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1.
J Bone Miner Res ; 36(7): 1211-1219, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33949002

RESUMO

Erythropoietin (EPO) is the primary regulator of bone marrow erythropoiesis. Mouse models have provided evidence that EPO also promotes bone remodeling and that EPO-stimulated erythropoiesis is accompanied by bone loss independent of increased red blood cell production. EPO has been used clinically for three decades to treat anemia in end-stage renal disease, and notably, although the incidence of hip fractures decreased in the United States generally after 1990, it rose among hemodialysis patients coincident with the introduction and subsequent dose escalation of EPO treatment. Given this clinical paradox and findings from studies in mice that elevated EPO affects bone health, we examined EPO treatment as a risk factor for fractures in hemodialysis patients. Relationships between EPO treatment and hip fractures were analyzed using United States Renal Data System (USRDS) datasets from 1997 to 2013 and Consolidated Renal Operations in a Web-enabled Network (CROWNWeb) datasets for 2013. Fracture risks for patients treated with <50 units of EPO/kg/week were compared to those receiving higher doses by multivariable Cox regression. Hip fracture rates for 747,832 patients in USRDS datasets (1997-2013) increased from 12.0 per 1000 patient years in 1997 to 18.9 in 2004, then decreased to 13.1 by 2013. Concomitantly, average EPO doses increased from 11,900 units/week in 1997 to 18,300 in 2004, then decreased to 8,800 by 2013. During this time, adjusted hazard ratios for hip fractures with EPO doses of 50-149, 150-299, and ≥ 300 units/kg/week compared to <50 units/kg/week were 1.08 (95% confidence interval [CI], 1.01-1.15), 1.22 (95% CI, 1.14-1.31), and 1.41 (95% CI, 1.31-1.52), respectively. Multivariable analyses of 128,941 patients in CROWNWeb datasets (2013) replicated these findings. This study implicates EPO treatment as an independent risk factor for hip fractures in hemodialysis patients and supports the conclusion that EPO treatment may have contributed to changing trends in fracture incidence for these patients during recent decades. Published 2021. This article is a U.S. Government work and is in the public domain in the USA. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Assuntos
Anemia , Eritropoetina , Fraturas do Quadril , Falência Renal Crônica , Anemia/complicações , Anemia/tratamento farmacológico , Anemia/epidemiologia , Animais , Fraturas do Quadril/epidemiologia , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Camundongos , Diálise Renal , Estados Unidos/epidemiologia
2.
Stem Cells ; 34(6): 1513-26, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26866427

RESUMO

In vitro generation of mature neutrophils from human induced pluripotent stem cells (iPSCs) requires hematopoietic progenitor development followed by myeloid differentiation. The purpose of our studies was to extensively characterize this process, focusing on the critical window of development between hemogenic endothelium, hematopoietic stem/progenitor cells (HSPCs), and myeloid commitment, to identify associated regulators and markers that might enable the stem cell field to improve the efficiency and efficacy of iPSC hematopoiesis. We utilized a four-stage differentiation protocol involving: embryoid body (EB) formation (stage-1); EB culture with hematopoietic cytokines (stage-2); HSPC expansion (stage-3); and neutrophil maturation (stage-4). CD34(+) CD45(-) putative hemogenic endothelial cells were observed in stage-3 cultures, and expressed VEGFR-2/Flk-1/KDR and VE-cadherin endothelial markers, GATA-2, AML1/RUNX1, and SCL/TAL1 transcription factors, and endothelial/HSPC-associated microRNAs miR-24, miR-125a-3p, miR-126/126*, and miR-155. Upon further culture, CD34(+) CD45(-) cells generated CD34(+) CD45(+) HSPCs that produced hematopoietic CFUs. Mid-stage-3 CD34(+) CD45(+) HSPCs exhibited increased expression of GATA-2, AML1/RUNX1, SCL/TAL1, C/EBPα, and PU.1 transcription factors, but exhibited decreased expression of HSPC-associated microRNAs, and failed to engraft in immune-deficient mice. Mid-stage-3 CD34(-) CD45(+) cells maintained PU.1 expression and exhibited increased expression of hematopoiesis-associated miR-142-3p/5p and a trend towards increased miR-223 expression, indicating myeloid commitment. By late Stage-4, increased CD15, CD16b, and C/EBPɛ expression were observed, with 25%-65% of cells exhibiting morphology and functions of mature neutrophils. These studies demonstrate that hematopoiesis and neutrophil differentiation from human iPSCs recapitulates many features of embryonic hematopoiesis and neutrophil production in marrow, but reveals unexpected molecular signatures that may serve as a guide for enhancing iPSC hematopoiesis. Stem Cells 2016;34:1513-1526.


