic significance of EZH2 genotypes in lymphomas was studied for the first time in this study. The frequencies of rs_2072407 genotypes were: AA - 24% (19), AG - 42% (34), and GG - 34% (27). AA and AG genotypes of the EZH2 gene in pts with FL were associated with an increased risk of death (compared to the GG genotype) : HR = 2.9 (95% CI: 1.2-10.6), p = 0.01 (Fig. 3). The GG variant in most cases was associated with wEZH2 (26/27 (96%)) with BCL-2 rearrangements (16/26 (62%)) and a favorable prognosis (26/27 (96%)) (p = 0.01). Index of proliferative activity Ki-67> 35% (n = 40) and Ki-67 ≤ 35% (n = 40) were equally common in the study group. With a Ki-67> 35%, the probability of death is 2.9 (95% CI 1.1-9.7) times higher. The frequency distribution of morphological grade was as follows: grade 3A - 53% (n = 43) and grade 1-2 - 47% (n = 37). At grade 3A, the probability of death is 2.5 (95% CI 1.1-7.8) times higher. The number of pts with tumor size >6 cm (bulky) and ≤ 6 cm in the sample is approximately the same (41 and 39, respectively), the presence of bulky increased the mortality risk by 2.1 (95% CI 1.0-6.5) times. A short time from the manifestation of the disease to appeal to medical care is a predictor of poor prognosis, but this result we received earlier on a large sample of pts was not significant on a smaller sample. Conclusions: As a result of the multivariable Cox regression analysis, we identified and confirmed the previously obtained factors (bulky, grade 3A, Ki-67 > 35%, short medical history), and discovered new biogenetic factors (BCL-2 rearrangements and the GG rs2072407 genotype of the EZH2 gene). The model based on these independent risk factors improves the accuracy of predicting adverse events and allows to use more personalized treatment options for patients with FL. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Context CD23 expression in follicular lymphoma (FL) is associated with better overall survival (OS). It is known that FL cases with inguinal lymph node lesions and large-cell morphology are characterized by CD23 expression, which is a distinctive feature of these patients whose prognosis is also favorable. However, the CD23 prognostic significance in various FL morphological grades and other tumor lesion localization is unclear. Objective To determine the CD23 expression prognostic value in different FL grades. Design CD23 expression pattern was evaluated by immunohistochemistry. Three groups of patients were identified: expression is absent (CD23neg), intense expression in all cells (CD23bright), expression is weak and/or only present in a portion of tumor cells (CD23dim). Patients The study included 206 FL patients, including 93 FL1–2 grade, 68 FL3A, 45 FL3B, and transformation into DLBCL. In 102 patients, inguinal region involvement was noted. Results In general, OS was similar for the CD23neg, CD23bright, and CD23dim groups. There was also no correlation between OS and CD23 expression in patients with and without iliac region involvement. However, we found that CD23 prognostic value depends on FL grade. In FL1–2 and aggressive FL, there was no association between OS and CD23 expression. In FL3A patients, OS in the CD23dim group was lower than in the CD23neg and CD23 bright groups. The 5-year OS in the CD23neg, CD23bright, and CD23dim groups were 91%, 87%, and 65%, respectively. The level of these differences tended to be significant (log-rank test, p=0.09). Conclusions The previously shown association between CD23 expression, lesion localization, and OS was not confirmed. However, CD23 expression pattern analysis revealed a fact not previously known. The intermediate CD23 expression pattern is an unfavorable prognostic factor in FL3A patients. It is worth noting that combining CD23dim with CD23neg into a single group resulted in a “favorable” status compared with the CD23bright group. Thus, expression cutoff is important, and we assume this phenomenon has not been previously noted because the true CD23bright value was not identified. The heterogeneous CD23 expression in the tumor population probably indicates clonal tumor heterogeneity, which correlates with an unfavorable disease course.

Background. Grade 3 follicular lymphoma (FL) is a heterogenetic group of tumors. The selections of patients with similar characteristics of the tumor process is important for classification 3 grade forms of FL and risk stratification, as well as for the development of new therapeutic approaches. Different morphological, immunohistochemical and cytogenetical characteristics of the tumor result in different clinical forms of the disease. Aim. To describe the clinical, morphological, immunohistochemical and cytogenetical characteristics of grade 3 FL and evaluate their prognostic value for R-CHOP-21 chemotherapy. Materials & Methods. We performed retrospective and prospective analysis of morphological, immunohistochemical and genetical characteristics of 93 primary patients with grade 3 FL (21-78 years, median 53 years, women to men - 1:1.4) admitted to National Medical Hematology Research Center from years 2001 to 2016. Morphological and immunohistochemical assessment of the affected lymph nodes and bone marrow biopsy material was performed. Data obtained from the standard cytogenetic and FISH assessment were compared to identify the BCL2 rearrangement. Results. We proposed an algorithm for differential diagnosis of the 2 types of grade 3 FL: de novo FL (n = 22) and transformed FL (n = 21). De novo grade 3 FL had the immunophenotype of CD10- in 19 (86 %) cases, MUM1++ (monomorphically) in 19 (90 %), and BCL-2 in 5 (22 %). It was characterized by the absence of the BCL2 rearrangement (n = 22, 100 %) and bone marrow involvement (n = 14, 67 %) and/or bone marrow involvement (n = 7, 100 %). Third grade FL transformed from grades 1 or 2 had was CD10+ (n = 19, 90 %), MUM1+ (heterogeneously, n = 16, 76 %) or MUM1-(n = 4, 19 %), BCL-2+ (n = 20, 95 %) and had BCL2 rearrangement (n = 19, 90 %). Small cell bone marrow involvement was observed in 71 % of cases, whereas large cell involvement was seen predominantly in de novo FL (p = 0.06). The analysis showed that 5-year relapse-free survival in patients with grade 3 de novo FL after R-CHOP-21 therapy was 87 % compared to 16 % with transformed FL (p = 0.06) for the median 41 months of follow up. Conclusion. We described the morphological, immunohistochemical and cytogenetical characteristics of grade 3 de novo FL and grade 3 FL, transformed from grades 1 or 2. The described variants show different sensitivity to immunochemotherapy.

The aim of the present paper was to evaluate the clinical features and risk of thrombotic events (TE) in patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF), depending on the molecular characteristics of disease. Clinical data and laboratory parameters were analyzed in 50 ET patients and 50 PMF ones who had been followed up at the Department for Standardization of Treatments, National Research Center for Hematology, Ministry of Health of the Russian Federation, from February 2015 to September 2016. The patients with ET and those with PMF were found to have a high risk of TE. The risk for TE in the patients with ET is higher (24% in the entire group) than in those with PMF (14% in the study group). In ET, there is a high thrombosis risk in the detection of JAK2 and CALR gene mutations as compared with triple-negative cases. The PMF patients with JAK2 V617F mutations are at high risk for TE compared to those who are CALR mutation carriers and in triple-negative cases. There was no significant association of TE with high thrombocytosis. A factor, such as age, was found to be of no negative prognostic value in the patients with PMF.Целью представляемой работы являлась оценка клинических особенностей, риска развития тромботических осложнений (ТО) у больных эссенциальной тромбоцитемией (ЭТ) и первичным миелофиброзом (ПМФ) в зависимости от молекулярной характеристики заболевания. Проведен анализ клинических данных, лабораторных показателей у 50 больных ЭТ и 50 больных ПМФ, наблюдавшихся в отделении стандартизации методов лечения ФГБУ ГНЦ МЗ РФ с февраля 2015 г. по сентябрь 2016 г. Выявлено, что больные ЭТ и ПМФ имеют высокий риск развития ТО. Риск развития ТО у пациентов с ЭТ выше (24% во всей группе), чем у больных ПМФ (14% в обследованной группе). При ЭТ имеется высокий риск тромбозов в случае выявления мутаций генов JAK2 и CALR в сравнении с 'тройными негативными' наблюдениями. Больные ПМФ с мутацией V617F гена JAK2 имеют высокий риск развития ТО по сравнению с пациентами - носителями мутации CALR и в 'тройных негативных' случаях. Не выявлено достоверной ассоциации ТО с высоким тромбоцитозом. У больных ПМФ не выявлено негативного прогностического значения такого фактора, как возраст.

Primary mediastinal large B-cell lymphoma (PMBCL) is a distinct type of large B-cell lymphoma. In this type of the disease, the neoplastic process is located in the anterior and superior mediastinum, frequently with compression of the superior vena cava and with tumor invasion into the adjacent organs and tissues: the pericardium, lung, pleura, etc. Despite the fact that in PMBCL progression, there may be involvement of extranodal organs, such as the kidney, adrenal glands, liver, and central nervous system, bone marrow (BM) injury is generally absent. Since BM injury in patients with diffuse large B-cell lymphoma is an independent poor prognostic indicator, there is reason to believe that BM involvement in PMBCL affects the prognosis. These cases may need intensified induction therapy followed by autologous hematopoietic stem cell transplantation; and BM injury should be monitored during the therapy. The paper gives reports of clinical cases of bone marrow involvement in 2 PMBCL patients treated at the National Research Center for Hematology, Ministry of Health of the Russian Federation.Первичная медиастинальная В-клеточная крупноклеточная лимфома (ПМВККЛ) является отдельной формой В-клеточной крупноклеточной лимфомы. При этой форме заболевания опухолевый процесс локализуется в переднем и верхнем средостении, нередко со сдавливанием верхней полой вены и прорастанием опухоли в прилежащие органы и ткани: в перикард, легкие, плевру и т.д. Несмотря на то что при прогрессии ПМВККЛ возможно вовлечение таких экстранодальных органов, как почки, надпочечники, печень и центральная нервная система, поражение костного мозга (КМ), как правило, отсутствует. Поскольку поражение КМ у больных ДВККЛ является независимым признаком неблагоприятного прогноза, есть основания предположить, что вовлечение КМ при ПМВККЛ влияет на прогноз. В подобных случаях, возможно, необходима интенсификация индукционной терапии с последующей трансплантацией аутологичных стволовых кроветворных клеток, а в ходе терапии следует проводить мониторинг поражения КМ. В статье представлены описания клинических случаев с поражением КМ у 2 больных ПМВККЛ в ФГБУ ГНЦ МЗ РФ.

Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) is a rare subgroup of lymphomas. This disease is predominantly found in older people and often has extranodal involvement including skin and soft tissues. To verify the diagnosis, it is necessary to perform histological and immunohistochemical tests, which show the expression of CD30 activation antigen in different proportions (less than 10 %, not more than 80 %) in addition to the expression of other T-cell antigens (CD2, CD4, CD5, CD7). When choosing the induction regimen in older people with relevant cardiac history, it is preferable to use non-anthracycline-containing chemotherapy courses. However, despite the low intensity of such regimens, treatment of elderly patients is associated with high risk of side effects. Using new drugs (monoclonal antibodies, epigenetic agents) in combination with polychemotherapy is a promising direction opening a possibility of successful management for all patients including those older than 65 years. In the described clinical case of PTCL-NOS, the patient had primary refractory disease. Significant clinical response (complete remission) was achieved as a result of targeted therapy with brentuximab vedotin containing anti-CD30 chimeric antibody conjugated to a microtubuledisrupting agent (monomethyl auristatin E) without toxicity and any infections. In case of ambiguous situation (an increase in the size of one of the tumor sites with regression of others, signs of infection – hyperemia, perifocal edema, the spread of the necrosis zone), histological verification is necessary to confirm the disease progression.

The diagnosis of myeloid tumors is based on a complex approach and causes significant difficulties especially in young children. Morphologic, immunologic, cytogenetic, molecular and biologic data on myeloid sarcoma are presented based on the literature data and own clinical case. Treatment results of myeloid sarcoma (especially in the high risk group) are unsatisfactory and should be improved.

Introduction: Myeloma cast nephropathy (MCN) is a main cause of acute kidney injury (AKI) at multiple myeloma (MM) onset. Wherein 5-9% of newly diagnosed MM patients are dialysis dependent. The introduction of novel agents has provided the achievement of rapid and deep hematologic response in most patients. However, the renal response in patients on dialysis is only 38-62.5%. The predictors of AKI reversibility in patients with MCN remain not enough studied. Aim: to determine clinical, morphological and immunohistochemical predictors of reversibility dialysis dependent AKI in patients with MCN. Materials and methods: 36 patients aged 38 to 74 years (median age=57 years) with newly diagnosed MM and dialysis dependent AKI stage 3 (AKIN, 2012) due to MCN were enrolled into the study from January 2006 till November 2019. The diagnosis of MM, hematologic and renal response were established according to the 2016 IMWG criteria. MCN was determined by renal biopsy performed prior to induction therapy. The assessment degree of acute tubular injury, tubular atrophy and interstitial fibrosis (IF/TA) were semi-quantitatively evaluated. The number of sclerotic glomerular were calculated manually. The median number of casts was defined by all casts in a section divided by number of fields observed (х100). Additionally, square of interstitial fibrosis, interstitial inflammation, expression of Immunohistochemical markers (E-cadherin, α-smooth muscle actin (α-SMA), vimentin) were measured by computerized quantitatively image analysis using the digital module Leica (Germany). The time from diagnosis of AKI to start of induction therapy did not exceed 3 months. Bortezomib based first line treatment regimen was used in 25 (69%) of patients; 9 (25%) patients received chemotherapeutic agents only, 2 (6%) dead before a start of induction therapy. Statistical software package SAS 9.4 was applied for calculations. Overall survival according to renal response was compared by using Kaplan-Meier curves. Also frequency, logistic, discriminant and ROC analysis were used. All estimates are shown with a 95%CI. Results: Hematologic partial response or better occurred in 19 (53%) of patients, median of 32 (13-129) days. Renal response - in 14 (39%). In 3 (8%) cases renal function improved after correction of dehydration before start of antimyeloma therapy, in the remaining 11 (30%) patients only when hematologic response was achieved (p = 0.001). The frequency of renal response was depending on start of antimyeloma therapy before and after 4 weeks from diagnosis of AKI and was 83% and 17%, respectively (p Patients with hematologic response were divided into two groups (Tab.). The main pathological findings associated with renal response were less frequent mild to severe IF/TA in patients with and without renal response (moderate 45% vs 75%, respectively, p=0.008), less area of interstitial fibrosis (24.9% vs 44.7%, respectively, p=0.001), percentage of proximal tubules with save epithelial phenotype and less area of expression E-cadherin at interstitium (15.9% vs 7.1%, respectively, p=0.006). The median number of casts per field was the same (6.4 and 6.3, p=0.64) as well as the percentage of tubule lumen obstruction by casts (13.6% and 15.1%, p=0.81). Statistically significant correlation between the expression area of E-cadherin and interstitial fibrosis was not found (Rs= -0.335, p= 0.065). Therefore, a combination of these factors can be used to predict renal response in the onset of AKI due to MCN (area under the ROC curve is 0.84). The prognostic model and logical rule allow to define groups of renal outcomes (Fig.). If expression area of E-cadherin is less than 10% and / or area of interstitial fibrosis is more than 40% of the interstitium, a renal response is unlikely (OR = 24.5) and will not be achieved in almost 90% of cases, despite hematological response. Discussion. Reversibility of dialysis dependent AKI due to MCN rely on the achievement of hematological response and the time from diagnosis of AKI to start of antimyeloma therapy. There are predictors of renal response of these patients determined by the severity of morphological changes: degree of IFTA, quantitative area of interstitial fibrosis and E-cadherin expression. Disclosures No relevant conflicts of interest to declare.

Context: Composite lymphomas (CL) can occur simultaneously or sequentially and are of a particular interest in hematology. Objective: Approaches to the diagnosis and treatment of CL are complex with a full range of modern laboratory methods. Design: Analysis of cases of CL with histological and molecular features of these cases. Setting: Study setting can be used in hematological inpatient and outpatient departments. Patients: There were 37 cases of CL (M:F=2:1, median age 64 (38-83 years)). Interventions: All patients underwent a full range of diagnostic procedures, including histological, immunophenotypic, cytogenetic and molecular tests. Main outcomes measures: Study the combination types of CL. Results: Metachronous CL were observed in 17 cases; synchronous CL in 20 cases. Metachronous CL cases: the most common type of the second lymphoma was diffuse B-large cell lymphoma (DBLCL) with 58.8% and Hodgkin's lymphoma (HL) with 29.4%. In 30% of cases, DBLCL developed after HL therapy, and in 30% - after therapy of angioimmunoblastic lymphoma. The median time to development of the second lymphoproliferative disease (LD) was 6 years (range 7 mo - 40 yrs). Synchronous CL were observed in 55% of cases; the most common were the combination of chronic lymphocytic leukemia (CLL) with other LD, hairy cell leukemia (HCL) 54.5%, large granular lymphocytic leukemia, marginal zone lymphoma (MZL), follicular lymphoma, multiple myeloma, and fungal mycosis. Combination of HL with other LD was observed in 25% of cases (HL+MZL represent 60% of cases). It is not clear whether HL in this combination represents a clonal transformation from MZL cells or it is a secondary tumor that develops de novo after MZL treatment. Since common IGVH gene rearrangements and somatic mutation status could be detected for both types of cells; this may indicate that MZL and HL cell clones may originate from a single B–cell of the follicular germinal center. Conclusions: Careful examination is needed in atypical clinical course of lymphomas to exclude the second LD, including clonally related. CL are excellent models for studying the complex process of tumor cells evolution during the course of the disease. Treatment of CL is a non-trivial task and aims to control both diseases.

Mediastinal gray-zone lymphoma (MGZL, lymphoma with features intermediate between classical Hodgkin lymphoma and diffuse large B-cell lymphoma) was declared as a separate entity in WHO classification of Tumors of Haematopoetic and Lymphoid Tissues in 2008 and 2017 years. Despite of similar pathomorphological characteristics between primary mediastinal B-cell lymphoma and Hodgkin lymphoma, clinical features and optimal therapeutic approach to MGZL are not clearly defined. Usually MGZL manifests with mediastinal lymphadenopathy, although extranodal lesions often occur (grey-zone lymphoma, GZL). Patients with MGZL have unfavorable prognosis, taking into account high rate of relapse. This article describes two cases of MGZL. First case manifested by arrhythmias due to primary heart involvement. In spite of cardiac failure antracycline-containing chemotherapy (6 courses of R-DA-EPOCH) it allowed to achieve a complete remission and resolving of arrhythmias. Second case was represented by metachronous tumors: primary mediastinal B-cell lymphoma at the time of disease onset and classical Hodgkin lymphoma, NS II, diagnosed after disease progression. Thus, we demonstrated two examples of MGZL that differ by clinical manifestation, response to chemotherapy, which emphasizes an importance of pathogenesis studying, and using of new therapeutic approaches.

At present diagnosis of acute leukemia does not represent any difficulties and is based on morphological and immunophenotypical bone marrow studies. The paper presents a non-standard verification algorithm of acute monoblastic leukemia in elderly female patient, with leukemic skin lesion. Morphologic and immunohistochemical studies of biopsy materials of skin, lymph node and bone marrow allow establishing a linear membership of tumor cells and promptly verifying the diagnosis of leukemia. Lack of the overall clinical examination in such cases leads to diagnostic errors and to late verification of the true diagnosis and significantly worsens the prognosis.

