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(1) Background: New therapeutic strategies have improved the prognosis of multiple myeloma (MM), changing the accepted view of this disease from being incurable to treatable. (2) Methods: We studied 1001 patients with MM between 1980 and 2020, grouping patients into ten-year periods by diagnosis 1980-1990, 1991-2000, 2001-2010 and 2011-2020. (3) Results: After 65.1 months of follow-up, the median OS of the cohort was 60.3 months, and OS increased significantly over time: 22.4 months in 1980-1990, 37.4 months in 1991-2000, 61.8 months in 2001-2010 and 103.6 months in 2011-2020 (p < 0.001). Using novel agents in the front-line setting for myeloma patients yielded a significantly better OS than in those treated with conventional therapies, especially when combinations of at least two novel agents were used. The median OS of patients treated with the combination of at least two novel agents in induction was significantly prolonged compared to those treated with a single novel agent or conventional therapy in induction: 143.3 vs. 61.0 vs. 42.2 months (p < 0.001). The improvement was apparent in all patients regardless of age at diagnosis. In addition, 132 (13.2%) patients were long-term survivors (median OS ≥ 10 years). Some independent clinical predictors of long-term survival were identified: ECOG < 1, age at diagnosis ≤ 65 years, non-IgA subtype, ISS-1 and standard-risk cytogenetic. Achieving CR and undergoing ASCT were positively associated with >10 years of survival. (4) Conclusions: The combination of novel agents appears to be the main factor for the improvement in survival in MM, which is becoming a chronic and even curable disease in a subtype of patients without high-risk features.
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FLT3-ITD mutations are detected in approximately 25% of newly diagnosed adult acute myeloid leukemia (AML) patients and confer an adverse prognosis. The FLT3-ITD allelic ratio has clear prognostic value. Nevertheless, there are numerous manuscripts with contradictory results regarding the prognostic relevance of the length and insertion site (IS) of the FLT3-ITD fragment. We aimed to assess the prognostic impact of these variables on the complete remission (CR) rates, overall survival (OS) and relapse-free survival (RFS) of AML patients with FLT3-ITDmutations. We studied the FLT3-ITD length of 362 adult AML patients included in the PETHEMA AML registry. We tried to validate the thresholds of ITD length previously published (i.e., 39 bp and 70 bp) in intensively treated AML patients (n = 161). We also analyzed the mutational profile of 118 FLT3-ITD AML patients with an NGS panel of 39 genes and correlated mutational status with the length and IS of ITD. The AUC of the ROC curve of the ITD length for OS prediction was 0.504, and no differences were found when applying any of the thresholds for OS, RFS or CR rate. Only four out of 106 patients had ITD IS in the TKD1 domain. Our results, alongside previous publications, confirm that FLT3-ITD length lacks prognostic value and clinical applicability.
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Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Tirosina Quinase 3 Semelhante a fms/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Prognóstico , Indução de Remissão/métodos , Estudos Retrospectivos , Adulto JovemRESUMO
Recommended genetic categorization of acute myeloid leukaemias (AML) includes a favourable-risk category, but not all these patients have good prognosis. Here, we used next-generation sequencing to evaluate the mutational profile of 166 low-risk AML patients: 30 core-binding factor (CBF)-AMLs, 33 nucleophosmin (NPM1)-AMLs, 4 biCEBPα-AMLs and 101 acute promyelocytic leukaemias (APLs). Functional categories of mutated genes differed among subgroups. NPM1-AMLs showed frequent variations in DNA-methylation genes (DNMT3A, TET2, IDH1/2) (79%), although without prognostic impact. Within this group, splicing-gene mutations were an independent factor for relapse-free (RFS) and overall survival (OS). In CBF-AML, poor independent factors for RFS and OS were mutations in RAS pathway and cohesin genes, respectively. In APL, the mutational profile differed according to the risk groups. High-risk APLs showed a high mutation rate in cell-signalling genes (P = 0·002), highlighting an increased incidence of FLT3 internal tandem duplication (ITD) (65%, P < 0·0001). Remarkably, in low-risk APLs (n = 28), NRAS mutations were strongly correlated with a shorter five-year RFS (25% vs. 100%, P < 0·0001). Overall, a high number of mutations (≥3) was the worst prognostic factor RFS (HR = 2·6, P = 0·003). These results suggest that gene mutations may identify conventional low-risk AML patients with poor prognosis and might be useful for better risk stratification and treatment decisions.
