[Therapy of mental disorders in patients with hematological malignancies]. / Terapiya nepsikhoticheskikh psikhicheskikh rasstroistv u bol'nykh s zabolevaniyami sistemy krovi.

OBJECTIVE: To assess the possibilities of therapy with minimal effective doses (MED) of psychotropic drugs for mental disorders (MD) that manifest during the treatment of hematological malignancies (HM). MATERIAL AND METHODS: A prospective study was conducted at the National Medical Research Center for Hematology of the Russian Ministry of Health (Moscow), which included 204 (39.4%) men and 314 (60.6%) women (518 patients in total), aged 17 to 83 years (median 45 years), with various HM, in which the manifestation of MD occurred during the treatment of the underlying disease. To minimize the side-effects of psychotropic drugs and given the relatively mild level of MD, psychopharmacotherapy of patients was carried out mainly at MED. The severity of MD, manifested in patients, was assessed by the illness severity scale of the Clinical Global Impression (CGI) scale, and the effectiveness of the treatment was assessed by the improvement scale (CGI-I). RESULTS: Mainly mild (188, 36%) and moderately pronounced (270, 52%) MD were noted in patients with HM during the treatment of the underlying disease. Severe psychopathological disorders (60, 12%) were observed much less often. Because of psychopharmacotherapy with MED, patients experienced a very significant (97, 19%) and significant improvement (354, 68%) of their mental state, less often the improvement was regarded as minimal (67, 13%). Therefore, almost all patients showed a stable relief of MD; in 87% (95% CI 84-90) of patients, this improvement was significant. CONCLUSION: The tactics of treatment MD that manifest in patients with HM with MED of psychotropic drugs turned out to be therapeutically effective according to the results of the assessment on CGI scales.

[Adherence to treatment of hematological malignancies patients with anxiety and depression].

AIM: To establish the features of the influence of anxiety and depressive disorders on treatment adherence, as well as to clarify the factors associated with it in hematologic malignancies patients. MATERIALS AND METHODS: The study included 117 patients: 51 men and 66 women, aged 19 to 67 years, with Hodgkin's lymphoma - 88, acute lymphoblastic leukemia - 16 and aplastic anemia - 13 patients. Patients were examined by psychiatrist using the Brief Psychiatric Rating Scale, as well as some psychometric methods. RESULTS: Anxiety-depressive spectrum disorders were detected in 36 (40.9%) patients with Hodgkin's lymphoma and 8 (50%) with acute lymphoblastic leukemia, in the aplastic anemia group there were three (23.1%) of such patients. It was found that the average adherence to treatment was in 2/3 of patients, low and high - in the remaining 1/3 of patients. With medium and low adherence to treatment, the risk of adverse events increases by an average of 1.7 times. The adherence to treatment it is significantly higher in patients older than 45 years. Signs of depression that negatively correlated with adherence to treatment were pessimism and disruption of social ties. Adherence to treatment significantly positively correlates with the following types of attitudes towards the disease: anosognosic, hypochondriac and egocentric, and significantly negatively correlates with the following types of attitudes towards the disease: anxious, melancholic and dysphoric. CONCLUSION: Anxiety/depressive disorders contribute to reduced adherence of hematologic malignancies patients to treatment. Their correction and increased adherence should be carried out jointly by hematologists and mental health professionals.

[Psychopharmacotherapy of mental disorders in hematological patients: security concerns]. / Psikhofarmakoterapiya psikhicheskikh rasstroistv u gematologicheskikh bol'nykh: problemy bezopasnosti.

OBJECTIVE: Evaluation of the safety of psychopharmacotherapy (PFT) of mental disorders in modern protocols for the treatment of patients with blood disorders. MATERIAL AND METHODS: The data of medical records of 552 patients with blood disorders who received PFT during treatment at the clinic of the National Medical Research Center for Hematology were analyzed. Any adverse events recorded while taking PFT were taken into account. Statistical analysis included descriptive statistics, frequency analysis, and assessment (Student's t-test) of changes in blood parameters (before and after taking psychotropic drugs). RESULTS: Signs of hematotoxicity were found only in 7.1% (n=37) patients, in all cases while taking benzodiazepines (n=12) in combination with hematotoxic drugs for the treatment of blood disorders. Other significant adverse events (which caused premature discontinuation or dose reduction) were detected in 4.8% (n=25) cases, of which 9 were associated with the appointment of anxiolytics (hydroxyzine, zopiclone), 11 with antidepressants (clomipramine, amitriptyline, duloxetine, trazodone, ademethionine) and 5 with antipsychotics (risperidone, alimemazine, haloperidol). CONCLUSION: Most psychotropic drugs are effective in relation to psychopathological disorders that develop in hematological patients and are safe when used at minimum/average therapeutic doses within the daily dosage ranges established by the official instructions for use.

[Predictors of severe lesions of the central nervous system in the treatment of blood system diseases]. / Prediktory tyazhelykh porazhenii tsentral'noi nervnoi sistemy pri lechenii zabolevanii sistemy krovi.