Stevens-Johnson syndrome is a severe delayed type systemic allergic reaction which affects the skin and mucous membranes. In adults, Stevens-Johnson syndrome is usually caused by the administration of drugs or a malignant process. The paper presents a case of Stevens-Johnson syndrome after the treatment of a female patient with small lymphocytic B-cell lymphoma, autoimmune hemolytic anemia and antiphospholipid antibody syndrome with rituximab. A rare combination of Stevens-Johnson syndrome and small lymphocytic B-cell lymphoma of small lymphocytes, as well as the development of severe delayed type systemic allergic reaction to introduction of rituximab are of special interest. A detailed medical history and the clinical manifestations of the disease allowed to diagnose Stevens-Johnson syndrome at early stages and prescribe an adequate therapy. As a result of the treatment, the patient’s condition has improved considerably. Symptoms of general toxicity were arrested completely; there was a complete epithelization of erosive defects. Therefore, the presented clinical observation shows that timely diagnosis, complex drug therapy, and comprehensive care can cure the diseases as soon as possible and prevent complications.

Aim. Pathomorphological, immunophenotypical and clinical characteristics of a new clinico-morphological form of pediatric-type follicular lymphoma (FL) in young adults discovered in 2008 (WHO classification). Background. FL is a heterogeneous disease according to its morphological, immunophenotypical and molecular-genetic characteristics. FL de novo includes transformed FL, FL without t(14;18), FL with diffuse growth associated with del(1p.36) and TNFRSF14 mutation. Pediatric-type FL in young adults is poorly studied; and it is especially interesting because of its clinical diversity and molecular-genetic heterogeneity of FL, in general. Methods. Biopsy materials taken from 5 patients (aged 18-25 years; median age: 22 years; the female/male ratio 3:2) were included in the study; all patients were examined, diagnosed and treated in the Hematology Research Center over the period from 2012 to 2016. Clinical stage I with isolated involvement a palatine tonsil or an inguinal lymph node was diagnosed in 4/5 patients; clinical stage II with involvement of a palatine tonsil and cervical lymph node was diagnosed in 1/5 patients. Morphological, immunophenotypical and FISH tests were performed with paraffin blocks. Results. The morphological pattern was typical for FL 3B (n = 2) and FL 3 with blastoid nucleus morphology (n = 3). Immunophenotypical features demonstrated an intermediate position between FL 3 de novo and transformed FL 3. No BCL-2 rearrangement was detected in any observation. Conclusion. The comparison of our data on characteristics of pediatric-type FL with those published in the literature demonstrated that lack or weak expression (< 30 % of tumor substrate cells) of MUM1 was the key feature of the experimental group of young adults with pediatric-type FL. This, in turn, indicates the absence of IRF4 rearrangements and possible presence of other genetic abnormalities. The clinical, morphological, and immunophenotypical characteristics broaden the FL heterogeneity spectrum in young adults.

Background. The most common diseases among cutaneous T-cell lymphomas are mycosis fungoides (MF) and its leukemic variant Sezary Syndrome (SS). These malignant tumors have a progressive character course. To date, no therapy for these diseases has proven effective, especially in the late stages of the disease. Aim. We aimed to assess the effectiveness of treating resistant forms of MF/SS with prolonged gemcitabine regimen after initial treatment failure. Materials & Methods. The study included 14 patients with drug-resistant forms of MF/SS (10 patients with MF, 3 patients with SS, and 1 patient with the transformation of MF into large cell lymphoma). The median age was 62 years (range 34-78 years). The study population included 9 males and 7 females. Gemcitabine was administered at a dosage of 250 mg/m2 as a 6-8 hour IV infusion weekly, in a cycle of 21-28 days. Results. The overall response was 79 % (29 % of patients with complete remission, 50 % of patients with partial remission). In 21 % of patients, the treatment results met the criteria for tumor stabilization. The disease progression was observed in 2 (14 %) patients. This study demonstrates the potential of using prolonged gemcitabine regimen in patients of different age groups with advanced resistant MF/SS who received at least two courses of previous ineffective therapy. In order to evaluate long-term results, further research is needed. Conclusion. The administration of prolonged gemcitabine regimen may be a treatment of choice in resistant forms of MF/SS after initial treatment failure in different age groups including elderly patients.

Purpose. The identifying of the clinical, morphological, immunophenotypic and cytogenetic features of double-hit and double-expressor lymphomas as well as the development of optimal tactics of treatment and evaluation of efficiency of the ASCT were the main purposes of the study. Material and methods. The study included 85 patients: 45 males and 40 females, the median was 46,6 years (15-73). 62 patients with DLBCL and 23 with BCLu were given BL-M-04/ m-NHL-BFM-90 regimes in Hematological Scientific Center and Municipal Clinical Hospital №52, 2001-2015. Results. Stage I was diagnosed in 5 (6%) patients, II - in 13 (15%) patients, III - in 7 (8%) patients, IV - in 60 (71%) patients. Double-hit lymphoma was diagnosed in 6 (7%) patients (5 MYC+/BCL2+, 1 MYC+/BCL6+), single-hit lymphoma was diagnosed in 6 patients. The translocation was detected in 5 of 12 cases t(8;14)(q24;q32), in 1 case of 12 - t(2;8)(p21;q24), in 2 cases of 12 - t(8;22)(q24;q11) (restructuring c-MYC and IGL gene loci have been identified), in 3 cases of 12 - restructuring of c-MYC with non-IG partner [translocation was absent t(8;14)(q24;q32) and restructuring IGK and IGL gene loci], the partner was not identified in one case of translocation with c-MYC gene [restructuring c-MYC gene loci was identified and translocation was absent t(8;14(q24;q32)]. 8 factors had prognostic significance in relation to OS: nosology - BCLu vs DLBCL (p=0.007; RR=4.5), bone marrow lesion (p=0.0004; RR=7.9), B-symptoms (p=0.0002; RR=8.4), BCL2 expression (I=0.01; RR=4.4), MYC/BCL2 coexpression (p=0.017; RR=0.08), double-hit or double-expressor lymphomas (p=0.009; RR=15.1), the absence of rituximab in therapy (p=0.03; RR=0.3), unfulfillment of ASCT (p=0.003; RR=0.06). Two factors were significant in relation to probability of development of recurrence/progression: double-hit or double-expressor lymphomas (p=0.0005; RR=4.0) and IPI (p=0.03; RR=4.9). Conclusions. Thus, complex diagnostic includes the antibody to the BCL2 (clone 124, Dako) and MYC (clone Y69, Epitomics), and the conduct of standard cytogenetic analysis (SCA) and FISH to detect rearrangements of MYC, BCL2, and BCL6 genes in addition to standard immunohistochemical panel for aggressive B-cell lymphomas. It allows not only to establish the correct diagnosis (DLBCL, BCLu or LB), but also to detect the double-hit and double-expressor lymphomas, which require intensive induction with rituximab and high-consolidation ASCT in first remission.

Anaplastic large cell lymphoma (ALCL) includes different types of the disease that are heterogeneous according to clinical, morphological, immunological, cytogenetic and molecular biological features. The review demonstrates not only main clinical and morphoimmunological characteristics of ALCL, but also presents data about expression and prognostic significance of STAT3, pSTAT3tyr705 (transcription factor), and survivin (apoptosis inhibitor). It demonstrates the value of defining the minimal disseminated disease (the minimal disseminated disease is evaluated using the PCR test before initiation of the treatment, and the minimal residual disease is evaluated during the treatment and after its completion), and clinical and molecular biological prognostic factors are also identified. There is still no a standard therapeutic regimen for pediatric ALCL patients. However, the following therapeutic protocols are considered most effective: NHL-BFM 90/95, CCG5941, SFOP-LM 89/91, UKCCSG, ALCL99-Vinblastine, POG АРО 9315, AIEOP LNH-92/97. Treatment outcomes are presented in this paper. Particular attention is paid to different molecular biological markers that allow further improvement of patients’ stratification in risk groups and possible use of target medications (multikinase inhibitors and monoclonal antibodies) improving the therapy outcomes.

Background: Anaplastic large cell ALK-positive lymphoma (ALCL ALK+) is a lymphoproliferative disease of the “young” age. ALCL ALK+ has a favourable prognosis. A failure in therapy (relapse) is diagnosed within the first 1.5-2 years of the follow up period. Aim: The aim of the present study was to compare the effectiveness of the NHL BFM-90 and CHOEP protocols intended for the treatment of adult patients presenting with the ALCL ALK+. Materials and methods: This prospective comparative randomized study was carried out based at the National Medical Research Centre of Hematology, Moscow, during the period from June 2014 to December 2019. It involved 23 patients with the ALCL ALK+ disease randomly allocated to two groups. One of them included 11 patients given a CHOEP, the other consisted of 12 patients treated using a high-dose CT in accordance with the NHL BFM-90 protocol (age medians 33 and 40 years respectively). Results: The 3-year OS and EFS rates among the patients receiving CHOEP was 91%, with all the members of this study group having completed the treatment regimen. All patients comprising the latter (NHL BFM-90) group achieved complete remission. However, only 9 of the 12 patients fully complied with the treatment protocol because of its toxic effects. It can be inferred that the two study groups are comparable in terms of the 3-year OS and EFS rates among the patients treated in accordance with the CHOEP and NHL BFM-90 programs, the differences between them being insignificant. Conclusion: High-dose CT based on the NHL BFM-90 protocol has no advantages over the less toxic CHOEP regimen as far as the treatment of the ALCL ALK+ is concerned (if the efficacy of both modalities is estimated in terms of the 3-year OS and EFS rates). However, additional studies with larger patient samples are needed to obtain statistically significant results before a definitive conclusion can be made as regards clinical feasibility of the use of high-dose therapeutic regimens for the treatment of adult patients presenting with the ALCL ALK+ disease.

