[The relationship between Sjogren's syndrome, systemic sclerosis and lymphoproliferative diseases].

Despite the large number of studies devoted to the study of systemic sclerosis (SSc), the high risk of developing lymphomas in this disease, the relationship of their development with certain subtypes of SSc and specific SSc-associated autoantibodies is still debated in the literature. AIM: To study demographic, clinical, laboratory and immunological characteristics of patients with a combination of primary Sjogrens syndrome (pSS) and SSc and diagnosed lymphoproliferative diseases (LPDs); to characterize morphological/immunomorphological variants and course of non-Hodgkins lymphomas (NHL), developing in patients with these rheumatic diseases (RDs). MATERIALS AND METHODS: In 19982018 at the Nasonova Research Institute of Rheumatology, 13 patients with clinical and laboratory manifestations of pSS (12) and SSc (13) were diagnosed with various lymphoproliferative diseases (LPDs). In 3 cases, an induced RD was observed: 1 case of a diffuse, rapidly progressive form of SSc, 2 cases of pSS in combination with a limited form of SSc after chemotherapy and radiation therapy of Hodgkins lymphoma (1), B-cell NHL (1) and CR of the breast (1) respectively. The first 2 cases were excluded from the analysis, since the development of lymphomas is not pathogenetically associated with RD. RESULTS: Of 11 patients with LPDs, 10 after a long course of RDs were diagnosed with NHL [MALT lymphoma of the parotid salivary glands 7, disseminated MALT lymphoma 2, disseminated MALT lymphoma with transformation into diffuse large B-cell lymphoma (DLBCL) 1]. RDs debuted with Raynauds phenomenon (RP) in 64.5% and pSS manifestations in 45.5% of patients. Stomatological manifestations of pSS were characterized by recurrent parotitis in 36%, significant parotid gland enlargement with massive infiltration of labial salivary glands (focus score 4) in 100%, severe xerostomia in 70%, extraglandular manifestations and lymphadenopathy in 50% of patients. The course of the SSc was characterized by mild RP with various types of capillaroscopic changes and mild lung changes and non-significant progression during long-term follow-up (median 22 years). The entire spectrum of SSс specific antibodies (anticentromere antibodies 60%, antibodies to ribonucleoprotease III 30%, Pm/Scl 10%), excepting antibodies to topoisomerase I, as well as pSS specific autoantibodies (antiRo/La 70%, RF (rheumatoid factor) 90%), were detected in patients with a combination of these RDs. CONCLUSION: pSS is often combined with a limited form of SSc regardless of the type of autoantibodies detected. The presence of pSS, rather than SSc, is a high-risk factor for the development of NHL in this group of patients. The patients with pSS and SSc are characterized by a steady progression of pSS with a slow and mild course of SSc throughout the observation period. The development of severe stomatological manifestations and high immunological activity of pSS contribute to the development of localized MALT lymphomas (70%) and disseminated MALT lymphomas (30%) with primary lesions of the salivary glands and transformation into DLBCL in case of their late diagnosis. The optimal method for preventing the development of NHL in this group of patients is the early diagnosis of pSS, the appointment of alkylating cytotoxic agents and/or anti-B-cell therapy in the early stages of pSS. Given the possibility of transformation of localized NHL into DLBCL, for early diagnosis, minimally invasive surgical biopsies of significantly enlarged parotid salivary glands should be performed before glucocorticoids are prescribed. Detection of positive B-cell clonality and lymphoepithelial lesions in the parotid salivary gland is considered a predictor of MALT lymphoma development during follow-up. Localized and disseminated MALT lymphomas in patients with pSS and SSc respond well to therapy, in contrast to MALT lymphomas transformed into DLBCL.

[Thrombosis of the cerebral veins in gynecological practice]. / Tromboz tserebral'nykh ven v akushersko-ginekologicheskoi praktike.

The review presents literature data on the risk factors of cerebral venous thrombosis (CVT), a rare life threatening disorder. Currently, the diagnosis of CVT is made more often due to the possibility of using neuroimaging methods of cerebral structures. Pregnancy, postpartum period, use of oral contraceptives are risk factors of CVT. A role of thrombophilia, in particular Factor V Leiden mutations and the prothrombin G20210A polymorphism, in the CVT pathogenesis is confirmed. The development of CVT is an example of the interaction between persistent risk factors increasing the likelihood of thrombotic complications and acquired risk factors. A focal neurological deficit during pregnancy, delivery and postpartum period is the best indicator of CVT diagnosis. Possibilities of the use of anticoagulants in treatment and prevention of CVT are analyzed.

[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.

[Use of anti-B-cell therapy in case of antisynthetase syndrome as the severest subtype of polymyositis/dermatomyositis].

Antisynthetase syndrome encompassing a symptom complex with severe interstitial lung disease is the severest subtype of polymyositis and dermatomyositis. The characteristic feature of antisynthetase syndrome is the insufficient efficiency of traditional therapy with glucocorticosteroids and cytostatics, which determines the prognosis of the disease and the need for new therapeutic approaches to treating these patients.

