A novel, dual pan-PIM/FLT3 inhibitor SEL24 exhibits broad therapeutic potential in acute myeloid leukemia.

Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is one of the most common genetic lesions in acute myeloid leukemia patients (AML). Although FLT3 tyrosine kinase inhibitors initially exhibit clinical activity, resistance to treatment inevitably occurs within months. PIM kinases are thought to be major drivers of the resistance phenotype and their inhibition in relapsed samples restores cell sensitivity to FLT3 inhibitors. Thus, simultaneous PIM and FLT3 inhibition represents a promising strategy in AML therapy. For such reasons, we have developed SEL24-B489 - a potent, dual PIM and FLT3-ITD inhibitor. SEL24-B489 exhibited significantly broader on-target activity in AML cell lines and primary AML blasts than selective FLT3-ITD or PIM inhibitors. SEL24-B489 also demonstrated marked activity in cells bearing FLT3 tyrosine kinase domain (TKD) mutations that lead to FLT3 inhibitor resistance. Moreover, SEL24-B489 inhibited the growth of a broad panel of AML cell lines in xenograft models with a clear pharmacodynamic-pharmacokinetic relationship. Taken together, our data highlight the unique dual activity of the SEL24-B489 that abrogates the activity of signaling circuits involved in proliferation, inhibition of apoptosis and protein translation/metabolism. These results underscore the therapeutic potential of the dual PIM/FLT3-ITD inhibitor for the treatment of AML.

Case-adjusted bortezomib-based strategy in routine therapy of relapsed/refractory multiple myeloma shown to be highly effective--a report by Polish Myeloma Study Group.

The observational study was aimed at evaluating response, survival and toxicity of bortezomib-based, case-adjusted regimens in real-life therapy of 708 relapsed/refractory MM patients. Bortezomib was combined with anthracyclines, steroids, thalidomide, alkylators or given in monotherapy. The ORR was 67.9% for refractory and 69.9% for relapsed MM. The median PFS was 14 months and OS 57 months. Patients responding to the therapy had the probability of a 4-year OS at 67.0%. No toxicity was noted in 33.1% of patients. Severe events (grade 3/4) were reported in 35.9% of patients: neurotoxicity (16.7%), neutropenia (9.2%), thrombocytopenia (8.5%), and infections (6.5%). Bortezomib-based, case-adjusted regimens are in real-life practice effective in salvage therapy offering reliable survival with acceptable toxicity for relapsed/refractory MM patients.

Bioimpedance vector pattern in Taiwanese and Polish college students detected by bioelectric impedance vector analysis: preliminary observations.

BACKGROUND AND OBJECTIVES: The study was conducted to evaluate soft tissue hydration and mass through pattern analysis of vector plots as height, normalized resistance, and reactance measurements by bioelectric impedance vector analysis in Taiwanese and Polish college students. METHODS: Whole-body measurements were made with ImpediMed bioimpedance analysis SFB7 BioImp v1.55 (Pinkenba Qld 4008, Australia) in 16 Taiwanese and Polish men and 16 Taiwanese and Polish women. RESULTS: Mean vectors of Taiwanese men and women groups versus the Polish men and women groups were characterized by almost the same normalized resistance component with reactance component (separate 95% confidence limits, P < 0.05) indicating that there were no differences of soft tissue hydration and mass. INTERPRETATION AND CONCLUSION: The evaluation of soft tissue hydration and mass through pattern analysis of vector plots as height, normalized resistance, and reactance measurements by bioelectric impedance vector analysis in Taiwanese and Polish college students did not differ between these two diverse ethnic groups. Further observational research investigating these properties in larger groups would be welcomed to elucidate and/or confirm these findings.

[Calcification of heart valves in hemodialized patients and their cardiosurgical correction]. / Kalcyfikacja zastawek serca u chorych hemodializowanych i ich kardiochirurgiczna korekta.

Development of vascular and systemic calcification is one of the more serious and often occurring complications in hemodialyzed patients. The cardiac valves calcifications are of the essential importance. They are result of the very complicated calcification process connected with hyperphosphataemia, hyperparathyroidism, calcium carbonate administering and active vitamin D3 metabolites as well as using dialysis fluids with high concentration of calcium. Elevated P and Ca x P product are both significant predictors of cardiovascular mortality in hemodialized patients. We describe two patients with cardiac failure because of cardiac valves calcification. Both patients underwent artificial valves implantation. The patients showed a marked improvement of the quality of life and haemodynamic status.