[AL-amyloidosis with cardiac involvement. Diagnostic capabilities of non-invasive methods].

There are presented the literature data and a description of the clinical course of the disease in isolated/predominant cardiac amyloidosis. Amyloid cardiomyopathy is the most common phenocopy of hypertrophic cardiomyopathy. The modern possibilities of non-invasive diagnostics using osteoscintigraphy for the differential diagnosis between amyloid cardiomyopathy caused by AL- and transthyretin amyloidosis are described in detail.

Role of molecular-genetic abnormalities in pathogenesis and risk stratification of multiple myeloma.

Over the past decades the studies have greatly improved our understanding of the molecular basis of multiple myeloma (MM) and mechanisms of disease progression. The majority of the most widespread chromosomal aberrations, revealing in MM, has independent predictive value and influence on a choice of optimal treatment. There were observed 190 MM patients in hematologic hospitals of St. Petersburg. Genetic anomalies (GA) were detected at 3l,3% of patients and did not depend on their age. Patients with ISS III had a detectability of GA higher than with ISS II and ISS I (48,°% (24/5°), 2l,2% (7/33) and 27,6% (8/29)). Translocation t(ll;l4) was found in 23,3% (3O/129) patients; dell3q - 20,8% (27/13°); dell7p - at 8,4% (7/83); t(4;l4) - at 6,9% (9/13O), that allowed to stratify patients in groups of risk according to mSMART version l. O and 2. O. Median overall survival (OS) modified mSMART l. O in group of standard risk was 7° months, high risk - 47,l months. Median OS mSMART 2. O in group of standard risk was 7° months, intermediate risk - 47 months, high risk - 45 months. OS did not depend on age, clinical manifestations, treatment and other factors.

[The synopsis of clinical cytometry: acute megakaryoblastic leukemia.]

The acute megakaryoblastic leukemia is a rather rare form of pathology even in practice of specialized oncological hematological departments. The data of cytometry analysis of 2363 patients monitored from 2007 to 2014 carried out in The Dmitrii Rogachev Federal research clinical center of children hematology, oncology and immunology and The academician I.P. Pavlov First St. Petersburg state medical university was used to diagnose acute megakaryoblastic leukemia. The corresponding diagnosis was established in 24 patients of various age categories, including 16 children (11 boys and 5 girls) and 8 adults (ratio male/female 1:1). The trisomy on chromosome 21 was revealed only in 4 children out of 13 of early age (younger than 3 years). The article describes characteristics of samples taking preparation and interpretation of data of multicolor with regard to experience of national and foreign colleges.

Personalized treatment of malignant tumors during pregnancy.

The combination of pregnancy and cancer is a challenge for the patient and a problematic clinical dilemma for the doctor. In this retrospective observational cohort study, we have tried to analyze our experience in the management of such patients. This review includes 41 patients with malignant neoplasms detected during pregnancy who received treatment at the Almazov National Medical Research Centre from 2015-2021. The majority of patients received treatment during pregnancy (n=26, 63.4%): chemotherapy - 19 (46.3%) (in 2 cases in combination with surgery), surgical treatment - 7 (17, 1%) patients. In most cases, delivery was at term (n=28, 68.3%). All children born at term were mature and had no growth restriction, regardless of whether the mothers received treatment during pregnancy or not. When detecting cancer during pregnancy, an immediate follow-up examination is required to assess the extent of the tumor and current fetal state. If pregnancy prolongation is requested, the treatment should not be postponed, except for systemic chemotherapy in the first trimester of pregnancy, pelvic radiation at any term.

Ambroxol increases glucocerebrosidase (GCase) activity and restores GCase translocation in primary patient-derived macrophages in Gaucher disease and Parkinsonism.