OBJECTIVE: To determine the types, frequency and key symptoms of severe lesions of the central nervous system (SLCNS) that occurred in patients with hematological malignancies (HM). MATERIALS AND METHODS: The authors conducted a retrospective exploratory study by analyzing the data of 3.620 patients with HM during the period from 01.01.18 to 31.12.19. Thirty-four patients (14 men and 20 women, median age 39 years), who developed SLCNS during treatment, were selected. For comparison with the main group of patients and exclusion of predictors associated with the development of SLCNS, a comparison group was added (by Kernel matching method). A comparison group consisted of 137 patients (59 men and 78 women, median age - 36 years) and was similar to the main group by clinical and laboratory characteristics. A neurological complication was marked as SLCNS if it was an indication for transfer to the intensive care unit (ICU). Statistical analysis included multivariate analysis - multiple binary logistic regression with stepwise inclusion of variables (that were found in the preliminary contingency table analysis) in the model, with control false results (by the false discovery rate method) and estimating the odds ratio, OR (95% CI). RESULTS: SLCNS in patients with HM developed in 0.94% of cases. The main SLCNS in patients with HM were: epileptic seizure (50.0%, n=17), ischemic stroke (20.6%, n=7), hemorrhagic stroke (17.6%, n=6) and meningoencephalitis (11.8%, n=4). The following independent significant (Wald test p≤0.05) predictors associated with the development of SLCNS in patients with HM during inpatient treatment were identified: antibiotic therapy (when more than 5 drugs are prescribed), OR=2.9 (1.2-7, four); polychemotherapy (if more than 4 drugs are prescribed), OR=2.9 (1.1-7.8); thrombocytopenia (with a platelet count less than 50·109 g/l), OR=2.3 (1.0-5.2) and delirium, OR=3.7 (1.3-10.8), and also the presence of neurological disorders in the patient's history, OR=2.6 (1.1-6.3). CONCLUSION: The main types of SLCNS in patients with HM were: epileptic seizure, ischemic and hemorrhagic strokes, and meningoencephalitis. Four predictors associated with the development of SLCNS in the course of HM treatment were identified: massive antibacterial (with more than 5 drugs) and chemotherapeutic (with more than 4 drugs) effects, thrombocytopenia and manifestation of delirium, as well as one risk factor: a history of neurological disorder. These factors need to be considered and monitored during treatment, because each of them increases the risk of developing SLCNS.

[Five year experience in ibrutinib therapy for relapsed and refractory mantle cell lymphoma in real world Russian clinical practice].

BACKGROUND: Mantle cell lymphoma (MCL) is a rare and clinically aggressive lymphoma subtype. Current approaches have greatly improved patients outcomes, but relapse is inevitable. In phase IIIII clinical trials, ibrutinib has shown significant activity in patients with relapsed or refractory (R/R) MCL. AIM: To assess efficacy and toxicity of ibrutinib monotherapy in patients with R/R MCL in routine practice outside of clinical trials. MATERIALS AND METHODS: The study enrolled patients with confirmed R/R MCL who had received at least one line of previous chemotherapy. ECOG 24, cytopenia, infectious complications, hemorrhagic syndrome were not exclusion criteria. Patients received daily oral ibrutinib 560 mg until progression or unacceptable toxicity. RESULTS: From May 2015 to September 2020 ibrutinib therapy was started in 106 patients with R/R MCL in 16 regions of Russia. The median age was 66 years; ECOG2 18%, blastoid variant (or Ki6740% or WBC50109/l) 43%. The median number of previous treatment lines was 2 (111). The ORR was 78.4% (CRR 27.4%). The median PFS was 13.6 months and OS 23.2 months. In the blastoid group the median PFS was 4.4 months vs 36.5 months in the alternative group (p0.001), the median OS 9.0 vs 41.0 (p=0.001). The median OS of patients after progression on ibrutinib was 3.2 months. The common complications are hemorrhages (63%), diarrhea (62%), myalgia and muscle cramps (60%), infections (31%), skin and nail toxicity 15%, arrhythmia 8%. None of recipients had to completely discontinue ibrutinib therapy due to complications. CONCLUSION: Ibrutinib is effective and well tolerated in routine practice of R/R MCL treatment and our results are consistent with international clinical trials. The favorable toxicity profile and the high response rate made it possible to prescribe ibrutinib in severe somatic status, cytopenia, and even in the presence of infectious complications.

[Carfilzomib, lenalidomide and dexamethasone in relapsed/refractory multiple myeloma patients: the real-life experience].

BACKGROUND: Carfilzomib, lenalidomide, and dexamethasone (KRd) have been approved for the treatment of relapsed and refractory multiple myeloma (RRMM) based on ASPIRE clinical trial. AIM: Analysis of efficacy and safety of KRd in routine clinical practice. MATERIALS AND METHODS: The prospective analysis included patients with MM who received at least one line of previous therapy. The inclusion criteria were relapse/progression; refractoriness; lack of very good partial response (VGPR) and more after the first line of therapy. Since February 2016, we used KRd like in ASPIRE trial, since October 2019, carfilzomib has been used at a dose of 56 mg/m2 on days 1, 8 and 15. Autologous hematopoietic stem cell transplantation (autoHSCT), consolidation (KRd) and maintenance therapy (Rd) were regarded as one line of therapy. RESULTS AND DISCUSSION: We evaluated 77 patients with median age at the time of diagnosis is 55 (3072) years. For 56% (n=43) of patients KRd was applied as the second line (group 1), for 44% (n=34) as the third and more (group 2). In 23/43 patients from group 1, an early change in therapy was made due to insufficient effectiveness (after 24 courses of VCD or PAD). KRd served as a "bridge" to autoHSCT in 25 (32%) patients (21 of 25 in group 1). Another 7 patients underwent collection of autoHSC (all from group 1). The overall response rate (ORR) was 80.5%, with 33.8% complete response (CR) and 26% VGPR. ORR in group 1 was 98% versus 65.6% in group 2; 24-month overall survival (OS) was 70%, progression free survival (PFS) 49.8%. In group 1, 24-month OS was 85.6% versus 50.0% in group 2, 24-month PFS was 67.8% versus 25.5% (p=0.01). CONCLUSION: Our analysis confirmed the high efficiency of KRd in the treatment of RRMM in real-life practice. Early correction of therapy with insufficient effectiveness of the first line made it possible to implement the strategy of high-dose consolidation and autoHSCT in a larger percentage of patients with MM.

