[Synchronous and metachronous myeloid and lymphoid tumors].

AIM: To determine the clinical features of multiple primary tumors (MPT) in patients with hemoblastoses, to develop treatment policy for synchronous and metachronous tumors, and to determine the impact of chemotherapy for one disease on the course and prognosis of another one. SUBJECTS AND METHODS: The investigation included 20 patients with multiple primary synchronous and metachronous myeloid and lymphoid tumors, who had been followed up at the Outpatient Department of the Hematology Research Center, Ministry of Health of the Russian Federation. The distribution of patients by nosological entities was as follows: 17 (85%) patients with myeloproliferative diseases (MPDs) concurrent with lymphoproliferative diseases (LPDs) and 3 (15%) with two types of MPD. A special group comprised 3 patients who successively developed 3 malignant diseases: cancer/B-cell chronic lymphocytic leukemia (B-CLL)/Ph-positive chronic myeloid leukemia (Ph+CML); cancer/polycythemia vera (PCV)/B-CLL; cancer/essential thrombocythemia (ETC)/multiple myeloma (MM). RESULTS: The Outpatient Department of the Hematology Research Center, Ministry of Health of the Russian Federation, followed up 20 patients with synchronous and metachronous tumors in 1996 to 2013. The patients' age was 42 to 82 years (64 years). The female/male ratio was 1:1.2. Metachronous tumors were 1.5-fold higher than synchronous ones. The time to detection of secondary hemoblastosis averaged 3.3 years; the longest interval was 14 years; the mean coexistence of 2 tumors was 4.8 years (1-11 years). The total length of the follow-up was 8 years (1-19 years). Among them, there were 17 (85%) patients with 2 chronic hematologic tumors with a myeloid or lymphoid phenotype; 3 (15%) of the 20 patients had 3 malignant diseases (cancer/ B-CLL)/Ph+CML, cancer/PCV/B-CLL, cancer/ETC/MM. In the group of 17 patients, 13 (76%) were diagnosed as having Ph-negative MPDs (PCV in 4 patients, primary myelofibrosis in 4, ETC in 4, undifferentiated MPD in1) and 4 (24%) patients had Ph+CML. This patient group was found to have the following LPDs: CLL in 5 (30%), hairy cell leukemia in 1 (5%), paraproteinemic hemoblastoses in 11 (65%). MPD preceded LPD in 8 (47%) patients; the development interval between two tumors averaged 6 years (1 to 14 years). LPD preceded MPD in 3 (18%) patients; the interval averaged 5 years (2 to 17 years). MPD and LPD appeared synchronously in 6 (35%) patients. CONCLUSION: The fact that 2 malignancies or more may occur in one patient determines the need for a careful follow-up of patients with blood system diseases. The activity of one hematologic disease or another is a leading criterion for choosing a therapeutic tactic.

[Differential diagnosis of rheumatic diseases and blood cancers involving the nasal cavity and accessory sinuses].

AIM: To provide the clinical, laboratory, radiological, morphological, and immunomorphological signs that permit the differential diagnosis to be made in patients with involvement of the nasal cavity and accessory sinuses (NCAS). SUBJECTS AND METHODS: In the period 2009 to 2013, the Laboratory for Intensive Therapy for Rheumatic Diseases, V.A. Nasonova Research Institute of Rheumatology, Russian Academy of Medical Sciences, associated the disease onset with NCAS involvement in 39 (7.6%) of 512 examinees. NCAS involvement was present at disease onset in 100% of the patients with natural killer (NK) cell lymphoma (NK/T lymphoma), in 84.5% of those with Wegener granulomatosis (WG), in 29.5% of those with IgG4-related disease (IgG4-RD), and in 17.5% of those with sarcoidosis. Such an onset could be extremely rarely observed in histiocytosis. RESULTS: Despite the similar clinical manifestations, NCAS involvements in NK/T lymphoma of nasal type and WG at disease onset show clear differences in the laboratory and systemic manifestations of these diseases. The patients with lymphoma have no characteristic laboratory abnormalities at disease onset, except the 100% presence of Epstein-Barr virus (EBV) DNA in blood and, only as a tumor grows, fever appears and there are elevated C-reactive protein and lactate dehydrogenase levels and pronounced destructive changes in the facial bones with mandatory hard palate destruction; at the same time the signs of systemic involvement are virtually absent. The patients with WG at disease onset have fever, high erythrocyte sedimentation rate, elevated C-reactive level, significant anemia, leukocytosis and 90% are found to have anti-neutrophil cytoplasmic antibodies with the rapid development of systemic manifestations: involvements of the lung, kidney, and peripheral nervous system. Destructive changes in the facial bones are minimal and hard palate destructions are absent. The patients with IgG4-RD, sarcoidosis, and juvenile xanthogranuloma have similar clinical and laboratory manifestations in the absence of hemorrhagic nasal discharge, nasal septal perforation, and facial bone destruction, with the practically involvement of the salivary/lacrimal glands and orbital regions. A third of the patients are observed to have different allergic manifestations, moderate eosinophilia, and signs of autoimmune disorders (the presence of rheumatoid and antinuclear factors, hypergammaglobulinemia). Elevated serum IgG4 levels are characteristic of IgG4-RD. CONCLUSION: Blood anti-neutrophil cytoplasmic antibodies, EBV DNA, and IgG4 levels should be determined in all patients with NCAS involvement. Mini-invasive incision biopsies of the nasal mucosa, orbital regions, and major salivary glands should be done, by morphologically verifying the diagnosis of sarcoidosis, histiocytosis, and WG and by making an immunomorphological examination to diagnose NK/T lymphoma and IgG4-RD.