[The first experience of using rituximab in Mikulicz disease].

The paper describes a case of Mikulicz's disease (MD) in a young woman (aged 19 years) with symmetrical large salivary gland lesion concurrent with the enlarged lacrimal glands. Immunomorphological and molecular studies of parotid gland biopsy specimens revealed the formation of MALT tissue without signs of B-cell clonality of an infiltrate. The diagnosis of lacrimal sac lymphoma was ruled out. MD was diagnosed. The use of rituximab in therapy for MD has first demonstrated a positive result in Russian and worldwide practice.

[Pathogenesis and prevention of thromboembolic complications in obstetric practice].

The study was designed to analyse risk factors of venous thromboembolism (VTE), elucidate the role of genetic forms of thrombophilia and antiphospholipid syndrome (APS) in pathogenesis of VTE during pregnancy. 38 pregnant patients with VTE (group I) and 35 healthy pregnant women (group 2, controls) were screened for genetic thrombophilia and antiphospholipid antibodies (APA). Deep vein and ovarian vein thrombosis was diagnosed in 21 and 1 patients of group 1 respectively. VTE occurred in 15 on weeks 20-38 of pregnancy and in 12 in the postpartum period. 38 and 59% of the patients had VTE in their hereditary and obstetric histories respectively. Multigenic thrombophilia was recorded in all patients with VTE (4-6 mutations including homozygous ones), combined defects of fibrinolysis in 86%, and APA in 59%. Multigenic thrombophilia occurred in 20% of the healthy women while APA were not detected. It is concluded that thrombophilia may be an essential pathogenetic mechanism of thromboembolism during pregnancy. Women with pregnancy-associated thromboembolism, thromboembolism in personal or family history, and with the history of obstetric complications should be screened for thrombophilia.

Interferon-alpha-2b and oral cytarabine ocfosfate for newly diagnosed chronic myeloid leukaemia.

BACKGROUND: Treatment with interferon and subcutaneous cytarabine produces superior cytogenetic responses in chronic myeloid leukaemia (CML) than treatment with interferon alone, but at the expense of greater toxicity. Cytarabine ocfosfate (YNK01) is an oral precursor of cytarabine that may overcome some of the inconvenience and toxicities associated with subcutaneous cytarabine administration. PATIENTS AND METHODS: We studied the efficacy and tolerability of combination therapy with interferon-alpha-2b and YNK01 in patients with newly diagnosed, untreated CML. Forty patients were treated with interferon-alpha-2b (5 MU/m2/day) plus monthly courses of YNK01 (600 mg/day for 10 days) for 1 year. RESULTS: The 6-month complete haematological response rate was 63% and the 1-year major cytogenetic response rate was 30%, with 10% of cytogenetic responses being complete. With a median follow-up of 57 months, the estimated 5-year overall survival was 86% (95% confidence interval 70% to 94%). Treatment tolerability was poor, with toxicity leading to discontinuation of one or both drugs in 60% of cases. The median daily dose of interferon alpha-2b was 7.75 MU and the median dose of YNK01 was 600 mg/day for each 10-day treatment cycle. CONCLUSIONS: Interferon-alpha-2b and YNK01 produce cytogenetic responses comparable to those achieved with interferon-alpha-2b and parenteral cytarabine, although toxicity was excessive. Alternate dosing strategies may enhance the tolerability of YNK01.

Elevated expression of the CC chemokine regulated on activation, normal T cell expressed and secreted (RANTES) in advanced breast carcinoma.

Breast carcinoma is the most common malignant disease among women and the second most lethal one. In search for a better understanding of the role of cellular mediators in the progression of this disease, we investigated the potential involvement of the CC chemokine Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) in breast carcinoma progression. To this end, RANTES expression was determined in breast tumor cell lines and in sections of breast carcinomas, followed by analysis of the incidence and intensity of its expression in different stages of the disease. Our study reveals that high and physiologically relevant levels of RANTES are constitutively produced by T47D and MCF-7 breast tumor cell lines. Analysis of RANTES expression in sections of breast carcinomas demonstrates a high incidence of RANTES expression in epithelial tumor cells; the chemokine was expressed in 74% of the sections. RANTES expression was rarely detected in normal duct epithelial cells or in epithelial cells that constitute benign breast lumps, which were located in proximity to tumor cells. High incidence and intensity of RANTES expression were detected in sections of most of the patients with stage II and stage III of the disease (expression was detected in 83 and 83.3%, respectively), whereas RANTES was expressed at a lower incidence and intensity in sections of patients with stage I of breast carcinoma (55% of the cases). Most importantly, the expression of RANTES was minimally detected in sections of patients diagnosed with benign breast disorders and of women that underwent reduction mammoplasty (15.4% of the cases). These results indicate that the expression of RANTES is directly correlated with a more advanced stage of disease, suggesting that RANTES may be involved in breast cancer progression. Moreover, it is possible that in patients diagnosed with benign breast disorders, RANTES expression may be indicative of an ongoing, but as yet undetectable, malignant process.