[Informativeness of whole-body diffusion-weighted magnetic resonance imaging and positron emission tomography with computed tomography in follicular lymphoma].

AIM: This study conducted the possibilities of diffusion-weighted magnetic resonance imaging of the whole body diffusion WB-MRI (in comparison with positron emission tomography with computed tomography PET/CT) in assessing the volume and prevalence of the tumor, as well as determining bone marrow (BM) damage (for various cytological types) in the diagnosis and staging of the disease in patients with FL. MATERIALS AND METHODS: A prospective comparative search study included 15 patients (4 men and 11 women, with a median age of 53 years) with newly diagnosed FL. Patients have not received antitumor chemotherapy previously. After the diagnosis was established, all patients (with the blindness of both the cases themselves and some specialists regarding the results of other specialists) were examined by PET/CT and diffusion WB-MRI, after which a BM examination was performed (histological examination and determination of B-cell clonality in BM puncture by PCR). Using the diffusion WB-MRI method, the prevalence of tumor lesion (nodal and extranodal foci) in each patient was estimated, and the total tumor volume was calculated, BM lesion was detected, and BM lesion volume was calculated. For lesions of different localization, the measured diffusion coefficient (DC) of the diffusion WB-MRI and the standardized rate of accumulation of the radiopharmaceutical in tissues (SUV) of the PET/CT method were determined and compared with each other (for the same areas). Statistical analysis was performed using the estimate of agreement (by Cohens kappa coefficient and asymptotic test) of the results of the compared methods. RESULTS: Estimates of the prevalence of tumor damage (lymph nodes and extranodal foci) using the diffusion WB-MRI and PET/CT methods were the same. High DC and SUV were observed in the peripheral lymph nodes, extranodal foci and bulky, low DC and SUV in the foci of BM. All 4 methods successfully determined BM damage, however, the diffusion WB-MRI had comparatively less negative results. The highest values of SUV and CD were noted in cases of the 3 grade of FL. Using the diffusion WB-MRI method, the prevalence of tumor lesion was assessed in each patient (nodal and extranodal foci were detected) and the total tumor volume was calculated, BM lesion detection was performed, and the volume of BM lesion was calculated. It is important to note that with the help of diffusion WB-MRI, it was possible to measure separately the total tumor volume (462025 cm3) and separately the volume of bulky (251358 cm3). The diffusion WB-MRI allowed us to differentiate the volume of tumor tissue (reduced as a result of treatment) and residual (fibrous-adipose) tissue in residual formations (which averaged 21% of the initial volume). The predictors of a poor antitumor response were the maximum SUV values (more than 14.0) and the minimum DC values (0.510-3mm2/s) in the BM foci. CONCLUSION: The diffusion WB-MRI allows for detailed visualization of BM lesions and surrounding soft tissues both in the debut of the FL and in the process of tracking the effectiveness of chemotherapy, which makes it possible to use it along with PET/CT. Diffusion WB-MRI allows to separately evaluate the volume of true tumor tissue and residual tissue. Cases of the 3 grade of FL (including the transformation of FL into diffuse B-large cell lymphoma) are isolated due to low DC values (and high SUV values) in the tumor tissue. BM foci of FL lesion also have (in comparison with nodal and extranodal foci) lower DC values. The predictors of a poor antitumor response were high (from 14.0 or more) SUV valuesin the tumor (and especially in bulky), and low (about 0.5103mm2/s) DC values of BM foci. The PET/CT and diffusion WB-MRI have proven to be reliable diagnostic tools for establishing the stage of FL and detecting BM damage. Diffusion WB-MRI for FL is an informative first-line diagnostic method that allows regular monitoring of the disease and early detection of foci of relapse and disease progression.

[Predictors of acute cerebral embolic lesions during carotid artery stenting]. / Prediktory ostrykh tserebral'nykh émbolicheskikh povrezhdenii pri stentirovanii sonnoi arterii.