Purpose of the study. To provide demographic, clinical, laboratory, ultrasound, radiological, morphological/ immunomorphological phenotype of IgG4-related ophthalmic diseases, which allowsmaking a differential diagnosis with granulomatous, autoimmune, inflammatory, endocrine and hematologic diseases affecting the eye and orbits. Materials and methods. From 2004 to 2016 108 (78.2%) of the 138 patients were diagnosed with non-tumoral lesions of eye and orbits. In 48 patients (35%) at admission and 5 patients in the follow were diagnosed IgG4-related ophthalmic disease. In the analysis of 82 (f-44, m-38) patients with IgG4-related disease, localization of lesions in orbit observed in 53 (f-36, m-17) and it was the most frequent involvement in patients with IgG4-related disease (64.5%). Only 7 patients had isolated IgG4-related ophthalmic disease, whereas 46 patients (87%) had involvement of 2-7 locations, as a manifestation of IgG4-related systemic disease.During the examination, the average age of patients with IgG4-related ophthalmic disease was 47.5 years (19-73 years). Median time to diagnosis was 52.8 months before 2004 and 36 months 2004-2016. Results. We noted the predominance of females in the ratio 2: 1 inthe group of patients with IgG4-related ophthalmic disease. Edema of the eyelids, nasal congestion (55-60%), tumor-like formations of the upper eyelids and increased lacrimation prevailed at the onset of the disease, whereas such functional impairment like limited mobility and pain in eyeballs, exophthalmos, ptosis and diplopia appeared later at 15-38% with a loss visual acuity in one case. Bilateral lesion (86%), mainly affecting the lacrimal glands (93.5%), infiltration of the extraocular muscles (83.5%) and retrobulbar tissue with a thickening of the optic nerve in one third of patients were the main localizations IgG4-related ophthalmic disease. Clinical symptoms were accompanied by the appearance of moderate inflammatory activity (38%), increased levels IgG (44%), IgG4(88%) and IgE (61%). Indicators of autoimmune disorders observed in 6-22% of patients, most often in patients with simultaneous involvement of the salivary glands. Significant lymphoplasmacytic infiltration (94%) with a ratio of plasma cells (IgG4/IgG) secreting IgG4> 40% (90%) with fibrosis formation (94%) and follicle formation (71%) with a moderate amount of eosinophils (34%) were the major morphological / immunomorphological manifestations of IgG4-related ophthalmic disease. Signs of vasculitis and obliterative phlebitis were found in a small amount of patients. Conclusion. Determination of elevated levels of IgG-4 / IgE in patients with edema, pseudotumor of the eyelid, sinusitis and increase of the palpebral lobe of the lacrimal gland suggests the presence of IgG4-related ophthalmic disease. Minimally invasive incisional biopsy of lacrimal glands and salivary glands followed by morphological / immunomorphological research is needed for the correct diagnosis. Diagnostic orbitotomy in ophthalmic hospitals in such cases is inexpedient, since it leads to the development of dry eye. Massive lymphoplasmacytic infiltration with IgG4 / IgG ratio more than 40%, advanced fibrosis in biopsiesof the orbits tissue or salivary glands when combined lesions are required for the making the diagnosis of IgG4-related ophthalmic disease.

Purpose of the study. A comparative evaluation of the effectiveness of different therapeutic strategies in patients with polycythemia vera (PV) and essential thrombocythemia (ET). Materials and methods. Patients with PV or ET, diagnosed according to the criteria WHO 2016 were included in the study. The primary endpoint - 6 months of therapy (clinical-hematological and molecular responses). The secondary endpoint - 12 months of therapy (clinico-hematologic, molecular, histological responses). Sixty three patients were included in the analysis: the first group consisted of 33 patients who received the therapy with ce-pegiterferone alpha-2b (ce-pegalpha-INF-α-2b), 10 of them received previous treatment; the second group - 23 patients btained hydroxycarbamide; the third group - 7 patients were treated with recombinant interferon alpha therapy (rINFα). In comparison groups, differences in age were revealed: patients receiving hydroxycarbamide therapy were older. Phlebotomy occurred in 36% of patients in the first group, 9% in the second group, and 14% in the third group. Results. By the 6th month of therapy, 43% of the patients receiving the ce-pegalpha-INF-α-2b had complete clinical-hematologic response, 36% had partial clinical-hematologic remission and stabilization of the disease was established in 21% cases. No disease progression occured. By the 12th month of therapy, statistically significant differences in terms of efficacy between the different therapeutic groups (p = 0.2462, Fisher's exact test). In all three groups, the allelic load of JAK2V617F decreased: from 50 to 19%, from 22.3 to 15.8%, from 50 to 7.19%, respectively. The lower the allele load positively correlated with better response to therapy, which was observed in all analyzed groups. Hematologic adverse events (AEs) were more frequently observed in patients receiving ce-pegalpha-INF-α-2b therapy. Local reactions developed on 3-7 days of therapy as a hyperemic macula at the injection site. Both these reactions and hair loss did not influence on patient’s condition. In the second group (patients with hydroxycarbamide therapy) there were changes in the skin and mucous membranes: dry skin, stomatitis, and in older patients new keratomas appeared. The flu-like syndrome was the most common adverse event associated with the therapy of ce-pegalpha-INF-α-2b, which fully relived during the first month of therapy. There was only one case with the flu-like syndrome we observed at the 11th month of therapy. As a rule, the biochemical blood test changes did not influence on patient’s condition, were mostly associated with dietary violations, had a tendency to self-resolution and did not require medical interventions. Serious AEs were reported in one case - pulmonary embolism in a patient treated with rINFα. The reasons for the therapy discontinue in group 1: toxic hepatitis, intolerance, by the request of the patient, inadequate efficacy of therapy; in group 2: skin toxicity, in group 3: thromboses. The conclusion. Treatment of ce-pegalpha-INF-α-2b in patients with PV and ET is highly effective - the most patients pbtained clinical and hematological responses. There were no statistically significant differences in these parameters in comparison with hydroxycarbamide and rINFα. The use of the ce-pegalpha-INF-α-2b had an acceptable safety profile. The estimated therapeutic dose should be calculated according to body weight. To reduce the frequency of hematologic AE, titration of the drug dose is required.

Background & Aims. Morphological, immunohistochemical, immunophenotypic, cytogenetic, molecular and genetic and other examinations of tissues affected by oncohematological diseases are obligatory. The aim of this paper is to evaluate findings of lung and pleura biopsies in different medical conditions using two basic techniques: thoracoscopy and diagnostic thoracotomy. Methods. Results of morphological examination of lung lesions in patients hospitalized in the Hematology Research Center under the Ministry of Health of the Russian Federation are presented. From 2004 till 2014, 76 biopsies of lung and/or parietal pleura were performed in 73 patients aged 19–77 years via thoracoscopic (48) and/or thoracotomic (28) approach. Results. No thoracoscopy- and thoracotomy-related complications were observed. Bioptate examinations proved to be informative in 66 (86.7%) patients. Lung lesions were most common in lymphoproliferative diseases. Lung involvement in cancer or metastases was twice as common as it has been expected before the biopsy. On the contrary, expected tuberculosis nature of lung lesions in 5 patients was confirmed only in 2 of them. In 18 cases (23.7 %), the cause of lung lesion was other than the expected one, and appropriate adjustments of the therapy were made. Conclusion. New less invasive methods of biopsy combined with complex laboratory diagnosing comply with current requirements and permit making a correct diagnosis of a pathological process located in lungs.

Extranodal NK/T-cell lymphoma – a rare lymphoproliferative disease characterized predominantly by extranodal localization, aggressive course and low efficiency of conventional chemotherapy. Clinical presentation is diverse and depends on tumor lesion localization. In this article, a literature review and case report of patient with generalized extranodal NK/T-cell lymphoma with bone marrow involvement, unusual intracranial tumor localization, tumor leukemization and central nervous system-leukemia were presented. Adequate treatment strategy made it possible to achieve long-term complete remission in a patient with poor prognosis.

Background. Unclassifiable splenic B-cell lymphoma/leukemia is a rare and poorly studied disorder introduced in the WHO classification of hematopoietic and lymphoid tissue malignancies for the first time in 2008. This type of lymphoma requires differential diagnosing between hairy cell leukemia-variant (HCL-V) and splenic diffuse red pulp small B-cell lymphoma (SDRPL). Aim. To develop criteria for diagnosis of SDRPL by comparison of bone marrow biopsies (BMB) and surgical specimens of the spleen. Methods. In the Department of Morbid Anatomy of the Hematology Research Center, preoperative BMBs and surgical specimens of the spleen (2013-2015) were compared in 71 patients (men/women ratio 1:2.6, age range 44-81, median age 58 years) using morphological and extended immunohistochemical studies. Sanger sequencing and PCR assay were carried out to analyze the mutational status of IgHV and to identify mutations in MAP2K1, NOTCH, BRAF. Results. SDRPL was diagnosed in 5 (7 %) of 71 patients. In 2 groups of patients (with normal and high WBC count), the morphological features of spleen tissue were similar to those of a neoplastic substrate of HCL-V. The immunohistochemical assay demonstrates monomorphic expression of CD20 and DBA.44 and heterogeneous expression of CD11c, TRAP, CD103, CD123 in all cases. In none of the 5 cases, expression of CD25, CD27, Cyclin D1, Annexin-1 was found. In bone marrow (unlike HCL and HCL-V), predominantly interstitial and intravascular scant CD20+ lymphoid infiltration (4 of 5 cases) was found without detectable nucleoli in nuclei of small lymphoid cells. In 1 case, there was a combined lymphoid infiltration: CD20+ microfocalinterstitial infiltration with an intravascular component. No persistent molecular mutations in the spleen tissue specimens were found. Conclusion. SDRPL is diagnosed in 7 % of splenic B-cell lymphomas. It is a rare disorder, whose verification requires an integrated approach taking into account clini cal and laboratory data, results of flow cytometry, cytological, morphological, extended IHC and molecular biological studies.