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Sequenciamento de Nucleotídeos em Larga Escala/métodos , Leucemia Mieloide Aguda/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia , Nucleofosmina , Fatores de RiscoRESUMO
Immunoglobulin M (IgM) monoclonal gammopathies show considerable variability, involving three different stages of presentation: IgM monoclonal gammopathy of undetermined significance (IgM-MGUS), asymptomatic Waldenström's macroglobulinemia (AWM), and symptomatic WM (SWM). Despite recent findings about the genomic and transcriptomic characteristics of such disorders, we know little about the causes of this clinical heterogeneity or the mechanisms involved in the progression from indolent to symptomatic forms. To clarify these matters, we have performed a gene expression and mutational study in a well-characterized cohort of 69 patients, distinguishing between the three disease presentations in an attempt to establish the relationship with the clinical and biological features of the patients. Results showed that the frequency of genetic alterations progressively increased from IgM-MGUS to AWM and SWM. This means that, in contrast to MYD88 p.L265P and CXCR4 WHIM mutations, present from the beginning of the pathogenesis, most of them would be acquired during the course of the disease. Moreover, the expression study revealed a higher level of expression of genes belonging to the Toll-like receptor (TLR) signaling pathway in symptomatic versus indolent forms, which was also reflected in the disease presentation and prognosis. In conclusion, our findings showed that IgM monoclonal gammopathies present higher mutational burden as the disease progresses, in parallel to the upregulation of relevant pathogenic pathways. This study provides a translational view of the genomic basis of WM pathogenesis.
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Heterogeneidade Genética , Imunoglobulina M/genética , Gamopatia Monoclonal de Significância Indeterminada/genética , Macroglobulinemia de Waldenstrom/genética , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/patologia , Prognóstico , Macroglobulinemia de Waldenstrom/patologiaRESUMO
The management of recurrent/refractory (R/R) Hodgkin lymphoma (HL) remains challenging. Previously published data have shown some efficacy of rituximab in this setting. The purpose of this phase II trial was to investigate the activity of ofatumumab in combination with etoposide, steroids, cytarabine and cisplatin (O-ESHAP) in 62 patients with R/R classical HL. Treatment consisted of ESHAP plus ofatumumab 1000 mg on days 1 and 8 of the first cycle and day 1 of the second and third cycles. O-ESHAP was well tolerated with only 3% of patients requiring treatment discontinuation because of adverse events. Overall response rate was 73% (44% complete metabolic response). In multivariate analysis, early relapse (P < 0·001), bulky disease (P < 0·001) and B symptoms (P < 0·001) were the most important prognostic factors for response. No failures of stem cell mobilization were observed. The high response rate, particularly the complete metabolic response rate, the low toxicity profile, and the high mobilizing potential of the O-ESHAP regimen suggest that patients with R/R HL may benefit from this salvage regimen. However, with the encouraging results observed with other new therapeutic agents in HL, the O-ESHAP regimen could be restricted to patients failing these agents or to those with R/R nodular lymphocyte-predominant HL.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Adolescente , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Terapia Combinada , Citarabina/efeitos adversos , Citarabina/uso terapêutico , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Feminino , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Recidiva , Retratamento , Terapia de Salvação , Análise de Sobrevida , Transplante Autólogo , Resultado do Tratamento , Adulto JovemRESUMO
A differential pulse anodic stripping voltammetric (DPASV) method, with an open circuit (OC) approach in the pre-concentration step has been developed for copper ion determination at very low concentration level using a sensor based on a polystyrene sulfonate-carbon nanopowders (PSS-CnP) composite. This composite material is easily prepared from ultrasonic assisted dispersions of CnP in aqueous solution of PSS. For preparation of sensor devices, a reproducible and inexpensive drop coating procedure of the surface of home-made pencil graphite electrodes (PGEs) using a CnP dispersion in PSS was performed. At the optimal conditions for accumulation (0.01molL(-1) KNO3 at pH 3) and measurement steps (a reduction potential of -0.5V for 60s and then, an anodic DPV scan) and using a pre-concentration time of 300s, the limit of detection was 0.11µgL(-1) (1.73nM). This OC-DPASV method using the PSS-CnP-PGE sensor was successfully employed for Cu(II) determination in mineral, river and sea water samples.
