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The paper focuses on analysing the current tax behaviour of Slovak citizens and their inclination to tax evasion. Inclination to tax evasion is defined in this research based on respondents' answers to questions focused on their tax morale. The data processed in this research was obtained from a questionnaire survey on a sample of 1067 respondents. Intentional sampling was used to ensure the same structure of respondents. In terms of tax evasion acceptance, we identified three groups of people: honest, dishonest, and unconscious. The research confirmed that 78% of the population is prone to tax evasion, and only 22% have never evaded paying taxes and would not do so knowingly or unconsciously. By applying the statistical hypothesis testing, we also found out that except for sex (women are less prone to tax evasion), inclination to tax evasion also depends on education, age, main source of income and experience. Finally, three types of logistic regression models to predict the inclination of a specific tax behaviour were constructed and evaluated based on the total accuracy metric and validated on the ex-post set. [ABSTRACT FROM AUTHOR]

We report the results of a phase 1 dose-escalation study of belinostat and bortezomib in adult patients with acute leukemia or MDS or CML with blast crisis. Thirty-eight patients received IV belinostat days 1-5 and 8-12 with IV bortezomib days 1, 4, 8, and 11 every 21 days. QTc prolongation was the only identified DLT. The RP2Ds were 1.3 mg/m2 bortezomib and 1000 mg/m2 belinostat. One patient with highly refractory MLL-ENL rearranged biphenotypic AML with multiple karyotypic aberrations had a complete pathologic and karyotypic response. One patient with post-MPN AML remained on study with stable disease (SD) for 32 cycles. Whole-exome sequencing revealed no aberrations in the first patient and a hyper-mutator genotype in the second. Eighteen patients had a best response of SD. We conclude that this treatment strategy is feasible but has limited activity in this population. Nevertheless, the factors that predict exceptional responses to this strategy warrant further investigation. [ABSTRACT FROM AUTHOR]

This phase 1, dose-finding study investigated ibrutinib and carfilzomib ± dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma (≥2 lines of therapy including bortezomib and an immunomodulatory agent). Of 43 patients enrolled, 74% were refractory to bortezomib and 23% had high-risk cytogenetics. No dose-limiting toxicities were observed. The recommended phase 2 dose was ibrutinib 840 mg and carfilzomib 36 mg/m2 with dexamethasone. The most common ≥ grade 3 (>10%) treatment-emergent adverse events were hypertension, anemia, pneumonia, fatigue, diarrhea, and thrombocytopenia. Overall response rate was 67% (very good partial response, 21%; stringent complete response, 2%), with an additional 9% minimal response. Median progression-free survival was 7.2 months and was not inferior in refractory nor high-risk patients. Median overall survival was not reached. Ibrutinib plus carfilzomib demonstrated encouraging responses with a manageable safety profile in this advanced population. [ABSTRACT FROM AUTHOR]

Excise taxes are one of the oldest taxes in the world. Countries have used these taxes to ensure profits of public finances. However, countries also have used these taxes as an indirect tool for removing negative externalities which cause damage the environment. One of the most significant excise taxes is the excise tax on mineral oils. This tax generates circa 10 per cent of all taxes coming to the public budget of the Slovak Republic. In Slovakia, the tax burden is the highest in our region. The state can influence the final price of gasoline products; however, it does not want to lose tax profits. It is due to the fact that these taxes generate remarkable profit in the Slovakian budget. We believe that there is a space for decreasing this tariff what would cause the decrement of gas and diesel prices. In this paper authors suggest a way how to use statistical methods based on linear regression and neural networks for modelling the decrement of excise tax tariff on gasoline with the same tax profits. We also suggest methodology of identification and modelling of these factors influencing the excise tax revenue. [ABSTRACT FROM AUTHOR]

A phase 1 study was conducted to determine the dose-limiting toxicities and maximum-tolerated dose (MTD) for bortezomib followed by romidepsin on days 1, 8, and 15 in patients with relapsed/refractory CLL/SLL or B- or T-cell lymphoma. Eighteen treated patients were evaluable for response. The MTD was 1.3 mg/m2bortezomib and 10 mg/m2romidepsin; median treatment duration was 3 cycles at this dose. The dose-limiting toxicities were grade 3 fatigue, vomiting, and chills. Two patients had partial responses, one lasting >2 years, 8 had stable disease, and 8 had progressive disease. The median duration of stable disease was 3.5 cycles. Correlative studies examining expression of NF-кB, XIAP, Bcl-xL, and Bim yielded variable results. The safety profile was consistent with that reported for single-agent bortezomib and romidepsin. This regimen has modest activity in heavily pretreated patients with relapsed/refractory CLL or B- or T-cell lymphoma. NCT00963274. [ABSTRACT FROM PUBLISHER]