Extramedullary lesions in multiple myeloma occur on the extension of neoplastic plasma cells outside the cortical bone. On the local tumor growth the extramedullary mass are found most commonly in vertebrae, ribs, sternum and skull. Single or multiple malignant mass can be found in the skin, liver, breast, kidney and lymph nodes via hematogenous spread of the malignant plasma cells. Incidence of extramedullary lesions in multiple myeloma patients is 7 to 18% at MM diagnosis and up from 2.3 to 20% at relapse or progression. In the last decade, we noted the increase of extramedullary lesions diagnosis at the beginning of the disease that was associated with the wide use of modern x-ray diagnostic methods. Thus, in 2009 the International Myeloma Working Group (IMWG) recommended undergoing the magnetic resonance imaging scans of the spine and pelvis, especially in the absence of osteolytic lesions according to the results of x-ray study. The results of computer tomography allow more accurately find the localization and the sizes of extramedullary mass. Nowadays, it is widely discussed the advantages of positron emission tomography using not only at the beginning of the disease, but also during the treatment, assessing anti-tumour response. The application of standard therapy in case of extramedullary plasmocytomas at the beginning of MM is associated with the reduction of both overall and progression-free survival. Several articles indicate the high efficiency of the programs including bortezomib, there are also some reports concerning the successful application of lenalidomide and pomalidomide in the treatment of MM associated with presence of extramedullary plasmocytomas.

Background/Objectives. At the present time results of some pediatric protocols (FAB/LMB96 with and without rituximab (±R), B-NHL-BFM90/95, B-NHL-2004m) were published but prognostic significance of markers, such as: non-GCB DLBCL subtype, C-MYC, pSTAT3, BCL2/C-MYC coexpression, C-MYC, BCL2/C-MYC gene rearrangements in childhood DLBCL is unknown. In this article there was presented results of treatment childhood DLBCL according to protocols IDM-NHL-BFM90, B-NHL-BFM95 ± rituximab in view of morpho-immunological tumor’s features.Design/Methods. From 1994 to 2015 fifty one pediatric patients with DLBCL were included in trials IDM-NHL-BFM90, B-NHL-BFM95 ± rituximab. Male/female ratio was 2/1. Median age - 9.9±0.5 years (range from 2 till 16). Stage III-IV were revealed in 29 patients (56.9%), R3-R4-risk group - in 26 (50.9%). GCB/non-GCB DLBCL subtypes were assessed by Hans, Tally and Visco-Young immunohistochemical algorithms. Cutoff values of 40% for MYC, 70% for BCL2, 50% for pSTAT3 were established. MYC gene rearrangement was assessed by FISH using locus-specific MYC (8q24) tricolor breakapart probe, MYC (8q24) SE8 control probe and locus-specific MYC, BCL2, BCL6 dual - color breakapart probes.Results. GCB/non-GCB DLBCL subtypes were revealed in 13 (54.2%) and 11 (45.8%) out of 24 cases; in 10 (41.7%)and 14 (58.3%) out of 24 cases according to Hans algorithm, 10 (43.5%) and 13 (56.5%) out of 23 cases according to Visco-Young algorithm; in 7 (63.6%) and 4 (36.4%) out of 11 cases according to Tally algorithm. There was a trend to determine the difference between GCB/non-GCB subgroups of DLBCL according immunohistochemical algorithms (p=0.058). Ten (62.5%) out of 16 DLBCL samples were positive for MYC, 9 (40.9%) out of 22 - for BCL2, 2 (18.2%) out of 11 - for BCL2/C-MYC coexpression, 1 (9.1%) out of 11 - for pSTAT3. MYC gene rearrangement was revealed in 3 (20%) out of 15 patients. There was determined a statistically significant relationship between MYC expression>70% and MYC gene rearrangement in patients with III - IV stages of disease and R3 - R4 risk group. BCL2 and BCL-6 gene rearrangements were not revealed. Five-year overall survival (OS), event-free survival (EFS) were 90.3±5.3%, a median follow-up was 63.3±7.9 months, relapse-free (RFS) was 100%, a median follow-up was 69.5±7.9 months. There is not revealed any influence of investigated markers on OS, EFS and RFS.Conclusion. Number of patients in this study is not enough to estimate authentic prognostic significance of these markers but high-intensive B-NHL-BFM95 ± rituximab chemotherapy showed good therapeutic effect in our patients. This study will be continued.

Background. At the present time results of some pediatric protocols (FAB/LMB96 with and without rituximab, B-NHL-BFM90/95, B-NHL-2004m) were published but prognostic and diagnostic significance of markers, such as: C-MYC, STAT3, pSTAT3, TRAF1 expression, C-MYC gene rearrangement and amplification in childhood large B-cell lymphomas with mediastinum involvement is unknown. In this article there were presented results of treatment childhood large B-cell lymphomas with mediastinum involvement according to protocols IDM-NHL-BFM90, B-NHL-BFM 95 ± rituximab in view of morpho-immunological tumor’s features.Design/Methods. From 1994 to 2015 twenty two pediatric patients with large B-cell lymphomas with mediastinum involvement were included in trials IDM-NHL-BFM90, B-NHL-BFM 95 ± rituximab. Male/female ratio was 1/2. Median age - 12.2±0.6 years (range from 5 till 18). Median of age was 13.5 years. Stage III-IV, R3-R4 risk groups were revealed in all patients (100%). GCB/non-GCB DLBCL subtypes were assessed by Hans and Visco-Young immunohistochemical algorithms. Cutoff values of 40% for MYC, 70% for BCL2, 20% for STAT3, 50% for pSTAT3tyr705, TRAF1, TNFAIP2 were established. MYC gene rearrangement and amplification were assessed by FISH using locus-specific MYC (8q24) tricolor breakapart probe and MYC (8q24) SE8 control probe.Results. According to the data of this clinical trial there were revealed distinctive features of molecular portrait childhood primary mediastinal (thymic) large B-cell lymphoma that include: CD20 expression in all patients, high frequency of CD23, CD30, C-MYC, PAX5, TRAF1, TNFAIP2 expression, absence of CD10, pSTAT3tyr705 expression, low frequency of IgM expression, absence of C- MYC gene rearrangement and/or amplification despite the level of C-MYC expression more 70%, high activity of JAK2-JMJD2C epigenetic regulation of pSTAT3tyr705 independent C-MYC expression. There is the tendency to the formation of molecular portrait of childhood diffuse large B-cell lymphoma with mediastinum involvement: CD20 expression in all patients, non-GCB variant, high frequency of C-MYC expression, C-MYC gene rearrangement, absence of CD23, TRAF1, TNFAIP2 expression, low frequency of CD30 expression.Using protocol B-NHL-BFM 95 plus rituximab we have achieved high level of relapse-free survival in patients with large B-cell lymphomas with mediastinum involvement. There is not revealed any influence of investigated markers (CD23, CD30, C-MYC) on overall survival, event-free survival and relapse-free survival.Conclusion. Number of patients in this study is not enough to estimate authentic prognostic significance of these markers but high-intensive B-NHL-BFM95 + rituximab chemotherapy showed good therapeutic effect in our patients. This study will be continued.

Aim: To assess the feasibility and informative value of T-cell clonality testing in peripheral T-cell lymphoma (PTCL). Patients and methods: Biopsies of involved sites, blood, and bone marrow samples from 30 PTCL patients are included in the study. Rearranged TCRG and TCRB gene fragments were PCR-amplified according to the BIOMED-2 protocol and analyzed by capillary electrophoresis on ABI PRISM 3130 (Applied Biosystems). Results: TCRG and TCRB gene clonality assay was valuable in confirming diagnosis in 97% of PTCL patients. T-cell clonality assay performed on blood or bone marrow samples reaffirmed lymphoma in 93% of cases, whereas morphological methods were informative in 73% of cases only. We observed multiple TCRG and TCRB gene rearrangements, loss of certain clones in the course of the disease, as well as acquisition of new clones in 63% of PTCL cases, which can be attributed to the genetic instability of the tumor. Conclusion: TCRG and TCRB gene clonality assay is beneficial for the diagnosis of PTCL. However, the presence of multiple clonal rearrangements should be considered. Clonal evolution in PTCL, particularly acquisition of new clones, should not be treated as a second tumor. Multiple TCRG and TCRB gene rearrangements may interfere with minimal residual disease monitoring in PTCL.

Diffuse large B-cell lymphoma (DLBCL) includes heterogeneous disease variants according to clinical, morphological, immunological, cytogenetic and molecular-biological features. Several different pediatric and adult protocols are presented in this article (AIEOP NHL92, B-NHL-BFM90, POG APO - IDM/HiDAC, B-NHL-BFM95, FAB/LMB96, BNHL03, FAB/LMB96 + rituximab, B-NHL2004m + rituximab, R-CHOP, DA-EPOCH-R, RB-CHOP, RBV-CHOP). There were revealed some factors of unfavorable outcome of disease in adult patients with DLBCL, that allow to improve risk group stratification and reduce chemotherapy intensiveness in some patients but require additional study in pediatric patients at the present time. Particular attention is paid to study of sensitiveness to target therapy (anti-CD20 monoclonal antibodies).