[Myoelectric activity of the rabbit stomach and duodenum following neurogenic and humoral effects]. / Mioélektricheskaia aktivnost' zheludka i dvenadtsatiperstnoi kishki krolikov pri neirogennykh i gumoral'nykh vozdeistviiakh.

Electrical activity of the duodenum increased after the immobilisation or haemorrhage stress to a greater extent than the stomach and pylorus myoelectrical activity. Pentagastrin or serotonine increased the electrical activity of the duodenum and decreased the stomach and pylorus myoelectrical activity. Chronophysiological mechanism of the gastro-duodenal discoordination is analysed.

Topical interferon alpha 2b for corneal haze after excimer laser photorefractive keratectomy. The Melbourne Excimer Laser Group.

PURPOSE: To determine whether topical interferon alpha 2b (IFN-alpha) prevents corneal haze after excimer laser photorefractive keratectomy (PRK). SETTING: Tertiary referral ophthalmic hospital. METHOD: A prospective, double-blind, placebo-controlled, randomized study of 31 patients was undertaken. After surgery in a single institution, patients received a drop of either a placebo or IFN-alpha (5 x 10(6) IU/ml) four times daily for 4 weeks. The main outcome measures were corneal haze, refraction, and visual acuity. RESULTS: The major side effect of interferon alpha treatment was a significant delay in epithelial healing by a mean of 2 days. The means of the average post-treatment clinical scores for haze in all patients up to 12 months after surgery were 0.46 +/- 0.25 for the IFN-alpha group and 0.64 +/- 0.43 for the placebo group (P = .20). Of patients with a correction of greater than 5.00 diopters (D), the IFN-alpha group had significantly less haze over the course of the study (0.39 +/- 0.23 versus 0.98 +/- 0.50; P = .03). After 12 months, the mean absolute spherical equivalent in the two groups was not significantly different (1.02 +/- 1.13 D versus 1.44 +/- 2.64 D). There was a tendency toward better uncorrected visual acuity in the INF-alpha group (P < .10, Kolmogorov-Smirnov). CONCLUSION: Topical IFN-alpha may merit further investigation as a treatment to reduce corneal haze after excimer laser PRK for corrections greater than 5.00 D.

Delayed expansion of V delta 2+ and V delta 1+ gamma delta T cells after acute Plasmodium falciparum and Plasmodium vivax malaria.

T lymphocytes that express T-cell receptors encoded by the gamma and delta T-cell receptor genes (gamma delta T cells), and preferentially those expressing the V gamma 9 and V delta 2 gene segments, are activated by microbial and parasitic organisms in vitro and have been implicated in the pathogenesis of the fever and rigors during acute malaria. We have found, in a cohort of nine nonimmune patients who contracted malaria during travel to endemic areas (five with Plasmodium falciparum and four with P. vivax infections) that gamma delta T lymphocytes expanded to comprise 17.92% +/- 11% of the peripheral blood mononuclear cells (vs 3.08% +/- 2.4% gamma delta cells in normal control subjects). Although V delta 2+ cells predominated among the gamma delta subset, gamma delta lymphocytes expressing the V delta 1 gene segment also expanded significantly in some patients. Importantly, the gamma delta cells continued to expand for 2 months after the infection, and the mean level of gamma delta cells peaked during the second month after the acute clinical syndrome, when patients were free of symptoms. Thus although gamma delta T cells may contribute to the pathogenesis of the acute clinical syndrome, our findings suggest that gamma delta lymphocytes could also play a role in generating an immune response to plasmodia.

A case of malignant lymphoma in the liver treated by percutaneous ethanol injection therapy under peritoneoscopic observation.

A 41-year-old woman with non-Hodgkin's lymphoma in the liver was treated with percutaneous ethanol injection therapy. Ethanol injection was performed twice under ultrasonographic guidance for a lesion inside the liver and once under peritoneoscopic observation for lesions on the surface of the liver. CT performed after treatment showed that sizes of the lesions decreased and that the lesions were not enhanced by contrast medium, indicating lack of blood supply and necrosis of the lesion. Ultrasonography performed after treatment did not show any lesions in the liver. There was no sign of recurrence or metastasis.

Ultrasound-guided percutaneous injection of ethanolamine oleate for hypersplenism. An experimental study in dogs.

In order to evaluate a possible therapy for hypersplenism, an experiment with animals was done. In nine dogs, 0.6 ml/kg body weight of 5% ethanolamine oleate was injected percutaneously into the spleen under ultrasound guidance. The injection was repeated three times at intervals of 1 week. Three dogs each were killed at 1, 4, and 8 weeks after the final injection. All dogs tolerated the procedure well and lived until they were killed. The platelet count and leukocyte count increased after the injections, and remained higher than the pretreatment level until death. This effect probably is due to depressed splenic function. The autopsy showed 40% of the spleen to be infarcted with complete destruction of the normal structure. No serious complications occurred. In addition, injection of ethanolamine oleate in six fully heparinized dogs showed that there was little risk of hemorrhage. Ultrasound-guided percutaneous injection of ethanolamine oleate might be a simple and effective therapy for hypersplenism.