[POEMS-syndrome: a literature review and case reports].

POEMS-syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, M-protein, and Skin Changes) is a rare nosological form occurred in patients with paraproteinemic hemoblastosis. Chronic progressive sensory-motor polyneuropathy is a key syndrome of the disease and it is a common reason for referral to neurologist. The paper presents data about POEMS-syndrome and own case reports with the analysis of disease features and results of examination.

[Multiple myeloma predominantly involving the spleen].

Extramedullary disease is an uncommon manifestation in multiple myeloma (MM) and can be observed at onset or develop at disease progression or relapse. Splenic involvement is very rare. The paper describes a 52-year-old female patient with MM who in 1990 was diagnosed with monoclonal gammopathy of undetermined significance with IgGkappa secretion and a considerably enlarged spleen. Specific therapy with bortezomib and dexamethasone was initiated in 2006 and proved to be inefficient. After splenectomy there was a 50% reduction in IgGkappa concentration. Splenic histological examination revealed monoclonal infiltration by the pleomorphic plasma cells expressing a kappa light chain.

[Morphological and immunochemical features of nephropathies in multiple myeloma and severe renal failure].

AIM: To study the pathomorphology of kidneys in patients with multiple myeloma (MM) and severe renal failure (RF) and to compare the results of morphological, immunohistochemical, and electron microscopic examinations of nephrobiopsy specimens with the pattern of monoclonal secretion and the type of proteinuria and paraproteinuria. SUBJECTS AND METHODS: A study group comprised 25 patients with MM and severe RF; 22 of them underwent programmed hemodialysis. Immunochemical study of serum and urine proteins, renal puncture biopsy with light, immunofluorescence and electron microscopy examination of its specimens were performed in all the patients. RESULTS: Cast nephropathy (CN) is the most common type of renal impairment in patients with MM and severe RF. CN concurrent with monoclonal immunoglobulin deposition disease was identified in 32% of cases. In the mixed lesion, it is CN that is a determinant in the development of acute and chronic RF. Rare variants of nephropathies as fibrillary glomerulonephritis, immunotactoid nephropathy, and crystalline histiocytosis were found in 16% of cases. In most cases, severe RF in MM develops in case of low monoclonal secretion. However, there are a larger number of secreted and excreted monoclonal light chains in CN than in other variants of kidney lesion. Urinary paraprotein G excretion suggests that the glomerular filter is damaged. Degenerative changes in the podocytes and a reduction in their small processes were detected in the majority of cases. In glomerular or mixed proteinuria, there were also unorganized and organized deposits in the glomerular basement membrane. CONCLUSION: The pattern of nephropathy does not determine a renal response after chemotherapy. The reversibility of CN in MM depends on the magnitude of interstitial fibrosis and podocyte changes. The pronounced changes in the podocytes as a reduction in their small processes serves as a poor sign in achieving renal responses following chemotherapy.

[Secondary autoimmune hemolytic anemia as a result of B19 parvovirus persistence in immunodeficient patients].