The authors carried out a prospective study aimed at revealing predictors of acute embolic lesions of cerebral vessels during angioplasty with stenting of the internal carotid artery. The study enrolled a total of 54 patients who between May 2015 and December 2018 underwent carotid angioplasty with stenting performed at the Department of Vascular and Endovascular Surgery of the Research Centre of Neurology. The procedure of internal carotid artery stenting may be accompanied by intraoperative acute embolic lesions. In order to reveal intraoperative acute embolic lesions of cerebral vessels all patients before and 24 hours after the intervention were subjected to diffusion-weighted magnetic resonance imaging. Thirty-six patients received classical carotid stents (Xact and Acculink) and 18 patients received Casper stents. The patients of both groups were comparable by 24 characteristics studied, including the incidence of intraoperative acute cerebral embolic lesions (18/36 for the classical stents and 10/18 for the Casper stent), which made it possible to unite them into one group in order to increase the power of the study. All acute embolic lesions detected by the diffusion-weighted magnetic resonance imaging (prior to stenting and 24 hours thereafter) were clinically, asymptomatic with no perioperative stroke observed. In order to reveal predictors of intraoperative acute embolic lesions of cerebral vessels we analysed 22 characteristics of the patients, with the obtained findings demonstrating the following signs: a low-intensity (below 20 dB) ultrasonographic signal reflected from fragments of an atherosclerotic plaque during ultrasound examination prior to stenting (p=0.001) - a sign strongly associated with acute embolic lesions (sensitivity - 75%, specificity - 92%); symptomatic stenosis according to the anamnestic data (p=0.02) - a sign significantly associated with acute embolic lesions; female gender (p=0.06) - a sign moderately associated with acute embolic lesions; a history previously endured (according to the anamnestic data) operations on coronary and/or carotid arteries (p=0.09) - a sign weakly associated with acute embolic lesions. Based on the obtained findings we proposed a prognostic scale to assess the risk of acute embolic lesions of cerebral vessels during internal carotid artery stenting. Knowing the factors associated with intraoperative acute embolic lesions will allow the endovascular surgeon to single out the patients at increased risk of acute embolic lesions.

[Risk - adapted intensive induction therapy, autologous stem cell transplantation, and rituximab maintenance allow to reach a high 7-year survival rate in patients with mantle cell lymphoma].

Mantle cell lymphoma (MCL) is aggressive B-cell neoplasm diagnosed predominantly among older men. R-CHOP-like regimens allow to achieve high response rate, but the overall survival (OS) are disappointingly short - 3-4 years. An addition of high - dose cytarabine to the upfront therapy and autoSCT significantly improved outcomes but remain feasible largely for medically fit patients. Based on the activity and good tolerance of gemcitabine - oxaliplatin schemes in relapsed and refractory MCL patients, we developed an alternative first - line course for patients who are not eligible for R-HD-MTX-AraC. AIM: Assess toxicity and efficacy of R-DA-EPOCH/ R-HD-MTX-AraC and R-DA-EPOCH/R-GIDIOX schemes, autoSCT and R-maintenance in untreated MCL patients. MATERIALS AND METHODS: 47 untreated MCL patients from 6 centers were enrolled in prospective study between April 2008 and September 2013. All patients have stage II-V; ECOG 0-3; median age 55 years (29-64); Male/Female 76%/24%. MIPIb: 28% low, 33% intermediate and 39% high risk. Following 1st R-EPOCH patients were assigned to receive either R-DA-EPOCH/ R-HD-MTX-AraC or R-DA-EPOCH/ R-GIDIOX regimen. In the absence of renal failure, hematological toxicity grade 4 more than 3 days and severe infections patients received R-HD-MTX-AraC scheme (R 375 mg/m2 Day 0, Methotrexate 1000 mg/m2/24 hours Day 1, AraC 3000 mg/m2 q 12 hrs Days 2-3). Patients who had at least one of these complications received R-GIDIOX scheme (R 375 mg/m2 day 0, gemcitabine 800 mg/m2 days 1 and 4, ifosfamide 1000 mg/m2 days 1-5, dexamethasone 10 mg/m2 IV days 1-5, irinotecan 100 mg/m2 day 3, oxaliplatin 120 mg/m2 day 2). Subsequently these courses were alternating with R-DA-EPOCH in each arm of the protocol. Depending on the time of achieving CR patients received 6 or 8 courses, unless they progressed on therapy. Those patients who achieved PR/CR/CRu underwent autoSCT (BEAM-R). Post - transplant R-maintenance was administered for 3 years (R - 375 mg/m2 every 3 months). RESULTS: 29/47 patients were treated on R-HD-MTX-AraC arm (median 50 years; MIPIb: 35.7% low, 28.6% intermediate, 35.7% high risk) and 18/47 patients were on R-GIDIOX arm (median 60 years; MIPIb: 16.7% low, 38.9% intermediate, 44.4% high risk). In R-HD-MTX-AraC arm CR rate was 96.5%. In R-GIDIOX arm OR and CR rates were 94.4% and 77.7% respectively. Main hematological toxicity of R-GIDIOX was leukopenia gr. 4 occurred in 74.1%. With median follow - up of 76 months, the estimated 7-years OS and EFS in R-HD-MTX-AraC arm are 76% and 57% respectively. In R-GIDIOX arm the estimated 7-years OS and EFS are 59% and 44%, respectively. There are no statistical differences in EFS (p=0.47) and OS (p=0.06) between two arms. CONCLUSIONS: The use of a risk - adapted strategy allowed 95.7% of patients achieve PR/CR/CRu, performed autoSCT and begun R-maintenance therapy with rituximab. None of the patients needed a premature discontinuation of therapy because of unacceptable toxicity. The performance of autoSCT and R-maintenance apparently allowed to partially offset differences in the intensity of induction therapy and to maintain comparable results of therapy in both induction arms.

[Follicular lymphoma: first - line selection criteria of treatment].