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Técnicas Biossensoriais/métodos , Carbono/química , Cobre/análise , Eletroquímica/métodos , Nanocompostos/química , Poliestirenos/química , Pós/química , Eletrodos , Grafite , Limite de Detecção , Rios/química , Água do Mar/análise , Espectrofotometria AtômicaRESUMO
BACKGROUND AND OBJECTIVE: We aimed to assess the incidence of haematological neoplasms (HNs) in Castilla y León (2,5 million inhabitants) and its distribution by age, gender and histological type. PATIENTS AND METHOD: The epidemiological profile based on the described variables of the 10,943 HNs diagnosed during a 10-years period was analyzed, compared with other studies. RESULTS: The overall age-adjusted incidence was 29.4 cases/10(5) inhabitants-year, with some geographical differences. The mean age was 67.3 years, with a turning point between the 6th-7th decades of life from which there was a very significant increase of incidence. Two relevant facts where simultaneous with advancing age: decreased lymphoid neoplasms incidence and increased low degree neoplasms incidence. Lymphoid low degree neoplasms accounted for half of the registered processes, showed the greatest preference for male and reached the mode before the rest of neoplasms. Myeloid neoplasms incidence (9.5) was higher than that reported in other European registries, specially compared to southern European countries, opposite to lymphoid neoplasms incidence (20.0). CONCLUSIONS: A higher myeloid neoplasms incidence and lower lymphoid one than expected was observed. The turning point of incidence is between the 6th-7th decades of life, with a preference for male that decreases with age. There is an increased incidence of HNs in the area where a higher density of potentially polluting facilities is concentrated.
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Neoplasias Hematológicas/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Poluição Ambiental/efeitos adversos , Feminino , Neoplasias Hematológicas/classificação , Humanos , Incidência , Lactente , Recém-Nascido , Transtornos Linfoproliferativos/epidemiologia , Masculino , Mastocitose/epidemiologia , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/epidemiologia , Doenças Mieloproliferativas-Mielodisplásicas/epidemiologia , Transtornos Mieloproliferativos/epidemiologia , Estudos Retrospectivos , Distribuição por Sexo , Espanha/epidemiologia , Adulto JovemRESUMO
INTRODUCTION: Phenolic compounds contained in essential oils from plants are responsible for their anti-oxidant capacity. The natural extract from each aromatic plant is characterised by a typical ratio of phenolic components, so each one of the essential oils shows different properties. OBJECTIVE: The development of a simple reversed-phase high-performance liquid chromatographic (RP-HPLC) method for the determination of phenolic compounds from aromatic plants using spectrophotometric detection with a diode-array and electrochemical detection with amperometric and coulometric detectors. METHODS: Chromatographic conditions are optimised to separate vanillin, eugenol, thymol and carvacrol using spectrophotometric detection. Acetonitrile and methanol are studied as mobile-phase organic modifiers. The hydrodynamic curves are obtained for both electrochemical detection modes and the principal values of merit are calculated. The proposed methodology is applied to determine the four analytes in real samples. RESULTS: The shortest elution times and the highest electrochemical signals are achieved using 65% methanol solution in 0.1 mol/L acetic acid-acetate buffer as the mobile phase. Potential values of 0.925 V for amperometric detection and 0.500 V for coulometric detection are chosen as working potentials. The limits of detection (LOD) for the compounds studied ranged between 9.7-17 µg/L and 0.81-3.1 µg/L in amperometric and coulometric detection modes, respectively. In general, the obtained LODs are better than those previously reported. CONCLUSION: The low LODs obtained using coulometric detection make this methodology very competitive and adequate for quality control of these phenolic compounds in comparison with others, such as GC-MS, that are more expensive and complicated to use than the RP-HPLC method with coulometric detection.
