RESUMO
The Norrbottnian type of Gaucher disease (GD), as described many years ago, is due to a unique neuronopathic variant (c.1448T>G; L444P) that may have appeared during or before the sixteenth century in northern Sweden. It is a well-defined nosological entity with a characteristic course of clinical manifestations. In particular, Norrbottnian patients described in Sweden and Poland seem to share identical clinical histories characterized by the early onset of significant hepatosplenomegaly, often requiring splenectomy at an early age. Neurological involvement generally appears during the first or second decade of life, and includes horizontal gaze palsy, epilepsy, myoclonic movements, ataxia, dementia and cognitive impairment. Osteopenia occurs primarily in the spine, causing a severe and progressive thoracic kyphosis, although the involvement of other skeletal sites cannot be excluded. Here, we report on four Gaucher type 3 patients with Southern Italian ancestry presenting with clinical features and disease progression comparable to those of the 'Norrbottnian' Swedish phenotype, particularly regarding skeletal involvement with poor responsiveness to any therapeutical approach. Although a common ancestry among Southern Italian and Swedish Norrbottnian GD patients could not be investigated, the genotype [L444P]+[L444P] is the most frequently encountered in Southern Italy.
Assuntos
Doença de Gaucher/epidemiologia , Doença de Gaucher/genética , beta-Glucosidase/genética , Adulto , Idade de Início , Feminino , Doença de Gaucher/fisiopatologia , Genótipo , Humanos , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Suécia/epidemiologiaRESUMO
PURPOSE: Empiric antibiotic monotherapy is considered the standard of treatment for febrile neutropenic patients with cancer, but this approach may be inadequate because of the increasing prevalence of infections caused by multidrug resistant (MDR) bacteria. PATIENTS AND METHODS: In this multicenter, open-label, randomized, superiority trial, adult, febrile, high-risk neutropenic patients (FhrNPs) with hematologic malignancies were randomly assigned to receive piperacillin/tazobactam (4.5 g intravenously every 8 hours) with or without tigecycline (50 mg intravenously every 12 hours; loading dose 100 mg). The primary end point was resolution of febrile episode without modifications of the initial allocated treatment. RESULTS: Three hundred ninety FhrNPs were enrolled (combination/monotherapy, 187/203) and were included in the intention-to-treat analysis (ITTA). The ITTA revealed a successful outcome in 67.9% v 44.3% of patients who had received combination therapy and monotherapy, respectively (127/187 v 90/203; absolute difference in risk (adr), 23.6%; 95% CI, 14% to 33%; P < .001). The combination regimen proved better than monotherapy in bacteremias (adr, 32.8%; 95% CI, 19% to 46%; P < .001) and in clinically documented infections (adr, 36%; 95% CI, 9% to 64%; P < .01). Mortality and number of adverse effects were limited and similar in the two groups. CONCLUSION: The combination of piperacillin/tazobactam and tigecycline is safe, well tolerated, and more effective than piperacillin/tazobactam alone in febrile, high-risk, neutropenic hematologic patients with cancer. In epidemiologic settings characterized by a high prevalence of infections because of MDR microorganisms, this combination could be considered as one of the first-line empiric antibiotic therapies.