Assuntos
Diferenciação Celular , Hematopoese , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Neutrófilos/citologia , Antígenos de Superfície/metabolismo , Ensaio de Unidades Formadoras de Colônias , Regulação da Expressão Gênica , Humanos , Cinética , MicroRNAs/genética , MicroRNAs/metabolismo , Fatores de Transcrição/metabolismo
3.
Clin J Am Soc Nephrol ; 10(10): 1822-30, 2015 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-26358266

RESUMO

BACKGROUND AND OBJECTIVES: Recombinant human erythropoietin (epoetin) is used routinely to increase blood hemoglobin levels in patients with ESRD and anemia. Although lower doses of epoetin are required to achieve equivalent hemoglobin responses when administered subcutaneously rather than intravenously, standard practice has been to administer epoetin to patients on hemodialysis intravenously. Randomized trials of alternative epoetin treatment regimens in patients with kidney failure have shown that risks of cardiovascular complications and death are related to the dose levels of epoetin used. Therefore, given the dose-sparing advantages of subcutaneous epoetin administration, the possibility that treatment of patients on hemodialysis with subcutaneous epoetin might be associated with more favorable outcomes compared with intravenous treatment was investigated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A retrospective cohort study of 62,710 adult patients on hemodialysis treated with either intravenous or subcutaneous epoetin-α and enrolled in the Centers for Medicare and Medicaid Services ESRD Clinical Performance Measures Project from 1997 to 2005 was carried out. Risks of death and/or hospitalization for cardiovascular complications (adverse composite event outcomes) during 2 years of follow-up were determined in relationship to epoetin dose and route of administration (intravenous versus subcutaneous) by multivariate Cox proportional hazard modeling adjusted for demographics and clinical parameters. RESULTS: Epoetin doses used to achieve equivalent hemoglobin responses in study patients were, on average, 25% higher when epoetin was administered intravenously rather than subcutaneously (as expected). Moreover, adverse composite event outcomes were found to be significantly more likely to occur during follow-up for patients on hemodialysis managed with intravenous rather than subcutaneous epoetin (adjusted hazard ratio for adverse events within 1 year [intravenous versus subcutaneous] was 1.11 [95% confidence interval, 1.04 to 1.18]). CONCLUSIONS: This study finds that treatment of patients on hemodialysis with subcutaneous epoetin is associated with more favorable clinical outcomes than those associated with intravenous epoetin treatment.


Assuntos
Anemia/tratamento farmacológico , Doenças Cardiovasculares/epidemiologia , Epoetina alfa/administração & dosagem , Hematínicos/administração & dosagem , Falência Renal Crônica/mortalidade , Falência Renal Crônica/terapia , Administração Intravenosa , Idoso , Anemia/sangue , Doenças Cardiovasculares/etiologia , Epoetina alfa/efeitos adversos , Feminino , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/etiologia , Hematínicos/efeitos adversos , Hemoglobinas/metabolismo , Hospitalização/estatística & dados numéricos , Humanos , Injeções Subcutâneas , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/etiologia , Diálise Renal , Estudos Retrospectivos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Estados Unidos/epidemiologia
4.
Biochem Biophys Res Commun ; 376(1): 200-5, 2008 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-18774771

RESUMO

Peptide nucleic acid (PNA) is highly stable and binds to complementary RNA and DNA with high affinity, but it resists cellular uptake, thereby limiting its bioavailability. We investigated whether protectiveantigen (PA, a non-toxic component of anthrax toxin) could transport antisense PNA oligomers into reporter cells that contain luciferase transgenes with mutant beta-globin IVS2 intronic inserts, which permit aberrant pre-mRNA splicing and impair luciferase expression. PNA oligomers antisense to mutant splice sites in these IVS2 inserts induced luciferase expression when effectively delivered into the cells. PNA 18-mers with C-terminal poly-lysine tails [PNA(Lys)(8)] demonstrated modest sequence-specific antisense activity by themselves at micromolar concentrations in luc-IVS2 reporter cell cultures. However, this activity was greatly amplified by PA. Antisense PNA(Lys)(8) with but not without PA also corrected the IVS2-654 beta-globin splice defect in cultured erythroid precursor cells from a patient with beta-thalassemia [genotype, IVS2-654(beta(0)/beta(E))], providing further evidence that anthrax PA can effectively transport antisense PNA oligomers into cells.