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Cromatografia Líquida de Alta Pressão/métodos , Óleos Voláteis/isolamento & purificação , Fenóis/isolamento & purificação , Óleos de Plantas/isolamento & purificação , Benzaldeídos/química , Benzaldeídos/isolamento & purificação , Calibragem , Cimenos , Técnicas Eletroquímicas , Eugenol/química , Eugenol/isolamento & purificação , Mentha piperita/química , Estrutura Molecular , Monoterpenos/química , Monoterpenos/isolamento & purificação , Ocimum basilicum/química , Óleos Voláteis/química , Origanum/química , Fenóis/química , Folhas de Planta/química , Óleos de Plantas/química , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Syzygium/química , Timol/química , Timol/isolamento & purificaçãoAssuntos
Antineoplásicos/uso terapêutico , Deleção Cromossômica , Cromossomos Humanos Par 5 , Leucemia Mieloide Aguda/tratamento farmacológico , Talidomida/análogos & derivados , Idoso , Feminino , Humanos , Lenalidomida , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/genética , Talidomida/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVES: To evaluate the effect of atorvastatin on bone mass and markers of bone remodeling in patients with acute coronary syndrome according to the Lys656Asn leptin receptor gene polymorphism. METHODS: Sixty-two patients with acute coronary syndrome were included. Patients were allocated to low and high doses of atorvastatin according to baseline levels of cholesterol and triglycerides and the index of vascular risk and were studied at hospital admission and at 12 months. Cholesterol, triglycerides, total calcium, phosphorus, magnesium, osteocalcin and urinary deoxypyridinoline were determined in all patients at baseline and at 12 months of follow up. Densitometric studies were conducted in the lumbar spine and hip. Patients with a T-score<-2.5 were considered osteoporotic. The Lys656Asn leptin receptor gene polymorphism was determined by PCR. RESULTS: Forty-two patients were Lys/Lys homozygotic and 20 Lys/Asn heterozygotic. The prevalence of osteoporosis was 31% for the Lys/Lys genotype and 27% for the Lys/Asn genotype with no significant differences between groups. There was a significant increase in bone mineral density in the lumbar spine (1.117 +/- 0.24 versus 1.135 +/- 0.24, P = 0.008) in patients with the Lys/Lys genotype. CONCLUSION: Atorvastatin increases lumbar spine bone mineral density only in patients with the Lys/Lys genotype of the Lys656Asn polymorphism.
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Síndrome Coronariana Aguda/genética , Densidade Óssea/genética , Remodelação Óssea/genética , Ácidos Heptanoicos/uso terapêutico , Pirróis/uso terapêutico , Receptores para Leptina/genética , Síndrome Coronariana Aguda/tratamento farmacológico , Idoso , Atorvastatina , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/genética , Polimorfismo GenéticoRESUMO
AIMS: To evaluate the effect of atorvastatin on bone mass and markers of bone remodeling in patients with acute coronary syndrome depending on the tumor necrosis factor-alpha (TNFalpha)-308 G/A polymorphism. METHODS: Sixty-two patients with acute coronary syndrome (35 males and 27 females), average age 60 +/- 10 years, were included. Patients were given low (10-20 mg) and high doses (40-80 mg) atorvastatin according to their baseline levels of cholesterol and triglycerides and their index of vascular risk. Patients were studied during hospital admission (baseline) and at 12 months of follow-up. Cholesterol, triglycerides, total calcium, phosphorus, magnesium, osteocalcin and urinary deoxypyridinoline were determined in all patients at baseline and at 12 months of follow-up. Densitometric studies were conducted in the lumbar spine (L(2)-L(4)), femoral neck and trochanter using an X-ray densitometer. The TNFalpha-308 G/A polymorphism was determined by the polymerase chain reaction. RESULTS: Forty-five patients were homozygous for G/G (72.5%) and 17 were heterozygous for G/A (27.5%). The prevalence of osteoporosis (T score < or = 2.5 in the lumbar spine and/or hip) was 33% for the G/G genotype and 35% for the G/A genotype, with no statistically significant differences between groups. There was a statistically significant increase in bone mineral density (BMD) in the lumbar spine (1.107 +/- 0.32 vs. 1.129 +/- 0.23; p = 0.0001) in patients with the G/G genotype. No changes were observed in patients with the G/A genotype. CONCLUSION: In patients with acute coronary syndrome, atorvastatin increases lumbar spine BMD solely in patients with the G/G genotype of the TNFalpha-308 G/A polymorphism.