Follicular lymphoma (FL) is a tumor that develops from the B cells of the germinal center; characterized by recurrent and remitting course of the disease, the transformation of a tumor into diffuse large B-cell lymphoma (DLBCL) is possible. In generalized lesions and progression of FL, the most commonly used courses are R-CHOP and R-B. The choice of therapy for different cytological types, clinical and laboratory parameters remains disputable. AIM: To analyze the clinical, laboratory, morphological parameters of patients with FL, who got R-B and R-CHOP therapy; determine the criteria for selecting induction therapy. MATERIALS AND METHODS: The study included 203 patients with FL from 2000 to 2018. R-CHOP treatment was initiated in 126 patients, 14 of whom later received high - dose therapy (HDT) (R-DHAP: rituximab, dexamethasone, cisplatin, cytarabine) without autologous stem cell transplantation (autoSCT), 21 - HDT with autoSCT; treatment of 89 patients was limited to courses of R-CHOP and maintenance therapy with rituximab, two patients (in whom the disease progressed, despite R-CHOP therapy) were assigned the mNHL-BFM-90 program. The efficacy of treatment on various treatment regimens was evaluated primarily by overall survival. RESULTS AND DISCUSSION: R-B. 77 patients received R-B therapy. Complete remission of the disease was achieved in 47/77 (61%) patients (3 of them later developed a relapse of the disease), partial remission was achieved in 15/77 (19%) patients, in 13/77 (17%) cases progression was recorded tumors. 70 patients had 1-2 cytological type of tumor, 6 patients - 3A cytological type. In cases of progression, 3 of 13 patients (46%) were diagnosed with 3A cytological type FL. Median observation (at the time of analysis) - 34 months. R-CHOP. 89 patients with FL received high - dose therapy with R-CHOP (6-8 courses) and maintenance therapy with rituximab. In 39 (44%) patients, the disease remained in remission, and in 50 (56%), a relapse of the disease developed. 50 patients had 1-2 cytological types, 39 - 3 cytological types. In cases of recurrence of FL, a 3A cytologic type (36%) was diagnosed in 18/50 patients. Median observation - 93 months. R-CHOP + HDT and autoSCT. 21 patients after the R-CHOP courses continued (due to insufficient antitumor response) high - dose chemotherapy (HDT) and auto-SCT were performed. In 18/21 (86%) cases, complete remission of the disease was achieved and maintained, in 3 (14%) cases relapse developed. 16 patients had 1-2 cytological types, 5 - 3 cytological types. Median observation - 81 months. R-CHOP + HDT without autoSCT. 14 patients started therapy under the R-CHOP program as induction therapy, but then (due to insufficient antitumor response), the treatment was continued according to the HDT without autoSCT. 11 (79%) patients are currently in remission of the disease, in 3 (21%) - there was a relapse. 10 patients had 2 cytological types of PL, 4 - 3 cytological types. 11 (79%) patients are currently in remission of the disease, in 3 (21%) - there was a relapse. Median observation - 80 months. 7-year OS of patients with FL on RB therapy was 89% (95% CI 75-99), on R-CHOP therapy - 85% (95% CI 73-90), on R-CHOP + HDT and autoSCT - 87% (95% CI 57-100), on R-CHOP + HDT without autoSCT - 82%. 7-year PFS of FL patients on RB therapy was 70% (95% CI 75-99), on R-CHOP therapy - 44% (95% CI 73-90), on R-CHOP + HDT and autoSCT - 74% (95% CI 57-100), on R-CHOP + HDT without autoSCT - 80%. CONCLUSION: The R-B is most effective in FL 1 and 2 cytological types. The cytological type does not correspond to the type of tumor growth: at 3A and 3A + 3B cytological types, nodular / nodular - diffuse and diffuse types of growth are found. When choosing an induction course, one should look at the cytological type of FL. A high proliferative activity index (according to Ki67) is a predictor of resistance to R-B therapy. The absence of an interfollicular T-cell reaction in tumor tissue FL is associated with tumor chemoresistance. The presence of the bulky factor is associated (in most patients) with the FLIPI index with values from 3 to 5, and is a predictor of a poor response to therapy. Patients with bulky, high (more than 35%) Ki67 index and FLIPI from 3 to 5 in the debut of the disease as the first line therapy, it is preferable to choose the R-CHOP mode, and in the absence of (after 4-6 courses) to complete or partial remission to continue conducting the HDT.

[Relation between ultrasonographic and morphological characteristics of atherosclerotic plaques of carotid sinus]. / Sviaz' ul'trazvukovykh i morfologicheskikh kharakteristik ateroskleroticheskikh bliashek karotidnogo sinusa.

The authors revealed relation between the structure of an atherosclerotic plaque (ASP) and intensity of the ultrasound signal reflected form the ASP. Our prospective pilot study included a total of 90 patients (71 men and 19 women aged from 47 to 79 years, with the median age 62 years) presenting with atherosclerotic stenosis of the carotid sinus (CS) and undergoing treatment at the Research Centre of Neurology (Moscow) from April 2015 to March 2016. All patients underwent ultrasonographic examination followed by morphological study of the structure of the plaques removed during carotid endarterectomy (CEA). It was revealed that intensity of the ultrasound signal from an ASP depended on the morphological structure of the ASP components: the foci of atheromatosis were associated with an ultrasound range of 1.1-5.6 dB, those of fibrosis - with the range 23.1-30.5 dB, and those of calcinosis - with the range 42.3-44.7 dB (presented are the values from the 15th to 85th percentiles). It was determined that an increase of intensity of the ultrasound signal reflected from the foci of atheromatosis and fibrosis in the ASP was associated with the presence of small calcificates therein, and a decrease of intensity of the ultrasound signal from the portions of fibrosis in the ASP - with large accumulation of lipophages or newly formed vessels in these portions.