To provide the demographic, clinical, laboratory, radiological, morphological, and immunomorphological characteristics of IgG4-related sialoadenitis (IgG4-S), which allow the differential diagnosis with neuroendocrine, granulomatous, blood cancer lesions of the salivary gland (SG).In the period 2004 to 2014, IgG4-S was diagnosed in 32 (11%) out of 289 patients with significantly enlarged parotid and submandibular glands (PG and SMG). Only 4 (9%) patients had isolated IgG4-related disease (IgG4-D) whereas involvement of a few organs ran as an IgG4-SD systemic disease in 29 (91%) patients.There was a slight preponderance of women with a median onset age of 42 years. Enlargement of the SMG (52.7%), lesions of the nasal cavity and paranasal sinuses (37.2%), and enlargement of the lacrimal gland and orbital pseudotumors (31%) are the most common clinical manifestations at disease onset. A follow-up study indicated that along with involvements of SMG (97%), PG (72%), eye sockets (72%), nasal cavity and paranasal sinuses (56%), one third of the patients were found to have generalized lymphadenopathy, to frequently develop pulmonary, hepatic, pancreatic, renal injuries; and the disease ran within IgG4-SD. The laboratory manifestations were characterized by moderate eosinophilia and elevated blood IgE levels in one-third of the patients and by moderately higher erythrocyte sedimentation rate and hypergammaglobulinemia in 50%. The increased blood level of IgG (84%) and its subclass IgG4 (86.4%) is an indication for further verification of IgG4-D in patients with involvement of the major SG. Immunohistochemical examination, by measuring the concentration of IgG4-secreting plasma cells (PCs), and determination of B-cell clonality in biopsy specimens should be done to verify a diagnosis with IgG4-D.The determination of blood IgG4 (2 g/l) in patients with considerably enlarged major SG may suggest the presence of IgG4-S. Minimally invasively incised PG and SMG biopsies with their subsequent morphological and immunomorphological examinations should be performed to make an accurate diagnosis. More than 40% of IgG4-secreting PCs detected in SG tissue is evidence to diagnose IgG4-D.Цель исследования. Предоставить демографическую, клиническую, лабораторную, рентгенорадиологическую, морфологическую и иммуноморфологическую характеристику сиалоаденитов, связанных с IgG4 (IgG4-С), позволяющую проводить дифференциальную диагностику с нейроэндокринными, гранулематозными и онкогематологическими поражениями слюнных желез (СЖ). Материалы и методы. В период с 2004 по 2014 г. у 32 (11%) из 289 больных со значительным увеличением околоушных СЖ (ОУСЖ) и поднижнечелюстных СЖ (ПНЧСЖ) диагностирован IgG4-С. Только у 3 (9%) больных имелось изолированное заболевание, связанное с IgG4 (IgG4-З), тогда как у 29 (91%) пациентов поражение нескольких органов протекало как системное заболевание, связанное с IgG4 (IgG4-СЗ). Результаты. Отмечено незначительное преобладание женщин с медианой дебюта заболевания в 42 года. Увеличение ПНЧСЖ (52,7%), поражение полости носа и околоносовых пазух (37,2%), увеличение слезных желез и псевдотумор глазниц (31%) - наиболее частые клинические проявления в дебюте заболевания. При динамическом наблюдении наряду с поражением ПНЧСЖ (97%), ОУСЖ (72%), глазниц (72%), полости носа и околоносовых пазух (56%) у 1/3 больных выявляется генерализованная лимфаденопатия, нередко развиваются поражения легких, печени, поджелудочной железы, почек, и заболевание протекает в рамках IgG4-СЗ. Лабораторные проявления характеризуются умеренной эозинофилией и повышением уровня IgE в крови у 1/3 больных, умеренным повышением СОЭ и гипергаммаглобулинемией у 50%. Повышение уровней IgG (84%) и особенно его подкласса IgG4 (86,4%) в крови служат показанием к дальнейшему подтверждению IgG4-З у больных с поражением больших СЖ. Для верификации диагноза с IgG4-З должны быть выполнены иммуногистохимическое исследование с определением концентрации плазматических клеток (ПК), секретирующих IgG4, и определение B-клеточной клональности в биоптатах. Заключение. Определение IgG4 в крови (2 г/л) у больных со значительным увеличением больших СЖ позволяет предположить наличие IgG4-С. Малоинвазивные инцизионные биопсии ОУСЖ и ПНЧСЖ с последующим морфологическим и иммуноморфологическим исследованием необходимо проводить для корректной постановки диагноза. Обнаружение более 40% ПК, секретирующих IgG4, в ткани СЖ является обязательным для постановки диагноза IgG4-З.

Breast implant-associated anaplastic large-cell lymphoma will be identified as a separate nosological entity in the 2017 adapted WHO classification due to differences in its clinical presentations, pathogenesis, and prognosis with those of nodal and cutaneous anaplastic large-cell lymphomas. The paper gives a review of the literature and describes the authors' own clinical case of common breast implant-associated anaplastic large-cell lymphoma involving breast tissue, axillary lymph nodes, anterior chest muscles, and bone marrow. The treatment policy chosen by the authors could achieve complete remission.Ассоциированная с имплантатом анапластическая крупноклеточная лимфома молочной железы будет выделена в отдельную нозологическую единицу в адаптированной классификации ВОЗ от 2017 г. в связи с различиями клинической картины, патогенеза и прогноза с нодальной и кожной анапластическими крупноклеточными лимфомами. В статье представлен обзор литературы и описано собственное клиническое наблюдение распространенной ассоциированной с имплантатом анапластической крупноклеточной лимфомы, протекающей с поражением ткани молочной железы, подмышечных лимфатических узлов, мышц передней грудной стенки и костного мозга. Выбранная нами тактика лечения позволила достигнуть полной ремиссии заболевания.

To characterize a group of patients with follicular lymphoma (FL) with leukemization and to evaluate the efficiency of different therapy options (R-CHOP/R-FMC/high-dose chemotherapy (HDCT)).18 (7.2%) out of 250 patients diagnosed with FL, who were examined and treated at the National Research Center for Hematology, Ministry of Health of the Russian Federation, were found to have leukemic FL (tumor cells in the peripheral blood smears were detected by cytology and flow cytofluorometry. Eight of the 18 patients had extranodal foci of involvement: lung, stomach, spleen, lumbar muscles, upper jaw, and vertebrae. Bone marrow was involved in 17 of the 18 patients. Tumor biopsy specimens displayed a morphological pattern of indolent FL in the majority of patients (10 of the 18 patients had cytological grade 1-2 tumors and 14 patients had a nodular or nodular-diffuse tumor growth pattern). The patients underwent R-CHOP/R-FMC) or HDCT cycles as first-line therapy, followed by autologous stem cell transplantation (auto-SCT).The median follow-up was 66 months (range 12-217 months). The 5-year overall survival (OS) and progression-free survival (PFS) rates were 70% (10% SEM) and 35% (15% SEM), respectively. The median OS was not reached; the median PFS was 3 years.Leukemic FL is characterized by low OS and PFS rates. The most effective chemotherapy regimens were R-CHOP, followed by HDCT and auto-SCT in first remission or R-FMC. These cycles can to a greater extent achieve a complete eradication of the bone marrow tumor clone. Due to the relapsing course of FL and the aggressiveness of leukemic FL, it is expedient to carry out auto-SCT in first remission.Цель исследования. Охарактеризовать группу больных фолликулярной лимфомой (ФЛ) с лейкемизацией и оценить эффективность разных вариантов терапии (R-CHOP/R-FMC/высокодозной химиотерапии - ВХТ). Материалы и методы. Из 250 пациентов с диагнозом ФЛ, которые обследовались и получали терапию в ФГБУ ГНЦ МЗ РФ, у 18 (7,2%) выявлен лейкемический вариант ФЛ (обнаружены опухолевые клетки в мазках периферической крови цитологически и методом проточной цитофлюориметрии - ПЦФМ). У 8 из 18 пациентов определялись экстранодальные очаги поражения: вовлечение легких, желудка, селезенки, поясничных мышц, верхней челюсти, позвонков. В 17 из 18 случаев вовлечен костный мозг. Морфологически в биоптате опухолей у большинства пациентов отмечалась картина индолентной ФЛ (у 10 из 18 I-II цитологический тип опухоли, у 14 из 18 нодулярный и нодулярно-диффузный характер опухолевого роста). В качестве терапии первой линии пациентам проводились курсы R-CHOP/R-FMC или ВХТ с последующей трансплантацией аутологичных стволовых клеток крови (ауто-ТСКК). Результаты. Медиана наблюдения составила 66 мес (12-217 мес). Пятилетняя общая выживаемость (ОВ) и выживаемость без прогрессирования (БПВ) составили 70% (стандартная ошибка 10%) и 35% (15%) соответственно. Медиана общей продолжительности жизни не достигнута, медиана продолжительности жизни без прогрессирования составила 3 года. Заключение. Лейкемический вариант ФЛ характеризуется низкими ОВ и БПВ. Наиболее эффективными оказались следующие химиотерапевтические режимы: R-CHOP c последующей ВХТ и ауто-ТСКК в первой ремиссии или R-FMC. Данные курсы позволяют в большей степени добиться полной эрадикации опухолевого клона в костном мозге. В связи с рецидивирующим течением ФЛ, а также агрессивностью лейкемического варианта ФЛ в первой ремиссии целесообразно проводить ауто-ТСКК.

Affine chromatography was used to isolate Lec antibodies from the sera of a healthy female donor with the high titers of these anti- bodies, which were labeled with biotin. The study enrolled 51 patients with primary breast cancer (BC). Antigen expression was found by immunohistochemistry and flow cytometry. With these two techniques being used, the detection rate of Lec expression in BC cells was 65% (33/51); the antigen was most frequently found by flow cytometry as compared with immunohistochemistry: 72 and 58% of cases, respectively.

In this article a rare case of monosystem form of congenital Langerhans cells histiocytosis (LCH) in 3 weeks of age girl was described. Local lesion of oral mucosa of the infant with LCH was first described. Morphological, immunological and clinical features of this rare disease have been characterized. Authors concluded that timely diagnostics is very important to risk-adapted therapy at children with LCH.

To evaluate the prognostic significance of tumor-associated cytotoxic lymphocytes and macro-phages, an immunohistochemical study of lymph node biopsies obtained from patients with follicular lymphoma (FL) was carried out. The immunohistochemical survey was performed using anti-granzyme B and anti-CD68 antibodies before the patients received the anti-FL treatment. It was shown that the number of cytotoxic lymphocytes (cytotoxic T lymphocytes and NK cells) in patients with good outcome (group 1, n = 31) was significantly higher (p ≤ 0.05) than in patients with poor outcome (group 2, n = 28). The number of CD68-positive macrophages in tumors with nodular-diffuse type of growth in group 2 was significantly higher (p ≤ 0.01) than in group 1. An increased number of cytotoxic lymphocytes may point to the activation of adaptive immunity that favors the good outcome of the disease. In contrast, an increased number of macrophages was associated with a poor outcome of FL. These data suggest that the parameters of cellular microenvironment can be used as prognostic criteria of the FL outcome. Further investigations are needed for the elucidation of the role of the cellular microenvironment in the FL development.

