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1.
Br J Haematol ; 180(6): 831-839, 2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29315478

RESUMEN

We report a multicentre retrospective study that analysed clinical characteristics and outcomes in 117 patients with primary plasma cell leukaemia (pPCL) treated at the participating institutions between January 2006 and December 2016. The median age at the time of pPCL diagnosis was 61 years. Ninety-eight patients were treated with novel agents, with an overall response rate of 78%. Fifty-five patients (64%) patients underwent upfront autologous stem cell transplantation (ASCT). The median follow-up time was 50 months (95% confidence interval [CI] 33; 76), with a median overall survival (OS) for the entire group of 23 months (95% CI 15; 34). The median OS time in patients who underwent upfront ASCT was 35 months (95% CI 24·3; 46) as compared to 13 months (95% CI 6·3; 35·8) in patients who did not receive ASCT (P = 0·001). Multivariate analyses identified age ≥60 years, platelet count ≤100 × 109 /l and peripheral blood plasma cell count ≥20 × 109 /l as independent predictors of worse survival. The median OS in patients with 0, 1 or 2-3 of these risk factors was 46, 27 and 12 months, respectively (P < 0·001). Our findings support the use of novel agents and ASCT as frontline treatment in patients with pPCL. The constructed prognostic score should be independently validated.


Asunto(s)
Leucemia de Células Plasmáticas/mortalidad , Leucemia de Células Plasmáticas/terapia , Trasplante de Células Madre , Adulto , Anciano , Anciano de 80 o más Años , Autoinjertos , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia de Células Plasmáticas/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia
2.
J Clin Med ; 10(23)2021 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-34884206

RESUMEN

Multiple myeloma (MM) is an incurable disease and patients become refractory to the treatment in the course of the disease. Bendamustine-based regimens containing steroids and other agents are among the therapeutic options offered to MM patients. Here, we investigated the safety and the efficacy of bendamustine used in patients with refractory/relapsed MM (RRMM). The patients were treated with bendamustine and steroids (n = 52) or bendamustine, steroids and immunomodulatory agents or proteasome inhibitors (n = 53). Response rates, progression-free survival (PFS), overall survival (OS) and frequency of adverse events were compared between both study groups. Most efficacy measurements were better in patients treated with three-drug regimens: overall response rate (55% versus 37%, p = 0.062), median PFS (9 months versus 4 months, p < 0.001), median OS survival (18 months versus 12 months, p = 0.679). The benefit from combining bendamustine and steroids with an additional agent was found in subgroups previously treated with both lenalidmide and bortezomib, with stem cell transplant and with more than two previous therapy lines. Toxicity was similar in both study groups and bendamustine-based therapies were generally well-tolerated. Our study suggests that bendamustine may be an effective treatment for patients with RRMM. Three-drug regimens containing bendamustine, steroids and novel agents produced better outcomes and had acceptable toxicity. The efficacy of bendamustine combined with steroids was limited.

3.
Hematology ; 26(1): 556-564, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34384334

RESUMEN

BACKGROUND: Azacitidine (AZA) is the standard of care for higher-risk myelodysplastic syndrome (HR-MDS) patients ineligible for intensive therapy. Clinical outcome discrepancies reported in clinical trials and real-life settings stimulate the search for new prognostic factors. METHODS: We retrospectively evaluated 315 MDS, 20-30% blast acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML) patients treated with azacitidine in 12 centers cooperating within the Polish Adult Leukemia Group (PALG). RESULTS: The median number of AZA cycles was 7 (1-69) and 24% patients received fewer than 4 cycles (early failure, EF). Serum albumin level was an independent predictor of EF occurrence. Complete remission (CR) was obtained in 20% and partial remission (PR) in 12% of patients. Hematologic improvement - erythroid (HI-E), neutrophil (HI-N), or platelet (HI-P) was achieved in 51%, 36%, and 48% of patients, respectively. No factors significantly predicted CR or PR in the multivariate analysis. For HI-E and HI-P, lower LDH level predicted response. Median survival was 15 (13-19) months. Lower serum albumin level, serious infection and receiving <4 AZA cycles independently predicted a worse overall survival (OS) (p < 0.05). CONCLUSION: Serum albumin assessment before azacitidine treatment can help to identify patients with higher risk of early failure and worse clinical outcome.


Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Albúmina Sérica Humana/análisis , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/sangre , Pronóstico , Estudios Retrospectivos , Resultado del Tratamiento
4.
Clin Lymphoma Myeloma Leuk ; 19(5): 264-274.e4, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30898482

RESUMEN

BACKGROUND: Myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML) patients, including those treated with azacitidine, are at increased risk for serious infections. The aim of our study was to identify patients with higher infectious risk at the beginning of azacitidine treatment. PATIENTS AND METHODS: We performed a retrospective evaluation of 298 MDS/CMML/AML patients and included in the analysis 232 patients who completed the first 3 cycles of azacitidine therapy or developed Grade III/IV infection before completing the third cycle. RESULTS: Overall, 143 patients (62%) experienced serious infection, and in 94 patients (41%) infection occurred within the first 3 cycles. The following variables were found to have the most significant effect on the infectious risk in multivariate analysis: red blood cell transfusion dependency (odds ratio [OR], 2.38; 97.5% confidence interval [CI], 1.21-4.79), neutropenia <0.8 × 109/L (OR, 3.03; 97.5% CI, 1.66-5.55), platelet count <50 × 109/L (OR, 2.63; 97.5% CI, 1.42-4.76), albumin level <35 g/dL (OR, 2.04; 97.5% CI, 1.01-4.16), and Eastern Cooperative Oncology Group performance status ≥2 (OR, 2.19; 97.5% CI, 1.40-3.54). Each of these variables is assigned 1 point, and the combined score represents the proposed Azacitidine Infection Risk Model. The infection rate in the first 3 cycles of therapy in lower-risk (0-2 score) and higher-risk (3-5 score) patients was 25% and 73%, respectively. The overall survival was significantly reduced in higher-risk patients compared with the lower-risk cohort (8 vs. 29 months). CONCLUSION: We selected a subset with high early risk for serious infection and worse clinical outcome among patients treated with azacitidine.


Asunto(s)
Antimetabolitos Antineoplásicos/efectos adversos , Azacitidina/efectos adversos , Infecciones Bacterianas/epidemiología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Micosis/epidemiología , Síndromes Mielodisplásicos/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/uso terapéutico , Profilaxis Antibiótica/métodos , Antifúngicos/uso terapéutico , Infecciones Bacterianas/inducido químicamente , Infecciones Bacterianas/inmunología , Infecciones Bacterianas/prevención & control , Femenino , Indicadores de Salud , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/mortalidad , Leucemia Mielomonocítica Crónica/inmunología , Leucemia Mielomonocítica Crónica/mortalidad , Masculino , Persona de Mediana Edad , Micosis/inducido químicamente , Micosis/inmunología , Micosis/prevención & control , Síndromes Mielodisplásicos/inmunología , Síndromes Mielodisplásicos/mortalidad , Polonia/epidemiología , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Medición de Riesgo/métodos , Resultado del Tratamiento
5.
Int J Biol Macromol ; 41(5): 558-63, 2007 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-17719085