Assuntos
Antígenos de Bactérias/metabolismo , Toxinas Bacterianas/metabolismo , Oligodesoxirribonucleotídeos Antissenso/metabolismo , Ácidos Nucleicos Peptídicos/metabolismo , Transfecção/métodos , Transporte Biológico , Globinas/genética , Humanos , Íntrons , Luciferases/genética , Oligodesoxirribonucleotídeos Antissenso/genética , Ácidos Nucleicos Peptídicos/genética , Sítios de Splice de RNA , Splicing de RNA , Talassemia beta/genética
6.
Am J Hematol ; 82(5): 363-7, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17205535

RESUMO

Acquired loss of functional von Willebrand factor (VWF) has been termed the acquired von Willebrand syndrome (AVWS). AVWS is a rare adult-onset bleeding diathesis that is clinically similar to congenital von Willebrand disease (VWD), and occurs with a variety of autoimmune, lymphoproliferative, or myeloproliferative disorders. We have identified four patients with AVWS in association with immunoglobulin light chain (AL) amyloidosis. These patients, lacking any pre-existing or family history of abnormal bleeding, developed cutaneous, mucosal, or gastrointestinal bleeding in the course of their disease without deficiency of clotting factor X or other factors; the activated partial thromboplastin time (aPTT) was prolonged in three out of the four cases. Despite normal VWF antigen levels, VWF ristocetin cofactor activity (VWF:RCo) was low. Electrophoresis patterns of high molecular weight (HMW) VWF multimers were abnormal in two of the four cases. Two of the patients were treated with high-dose intravenous melphalan followed by autologous stem cell transplantation (HDM/SCT) and achieved hematologic remission. In these two patients, the bleeding diathesis improved and the coagulation parameters normalized, confirming a causal relationship between the plasma cell dyscrasia and the AVWS. AVWS should be considered in AL amyloidosis patients with hemorrhagic diatheses and normal clotting factor levels.


Assuntos
Amiloidose/complicações , Doenças de von Willebrand/etiologia , Adulto , Amiloidose/sangue , Amiloidose/tratamento farmacológico , Amiloidose/cirurgia , Antígenos/análise , Eletroforese das Proteínas Sanguíneas , Eletroforese em Gel de Ágar , Hemorragia/etiologia , Humanos , Cadeias Leves de Imunoglobulina/análise , Masculino , Melfalan/uso terapêutico , Peso Molecular , Tempo de Tromboplastina Parcial , Transplante de Células-Tronco de Sangue Periférico , Indução de Remissão , Ristocetina/farmacologia , Transplante Autólogo , Doenças de von Willebrand/imunologia , Fator de von Willebrand/imunologia
7.
Blood ; 109(2): 492-6, 2007 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-16960148

RESUMO

In immunoglobulin light chain (AL) amyloidosis, amyloid fibril deposits derived from immunoglobulin light chains produced by a clonal plasma cell dyscrasia accumulate in tissues and damage vital organs. Treatment regimens used in multiple myeloma can be effective in AL amyloidosis; however, patients with this disease often tolerate these regimens poorly because of multisystem organ dysfunction. Thalidomide and lenalidomide have both been shown to be effective in myeloma. In this report, we describe results of a phase 2 trial of the use of lenalidomide, as a single agent and in combination with dexamethasone, for the treatment of AL amyloidosis. Thirty-four patients with AL amyloidosis, most with prior therapies, were enrolled in the trial. The initial dose of lenalidomide used (25 mg/d) was poorly tolerated; however, a reduced dose of 15 mg/d was generally well tolerated. Of 24 evaluable patients, 7 (29%) achieved a hematologic complete response and 9 (38%) achieved a partial hematologic response, for an overall hematologic response rate of 67%. Hematologic responses were also associated with clinical responses. Fatigue and myelosuppression were the most common treatment-related adverse events (35%), while thromboembolic complications (9%) were the most serious. Findings from this trial indicate that lenalidomide can be effective in treating AL amyloidosis.