Background. Ph-negative chronic myeloproliferative neoplasms (MPNs) are characterized by proliferation of one or more myeloid cell lineages and include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Somatic Jak2, MPL and CALR gene mutations are responsible for more than 90% of NPM cases. These mutations affect sequential stages of prolipherative signal transduction and therefore after the emergence of one type of mutation another types basically should not have any selective advantages for clonal expansion. However, simultaneous findings of these mutations have been reported by different investigators in up to 10% of MPN cases. Aim. To evaluate frequencies of MPL and CALR mutations in Jak2 positive MPN cases for Russian cohort of patients. Methods. Archival DNA samples from MPN patients followed up at the National Research Center for Hematology between 2014 and 2019 included into retrospective study. DNAs and RNAs were extracted from blood using reagent kit from Interlabservice (Russia). Jak2 V617F mutation was quantified by real-time PCR kit from Syntol (Russia) according to manufacturers instructions. CALR exon 9 deletions/insertions were analyzed by fragment analysis (sensitivity >= 3%). MPL W515L/K mutations were assessed by in-house allele specific PCR. All cases were tested for phi-negativity using BCR-ABl p210 PCR kit from Interlabservice (Russia). Results. At least one of the mutations was found in 3863 cases. Jak2 V617F mutation - 3385 cases (87.6%); CALR insertion or deletion - 471 case (12.2%); MPLW515L/K mutation - 31 case (0.8%). We have found 28 cases (0.7%) with Jak2 and CALR mutations combined and 3 cases (0.1%) with Jak2 and MPL mutations in the cohort studied. Matched measures were obtained at least twice at different time points during the course of disease for these cases. No cases with simultaneous CALR and MPL mutations were detected. In 23 from 31 (74%) cases with combined mutations Jak2 V617F allele burden was lower than 3%. Among cases with combined mutations 5 were diagnosed with PV, 8 - with ET, 8 - with PMF and 10 with unclassified MPN. No correlations between diagnosis, mutation combination or allele burden were found. Conclusions. Based on the data, obtained on retrospective DNA samples we cannot state whether combined mutations are present in different clones of myeloid cells or in one. Indirectly, the fact that more often mutations in CALR and MPL genes were found in the cases with a low Jak2 V617F allele burden may indicate that additional mutations occur in the "competing" cell clone. Further prospective studies with mutation monitoring over the therapy are required to assess the value of combined mutations for MPN pathogenesis. Disclosures No relevant conflicts of interest to declare.

Background. Response to the induction chemotherapy is an important predictor of favorable outcome in aggressive lymphomas. As it was shown recently (Kurtz et al.2018) combination of interim PET/CT (iPET/CT) negativity and early molecular response detected by cell-free DNA (cfDNA) analysis, robustly stratify EFS and OS in patients (pts) with diffuse large B-cell lymphoma. There is no consensus on the most optimal program for primary mediastinal lymphoma (PML) treatment. Both R-CHOP+\-RT and R-DA-EPOCH are highly effective frontline options for PML, but about 10-15% of pts develop relapse/progression mainly within 2 years from diagnosis. We hypothesize that intensification of induction with 2 courses of modified R-NHL-BFM-90 program (R-m-NHL-BFM-90), followed by 4 courses of R-EPOCH without dose escalation might improve treatment outcome in PML. Aim. To assess the efficacy of R-m-NHL-BFM-90/R-EPOCH regimen for untreated PML pts by means of PET/CT and cfDNA evaluation. Methods. Overall, 18 pts were enrolled in prospective study between 2015 and 2019 years; median age 34 (19-50); M/F=4/14; Ann Arbor stage >I in 18 (100%); adverse factors in 12 pts (bulky disease>10 cm in 11 pts, involvement of the soft tissues in 9 pts and breast in 4 pts, pleural effusion in 6 pts, elevated lactate dehydrogenase level in 10 pts). The treatment plan consisted of: (i) induction of remission (blocks A and B of R-mNHL-BFM-90 program); (ii) consolidation with 4 courses of R-EPOCH. PET/CT was performed in all pts before therapy, after 2 courses of induction and after the end of therapy. B-cell clonality was assessed detecting immunoglobulin heavy chain gene rearrangements IGH (VH-JH FR2) and immunoglobulin light kappa chain gene rearrangement (IGK), by the use of multiplex Biomed-2 primer system for PCR and Gene-Scan analysis. cfDNA was obtained before the start of the treatment, after the induction and after the end of therapy in 4 pts. DNA concentration was measured by real time PCR with beta-globin primers. Results. All 18 pts completed induction phase. After 2 courses of R-mNHL-BFM-90 PET/CT Deauville score (DS) were DS1-3 in 9 pts (50%) and DS4 in 9 pts (50%). 16 pts completed treatment; from these 12 pts received all 4 courses of R-EPOCH. 2 pts received 2 courses and 2 pts only 1 course due to hematologic toxicity grade 3-4 and infectious complications. After the end of therapy PET/CT were DS1-3 in 15 out of 16 (94%) pts. Only 1 patient response was assessed as DS4; after she received autologous HSCT PET/CT negativity was achieved. cfDNA assessment at all stages of treatment was available in 4 patients (Table 1). In all cases before treatment there were no clonal rearrangements in blood samples. Clonal rearrangements in cfDNA before treatment and in tumor samples were the same in all cases. After induction treatment in one case B-cell clonality persisted in cfDNA, but after the end of the treatment there was no amplification of cfDNA from all pts. Overall, with a median follow-up of 14 months (range 1-40) 16/16 pts (100%) are alive in complete remission. Of note, all 4 pts who received only 1-2 courses of R-EPOCH are in complete remission for 4, 13, 16 and 17 months. Conclusions. Our results suggest that R-m-NHL-BFM-90/R-EPOCH protocol is highly effective for treatment of patients with PML. Given our results, we consider the possibility of reducing the number of cycles of chemotherapy. We suggest that detection of the tumor markers in cfDNA could be used as a biomarker to adapt treatment strategies in the future. Disclosures No relevant conflicts of interest to declare.

to evaluate the efficiency of high-dose chemotherapy (HDCT) with further autologous blood stem cell transplantation (auto-BSCT) in the first-line therapy of patients with follicular lymphoma (FL) and poor prognostic factors.In 2000 to 2015, the National Research Center for Hematology, Ministry of Health of the Russian Federation, performed therapy in 39 patients with FL and poor prognostic factors (a total of 215 patients with FL). The R-CHOP treatment was done as induction therapy. Sequential HCT and further auto-BSCT were performed in 29 (74%) of the 39 patients, who had shown a partial tumor response to the induction therapy or achieved partial remission after 4-6 cycles of CT, but had poor prognostic factors. 22 of the 29 patients underwent auto-BSCT in first-line therapy after induction R-CHOP regimens. Among them, there were 17 men with a median age of 46 years (31-68 years). 21 of the 22 patients were recorded to have Stage IV by the Ann Arbor staging classification. Bulky peritoneal and retroperitoneal tumors larger than 7 cm were detectable at disease onset in 14 of the 22 cases. Two patients were noted to have phenomena of leukemization. 16 patients had bone marrow (BM) involvement. According to the Follicular Lymphoma International Prognostic Index-1 (FLIPI-1), the patients were divided into 3 groups: 1) a low risk (n=5); 2) an intermediate risk (n=3); a high risk (n=14). B-symptoms were observed in 16 cases. 16 patients were diagnosed with cytological grade I-II FL and 6 had grade IIIA. According to the tumor proliferative pattern, the distribution turned out to be as follows: nodular (n=6), nodular-diffuse (n=13), and diffuse (n=3). The proliferative activity index averaged 30% (8-90%). Serum and urine proteins were immmunochemically assayed in 18 cases, out of them 8 patients were diagnosed as having serum β2-microglobulin concentrations above normal as a poor prognostic factor. In 14 of the 22 patients, the activity of lactate dehydrogenase was greater than normal (266-7806 U/l).Out of the 22 patients, 20 who have undergone auto-BSCT in first-line therapy are survivors and have remission of the underlying disease: 18 and 2 patients achieved complete and partial remission, respectively. The follow-up period was 7 to 178 months (median, 32 months). After auto-BSCT in the first remission, 2 patients developed disease recurrences: an early recurrence after 9 months in one case and a late recurrence 6 years after completion of therapy in the other.The first prospective study of intensive therapy for FL in Russia has demonstrated that HDCT with further auto-BSCT in first-line therapy allows complete remission in patients with poor prognostic factors and higher overall and progression-free survival rates.Цель исследования. Оценить эффективность высокодозной химиотерапии (ХТ) с последующей трансплантацией аутологичных стволовых клеток крови (ауто-ТСКК) в терапии первой линии у больных с фолликулярной лимфомой (ФЛ) и факторами неблагоприятного прогноза. Материалы и методы. В период с 2000 по 2015 г. в ФГБУ Гематологический научный центр МЗ РФ проводилась терапия 39 пациентам с ФЛ и факторами неблагоприятного прогноза (всего 215 больных с ФЛ). В качестве индукционной терапии проведено лечение по программе R-CHOP. У 29 (74%) из 39 пациентов в случае частичного ответа опухоли на индукционную терапию или достижения частичной ремиссии после 4-6 курсов ХТ, но при наличии факторов неблагоприятного прогноза, выполнена последовательная высокодозная химиотерапия (ПВХТ) с последующей ауто-ТСКК. Из 29 больных ауто-ТСКК в терапии первой линии после индукционных режимов по программе R-CHOP выполнена 22 больным. Из них 17 мужчин с медианой возраста 46 (31-68) лет. У 21 из 22 больных констатирована IV стадия заболевания по классификации Ann Arbor. В 14 из 22 случаев в дебюте заболевания определялись опухолевые конгломераты более 7 см внутрибрюшной или забрюшинной локализаций (bulky). У 2 больных отмечались явления лейкемизации. У 16 пациентов имелось поражение костного мозга (КМ). По критериям FLIPI-1 пациентов разделили на 3 группы: в 1-й группе риска было 5 больных, во 2-й - 3, в 3-4-й - 14. В 16 случаях наблюдалось наличие В-симптомов. У 16 пациентов диагностирован I-II цитологический тип ФЛ, у 6 - IIIА. По характеру пролиферации опухоли распределение оказалось следующим: нодулярный у 6 больных, нодулярно-диффузный - у 13, диффузный - у 3. Индекс пролиферативной активности в среднем составил 30% (8-90%). Иммунохимическое исследование белков сыворотки крови и мочи проведено в 18 случаях, из них концентрация β2-микроглобулина в сыворотке выше нормы, как фактор неблагоприятного прогноза, диагностирована у 8 из 18 больных. Активность лактатдегидрогеназы превышала норму (266-7806 ед/л) у 14 из 22 пациентов. Результаты. Из 22 пациентов 20, перенесшие ауто-ТСКК в терапии первой линии, живы и находятся в ремиссии по основному заболеванию: полная ремиссия достигнута у 18, частичная - у 2. Период наблюдения составляет от 7 до 178 (медиана 32) мес. У 2 пациентов после ауто-ТСКК в первой ремиссии развились рецидивы заболевания: в одном случае - ранний спустя 9 мес, во втором случае - поздний спустя 6 лет от окончания терапии. Заключение. Результаты первого проспективного исследования интенсивной терапии у больных ФЛ в России демонстрируют, что ПВХТ с последующей ауто-ТСКК в терапии первой линии позволяет достичь полной ремиссии заболевания у пациентов с факторами неблагоприятного прогноза, а также увеличить общую и беспрогрессивную выживаемость.