Assuntos
Antibacterianos/administração & dosagem , Neutropenia Febril Induzida por Quimioterapia/tratamento farmacológico , Minociclina/análogos & derivados , Ácido Penicilânico/análogos & derivados , Adolescente , Adulto , Idoso , Antineoplásicos/efeitos adversos , Bacteriemia/tratamento farmacológico , Bacteriemia/etiologia , Bacteriemia/mortalidade , Neutropenia Febril Induzida por Quimioterapia/mortalidade , Combinação de Medicamentos , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Minociclina/administração & dosagem , Ácido Penicilânico/administração & dosagem , Piperacilina/administração & dosagem , Combinação Piperacilina e Tazobactam , Fatores de Risco , Tigeciclina , Adulto JovemAssuntos
Arteriopatias Oclusivas/induzido quimicamente , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Doença Arterial Periférica/induzido quimicamente , Pirimidinas/efeitos adversos , Idoso , Arteriopatias Oclusivas/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/mortalidade , Pirimidinas/administração & dosagem , Estudos Retrospectivos , Taxa de SobrevidaAssuntos
Leucemia Linfocítica Crônica de Células B/genética , Mutação , Domínios e Motivos de Interação entre Proteínas/genética , Receptor Notch1/genética , Idoso , Análise Mutacional de DNA , Evolução Fatal , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Masculino , Receptor Notch1/químicaAssuntos
Ácidos Borônicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Imunossupressores/uso terapêutico , Leishmaniose Visceral/imunologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/imunologia , Infecções Oportunistas/imunologia , Pirazinas/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Antiprotozoários/uso terapêutico , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Células da Medula Óssea/parasitologia , Células da Medula Óssea/patologia , Ácidos Borônicos/efeitos adversos , Bortezomib , Humanos , Imunossupressores/efeitos adversos , Itália , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/isolamento & purificação , Leishmaniose Visceral/complicações , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/parasitologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Infecções Oportunistas/complicações , Infecções Oportunistas/tratamento farmacológico , Infecções Oportunistas/parasitologia , Inibidores de Proteassoma/efeitos adversos , Inibidores de Proteassoma/uso terapêutico , Pirazinas/efeitos adversos , Resultado do TratamentoRESUMO
PURPOSE: The control of nausea and vomiting induced by chemotherapy is paramount for overall treatment success in cancer patients. Antiemetic therapy during chemotherapy in lymphoma patients generally consists of anti-serotoninergic drugs and dexamethasone. The aim of this trial was to evaluate the efficacy of a single dose of palonosetron, a second-generation serotonin type 3 (5-HT(3)) receptor antagonist, in patients with aggressive non-Hodgkin's lymphoma receiving moderately emetogenic chemotherapy (MEC) containing steroids. METHODS: Patients received a single intravenous bolus of palonosetron (0.25 mg) before administration of chemotherapy. Complete response (CR) defined as no vomiting and no rescue therapy during overall phase (0-120 h) was the primary endpoint. Complete control (CC) defined as CR and only mild nausea was a secondary endpoint. RESULTS: Eighty-six evaluable patients entered in the study. A CR was observed in 74 patients (86.0%) during the overall phase; the CR during the acute (0-24 h) and delayed (24-120 h) phases was 90.7% and 88.4%, respectively. CC was 89.5% during the acute and 84.9% during the delayed phase; the overall CC was 82.6%. CONCLUSIONS: This was the first trial, which demonstrated the efficacy of a single dose of palonosetron in control CINV in patients with aggressive non-Hodgkin's lymphoma receiving MEC regimen containing steroids.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Isoquinolinas/uso terapêutico , Náusea/prevenção & controle , Quinuclidinas/uso terapêutico , Vômito/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Antieméticos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/administração & dosagem , Feminino , Glucocorticoides/administração & dosagem , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/patologia , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Palonossetrom , Estudos Prospectivos , Antagonistas do Receptor 5-HT3 de Serotonina/uso terapêutico , Resultado do Tratamento , Vômito/induzido quimicamente , Adulto JovemRESUMO
Hairy cell leukemia (HCL) is generally responsive to single-agent cladribine, and only a minority of patients are refractory and with poor prognosis. HCLs generally express mutated (M) and, in a minority, unmutated (UM) IGHV. In a multicenter clinical trial in newly diagnosed HCL, we prospectively investigated clinical and molecular parameters predicting response and event-free survival after single-agent cladribine. Of 58 HCLs, 6 expressed UM-IGHV (UM-HCL) and 52 M-IGHV (M-HCL). Beneficial responses were obtained in 53 of 58 patients (91%), whereas treatment failures were observed in 5 of 58 patients (9%). Failures were associated significantly with UM-IGHV (5 of 5 failures vs 1 of 53 beneficial responses had UM-IGHV, P < .001), leukocytosis (3 of 5 vs 3 of 53, P = .006), and bulky spleen (4 of 5 vs 4 of 53, P < .001). The UM-HCL not benefiting from cladribine characteristically had bulky spleen (4 of 5, 80%), leukocytosis (3 of 5, 60%), and TP53 defects (2 of 5, 40%), and progressed rapidly after first treatment (median event-free survival, 7.5 months). Our data suggest that UM-HCLs identify the minor subgroup failing cladribine treatment and with more aggressive disease. High incidence of TP53 dysfunction indicates a potential mechanism of resistance to cladribine in the UM-HCL group. Overall, our data provide new molecular elements relevant for treatment concerns in HCL.