Assuntos
Amiloidose/tratamento farmacológico , Dexametasona/administração & dosagem , Cadeias Leves de Imunoglobulina/sangue , Talidomida/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Amiloidose/sangue , Amiloidose/diagnóstico , Dexametasona/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Tolerância a Medicamentos , Feminino , Humanos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Taxa de Sobrevida , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Resultado do Tratamento
8.
Blood ; 108(12): 3945-7, 2006 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-16926284

RESUMO

Recently, protocols using high-dose melphalan chemotherapy and autologous peripheral blood stem cell transplantation (HDM/SCT) have been developed for the treatment of patients with immunoglobulin light chain (AL) amyloidosis. Although peritransplantation mortality is greater than for other hematologic diseases, treatment leads to durable hematologic complete responses, improvements in organ function and quality of life, and extended survival in a substantial proportion of patients. To determine whether this treatment can be applied to older patients, we have analyzed HDM/SCT treatment outcomes for 65 patients (aged 65 years or older) with AL amyloidosis compared with outcomes for 280 younger patients. For patients over age 65 years who meet the same eligibility criteria as younger patients, toxicity, hematologic remission rate, and survival were not significantly different from those observed in younger patients, indicating that older patients should not be excluded a priori from consideration for HDM/SCT treatment.


Assuntos
Envelhecimento , Amiloidose/terapia , Antineoplásicos Alquilantes/administração & dosagem , Cadeias Leves de Imunoglobulina , Melfalan/administração & dosagem , Transplante de Células-Tronco de Sangue Periférico , Adulto , Idoso , Amiloidose/mortalidade , Antineoplásicos Alquilantes/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Transplante de Células-Tronco de Sangue Periférico/mortalidade , Qualidade de Vida , Recuperação de Função Fisiológica , Indução de Remissão , Estudos Retrospectivos , Taxa de Sobrevida , Transplante Autólogo
9.
Leuk Res ; 28(11): 1125-36, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15380335

RESUMO

Six patients with bcr-abl positive AML or chronic myelogenous leukemia in blast crisis (CML-BC) were treated with the IMP-dehydrogenase (IMPDH) inhibitor, Tiazofurin, in a Phase-II trial. Tiazofurin was given by IV infusion (2200-2700 mg/m2 per day) for up to 10 days. Leukemia blasts rapidly disappeared from the circulation of patients during treatment, while mature myeloid cells in the marrow increased in number. Although these hematologic responses were transient, persisting less than 3-4 weeks, our findings confirm that Tiazofurin has anti-leukemia activity. This drug warrants further study in combination regimens with other chemotherapeutic agents for the treatment of bcr-abl positive AML and CML-BC.


Assuntos
Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Genes abl , IMP Desidrogenase/antagonistas & inibidores , Leucemia Mieloide Aguda/tratamento farmacológico , Ribavirina/análogos & derivados , Ribavirina/uso terapêutico , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
10.
Leuk Res ; 28(11): 1137-43, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15380336

RESUMO

Inosine-5'-monophosphate-dehydrogenase (IMPDH) regulates the de novo synthesis of guanine ribonucleotides (GNT). IMPDH activity varies inversely with intracellular [GNT] and is linked to cellular proliferation. K562 leukemia cell growth was studied relative to IMPDH expression and activity following culture of the cells with Tiazofurin, an IMPDH inhibitor. Tiazofurin depressed IMPDH activity and [GTP] in K562 cells, and also increased IMPDH mRNA expression. Following exposure to Tiazofurin, K562 cell proliferation, entry into cycle, and sensitivity to cycle-active cytotoxic agents were increased. These findings indicate that the efficacy of standard chemotherapy in bcr-abl positive leukemias might be enhanced if combined sequentially with Tiazofurin.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Ribavirina/análogos & derivados , Ribavirina/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , IMP Desidrogenase/genética , IMP Desidrogenase/metabolismo , Técnicas In Vitro , Células K562 , RNA Mensageiro/genética
11.
Blood ; 104(6): 1888-93, 2004 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-15155460