A phase 1 study with carfilzomib and vorinostat was conducted in 20 B-cell lymphoma patients. Vorinostat was given orally twice daily on days 1, 2, 3, 8, 9, 10, 15, 16, and 17 followed by carfilzomib (given as a 30-min infusion) on days 1, 2, 8, 9, 15, and 16. A treatment cycle was 28 days. Dose escalation initially followed a standard 3 + 3 design, but adapted a more conservative accrual rule following dose de-escalation. The maximum tolerated dose was 20 mg/m² carfilzomib and 100 mg vorinostat (twice daily). The dose-limiting toxicities were grade 3 pneumonitis, hyponatremia, and febrile neutropenia. One patient had a partial response and two patients had stable disease. Correlative studies showed a decrease in NF-κB activation and an increase in Bim levels in some patients, but these changes did not correlate with clinical response. [ABSTRACT FROM AUTHOR]

Breast involvement with non-Hodgkin's lymphoma (NHL) is rare. Patients with AIDS have an increased incidence of NHL, often with high-grade histology, extranodal presentation and aggressive clinical course. Lymphoma of the breast in patients with HIV-1 infection has not been reported. We reviewed our tumor registry database of all AIDS-associated NHL and report on the clinical presentation and long-term outcome of 3 patients with AIDS who presented with lymphomatous involvement of the breast. [ABSTRACT FROM AUTHOR]

Belantamab mafodotin (belamaf) is a BCMA-targeted antibody-drug conjugate recently approved as monotherapy for adults with relapsed/refractory multiple myeloma who have received ≥4 prior therapies. Belamaf binds to BCMA and eliminates myeloma cells by multimodal mechanisms of action. The cytotoxic and potential immunomodulatory properties of belamaf have led to novel combination studies with other anticancer therapies. Here, we describe the rationale and design of DREAMM-5, an ongoing Phase I/II platform study evaluating the safety and efficacy of belamaf combined with novel agents, including GSK3174998 (OX40 agonist), feladilimab (an ICOS; GSK3359609), nirogacestat (a gamma-secretase inhibitor; PF-03084014) and dostarlimab (a PD-1 blocker) versus belamaf monotherapy for patients with relapsed/refractory multiple myeloma. Clinical trial registration: NCT04126200 (ClinicalTrials.gov).

Interactions between the polo-like kinase 1 (PLK1) inhibitor volasertib and the histone deacetylase inhibitor (HDACI) belinostat were examined in diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells in vitro and in vivo. Exposure of DLBCL cells to very low concentrations of volasertib in combination with belinostat synergistically increased cell death (apoptosis). Similar interactions occurred in GC-, ABC-, double-hit DLBCL cells, MCL cells, bortezomib-resistant cells and primary lymphoma cells. Co-exposure to volasertib/belinostat induced a marked increase in M-phase arrest, phospho-histone H3, mitotic errors, cell death in M-phase, and DNA damage. Belinostat diminished c-Myc mRNA and protein expression, an effect significantly enhanced by volasertib co-exposure. c-Myc knock-down increased DNA damage and cell death in response to volasertib, arguing that c-Myc down-regulation plays a functional role in the lethality of this regimen. Notably, PLK1 knock-down in DLBCL cells significantly increased belinostat-induced M-phase accumulation, phospho-histone H3, γH2AX, and cell death. Co-administration of volasertib and belinostat dramatically reduced tumor growth in an ABC-DLBCL flank model (U2932) and a systemic double-hit lymphoma model (OCI-Ly18), accompanied by a pronounced increase in survival without significant weight loss or other toxicities. Together, these findings indicate that PLK1/HDAC inhibition warrants attention as a therapeutic strategy in NHL.

We report a case of a 60-year-old man who was referred to a palliative care clinic with monoclonal gammopathy of undetermined significance (MGUS)-associated neuropathy, responding to a therapeutic trial of warfarin. Electromyography showed distal symmetric sensory axonal neuropathy. The patient reported having had improvement of his neuropathic symptoms while taking warfarin postoperatively for thromboprophylaxis 1 year prior, and recurrence of his symptoms after the warfarin was discontinued. The patient was rechallenged with a trial of warfarin, targeting an international normalised ratio of 1.5-2.0. His pain scores decreased from 5/10 to 3/10 at 1 month and symptom improvement was maintained through 24 months of follow-up. Warfarin had a remarkable impact on our patient's symptoms and quality of life. The mechanisms mediating the symptomatic benefit with warfarin are unclear; however, a placebo effect is unlikely. Further studies may help guide the use of warfarin for MGUS-associated neuropathy., (2016 BMJ Publishing Group Ltd.)