Mutations in the glucocerebrosidase gene (GBA) encoding the lysosomal enzyme glucocerebrosidase (GCase) cause Gaucher disease (GD) and are the most commonly known genetic risk factor for Parkinson disease (PD). Ambroxol is one of the most effective pharmacological chaperones of GCase. Fourteen GD patients, six PD patients with mutations in the GBA gene (GBA-PD), and thirty controls were enrolled. GCase activity and hexosylsphingosine (HexSph) concentration were measured in dried blood and macrophage spots using liquid chromatography coupled with tandem mass spectrometry. The effect of ambroxol on GCase translocation to lysosomes was assessed using confocal microscopy. The results showed that ambroxol treatment significantly increased GCase activity in cultured macrophages derived from patient blood monocytic cell (PBMC) of GD (by 3.3-fold) and GBA-PD patients (by 3.5-fold) compared to untreated cells (p < 0.0001 and p < 0.0001, respectively) four days after cultivation. Ambroxol treatment significantly reduced HexSph concentration in GD (by 2.1-fold) and GBA-PD patients (by 1.6-fold) (p < 0.0001 and p < 0.0001, respectively). GD macrophage treatment resulted in increased GCase level and increased enzyme colocalization with the lysosomal marker LAMP2. The possible binding modes of ambroxol to mutant GCase carrying N370S amino acid substitution at pH 4.7 were examined using molecular docking and molecular dynamics simulations. The ambroxol position characterized by minimal binding free energy was observed in close vicinity to the residue, at position 370. Taken together, these data showed that PBMC-derived macrophages could be used for assessing ambroxol therapy response for GD patients and also for GBA-PD patients.

[Prognostic significance of immunoglobulin variable region gene mutations in B-CLL patients treated with combination therapy fludarabine plus cyclophosphamide].

AIM: To study prognostic factors in previously untreated patients receiving FC regimen (fludarabine plus cyclophosphamide). MATERIAL AND METHODS: We conducted a retrospective analysis of B-CLL patients observed in Hematology Research Center of Russia (Moscow) and Faculty Therapy Clinic of St. Petersburg State Medical University (St. Petersburg). All patients received FC regimen as a first line treatment (fludarabine 50 mg plus cyclophosphamide 250 mg/m2 for 3 days intravenously, repeated every 28 days). RESULTS: 54 patients were included into the study. The median age was 57.5 yrs (range 40-78 yrs). There were 38 males and 16 females. Before the treatment 22% patients had Binet stage A, 41%--stage B and 37%--stage C. 62% patients had unmutated subtype of B-CLL and 38% mutated subtype. 12 patients (22%) received less than 4 cycles of chemotherapy. In 8 patients (15%) there were significant delays between cycles (more than 2 months). In the whole cohort the median overall survival calculated from the time of treatment initiation was 57.4 months, the median progression free survival--24 months, and the median relapse free survival--27 moths. Mutational status of immunoglobulin variable region genes significantly influenced survival. In patients with unmutated subtype the median progression free survival was 23.6 months, while in patients with mutated subset it was not reached: 75% survival at 22.7 months (p = 0.027). Difference in progression free survival by stages (A versus B+C, A+B versus C) was not significant. CONCLUSION: Our data show that mutational status of immunoglobulin variable region genes remains a significant prognostic factor in patients receiving combined therapy with cyclophosphamide and fludarabine.

Rare form of erdheim-chester disease presenting with isolated central skeletal lesions treated with a combination of alfa-interferon and zoledronic Acid.

Erdheim-Chester disease (ECD) represents a clonal non-Langerhans histiocytosis, which manifests under an extensive variety of clinical symptoms. This creates a challenge for the physician, who is required to recognize and diagnose the disease in the early stages. Despite this considerable challenge, in the last decade there has been a dramatic increase in ECD diagnoses, in most part due to an increasing awareness of this rare disorder. Involvement of the axial skeleton is exclusively uncommon with no official recommendations for the treatment of the bone lesions. Here, we present a case report of a young male patient with isolated lesions of the spine, ribs, and pelvis, who was successfully treated with a combination therapy of alfa-interferon and zoledronic acid.

[The use of interferon-alfa (reaferon) in patients with chronic myeloleukemia]. / Primenenie interferona-al'fa (reaferona) u bol'nykh khronicheskim mieloleikozom.

Data on long-term interferon-alpha (reaferon) therapy in 6 patients with CML (5 in chronic phase, 1 in acceleration phase) are presented. Clinicohematological remission was achieved in all the patients in a chronic phase irrespective of their group of risk. Cytogenetic improvement occurred only in one patient from a low-risk group. Reaferon had no effect in the patient in the acceleration phase. Tumor necrosis factor neither influenced viability of mononuclear bone marrow cells of patients before treatment nor suppressed proliferation. Dose independent reduction of cell viability was revealed in a patient in remission after reaferon therapy. There were no cases of apoptosis induction. Mechanisms of CML pathogenesis and interferon action in CML chronic phase are discussed.