AIM: To ascertain informative value of immunological diagnosis of B19 parvovirus in combination with polymerase chain reaction (PCR); to analyse frequency of development of secondary autoimmune hemolytic anemia (AIHA) in immunodeficient patients as a result of virus persistence--persistent infection eliminated only by treatment causing suppression of erythropoiesis. MATERIAL AND METHODS: B19 parvovirus detection was performed in blood serum of 207 subjects: 144 patients with anemia (Hb < 100 g/1) and 500 blood donors. DNA of parvovirus B19 was detected in the sera by PCR, antibodies to this virus--by enzyme immunoassay (EIA). IgG, IgM, IgA and components of compliment Clq, C3 on the surface of erythrocytes were detected by EIA in anemic patients. RESULTS: Parvovirus infection was registered in 30% patients, in 70% the infection was persistent. The latter were diagnosed to have secondary AIHA. CONCLUSION: Combined application of PCR and EIA extends potentialities of diagnosis of infection caused by B19 parvovirus. Persistence of the parvovirus provokes onset of symptomatic hemolytic anemia in immunodeficient patients.

[The role of parotid gland biopsy in early detection of lymphoma in primary Sjogren's syndrome].

AIM: To investigate the incidence of MALT-lymphoma in Sjogren's disease by means of biopsy of the enlarged parotid glands. MATERIAL AND METHODS: The incisional parotid biopsy was performed in 57 primary Sjogren's syndrome (pSS) patients with existing parotid enlargement. The median age was 54 years (range 19-75 years). The median pSS duration was 7 years (range 1-30 years). The palpable parotid enlargement was defined as grade 1 and massive (visional) enlargement of the parotid glands was defined as grade 2. Histologic and immunohistochemical examinations for diagnosis of lymphoma were made. High resolution electrophoresis and immunofixation were performed for detection of monoclonal immunoglobulins in the serum and their free light chains in the urine. RESULTS: Biopsy of the enlarged parotid glands identified MALT-lymphoma in 37 of 57 (64.9%) pSS patients. Of 37 pSS patients with parotid enlargement of grade 2, diagnosis of MALT-lymphoma was made in 89.2%. Of 20 pSS patients who had parotid enlargement of grade 1, MALT-lymphoma was diagnosed in 20%. In patients with grade 1 enlarged parotid glands MALT-lymphoma was identified only in cases with the presence of monoclonal immunoglobulins in the serum and their free light chains in the urine (3 of 4 patients) or in case of disseminated disease (lymphoma involved regional lymph nodes and soft tissues of the face)--1 of 4 patients. In patients with grade 2 enlargement of parotid glands MALT-lymphoma located most frequently in affected parotid glands (69.6%). CONCLUSION: The incisional biopsy of enlarged parotid glands is necessary for detection of MALT lymphoma in pSS patients.

[Syndrome of extrahepatic portal hypertension and chronic abdominal ischemia in patient with subleukemic myelosis and congenital immunodeficiency].

The article demonstrates objective difficulties and subjective mistakes in assessment of a clinical picture in a patient with subleukemic myelosis and thrombosis of the portal system. A careful examination of such patients is necessary to reveal latent disorders (in this case--a complete selective IgA deficiency) influencing treatment policy.

[First experience with the application of rituximab for the treatment of patients with Sjogren's syndrome and disease].

Efficiency and tolerability of rituximab therapy were assessed in 13 patients with Sjogren's syndrome and disease (10) (SLE-1, RA-2). Nine patients (SD-8, PA-1) presented with lymphomas and 4 with systemic manifestations of the disease. Complete and partial remission of lymphoma was achieved in 7 (78%) and 2 (22%) patients respectively. Beneficial effect of therapy on systemic manifestations of the disease was recorded in 3 (75%) of the 4 cases and only 1 patient had cryoglubulinemic glomerulonephritis resistant to rutiximab. Subjective improvement of glandular manifestations was reported by 12 (92%) patients. Objective improvement of salivation and lacrimation was documented in 7 (54%) and 6 (48%) patients who had residual secretion before therapy. Positive outcome of therapy in 12 patients was associated with complete depletion of CD20+ lymphocytes in peripheral blood. These cells were found in a patient who died despite the treatment. Rutiximab significantly decreased medians of ESR, IgG, IgA, IgM, gamma-globulin, and RF levels (p = 0.05-0.002). In 8 patients, therapy resulted in the disappearance of blood cryoglobulins. Intravenous premedication with 500 mg methylprednisolone prevented side effects of rutiximab. The study showed high efficiency and good tolerability of rituximab in combination with pulsed therapy with alkylating cytostatics and courses of polychemotherapy for the treatment of lymphoma and cryoglobuliemic vasculitis in patients with Sjorgen's syndrome and disease. Combination of rutiximab and pulsed therapy was more efficient than rutiximab monotherpy in patients with grade I-IIE MALT-type lymphomas. Rutiximab decreased systemic and glandular manifestations of Sjogren's disease and syndrome in 75 and 48-54% of the patients respectively.