RESUMEN

The interactions of G-quadruplex DNA with two oxidation products of papaverine, 6a,12a-diazadibenzo-[a,g]fluorenylium derivative (1) and 2,3,9,10-tetramethoxy-12-oxo-12H-indolo[2,1-a]isoquinolinium cation (2) were investigated. Their activity against telomerase was assessed using the conventional telomeric repeat amplification protocol (TRAP) assay. Effect of TRAP buffer and oligonucleotide length on the DNA-binding affinity of 1 and 2 were also studied. Three quadruplex-forming oligonucleotides with human telomeric sequence: dG(3)(T(2)AG(3))(3) (htel21), dAG(3)(T(2)AG(3))(3) (htel22), and d(T(2)AG(3))(4) (htel24) were used in these investigations. Both ligands were capable of interacting with G4 DNA with binding stoichiometry indicating that two ligand molecules bind to G-quadruplex, which agrees with the binding model of end-stacking on terminal G-tetrads. Circular dichroism spectra revealed that preferences of quadruplex-forming oligonucleotide to adopt a particular topological structure may be also affected by the external ligand that binds to quadruplex. Telomerase activity was suppressed at very low ligand 1 and ligand 2 concentrations with an appreciable selectivity comparing with inhibition of Taq polymerase.


Asunto(s)
ADN/química , Papaverina/análogos & derivados , Papaverina/química , Sitios de Unión , Cinética , Ligandos , Modelos Moleculares , Espectrofotometría Ultravioleta
6.
Pol Arch Intern Med ; 127(11): 765-774, 2017 11 30.
Artículo en Inglés | MEDLINE | ID: mdl-28906482

RESUMEN

INTRODUCTION    Bortezomib was the first proteasome inhibitor approved for the therapy of multiple myeloma (MM). Currently, VMP (bortezomib, melphalan, prednisone) is one of the standard regimens recommended as the first­line therapy for patients with MM ineligible for high­dose chemotherapy (HDT) with autologous stem­cell transplantation (auto­SCT). OBJECTIVES    Participants of clinical trials are highly selected populations; therefore, the aim of this study was to present observations from real practice that might provide important information for practitioners. PATIENTS AND METHODS    We retrospectively analyzed the data on the efficacy and safety of bortezomib­based regimens in 154 patients with newly diagnosed MM ineligible for HDT with auto­SCT (median age, 73 years; range, 39-89 years) with particular attention to the effect of age, performance status, and concomitant diseases. RESULTS    Patients aged 75 years or older constituted 53.2% of the study cohort. Performance status was impaired in 34.4% of the patients, according to the Eastern Cooperative Oncology Group scale. Comorbidities were reported in 83.8% of the patients (mainly arterial hypertension and atherosclerotic vascular disease). A total of 798 courses of bortezomib­based regimens (mainly VMP, 86%) were administered. The overall response rate was 81.7%, including 12.7% for complete response and 29.6% for very good partial response. The median progression­free survival (PFS) and event­free survival were 17.3 and 7.1 months, respectively. The impaired performance status and age of 75 or older were negative predictors of PFS. The most common severe adverse events were neuropathy (19.4%), infections (19.2%), and neutropenia (14.9%). CONCLUSIONS    Bortezomib­based regimens are effective and well tolerated in the first­line therapy of elderly patients with MM and comorbidities, with advanced disease, and light chain MM. A more detailed assessment of patients' frailty is needed to increase the efficacy of treatment.


Asunto(s)
Bortezomib/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Bortezomib/efectos adversos , Comorbilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/epidemiología , Polonia , Estudios Retrospectivos , Resultado del Tratamiento
7.
Leuk Res ; 38(7): 788-94, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24862794

RESUMEN

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.


Asunto(s)
Antineoplásicos/uso terapéutico , Ácidos Borónicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Pirazinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Ácidos Borónicos/efectos adversos , Bortezomib , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/mortalidad , Pirazinas/efectos adversos , Recurrencia
8.
Pathol Oncol Res ; 18(2): 479-89, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22094905