Assuntos
Antineoplásicos/uso terapêutico , Cladribina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Cadeias Pesadas de Imunoglobulinas/genética , Leucemia de Células Pilosas/tratamento farmacológico , Leucemia de Células Pilosas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Intervalo Livre de Doença , Feminino , Humanos , Região Variável de Imunoglobulina , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Resultado do Tratamento , Proteína Supressora de Tumor p53/genéticaRESUMO
In a patient with chronic lymphocytic leukemia (CLL) molecular cytogenetics showed terminal del(14)(q24). Fluorescence in situ hybridisation (FISH) narrowed the deletion to a 35 megabases DNA segment, with the proximal breakpoint between two partially overlapping clones, RP1-116J24 and RP5-1119N5. Besides loss of material at 14q24-qter, comparative genomic hybridisation (CGH) showed loss of 3p21.3-pter, 4p11-p15.1, 8p12-pter, 13q12-q14, and 15q11-q15, and gain of 3q25-qter. Del(13)(q12-14) included the RB-1 gene but not D13S319 and D13S25 loci. The patient was refractory to fludarabine and rituximab. Our findings and data from other reports suggest del(14)(q24) is indicative of aggressive course and is closely associated with del(13)(q14) in CLL.
Assuntos
Cromossomos Humanos Par 14/genética , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/genética , Idoso , Deleção Cromossômica , Humanos , Hibridização in Situ Fluorescente/métodos , Masculino , Hibridização de Ácido Nucleico/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Prognóstico , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: The prophylactic use of fluoroquinolones in patients with cancer and neutropenia is controversial and is not a recommended intervention. METHODS: We randomly assigned 760 consecutive adult patients with cancer in whom chemotherapy-induced neutropenia (<1000 neutrophils per cubic millimeter) was expected to occur for more than seven days to receive either oral levofloxacin (500 mg daily) or placebo from the start of chemotherapy until the resolution of neutropenia. Patients were stratified according to their underlying disease (acute leukemia vs. solid tumor or lymphoma). RESULTS: An intention-to-treat analysis showed that fever was present for the duration of neutropenia in 65 percent of patients who received levofloxacin prophylaxis, as compared with 85 percent of those receiving placebo (243 of 375 vs. 308 of 363; relative risk, 0.76; absolute difference in risk, -20 percent; 95 percent confidence interval, -26 to -14 percent; P=0.001). The levofloxacin group had a lower rate of microbiologically documented infections (absolute difference in risk, -17 percent; 95 percent confidence interval, -24 to -10 percent; P<0.001), bacteremias (difference in risk, -16 percent; 95 percent confidence interval, -22 to -9 percent; P<0.001), and single-agent gram-negative bacteremias (difference in risk, -7 percent; 95 percent confidence interval, -10 to -2 percent; P<0.01) than did the placebo group. Mortality and tolerability were similar in the two groups. The effects of prophylaxis were also similar between patients with acute leukemia and those with solid tumors or lymphoma. CONCLUSIONS: Prophylactic treatment with levofloxacin is an effective and well-tolerated way of preventing febrile episodes and other relevant infection-related outcomes in patients with cancer and profound and protracted neutropenia. The long-term effect of this intervention on microbial resistance in the community is not known.