[Renal insufficiency due to interstitial nephritis in sarcoidosis].

The authors present their experience in diagnosing and treating interstitial nephritis with the development of chronic renal failure in a patient with generalized sarcoidosis, by involving the intrathoracic and peripheral lymph nodes, liver, spleen, subcutaneous fat, lung, as well as with the severe salivary and lachrymal gland lesions that imitate the clinical picture of Schogren's disease.

[Hairy cell leukemia in young patients].

AIM: To characterize clinical symptoms, course, immediate and long-term treatment results in young patients with hair cell leukemia (HCL). MATERIAL AND METHODS: The data on 41 HCL patients were analysed. The diagnosis was made by standard diagnostic protocol for HCL detection. RESULTS: The analysis of the age of 160 HCL patients studied demonstrated high (26%) incidence of HCL at young age. Young patients with HCL had special clinical manifestations and specific long-term outcomes of treatment with standard schemes. CONCLUSION: Differences in occurrence of recurrences after standard therapy make it necessary to consider young HCL patients as a separate group who need adjuvant treatment to prolong remission.

[MALT-lymphomas in Sjogren's disease].

AIM: To develop algorithm of early diagnosis of extranodal lymphoma arising in patients with Sjorgen's disease (SD). MATERIAL AND METHODS: SD diagnosis was made in 457 patients treated in Rheumatology Institute clinic in 1999-2004, 38 (8.3%) females aged 19-82 had lymphoproliferative diseases. MALT-lymphomas were diagnosed in 15 (42.2%) patients. All the patients have undergone morphological, immunomorphological investigations of the salivary glands, postoperative material was analysed in some patients. In addition, the following investigations were made: ultrasonography of the salivary glands, lymph nodes, viscera; scintigraphy; trephine biopsy of the bone marrow; myelograms; CT of the chest, abdomena and brain; tests for monoclonal immunoglobulins in the serum and light chains in urine; biopsy of the parotid gland. Clinical, morphological and immunophenotypical characteristics of MALT-lymphomas were assessed by WHO classification. Lymphoma stages were classified according to Ann Arbor. RESULTS: Parotid glands were affected with MALT-lymphoma most frequently. Predominant were extranodal lymphomas of the parotid submandibular, minor salivary glands of the lip and lacrimal glands of stage I E-II E. Extranodal lymphoma with nodal lesion of stage IV occurred less frequently. Untreated long existing MALT-lymphomas of the parotid glands may transform into B-large cell lymphomas deteriorating SD prognosis. The presence of long-term (> 12 months) massive enlargement of parotid/submandibular salivary and lacrimal glands, massive infiltration, monoclonal immunoglobulins in blood serum and their light chains in the urine predict development of MALT-lymphoma in SD. CONCLUSION: In SD, MALT-lymphomas develop primarily in target organs--salivary and lacrimal glands. SD patients with persistent enlargement of the parotid glands need biopsy for early detection of malignant lymphoproliferation.

[A comparative structural analysis of Fab-fragments of monoclonal rheumatoid and non-rheumatoid immunoglobulins M].

The spin-labeling method was used to study the Fab- and Fab-RF-fragments of IgM and IgM-RF, respectively. The spin-label 2,2,6,6-tetramethyl-4-dichloro-sym-triazinyl-aminopiperidine-1-oxyl was introduced into the peptide moiety of the proteins. The rotational correlation time t of the spin-label carrier was determined based on the temperature-viscosity dependence of the EPR spectra parameters of the spin-labeled proteins. The tau values for Fab- and Fab-RF-fragments were 21 +/- 2 and 12 +/- 1 ns, respectively. The data strongly suggest that the significantly lower tau value for the Fab-RF-fragment may be due to the local structural flexibility of the fragment, which in turn may explain the peculiarities of IgM-RF as an autoantibody.

[Prognostic implications of mixed monoclonal cryoglobulinemia in Sjogren's disease]. / Prognosticheskoe znachenie smeshannoi monoclonal'noi krioglobulinemii pri bolezni Shegrena.

