[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.

[Investigation of miR-155 level in the blood of patients with chronic lymphocytic leukemia and Ph-negative myeloproliferative neoplasms.]

MiR-155 is involved in various physiological processes in the cell, including hematopoiesis, immunity, inflammation and differentiation. Increased expression of miR-155 is observed in many malignant diseases, including lymphomas, acute myeloid leukemia and CLL. However, a comparative study of the miR-155 expression in the blood leukocytes in patients with chronic myeloid and lymphoproliferative diseases has not yet been carried out. To investigate the expression of miR-155 in the blood cells of patients with lympho- and ph-negative myeloproliferative neoplasms. MiR-155 expression were studied in the blood leukocytes of 28 patients with B-CLL, 52 patients with MPN and 51 donors by "real time" PCR method. The study revealed an increase in miR-155 in blood leukocytes in both patients with CLL and patients with MPN compared with the control group. In accordance with the results of the ROC analysis, the sensitivity and specificity of blood leukocytes testing on miR-155 expression level was 81.8% and 78.4%, respectively, for CLL and 55.1% and 82.4%, respectively, for MPN. At the same time, in patients with CLL who received therapy, the level of miR-155 was significantly lower compared with those who did not receive therapy. Thus, the involvement of miR-155 in the pathogenesis of chronic myeloid and lymphoproliferative diseases was demonstrated.

Effects of intranasal administration of the peptide antagonist of type I vaniloid receptor (TRPV1) in the rodent central nervous system.

Intranasal administration of the polypeptide APHC3, an antagonist of the TRPV1 receptor, had acute anxiolytic and antidepressant effects, as well as an ability to modify the microglial response to proinflammatory stress and cytokine profile of the hippocampus. However, the acute antidepressant effect of the polypeptide was not related to the attenuation of neuroiflammation and probably had a different mechanism. The use of intranasal administration of the APHC3 peptide as a therapeutic approach aimed at decreasing depression symptoms needs additional studies in order to find the mechanism of action of this polypeptide in the central nervous system (CNS).

Upregulation of IFN-γ and IL-12 is associated with a milder form of hantavirus hemorrhagic fever with renal syndrome.

Hantavirus hemorrhagic fever with renal syndrome (HFRS) is a zoonotic disease characterized by acute onset, fever, malaise, and back pain. As the disease progresses, hemorrhagic disturbances and kidney dysfunctions predominate. The examination of tissue collected postmortem supports the premise that virus replication is not responsible for this pathology; therefore, it is widely believed that virus-induced immune responses lead to the clinical manifestations associated with HFRS. The overproduction of inflammatory cytokines is commonly reported in subjects with HFRS and has given rise to the hypothesis that a so-called "cytokine storm" may play a pivotal role in the pathogenesis of this disease. Currently, supportive care remains the only effective treatment for HFRS. Our data show that serum levels of interferon (IFN)-γ, interleukin (IL)-10, CCL2, and IL-12 are upregulated in HFRS cases when compared to healthy controls and the level of upregulation is dependent on the phase and severity of the disease. Furthermore, we observed an association between the mild form of the disease and elevated serum levels of IFN-γ and IL-12. Collectively, these observations suggest that the administration of exogenous IFN-γ and IL-12 may provide antiviral benefits for the treatment of HFRS and, thus, warrants further investigations.

[The fibrinolytic system in the hypercoagulation syndrome in patients with pulmonary tuberculosis].

One hundred and twenty-four patients with different forms of active pulmonary tuberculosis were examined. The fibrinolytic system was assessed from the time of plasma fibrin clot lysis, plasminogen (PG) concentrations, and alpha2-antiplasmin (alpha2-AP) activity. The findings were compared with the recordings of a coagulogram, the concentration ofintravascular coagulation (IVC) markers--soluble fibrinmonomer complexes (SFMC) and D-dimers (DD), as well as with systemic inflammation indices (C-reactive protein and haptoglobin). The patients with pulmonary tuberculosis were found to have a hypercoagulation shift in the hemostatic system, which was accompanied by IVC events and quantitatively associated with the degree of systemic inflammation. This was followed by the moderately elevated PG concentrations in a third of patients and enhanced alpha2-AP activity in two thirds. The prevailing alpha2-AP rise resulted in delayed forming fibrin lysis. When influenced by a number of competitive factors, the values of PG and alpha2-AP directly correlated only with fibrinogen levels (directly). The concentration of DD directly correlated with the markers of systemic inflammation and SFMC, showed no correlations with the indices of the fibrinolytic and hemostatic systems. No correlations between PG, alpha2-AP, and DD suggests that in addition to secretion of corresponding factors, processes of their uptake play a large role in the formation of the functional status of the fibrinolytic system.

[Blood anticoagulation system in the hypercoagulation syndrome in patients with pulmonary tuberculosis].

The authors determined the state of the hemostatic system, the duration of fibrinolysis, intravascular coagulation (IVC) markers, and anticoagulation system activity by the values of antithrombin III (AIII), protein C (PC) and protein S (PS), as well as the depth of systemic inflammation by the values of acute phase reagents. Patients with pulmonary tuberculosis were found to have a hypercoagulation shift associated with prolonged fibrinolysis and accompanied by IVC. There was concurrently a decrease in the activity of the prothrombin complex and the D-dimers arising from IVC began to act as secondary anticoagulants. The hypercoagulation shift is attended by a moderate rise in the activity of AIII and PC with a simultaneous decrease in PS. As systemic inflammation and hypercoagulation syndrome progress, there is a gradual decompensation of the anticoagulation system. The changes in the values of prothrombin index, AIII, and PC are directly and inversely related to the degree of the hypercoagulation syndrome and systemic inflammation. PS showed no correlations.

[Retrospective evaluation of the safe reduction of surgical margins of resected stage-IIA cutaneous melanoma of the trunk and extremities]. / Retrospektivnaia otsenka bezopasnogo umen'sheniia granits rezektsii dlia melanomy kozhi tulovishcha i konechnostei IIA stadii.

The paper deals with analysis of 102 case histories locally-advanced 1.51-4.00 mm-thick cutaneous melanomas (CM) of the trunk and arms and legs operated on at the Center's Clinics and 52--at the Regional Oncological Dispensary, Samara. The effectiveness of relatively conservative procedures of treating CM of "medium" thickness and "intermediate" prognosis were assessed by histological analysis of resected material. CMs with such characteristics conform to the specifications of stage IIA of the criteria used by the American Joint Committee on Staging of Cancer (AJCC). The study of the time and frequency of relapse and dissemination of tumor in 154 patients provided the guide-lines for determining optimal extent of surgery to excise CM stage IIA of the trunk and arms and legs. Excision of 1.5-4.00 mm-thick CMs with 2 cm-wide margins left should be considered safe and less traumatic.

[Intravascular coagulation as a typical concomitant of acute pulmonary tuberculosis]. / Vnutrisosudistaia koaguliatsiia krovi kak kharakternyí sputnik aktivnogo tuberkuleza legkikh.

Hemostasis and fibrinolysis, markers of intravascular coagulation (IC), hemorrhagic parameters, and platelet aggregatory properties were studied in 119 patients with various types of pulmonary tuberculosis. In patients with active pulmonary tuberculosis, IC was found to be a persistent and important component of a pathological process which both plasma factors and circulating cells were involved in. In most critical patients, the degree and rate of spontaneous and stimulated platelet aggregation were decreased, when stimulated, the rate of increases in the mean volume of aggregates was yet higher in these patients than in the controls. The latter created an additional prerequisite for progression of microthrombogenesis.