Purpose: AZD6244 is a MEK1/2 inhibitor with significant preclinical activity in multiple myeloma cells. This phase II study used a two-stage Simon design to determine the AZD6244 response rate in patients with relapsed or refractory multiple myeloma., Experimental Design: AZD6244 (75 mg) was administered orally, twice a day, continuously for 28-day cycles. Response was evaluated after three cycles., Results: Thirty-six patients received therapy. The median age was 65 years (range: 43-81) and the median number of prior therapies was 5 (range: 2-11). The most common grade 3 and 4 toxicities included anemia, neutropenia, thrombocytopenia, diarrhea, and fatigue. Three deaths occurred possibly related to AZD6244 (2 due to sepsis, 1 due to acute kidney injury). After AZD6244 discontinuation, three additional deaths occurred due to disease progression. The response rate (CR + PR) was 5.6% with a mean duration of response of 4.95 months and median progression-free survival time of 3.52 months. One patient had a very good partial response (VGPR), 1 patient had a partial response, 17 patients had stable disease, 13 patients had progressive disease, and 4 patients could not be assessed for response. Pharmacodynamic studies revealed variable effects on bone marrow CD138(+) cell MEK1/2 and ERK1/2 phosphorylation. The best clinical response, a prolonged VGPR, occurred in a patient with an MMSET translocation., Conclusions: Single-agent AZD6244 was tolerable and had minimal activity in this heavily pretreated population., (©2015 American Association for Cancer Research.)

Purpose: This phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, Waldenstrom macroglobulinemia, and mantle cell lymphoma)., Experimental Design: Patients received bortezomib (intravenous push), followed by alvocidib (1-hour infusion), on days 1, 4, 8, and 11 of a 21-day treatment cycle. Patients experiencing responses or stable disease continued on treatment at the investigator's discretion. A standard 3+3 dose-escalation design was used to identify the MTD based on DLTs, and pharmacokinetic and pharmacodynamic studies were conducted., Results: A total of 44 patients were enrolled, with 39 patients assessed for response. The MTD was established as 1.3 mg/m(2) for bortezomib and 40 mg/m(2) for alvocidib. The most common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. The most common nonhematologic toxicities included diarrhea, fatigue, and sensory neuropathy. Three complete remissions (8%) and 10 partial remissions (26%) were observed for a total response rate of 33%. Pharmacokinetic findings with the current dosing regimen were consistent with the comparable literature and the hybrid dosing regimen. Pharmacodynamic study results did not correlate with clinical responses., Conclusions: The combination of bortezomib and alvocidib is tolerable, and an MTD has been established for this schedule. The regimen appears to be efficacious in patients with relapsed/refractory multiple myeloma or indolent non-Hodgkin lymphoma. As the nonhybrid regimen is less cumbersome than the previous hybrid dosing schedule regimen, the current schedule is recommended for successor studies., (©2014 American Association for Cancer Research.)

Introduction: Bortezomib , the first proteasome inhibitor (PI) to be evaluated in humans, is approved in the USA and Europe for the treatment of patients with multiple myeloma, and in the USA for patients with relapsed mantle cell lymphoma (MCL)., Areas Covered: This review examines the role of bortezomib in the therapy of non-Hodgkin's lymphoma (NHL). Bortezomib may be particularly effective against the NF-κB-dependent activated B-cell subtype of diffuse large B-cell lymphoma. The combination of bortezomib with rituximab and dexamethasone represents a standard approach for the treatment of Waldenström's macroglobulinemia, and that with bendamustine and rituximab has demonstrated excellent efficacy in follicular lymphoma. Combinations with other novel agents, such as inhibitors of cyclin-dependent kinases or histone deacetylases, also hold substantial promise in NHL. Unmet needs in NHL, competitor compounds, chemistry, pharmacokinetics, pharmacodynamics and safety and tolerability of bortezomib are also discussed., Expert Opinion: The success of bortezomib in MCL has validated the proteasome as a therapeutic target in NHL. Rational combinations, for example, with Bruton's tyrosine kinase inhibitors or BH3-mimetics, may hold the key to optimizing the therapeutic potential of PIs in NHL. Future trials are likely to involve newer agents with improved pharmacodynamic (e.g., carfilzomib, marizomib) or pharmacokinetic (e.g., ixazomib, oprozomib) properties.