[Multiple myeloma: Maintenance therapy after autologous hematopoietic stem cell transplantation, depending on minimal residual disease]. / Mnozhestvennaia mieloma: podderzhivaiushchaia terapiia posle transplantatsii autologichnykh gemopoéticheskikh stvolovykh kletok v zavisimosti ot minimal'noi ostatochnoi bolezni.

AIM: To determine the efficiency of maintenance therapy with bortezomib in patients with multiple myeloma (MM) who have achieved complete remission (CR) after autologous hematopoietic stem cell (auto-HSCT), depending on the presence of minimal residual disease (MRD). SUBJECTS AND METHODS: In January 2014 to February 2016, fifty-two MM patients (19 men and 33 women) aged 24 to 66 years (median 54 years), who had achieved CR after auto-HSCT, were randomized to perform maintenance therapy with bortezomib during a year. On day 100 after auto-HSCT, all the patients underwent immunophenotyping of bone marrow plasma cells by 6-color flow cytometry to detect MRD. Relapse-free survival (RFS) was chosen as a criterion for evaluating the efficiency of maintenance therapy. RESULTS: After auto-HSCT, MRD-negative patients had a statistically significantly higher 2-year RFS rate than MRD-positive patients: 52.9% (95% confidence interval (CI), 35.5 to 70.5%) versus 37.2% (95% CI, 25.4 to 49.3%) (p=0.05). The presence of MRD statistically significantly increased the risk of relapse (odds ratio 1.7; 95% CI, 1.2 to 3.4; p=0.05). Two-year cumulative risk of relapse (using the Kaplan-Meier) after auto-HSCT did not statistically significantly differ in MRD-negative patients receiving (n=15) and not receiving (n=10) maintenance therapy with bortezomib (p=0.58). After completion of maintenance treatment, 42% of the MRD-positive patients achieved a negative status. In the MRD-positive patients who had received maintenance therapy, the average time to recurrence was 5 months longer than that in the naïve patients: 17.3 versus 12.3 months. CONCLUSION: The MRD status determined in MM patients who have achieved CR after auto-HSCT is an important factor for deciding on the use of maintenance therapy.

[Leukemization of follicular lymphoma: The features of diagnostic and clinical course of a rare form of the disease]. / Leikemizatsiia follikuliarnoi limfomy: osobennosti diagnostiki i klinicheskogo techeniia redkoi formy zabolevaniia.

AIM: 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)). SUBJECTS AND METHODS: 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). RESULTS: 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. CONCLUSION: 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.

[Prediction of ischaemic lesions of the brain in reconstructive operations on internal carotid arteries]. / Prognozirovanie ishemicheskikh povrezhdenii golovnogo mozga pri rekonstruktivnykh operatsiiakh na vnutrennikh sonnykh arteriiakh.

The present study was undertaken to examine the relationship between the level of the intensity of the ultrasonic signal reflected from atherosclerotic plaques (ATP) of carotid arteries and the risk for formation of an ischaemic lesion in the brain matter, detected during diffusion-weighted magnetic resonance imaging (DW-MRI) performed 24 hours after carotid endarterectomy (CEA) or carotid angioplasty and stenting (CAS). Our prospective study included a total of 78 patients presenting with stenosis of the sinus of the interior carotid artery. Of these, 42 patients were subjected to CEA and 36 subjects endured CAS. All patients in the preoperative period underwent ultrasonographic examination with determination of the degree of heterogeneity of ATPs and registration of the values of the intensity of acoustic characteristics of the signal. The condition of the brain matter before and 24 hours after the intervention was assesses by the findings of DW-MRI. None of the patients after the reconstructive intervention during the postoperative period demonstrated any evidence of acute cerebral circulation disorders. DW-MRI carried out 24 hours after the operation revealed acute ischaemia foci (AIF) in 9 (21.4%) patients after CEA and in 18 (50%) patients after CAS (p=0.05). It was revealed that the postoperative occurrence of AIF was related to the intensity of the ultrasonographic signal prior to the operation: in the CEA group patients the postoperative ischaemic foci were associated with high-intensity ultrasonographic signals (more than 25 dB), whereas in the CAS group patients, vice versa - with low-intensity signals (less than 25dB). For CEA, sensitivity and specificity of the preoperative ultrasonographic method of predicting postoperative embolic lesions of the brain appeared to be similar, amounting to 100% each (with the cut-off point of high- and low-intensity signals equaling 25 dB), and for CAS, sensitivity of the method turned out to be 75% and specificity - 100% (with the same cut-off point of 25 dB). A conclusion was drawn that quantitative characteristics of the intensity of an ultrasonographic signal from fragments of atherosclerotic plaques of the sinus of the internal carotid artery made it possible with high probability to predict the risk for the development of AIF in the brain matter after both CEA and CAS and may therefore serve as a reliable criterion for appropriate therapeutic decision-making with the lowest risk of inflicting lesions in a particular case. The threshold cut-off points of high- and low-intensity ultrasonographic signals, as well as their clinical significance are yet to be specified and verified with the growing number of cases.