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Anticolesterolemiantes/efeitos adversos , Densidade Óssea/efeitos dos fármacos , Ácidos Heptanoicos/efeitos adversos , Osteoporose/epidemiologia , Polimorfismo Genético , Pirróis/efeitos adversos , Fator de Necrose Tumoral alfa/genética , Absorciometria de Fóton/métodos , Síndrome Coronariana Aguda/tratamento farmacológico , Aminoácidos/urina , Anticolesterolemiantes/uso terapêutico , Atorvastatina , Cálcio/sangue , Colesterol/sangue , Relação Dose-Resposta a Droga , Feminino , Colo do Fêmur/efeitos dos fármacos , Colo do Fêmur/metabolismo , Seguimentos , Genótipo , Ácidos Heptanoicos/uso terapêutico , Humanos , Magnésio/sangue , Masculino , Pessoa de Meia-Idade , Osteocalcina/sangue , Fósforo/sangue , Reação em Cadeia da Polimerase/métodos , Pirróis/uso terapêutico , Fatores de Risco , Triglicerídeos/sangueRESUMO
The objective of this study was to evaluate the relationship between coronary disease and osteoporosis and determine the effect of osteoprotegerin (OPG) on bone remodeling and bone mineral density (BMD) in a group of patients with acute coronary syndrome. Eighty-three patients (52 males and 31 women) with acute coronary syndrome (75 patients with acute myocardial infarction and 8 with unstable angina) with an average age of 61+/-10 years were studied. Levels of osteocalcin, urinarydeoxypyridinoline, OPG and the receptor activator of nuclear factor-kappaB ligand (RANKL) were determined during the hospital stay. Femoral neck, trochanter and lumbar spine densitometry was carried out using a DXA densitometer. Thirty percent of patients presented osteoporosis (39% of females and 26% of males). Osteoporotic patients were older and had a lower weight and height and elevated serum levels of osteocalcin (3.6+/-2.25 2.63 versus +/-1.55, p=0.05). Levels of OPG and RANKL were similar in both groups and showed no relationship with BMD. In conclusion, no relationship was observed between the OPG/RANKL system and BMD in these patients.
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Síndrome Coronariana Aguda/metabolismo , Densidade Óssea/fisiologia , Remodelação Óssea/fisiologia , Osteoprotegerina/metabolismo , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/fisiopatologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteoporose/diagnóstico , Osteoporose/metabolismo , Osteoporose/fisiopatologiaRESUMO
Bone marrow mononuclear cells (BMCs) from 20 patients with extensive reperfused myocardial infarction (MI) were used to assess their myocardial regenerative capability "in vitro" and their effect on postinfarction left ventricular (LV) remodeling. Human BMCs were labeled, seeded on top of cryoinjured mice heart slices, and cultured. BMCs showed tropism for and ability to graft into the damaged mouse cardiac tissue and, after 1 week, acquired a cardiomyocyte phenotype and expressed cardiac proteins, including connexin43. In the clinical trial, autologous BMCs (78+/-41x10(6) per patient) were intracoronarily transplanted 13.5+/-5.5 days after MI. There were no adverse effects on microvascular function or myocardial injury. No major cardiac events occurred up to 11+/-5 months. At 6 months, magnetic resonance showed a decrease in the end-systolic volume, improvement of regional and global LV function, and increased thickness of the infarcted wall, whereas coronary restenosis was only 15%. No changes were found in a nonrandomized contemporary control group. Thus, BMCs are capable of nesting into the damaged myocardium and acquire a cardiac cell phenotype in vitro as well as safely benefiting ventricular remodeling in vivo. Large-scale randomized trials are needed now to assess the clinical efficacy of this treatment.
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Células da Medula Óssea/fisiologia , Infarto do Miocárdio/terapia , Transplante de Células-Tronco , Remodelação Ventricular/fisiologia , Idoso , Animais , Cateterismo Cardíaco , Diferenciação Celular , Temperatura Baixa/efeitos adversos , Terapia Combinada , Conexina 43/biossíntese , Conexina 43/genética , Reestenose Coronária/prevenção & controle , Ecocardiografia sob Estresse , Feminino , Fibrinolíticos/uso terapêutico , Regulação da Expressão Gênica , Coração/fisiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Reperfusão Miocárdica , Miócitos Cardíacos/citologia , Técnicas de Cultura de Órgãos , Regeneração , Stents , Volume Sistólico , Tenecteplase , Terapia Trombolítica , Ativador de Plasminogênio Tecidual/uso terapêutico , Transplante AutólogoRESUMO
Emphysematous gastritis is a life-threatening disease. It is characterized by the presence of gas within the wall of the stomach. The etiology includes firstly infections with gas-forming organisms; other predisposing causes are the ingestion of corrosive substances and alcohol abuse. Diagnosis is based on radiological techniques, mainly computed tomographic scan (CT). The election treatment is antibiotics and surgery. The evolution is generally fatal. We present the first known case reported, which is associated with aplastic anemia with immunosuppressive therapy, its evolution with medical treatment and a literature review.