RESUMEN

UNLABELLED: Cervical cancer (CC) occurs more frequently in women who are immunosuppressed, suggesting that both local and systemic immune abnormalities may be involved in the evolution of the disease. Costimulatory CD28 and inhibitory CTLA-4 molecules expressed in T cells play a key role in the balanced immune responses. There has been demonstrated a relation between CD28, CTLA-4, and IFN genes in susceptibility to CC, suggesting their importance in CC development. Therefore, we assessed the pattern of CD28 and CTLA-4 expression in T cells from PB of CC patients with advanced CC (stages III and IV according to FIGO) compared to controls. We also examined the ability of PBMCs to secrete IFN-gamma. We found lower frequencies of freshly isolated and ex vivo stimulated CD4 + CD28+ and CD8 + CD28+ T cells in CC patients than in controls. Loss of CD28 expression was more pronounced in the CD8+ T subset. Markedly increased proportions of CTLA-4+ T cells in CC patients before and after culture compared to controls were also observed. In addition, patients' T cells exhibited abnormal kinetics of surface CTLA-4 expression, with the peak at 24 h of stimulation, which was in contrast to corresponding normal T cells, revealing maximum CTLA-4 expression at 72 h of stimulation. Of note, markedly higher IFN-gamma concentrations were shown in supernatants of stimulated PBMCs from CC patients. CONCLUSIONS: Our report shows the dysregulated CD28 and CTLA-4 expression in PB T cells of CC patients, which may lead to impaired function of these lymphocytes and systemic immunosuppression related to disease progression.


Asunto(s)
Antígenos CD28/metabolismo , Antígeno CTLA-4/metabolismo , Carcinoma de Células Escamosas/inmunología , Cuello del Útero/inmunología , Linfocitos T/inmunología , Neoplasias del Cuello Uterino/inmunología , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Estudios de Casos y Controles , Células Cultivadas , Cuello del Útero/metabolismo , Cuello del Útero/patología , Progresión de la Enfermedad , Femenino , Citometría de Flujo , Estudios de Seguimiento , Humanos , Tolerancia Inmunológica , Terapia de Inmunosupresión , Interferón gamma/metabolismo , Activación de Linfocitos , Persona de Mediana Edad , Pronóstico , Linfocitos T/metabolismo , Linfocitos T/patología , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología
9.
J Phys Chem A ; 109(5): 759-66, 2005 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-16838944

RESUMEN

A novel solvatochromic betaine dye has been synthesized from xanthosine and characterized spectroscopically by UV-vis in a broad range of solvents. The dye 9-(2',3',5'-tri-O-acetyl-beta-d-ribofuranosyl)-2-(pyridinium-1-yl)-9H-purin-6-olate, 1a, exhibits solvent-induced spectral band shifts that are (2)/(3) as large as that of the betaine known as Reichardt's dye, which forms the basis of the E(T)(30) solvent polarity scale. Moreover, the dye 1a is a ribonucleoside and hence has the potential application as a polarity probe for application in RNA oligonucleotides. The isomeric dye 6-(pyridinium-1)-yl-9H-purin-2-olate, 2a, has also been synthesized and exhibits slightly smaller solvatochromic band shifts. The new betaine dyes have also been studied by comparing the experimental and calculated solvatochromic shifts based on the calculation of the UV/vis absorption spectra, using a combination of methods with density functional theory (DFT). The COSMO continuum dielectric method, an applied electric field term in the Hamiltonian, and time-dependent density functional theory (TD-DFT) methods were used to obtain absorption energies, ground-state dipole moments, and the difference dipole moment between the ground and excited states. The calculations predict a lower energy absorption band of charge-transfer character that is highly solvatochromic, and a higher energy absorption band that has pi-pi character which is not solvatochromic, in agreement with the experimental data. For Reichardt's dye the difference dipole moment between the ground and excited state (Deltamu = mu(e) - mu(g)) was also calculated and compared to experiment: Deltamu(calcd) = -6 D and Deltamu(exptl) = -9 +/- 1 D.(1) The ground-state dipole moment was found to be mu(g)(calcd) = 18 D and mu(g)(exptl) = 14.8 +/- 1.2 D.(1).


Asunto(s)
Betaína/química , Colorantes/química , Colorantes/síntesis química , Purinas/química , Concentración de Iones de Hidrógeno , Modelos Moleculares , Estructura Molecular , Análisis Espectral
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