[Perianal infection in patients with hemoblastosis: Risk factors and possibilities of prevention]. / Perianal'naya infektsiya u bol'nykh gemoblastozami: faktory riska i vozmozhnosti profilaktiki.

AIM: to identify poor prognostic factors for perianal infection (PI) in patients with hemoblastosis and to define an effective tactic for preventive and therapeutic measures. SUBJECTS AND METHODS: The prospective study enrolled 72 patients (37 men and 35 women; mean age, 47 years) with hemoblastosis that was complicated by the development of one of the following forms of PI: abscess, infiltrate, multiple ulcers. Different clinical and laboratory characteristics of the patients were examined to identify risk factors for PI. The species-specific concordance of microorganisms isolated from the anus and blood in the development of PI was assessed to record the latter as a source of sepsis. Treatment policy was defined according to the clinical form of PI. RESULTS: Acute myeloid leukemias and lymphomas were the most common background diseases in 30 (41.7%) and 22 (30.6%) patients, respectively. During induction chemotherapy cycles, perianal tissue infection occurred twice more frequently (66%) than totally at the onset of hemoblastosis (13%) and after achievement of remission (during consolidation and maintenance therapy) (21%; Fisher's exact test; p=0.01). PI in agranulocytosis was more than twice as common as in its absence: 69.4% vs 30.6% (p=0.01) and was responsible for sepsis in 9 (18%) of 50 patients. The main source of perianal tissue infection in patients with granulocytopenia was anal fissures and fistulas and ulcers of the anal canal: 44 (88%) cases of the 50 cases. In PI as an abscess, the average white blood cell count was 5 times higher (p=0.01) than that in PI as an infiltrate (or multiple ulcers): 6.6·109/l and 1.2·109 g/l. Abscess formation was observed in 16 (22.2%) patients and an indication for surgical drain. The inflammatory infiltrate was found to develop in 48 (66.7%) patients; multiple ulcers were seen in 8 (11.1%); in this group, parenteral antimicrobial therapy proved to be effective in 36 (78%) patients. 29 patients were operated on for anal fissures and fistulas at intercycle intervals. After continuing CT, PI recurrences were observed in 4 (9.1%) patients. In the operated versus medically treated patients, the risk of complications associated with abnormalities in the perianal area during continued CT was 5 times statistically significantly lower (odds ratio=0.2; 95% confidence interval 0.1 to 0.5; p=0.04; Cochran-Mantel test). CONCLUSION: Induction CT cycles, the status of granulocytopenia, and the presence of infection sources in the anal canal as an anal fissure, skin ulcerations, or a fistula should be considered as independent statistically significant prognostic risk factors for PI. The number of granulocytes determines the form of inflammation, the course of infection, and the chance of developing sepsis. The effective prevention encompassing surgical treatment for anal canal diseases reduces the risk of septic complications and the number of paraproctitis recurrences, contributing to the implementation of a planned CT program in patients with hemoblastosis.

[Follicular lymphoma. High-dose immunochemotherapy with autologous blood stem cell transplantation: Results of the first prospective study in Russia]. / Follikulyarnaya limfoma. Vysokodoznaya immunokhimioterapiya s transplantatsiei autologichnykh stvolovykh kletok krovi: rezul'taty pervogo prospektivnogo issledovaniya v Rossii.

AIM: 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. SUBJECTS AND METHODS: 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 ß2-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). RESULTS: 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. CONCLUSION: 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.

[Efficiency of interferon therapy in patients with essential thrombocythemia or polycythemia vera]. / Effektivnost' interferonoterapii u bol'nykh essentsial'noi trombotsitemiei i istinnoi politsitemiei.

AIM: To evaluate the efficiency of interferon (IFN) therapy in patients with essential thrombocythemia (ET) and polycythemia vera (PV). SUBJECTS AND METHODS: A total of 61 patients (41 with ET and 20 with PV) were examined. Prior to study enrolment, 44 (72%) patients with ET or PV received one or other therapy (aspirin was not taken into account). The mean Jak2V617F mutant allele at baseline was 23% (6-54%) in the patients with ET and 40% (11-88%) in those with PV. The median time from diagnosis to enrollment was 49 months. RESULTS: The paper presents the clinical and molecular findings of long-term INF-α therapy in patients with ET or PV. The median follow-up was 52 months. Recombinant IFN-α2 showed its ability to induce complete hematologic remission (ET (76%), PV (70%)) and a complete molecular response. 22 (69%) out of 32 patients were noted to have a smaller number of cells with the Jak2V617F mutation. In the patients with PV and in those with ET, the relative reduction in the proportion of cells with the Jak2V617F mutant gene averaged 85% and 56% of the baseline values, respectively. There was a reduction in the proportion of cells expressing the Jak2V617F mutation in both the ET (from 12 to 2.2%; p=0.001) and PV (from 32.7% to 3.2%) groups (р=0.001). Ten (31%) patients achieved a deep molecular remission (≤2% Jak2V617F allele); among them, 5 patients were not found to have Jak2V617F mutation. The obtained molecular response remained in 7 of the 10 patients untreated for 11 to 86 months. The long-term treatment with IFN-α led to normalization of the morphological pattern of bone marrow in 5 of the 7 PV or ET patients. CONCLUSION: Significant molecular remissions achieved by therapy with recombinant interferon-α2 confirm the appropriateness of this treatment option in in the majority of patients with ET or PV.