RESUMO

Treatment of AL amyloidosis patients with high-dose melphalan chemotherapy followed by autologous peripheral blood stem cell transplantation (HDM/SCT) can produce hematologic complete responses (CRs) and improvement in organ function. To determine whether these responses are accompanied by improvement in quality of life (QOL), we employed the Medical Outcomes Study (MOS) 36-item Short Form General Health Survey (SF-36) questionnaire for 544 patients evaluated between 1994 and 2002. At baseline, the scores were significantly lower on all 8 SF-36 scales compared with age-matched population norms: the composite physical component summary (PCS) for the AL patients was 34.5 versus the population norm of 46.8, and the mental component summary (MCS) was 45.0 versus the norm of 51.5. All SF-36 scores improved at 1 year, with the MCS reaching the population norm. The PCS, though improved, was still lower than normal but was greater in the subgroup of patients who achieved a hematologic CR; the PCS normalized at 2 years in these patients. Thus, treatment of AL amyloidosis patients with HDM/SCT produces measurable and sustained improvements in quality of life, particularly in those patients who achieve hematologic CR.


Assuntos
Amiloidose/tratamento farmacológico , Amiloidose/cirurgia , Melfalan/administração & dosagem , Melfalan/uso terapêutico , Qualidade de Vida , Transplante de Células-Tronco , Seguimentos , Inquéritos Epidemiológicos , Humanos , Pessoa de Meia-Idade , Inquéritos e Questionários , Taxa de Sobrevida , Resultado do Tratamento
12.
Ann Intern Med ; 140(2): 85-93, 2004 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-14734330

RESUMO

BACKGROUND: AL amyloidosis is a fatal disease resulting from tissue deposition of amyloid fibrils derived from monoclonal immunoglobulin light chains. Treatment with oral chemotherapy is minimally effective. OBJECTIVE: To test survival and organ response in a large sample of patients treated with high-dose intravenous melphalan (100 to 200 mg/m2) and autologous blood stem-cell transplantation. DESIGN: 8-year longitudinal analysis of clinical effectiveness. SETTING: University-affiliated specialty referral clinic. PATIENTS: 701 consecutive new patients with AL amyloidosis. INTERVENTION: High-dose chemotherapy and autologous stem-cell transplantation for patients who met eligibility requirements based on organ involvement and clinical status. MEASUREMENTS: Survival analysis of all patients evaluated and a detailed analysis of treatment outcome in the subgroup that received high-dose melphalan and stem-cell transplantation. RESULTS: Among 701 patients with AL amyloidosis, 394 (56%) were eligible for high-dose melphalan and stem-cell transplantation; 82 did not proceed with treatment because of patient choice or disease progression. Median survival of the 312 patients who initiated treatment was 4.6 years. A complete hematologic response, defined as no evidence of an underlying plasma cell dyscrasia 1 year after treatment, was achieved in 40% of patients and was associated with prolonged survival. Statistically significant improvements occurred in end-organ disease and were greater in patients with a complete hematologic response. Mortality rate within 100 days of treatment with high-dose melphalan and stem-cell transplantation was 13%; patients with cardiomyopathy had the highest mortality rates. CONCLUSIONS: Treatment of selected patients with AL amyloidosis by using high-dose melphalan and stem-cell transplantation resulted in hematologic remission, improved 5-year survival, and reversal of amyloid-related disease in a substantial proportion.


Assuntos
Amiloidose/terapia , Melfalan/administração & dosagem , Transplante de Células-Tronco , Idoso , Amiloidose/sangue , Amiloidose/complicações , Amiloidose/mortalidade , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Transplante Autólogo
13.
Clin Lymphoma ; 3(4): 241-6, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12672274

RESUMO

Thalidomide is an effective therapy for multiple myeloma, although its mechanisms of action remain unclear. Light chain-associated (AL) amyloidosis is a plasma cell disorder related to multiple myeloma, but in AL amyloidosis, fibrillar tissue deposits of clonal immunoglobulin light chains produce organ dysfunction. To test the toxicity and efficacy of thalidomide in AL amyloidosis we initiated a phase I/II trial for patients with AL amyloidosis, most of whom had failed prior therapy with high-dose melphalan and autologous stem cell transplantation. This trial was designed as an individualized 6-month dose-escalation study with reevaluation of bone marrow plasmacytosis and serum and urine monoclonal proteins after 3 and 6 months. Sixteen patients were enrolled in the study with a median age of 62 years (range, 37-70 years). Fourteen patients had renal involvement, 4 had cardiac involvement, 4 had liver involvement, and 2 had predominant soft tissue or lymph node involvement. The median maximum tolerated dose was 300 mg, with fatigue and other central nervous system side effects being the major dose-limiting toxicities. Side effects not frequently reported for other patient populations included exacerbation of peripheral and pulmonary edema and worsening azotemia. In all, 50% of patients experienced grade 3/4 toxicity, and 25% had to discontinue the study drug. No complete hematologic responses were seen, but 25% of patients had a significant reduction in Bence-Jones proteinuria. Thus, while thalidomide has activity in AL amyloidosis, it also has significant toxicity in this patient population.