AIM: To specify the risk of severe systemic manifestations and transformation into malignant lymphoma in Sjogren's disease (SD) patients with monoclonal mixed cryoglobulinemia (MMC). MATERIAL AND METHODS: A prospective study performed in 1985-1990 included 248 SD patients followed up after the initial detection of monoclonal immunoglobulins (Ig) with serum active rheumatoid factor (RF). The patients' cryoglobulins (CG) were examined. The type of CG was determined by electrophoresis in agarose gel combined with immunofixation and immunoelectrophoresis with mono-specific antisera to heavy and light Ig chains. Biopsies of the lower lip salivary glands and skin were made in all the patients with MMC and 40 patients without CG. The biopsies were studied histologically, histochemically and immunomorphologically. Clinical symptoms and prognosis were studied in all the patients observed in 1985-2000 after the initial diagnosis of MMC. In suspected lymphoma development, histological and immunophenotypical studies of lymph node, bone marrow biopsies, trephine biopsies were made as well as myelograms, Ga-67 scintigraphy, CT of the thoracic and abdominal cavities. The total of clinical, morphological, immunophenotypical and cytogenetic characteristics of lymphoma was estimated by REAL classification. RESULTS: CG at first examination was detected in 50 (20.2%) of 248 patients with SD. 20 (40%) of 50 patients were diagnosed to have MMC with monoclonal IgMchi (19) and IgA (1) in the serum with RF activity. Ten (50%) patients with MMC developed lymphoma after 10.9 +/- 3.3 years, on the average. In the absence of CG lymphoma developed in 5.5% (p < 0.001). B-cell intoxication in patients with diffuse lymphadenopathy, foci of lymphoid infiltration in the lungs, ulcers of the crus and such indices as stab neutrophilic shift, monocytosis, hypoproteinemia with hypogammaglobulinemia, disappearance of the RF, CG, low CIC level, immunodeficiency of monoclonal Ig and appearance of the protein BJ in the urine are markers of developing large B-cell immunosecreting lymphomas. Highly aggressive diffuse LCL resulted in death of 70% SD patients with MMC; 30% died of immunocomplex cryoglobulinemic vasculitis. 10-15-year survival of SD patients after detection of MMC was 50%, free of CG - 97% (p < 0.001). CONCLUSION: MMC is a definite serological marker of developing lymphoma and ulcerative-necrotic vasculitis in SD. In detection of MMC in SD patients it is necessary to prescribe early pathogenetically validated treatment before development of life threatening manifestations.

[Fludarabine treatment of chronic lymphoid leukemia]. / Fliudarabin v lechenii khronicheskogo limfoleikoza.

AIM: To try effectiveness of fludarabine monotherapy in verified chronic lymphoid leukemia (CLL) in pretreated patients. MATERIAL AND METHODS: The treatment effectiveness according to the international criteria of complete and partial remission was assessed in 37 patients with progressive, splenic, tumor and bone marrow forms of CLL given 5-day courses of fludarabine in a single daily dose 25 mg. RESULTS: In progressive CLL, the remission was achieved in 45% of the patients (10% complete and 35% partial), in splenic form--62.5% (12.5% complete, 50% partial), in tumor form--50% (100% partial). In bone marrow form no remissions were obtained. CONCLUSION: Fludarabine is effective in therapy of pretreated CLL patients. The treatment should be adjusted to CLL form.

[Modification of surface residues of lysine in immunoglobulin G using the spin marker 2,2,5,5-tetramethyl-3-maleimidopyrrolidine-1-oxyl]. / Modifikatsiia poverkhnostnykh ostatkov lizina v immunoglobuline G spin-metkoi 2,2,5,5-tetrametil-3-maleimidopirrolidin-1-oksilom.

Exposed lysine residues of human IgG were modified by a spin-label, 2,2,5,5-tetramethyl-3-male-imidopyrrolidine-1-oxyl at pH 9.2. Under these conditions, the degree of modification was about 10 lysine residues per protein molecule. The ESR spectrum of the spin-labeled immunoglobulin was much more mobile than that of spin-labeled immunoglobulin with the modification degree of about 1 residue that was obtained at pH 7.0. Thus, the sharp increase in the modification degree due to the increase in pH by two units leads to a marked loosening of the tertiary structure of the protein in solution, which is just indicated by the mobile ESR spectrum. Lithium chloride added to the solution of spin-labeled immunoglobulin induces a similar "immobilization" of its ESR spectra as sucrose.