[Hepatosplenic T-cell lymphoma: The problems of diagnosis and treatment]. / Gepatolienal'naia T-kletochnaia limfoma: problemy diagnostiki i lecheniia.

In the past decade, a notable advance has been made in the understanding of the pathogenesis of NK/T-cell lymphomas; however, their diagnosis remains difficult because of their rarity and clinical and morphological variabilities. The paper generalizes the ten-year experience of the Hematology Research Center, Ministry of Health of Russia, in diagnosing and treating hepatosplenic T-cell lymphoma (HSTL), considers the problems of differential diagnosis with other hematological diseases occurring with similar clinical and laboratory symptoms, and lays down current approaches to the diagnosis and treatment of this condition. A clinician's view of the problem of diagnosis and treatment of this disease is given. HSTL is shown to be a heterogeneous group of diseases differing in a T-cell receptor chain gene rearrangement, the clinical course of the disease, and overall survival (OS). According to our data, 3-year OS was 12%; the median survival was 26 months. Two-year OS for γδ and αß HSTL was equal to 25 and 70%, respectively. The difference in OS for the variants of HSTL failed to reach statistical significance (because the sample might be insufficient).

[Molecular analysis of immunoglobulin genes in the tumor B cells in splenic marginal zone lymphoma].

AIM: To determine the immunoglobulin variable heavy chain (gVH) genes and their somatic mutations and to compare these data with the clinical and laboratory parameters of patients and the outcomes of the disease. SUBJECTS AND METHODS: The investigation enrolled 24 patients (9 men and 15 women whose age was 32 to 77 years (median age, 60 years) with splenic marginal zone B-cell lymphoma (SMZBCL). The latter was diagnosed on the basis of histological and immunohistochemical examinations of a bone marrow trephine biopsy specimen, immunophenotyping of peripheral lymphoid cells or bone marrow aspirates. RESULTS: The mutational status of the IgVH genes was analyzed in all the 24 patients. It was found that the tumor cells contained mutated IgVH genes (the VH1-family genes participated in most cases) in 15 (62.5%) patients with SMZBCL and unmutated ones in 9 (37.5%). There was a tendency towards more common tumor progression in patients with unmutated IgVH genes than in those with mutated ones. CONCLUSION: The presence of SMZBCL cases with both mutated and unmutated IgVH genes and the higher frequency of the VH1-2 gene are likely to indicate the molecular heterogeneity of the origin of this lymphoma.

[Clinical and morphological features of different types of Castleman's disease].

AIM: To study the clinical features of Castleman's disease (CD) and to elaborate therapeutic approaches in its different morphological types. SUBJECTS AND METHODS: The clinical and laboratory data were studied in 59 prospectively examined patients and 17 retrospectively examined ones with CD who had been treated at the Outpatient Department, Hematology Research Centre, in 1996 to 2014. There were a total of 37 men (median age, 36 years) and 39 women (median age, 34 years). The diagnosis was established from the results of histological and immunohistochemical examinations of removed lymph nodes (LN) or tumors in all the cases. RESULTS: A hyaline vascular variant (HVV) with local LN involvement was diagnosed in 38 (50%) patients; a plasma cell variant (PCV) was in 38 (50%); among the latter, 17 (22%) patients were found to have local involvement and 21 (28%) had generalized (multicentriC) involvement (multicentric Castleman's diseases (MCD)). Five (24%) patients with MCD were established to be infected with human herpesvirus type 8 (HHV-8). HVV was more frequently diagnosed in women (4%) than in men (29%); PCV was equally common in both men (47%) and women (53%); MCD was statistically significantly more frequently encountered in men (86%) than in women (14%) (p=0.05). The basic involvement areas in local HVV and PCV were peripheral (38%), mediastinal (29), retroperitoneal (18%), abdominal (9%), and small pelvic (6%) LNs. HVV and local PCV were benign and these were cured by surgical removal of LNs involved in the pathological process. MCD took its aggressive course with obvious constitutional symptoms, generalized lymphadenopathy, hepatosplenomegaly, hypergammaglobulinemia, autoimmune hemolysis, thrombocytopenia, and involvement of extranodal foci in the pathological process. MCD transformation to plasmablastic lymphoma was observed in 4 of the 5 HHV8-positive patients and followed by a poor outcome. The prognosis of untreated MCD was unfavorable. In a number of cases prednisolone monotherapy worsened prognosis and the MCD patients receiving timely multiple-drug R-CHOP or R-VD chemotherapy could achieve sustained remission (the 5-year overall survival was 55%). CONCLUSION: CD must be included into the differential diagnosis of lymphadenopathies. When specific treatment is performed, the prognosis of HVV and local PCV is favorable: the disease is surgically cured in 95% of cases. Multidrug chemotherapy according to the B-cell lymphoproliferative disease program is indicated for the treatment of MCD: sustained remission can be achieved by the use of R-CHOP or R-VD programs. The HHV-8-positive variants of MCD increase the probability of transforming the disease to incurable plasmablastic lymphoma. Overall, prognosis and therapy choice in HIV-negative patients with CD depend on the histological variant of the disease, the extent of a tumor, and HHV-8 infection.