Assuntos
Amiloidose/tratamento farmacológico , Cadeias Leves de Imunoglobulina/imunologia , Imunossupressores/administração & dosagem , Paraproteinemias/tratamento farmacológico , Talidomida/administração & dosagem , Adulto , Idoso , Amiloidose/imunologia , Feminino , Humanos , Imunossupressores/efeitos adversos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Paraproteinemias/imunologia , Prognóstico , Proteinúria/etiologia , Terapia de Salvação , Talidomida/efeitos adversos , Resultado do Tratamento
14.
Kidney Int ; 63(5): 1868-73, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12675865

RESUMO

BACKGROUND: High-dose intravenous melphalan and autologous peripheral blood stem cell transplantation (HDM/SCT) is an effective treatment for AL amyloidosis but is associated with significant toxicity, including the development of acute renal failure (ARF). The incidence and outcome of ARF as a complication of such treatment is not known. METHODS: All AL amyloidosis patients treated with HDM/SCT at a single institution between July 1, 1994 and May 31, 2000 were included in the analysis unless they were dialysis-dependent prior to treatment. Baseline data were collected prospectively. Treatment-related data were obtained from a prospectively maintained database and medical record review. ARF was defined as either a >/=1 mg/dL increase in serum creatinine or a doubling of serum creatinine to >/=1.5 mg/dL for at least 2 days. Recovery of renal function was defined as a return of serum creatinine to less than or within 0.5 mg/dL of the pretreatment value or the ability to discontinue dialysis initiated as a result of ARF. RESULTS: ARF occurred in 37 of 173 patients (21%). Initiation of dialysis was required in nine patients (5%). Forty-six percent of patients with ARF, including four of nine who required dialysis, had recovery of renal function. Baseline clinical variables that were independent predictors of transplant-associated ARF included creatinine clearance, proteinuria, and cardiac amyloidosis. Treatment-related variables associated with ARF included melphalan dose and bacteremia. ARF was associated with reduced survival at 90 days but did not have an impact on overall survival at a median follow-up of 2.9 years. CONCLUSION: ARF is a frequent but often reversible complication of HDM/SCT for AL amyloidosis. Specific clinical and treatment-related factors are associated with the development of this complication.


Assuntos
Injúria Renal Aguda/etiologia , Injúria Renal Aguda/mortalidade , Amiloidose/terapia , Transplante de Células-Tronco/efeitos adversos , Injúria Renal Aguda/terapia , Idoso , Amiloidose/mortalidade , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Análise de Sobrevida , Transplante Autólogo , Resultado do Tratamento
15.
Kidney Int ; 63(3): 1051-7, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12631087

RESUMO

BACKGROUND: The development of end-stage renal disease (ESRD) is common among patients with amyloid light-chain AL amyloidosis-associated renal disease and survival of these patients is poor. High-dose intravenous melphalan and autologous stem cell transplantation induce remission of the plasma cell dyscrasia in a significant proportion of patients with AL amyloidosis. The efficacy and tolerability of such treatment for patients with AL amyloidosis-associated ESRD are unknown. METHODS: Between June 1994 and June 2000, 15 patients with AL amyloidosis-associated ESRD were treated with intravenous melphalan (70 to 200 mg/m2) and autologous peripheral blood stem cell transplantation. Clinical and laboratory data were prospectively collected prior to treatment, during the peritransplant period, and at 3 months, 12 months, and annually thereafter. Treatment outcomes and toxicities were compared with 180 non-ESRD patients treated during the study period. RESULTS: Eight of 15 patients (53%) had a hematologic complete response following treatment. Two patients (13%) died during the peritransplant period. Transfusion requirements were greater and there was a trend toward increased severity of mucositis in the ESRD patients compared with the non-ESRD patients. Median survival for the ESRD patients with a hematologic complete response was 4.5 years. Five patients with hematologic complete response have either undergone or are awaiting renal transplantation. CONCLUSION: High-dose intravenous melphalan with stem cell transplantation is an effective treatment in selected patients with AL amyloidosis-associated ESRD. Although the toxicity profile is greater in ESRD patients, the treatment offers the possibility of successful renal transplantation if hematologic remission is achieved. This treatment should be considered for patients with AL amyloidosis-associated ESRD.