Purpose: This phase I study was conducted to identify the maximum-tolerated dose (MTD) of alvocidib when combined with vorinostat in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2. Secondary objectives included investigating the pharmacokinetic and pharmacodynamic effects of the combination., Experimental Design: Patients received vorinostat (200 mg orally, three times a day, for 14 days) on a 21-day cycle, combined with 2 different alvocidib administration schedules: a 1-hour intravenous infusion, daily × 5; or a 30-minute loading infusion followed by a 4-hour maintenance infusion, weekly × 2. The alvocidib dose was escalated using a standard 3+3 design., Results: Twenty-eight patients were enrolled and treated. The alvocidib MTD was 20 mg/m(2) (30-minute loading infusion) followed by 20 mg/m(2) (4-hour maintenance infusion) on days one and eight, in combination with vorinostat. The most frequently encountered toxicities were cytopenias, fatigue, hyperglycemia, hypokalemia, hypophosphatemia, and QT prolongation. Dose-limiting toxicities (DLT) were cardiac arrhythmia-atrial fibrillation and QT prolongation. No objective responses were achieved although 13 of 26 evaluable patients exhibited stable disease. Alvocidib seemed to alter vorinostat pharmacokinetics, whereas alvocidib pharmacokinetics were unaffected by vorinostat. Ex vivo exposure of leukemia cells to plasma obtained from patients after alvocidib treatment blocked vorinostat-mediated p21(CIP1) induction and downregulated Mcl-1 and p-RNA Pol II for some specimens, although parallel in vivo bone marrow responses were infrequent., Conclusions: Alvocidib combined with vorinostat is well tolerated. Although disease stabilization occurred in some heavily pretreated patients, objective responses were not obtained with these schedules., (©2013 AACR.)

Purpose: A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, and mantle cell lymphoma)., Experimental Design: Patients received bortezomib by intravenous push on days 1, 4, 8, and 11. Patients also received alvocidib on days 1 and 8 by 30-minute bolus infusion followed by a 4-hour continuous infusion. Treatment was on a 21-day cycle, with indefinite continuation for patients experiencing responses or stable disease. Dose escalation employed a standard 3 + 3 design until the MTD was identified on the basis of DLTs. Pharmacokinetic studies and pharmacodynamic studies were conducted., Results: Sixteen patients were treated. The MTD was established as 1.3 mg/m(2) for bortezomib and 30 mg/m(2) for alvocidib (both the 30-minute bolus and 4-hour infusions). Common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. Common nonhematologic toxicities included fatigue and febrile neutropenia. DLTs included fatigue, febrile neutropenia, and elevated aspartate aminotransferase (AST) levels. Two complete responses (CR; 12%) and five partial responses (PR; 31%) were observed at the MTD (overall response rate = 44%). Pharmacokinetic results were typical for alvocidib and pharmacodynamic studies yielded variable results., Conclusions: The combination of bortezomib and alvocidib is tolerable and an MTD has been established for the tested schedule. The regimen appears active in patients with relapsed and/or refractory multiple myeloma or non-Hodgkin's lymphoma, justifying phase II studies to determine the activity of this regimen more definitively., (©2011 AACR.)

New thalidomide derivatives CC-5013 and CC-4047 (immunomodulatory drugs, IMiD) are up to 10,000 times more potent than Thalidomide. The biological effects of IMiDs are presumed to be mediated by (a) activation of some components of the innate [natural killer (NK) cells] or adoptive immune system (T cells), (b) modification of cytokine microenvironment in the tumor bed, or by (c) inhibition of angiogenesis. In this article, we tested an innovative combination strategy involving rituximab and IMiDs in aggressive lymphoma cell lines and human lymphoma xenografts. Treatment of non-Hodgkin's lymphoma cells with CC-5013 resulted in a 40% to 70% growth inhibition when compared with controls (P < 0.05). Exposure of lymphoma cells to CC-4047 resulted in a lesser degree of growth inhibition. Induction of apoptosis was shown in 10% to 26% of lymphoma cells 24 hours following exposure to either IMiD. In vivo studies in severe combined immunodeficient mice showed synergistic activity between CC-4047 (and to a lesser degree, CC-5013) plus rituximab. Animals treated with the CC-4047/rituximab combination had a median survival of 74 days (P = 0.0012) compared with 58 days (P = 0.167) in CC-5013/rituximab-treated animals compared with 45 days in rituximab monotherapy-treated animals. The synergistic effect between IMiDs and rituximab in our mouse model was attributed to NK cell expansion. The enhancement of rituximab activity by IMiDs was abrogated by in vivo depletion of NK cells. Augmenting NK cell function by CC-4047 or CC-5013 exposure may increase the antitumor effects of rituximab against B-cell lymphomas and warrants further exploration in the context of a clinical trial.

Seckel syndrome is a rare autosomal recessive disorder with characteristic craniofacial dysmorphism, skeletal defects, mental and prenatal growth retardation. About 50 cases have been reported in the literature. Hematologic abnormalities with associated chromosomal fragility have been noted in about 15% of the reported cases. We report a patient with Seckel syndrome with myelodysplastic features and clonal T-cells in the bone marrow but no evidence of chromosomal fragility. After 5 years of follow-up, this patient remains asymptomatic without any treatment and with stable peripheral blood counts.