Myeloproliferative disease associated with FGFR1 rearrangement (8p11), which is included in the 2008 WHO Classification of Myeloid Neoplasms, is a rare and extremely aggressive abnormality. The paper describes a clinical case of a 39-year-old female patient who was detected to have leukocytosis (as high as 47.2·109/l), absolute eosinophilia (as high as 3.1·109/l), and enlarged peripheral lymph nodes during her visit to a doctor. The bone marrow (BM) showed the changes typically encountered in myeloproliferative disease with eosinophilia. The patient was found to have t(8;13)(p11;q12) translocation associated with the rearrangement of the FGFR1 gene located at the 8p11 locus. Molecular and cytogenetic examinations failed to reveal BCR-ABL chimeric transcript, Jak2 V617F mutation, and deletions and translocations involving PDGFRA (4q12) and PDGFRB (5q32-33). The similar changes in the karyotype were also found in the lymph node cells. The undertaken treatment with hydroxyurea and the tyrosine kinase inhibitor dasatinib turned out to be ineffective. The patient underwent allogeneic BM transplantation from a HLA-identical sibling. Graft rejection occurred 6 months later. Allogeneic BM transplantation from the same donor (100% donor chimerism; FGFR1/8р11 translocation was not detected), which was complicated by the development of chronic graft-versus-host reaction, was performed again in March 2015. The patient is being followed up and continues to receive immunosuppressive therapy.Миелопролиферативное заболевание, ассоциированное с реаранжировкой гена FGFR1 (8р11), включенное в классификацию миелоидных новообразований ВОЗ, 2008 г., - редко встречающаяся патология, протекающая чрезвычайно агрессивно. Приведено клиническое наблюдение 39-летней пациентки, у которой при обращении к врачу выявлены лейкоцитоз (до 47,2·109/л), абсолютная эозинофилия (до 3,1·109/л), увеличение периферических лимфатических узлов. В костном мозге (КМ) наблюдались изменения, характерные для миелопролиферативного заболевания с эозинофилией. У больной выявлена транслокация t(8;13)(p11;q12), связанная с перестройкой гена FGFR1, расположенного в локусе 8p11. При молекулярном и цитогенетическом исследованиях химерный транскрипт BCR-ABL, мутация V617F гена Jak2, делеции и транслокации с вовлечением локусов генов PDGFRA (4q12) и PDGFRB (5q32-33) не обнаружены. Аналогичные изменения кариотипа выявлены и в клетках лимфатического узла. Предпринятое лечение больной гидроксимочевиной и ингибитором тирозинкиназ дазатинибом оказалось неэффективным. Выполнена трансплантация аллогенного КМ от сиблинга, совместимого по HLA. Спустя 6 мес произошло отторжение трансплантата. В марте 2015 г. проведена повторная аллотрансплантация КМ от того же донора (100% донорский химеризм, транслокация FGFR1/8р11 не выявляется), осложнившаяся развитием хронической реакции трансплантат против хозяина. Пациентка остается под наблюдением, продолжает получать иммуносупрессивную терапию.

to identify the clinical features of latent polycythemia vera (PV) as an independent nosological entity.The investigation enrolled 81 patients (50 with extensive (manifest) PV and 31 with latent PV) who had visited the Outpatient Department, Hematology Research Center, Ministry of Health of Russia, in 2014 to October 2015.The gender distribution of the patients was statistically comparable in the analyzed groups. The patients with manifest PV were slightly older than those with latent PV: the median age in the compared groups was 56 and 44 years, respectively. Red blood cell counts, hemoglobin concentrations, and packed cell volume were higher in the patients with manifest PV. Blood platelet counts were higher in the latent PV group. There were no differences in the number of white blood cells in the compared groups. All the patients were JAK2 V617F mutation carriers. The JAK2 allele load was significantly higher in the manifest PV group than in the latent PV group. The compared patient groups differed in the rate of thromboses in the history or at diagnosis. In the patients with latent PV, thromboses were detected in 38% of cases versus 16% in those with manifest PV. In latent PV, there were mainly venous thromboses; abdominal vascular thromboses were diagnosed with a high frequency. Arterial thromboses were revealed in only 2 cases.Chronic myeloproliferative disease that is characterized by the JAK2 V617F mutation, borderline hemoglobin counts, and morphological features of a bone marrow trephine biopsy specimen, which are specific for PV, is an independent PV variant, namely: latent PV.Цель исследования. Выделение клинических особенностей латентной истинной полицитемии (ИП) как отдельного нозологического варианта. Материалы и методы. В исследование включили 81 больного, обратившегося в поликлиническое отделение ФГБУ 'Гематологический научный центр' с 2014 г. по октябрь 2015 г.: 50 больных с развернутой (явной) ИП и 31 больной с латентной ИП. Результаты. В анализируемых группах распределение больных по полу было статистически сопоставимым. Больные с явной ИП несколько старше по сравнению с пациентами с латентной ИП: медиана возраста 56 и 44 года в сравниваемых группах. Количество эритроцитов, концентрация гемоглобина и гематокрит выше у больных с явной ИП. Тромбоцитоз выше в группе больных с латентной ИП. Различий по числу лейкоцитов в сравниваемых группах не выявлено. Все больные являются носителями мутации V617F гена JAK2. Аллельная нагрузка JAK2 достоверно выше в группе больных с явной ИП по сравнению с латентной ИП. Сравниваемые группы больных различались по частоте развития тромбозов в анамнезе на момент установления диагноза. У больных с латентной ИП тромбозы выявлены в 38% наблюдений по сравнению с 16% в случае явной ИП. При латентной ИП выявлялись преимущественно венозные тромбозы с высокой частотой диагностированы тромбозы абдоминальных сосудов. Артериальные тромбозы выявлены только в 2 наблюдениях. Заключение. Хроническое миелопролиферативное заболевание, которое характеризуется наличием мутации V617F гена JAK2, пограничным содержанием гемоглобина, морфологическими особенностями трепанобиоптата костного мозга, характерными для ИП, представляет собой отдельный вариант ИП - латентную ИП.

IgG4-related disease (IgG4-RD) is a systemic immune-related disease that may involve the pancreas, liver, retroperitoneal space, biliary tract, salivary and lacrimal glands, eye socket, lung, and kidney. In term of pathomorphogenesis, it is a fibroinflammatory disease manifesting as a tumor-like lesion of organs, elevated serum IgG4 levels, and a morphofunctional substrate - the development of marked fibrosis and lymphoplasmacytic infiltration in the tissues with the high content of IgG4-positive plasma cells. The detection of a tumor-like nodule frequently leads to that the patients with IgG4-RD undergo major traumatic surgery for presumed cancer. At the same time, a number of investigations show the association of IgG4-RD with the development of cancer and lymphoproliferative diseases. The paper describes two clinical cases: Russia's first diagnosis of MALT lymphoma of the lacrimal gland, IgG4-positive and IgG4-RD with a rare onset with a destruction focus in the cervical vertebrae, multiple organ dysfunction, B-cell clonality in salivary gland tissue and PIgMκ secretion. It also reviews world literature on the development of lymphoproliferative diseases in the presence of IgG4-RD.Связанное с IgG4 заболевание (IgG4-СЗ) - системное иммуноопосредованное заболевание, которое может вовлекать поджелудочную железу, печень, забрюшинное пространство, желчевыводящие пути, слюнные и слезные железы, глазницу, легкие, почки. С учетом патоморфогенеза это фибровоспалительное заболевание, проявляющееся опухолеподобным поражением органов, повышением уровня IgG4 в сыворотке крови и морфологическим субстратом - формированием выраженного фиброза и лимфоплазмоцитарного инфильтрата в тканях с высоким содержанием IgG4-позитивных плазматических клеток. Обнаружение опухолеподобного узла зачастую приводит к тому, что пациенты с IgG4-СЗ подвергаются обширным травматичным операциям по поводу предполагаемых онкологических заболеваний. В то же время в ряде исследований показана ассоциация IgG4-СЗ с развитием онкологических и лимфопролиферативных заболеваний процессов. В статье авторы приводят описание двух клинических случаев: первой в России диагностики MALT-лимфомы слезной железы, IgG4-позитивной и IgG4-СЗ с редким дебютом с очага деструкции в шейных позвонках, мультиорганным поражением, наличием В-клеточной клональности в ткани слюнной железы и секрецией PIgMκ. Приведен обзор мировой литературы о развитии лимфопролиферативных заболеваний на фоне IgG4-СЗ.