Increased plasma oligomeric alpha-synuclein in patients with lysosomal storage diseases.

A link between lysosomal storage diseases (LSDs) and neurodegenerative disorders associated with accumulation of presynaptic protein alpha-synuclein has been shown. Particularly, Gaucher disease (GD) patients with a deficiency of the lysosomal enzyme glucocerebrosidase (GBA) and carriers of GBA mutations are at increased risk of Parkinson's disease (PD). It remains unclear whether this link is due to increased alpha-synuclein oligomerization. Here we show that level of oligomeric alpha-synuclein form, associated with PD development, is increased in plasma of GD patients (n=41, median=22.9pg/mL, range1.57-444.58pg/mL; controls (n=40, median=6.02pg/mL, range 1.05-103.14pg/mL, p<0.0001). This difference is absent in GD patients receiving enzyme replacement therapy (ERT) for more than 5 years. Moreover, the levels of alpha-synuclein oligomers in plasma are also higher in patients with other LSDs (Niemann-Pick type C, Krabbe disease, Wolman disease) compared to the median value in controls. Therefore, we suggest that mutations in the GBA gene and at least in several other LSDs genes may be associated with an increase in oligomeric alpha-synuclein in plasma. ERT applied for recovering of GBA functions in GD treatment might decrease formation of plasma oligomeric alpha-synuclein.

Interphase ribosomal RNA cistron staining in chronic myeloid leukaemia.

Aim-To evaluate the haemopoietic function of bone marrow blood forming cells in human chronic myeloid leukaemia (CML) by means of silver staining of nucleolar organiser region (AgNOR).Methods-Nucleoli were investigated in bone marrow blast cells and in erythroid, granulocytic, and megakaryocytic cells from 10 haematologically healthy subjects and from 26 patients with chronic myeloid leukemia (17 in benign phase, nine with blast crisis). The investigation was done before treatment, by means of a one step silver staining method. In every case 50 to 100 blasts, promyelocytes, myelocytes, immature (pronormoblastic and basophilic normoblastic) and mature (polychromatic normoblastic) erythroid elements, and megakaryocytes were evaluated for the mean numbers of nucleoli and for the average number of AgNORs per nucleus. Student's t test was used to compare the patient and control groups. Other statistical analyses were carried out by means of the computer assisted "HEMA" system.Results-Compared with controls, activation of NORs was noticed only in CML blasts, while there was a decrease in NORs in the erythroid elements, promyelocytes, and megakaryocytes. The AgNOR score of polychromatic normoblasts and megakaryocytes started to decrease in the benign stage of CML, whereas a similar decrease in pronormoblasts, basophilic normoblasts, and promyelocytes was detected only in patients with CML blast crisis.Conclusions-The loss of AgNOR sites in cell series in CML may be related to intrinsic defects in their proliferation.

Interphase ribosomal RNA cistron silver staining in refractory anaemias with and without excess blasts.

AIM: To evaluate the haemopoietic function of bone marrow blood forming cells in human myelodysplastic syndromes (MDS) by silver staining of nucleolar organiser regions (AgNORs). METHODS: Nucleoli were investigated in bone marrow blast cells and in erythroid, granulocytic, and megakaryocytic cells from 12 haematologically healthy subjects, and from 26 patients with MDS, including 14 with refractory anaemia (RA), nine with RA with excess blasts (RAEB), and three with RAEB in transformation (RAEB-t). The investigation was performed before treatment using a one step silver staining method. In each case 50 to 100 blasts, promyelocytes, myelocytes, immature (pronormoblastic and basophilic normoblastic) and mature (polychromatic normoblastic) erythroid elements, and megakaryocytes were evaluated for the mean numbers of nucleoli and AgNORs per nucleus. Student's t test was used to compare the patient and control groups. Other statistical analyses were carried out by the computer assisted "HEMA" system. RESULTS: Compared with controls, the number of AgNORs in blasts, promyelocytes, immature erythroid elements, and megakaryocytes was decreased, whereas in myelocytes and polychromatic normoblasts it was similar. There was also a difference in the AgNOR scores in blood forming cells from patients with RAEB/ RAEB-t v RA. CONCLUSIONS: The loss of AgNOR sites in cellular series in MDS may result from the decrease of their proliferative potential with disease progression, intrinsic defects in maturation, and extensive apoptosis.