Assuntos
Amiloidose/tratamento farmacológico , Antineoplásicos Alquilantes/administração & dosagem , Falência Renal Crônica/tratamento farmacológico , Melfalan/administração & dosagem , Transplante de Células-Tronco , Adulto , Idoso , Amiloidose/complicações , Amiloidose/mortalidade , Antineoplásicos Alquilantes/efeitos adversos , Feminino , Humanos , Injeções Intravenosas , Falência Renal Crônica/etiologia , Falência Renal Crônica/mortalidade , Masculino , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Estudos Prospectivos , Indução de Remissão , Análise de Sobrevida , Transplante Autólogo
16.
Am J Hematol ; 72(1): 13-9, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12508262

RESUMO

Severe neutropenia following cytotoxic, anti-cancer chemotherapy is well-known to be associated with an increased risk of infections that may be life-threatening, particularly if not treated immediately. Consequently, serial measurements of neutrophil counts in peripheral blood are done routinely following the administration of high-dose myelosuppressive chemotherapy in order to monitor the onset, severity, and duration of iatrogenic neutropenia. We have studied a non-invasive method of quantifying neutrophils recoverable from the oral mucosa, a normal tissue site of neutrophil turnover, as an alternative approach for monitoring severe, chemotherapy-induced neutropenia. This method is based on the quantification of fluorochrome-stained neutrophils present in timed mouthwash specimens. Blood neutrophil (ANC) and mucosal neutrophil counts (MNC) were measured repeatedly in 23 patients who had been treated with dose-intensive chemotherapy for a variety of indications. All 23 patients developed profound neutropenia (ANC < 100/mm3), and 19 developed neutropenic fever (>101 degrees F) during the 2 weeks following treatment. Nadirs of neutropenia defined by MNC were significantly less prolonged than those defined by the ANC. Furthermore, the onset and resolution of neutropenic fever coincided more precisely with nadirs of neutropenia defined by the MNC than with those defined by the ANC. Our findings indicate that oral mucosal neutrophil counts predict the timing of clinical events associated with neutropenia (e.g., the onset and resolution of fever) with significantly greater accuracy than blood neutrophil counts.


Assuntos
Laranja de Acridina/análise , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Contagem de Células , Corantes Fluorescentes/análise , Microscopia de Fluorescência , Mucosa Bucal/patologia , Neutropenia/diagnóstico , Neutrófilos , Coloração e Rotulagem/métodos , Adolescente , Adulto , Idoso , Contagem de Células Sanguíneas , Transplante de Medula Óssea , Movimento Celular , Terapia Combinada , Convalescença , Feminino , Febre/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/imunologia , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/terapia , Neutropenia/sangue , Neutropenia/induzido quimicamente , Transplante de Células-Tronco de Sangue Periférico , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Irrigação Terapêutica
17.
Br J Haematol ; 117(4): 886-9, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12060126

RESUMO

Median survival of patients with AL amyloidosis with clinically significant cardiac involvement is 5 months when treated with cyclic melphalan and prednisone. We investigated a regimen of continuous oral melphalan as a single agent for patients with cardiac amyloidosis who were unable to tolerate prednisone or more aggressive chemotherapy. Thirty patients with amyloid cardiomyopathy were treated with continuous oral melphalan. Seven of 13 patients, evaluable after 3-4 months of treatment, achieved a partial haematological response and three achieved a complete haematological response; six patients have survived for > 1 year. This regimen appeared to be effective in inducing haematological responses in patients who received total doses of melphalan > 300 mg.


Assuntos
Amiloidose/tratamento farmacológico , Antineoplásicos Alquilantes/administração & dosagem , Cardiopatias/tratamento farmacológico , Melfalan/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Amiloidose/mortalidade , Antineoplásicos Alquilantes/uso terapêutico , Esquema de Medicação , Feminino , Cardiopatias/mortalidade , Humanos , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Análise de Sobrevida
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