RESUMO
The aim was to provide a translation into Italian with cross-cultural adaptation of the French FLARE-Rheumatoid Arthritis (RA) questionnaire, and to test its acceptability, feasibility, reliability and construct validity in a single-centre cohort study. The French version of the FLARE-RA questionnaire was cross-culturally adapted and translated into Italian following an established forward-backward translation procedure, with independent translations and backtranslations. To validate the Italian version we tested the internal validity with Cronbach's alpha, test-retest reliability with the intraclass correlation coefficient, agreement between assessments with Bland-Altman plots and construct validity with Spearman's correlation coefficients. The questionnaire was tested on 283 consecutive RA outpatients (mean age 56.1±13.9 years, 226/283 females, median disease duration 12.6 years ranging from 0.2 to 70.6). For the global score (11 items) the Cronbach's alpha coefficient was 0.94. The intraclass correlation coefficient was 0.87 (95% CI, 0.76-0.96). The correlation of FLARE-RA global score was 0.59 (95% CI, 0.50-0.66) with the Disease Activity Score on 28 joints, 0.63 (95% CI, 0.55-0.71) with the Simplified Disease Activity Index, 0.77 (95% CI, 0.71-0.83) with the RA Impact of Disease and 0.67 (95% CI, 0.59-0.73) with the Health Assessment Questionnaire. The Italian version of the FLARE-RA is feasible, brief and easy to administer. The translated and cross-cultural adapted showed accordingly to be valid and reliable. This questionnaire has some practical advantages, such as clarity, comprehensiveness, simplicity, and a minimum filling time. The development of cross-cultural adapted questionnaires in different languages is of pivotal importance to obtain standardized and comparable data across countries.
Assuntos
Artrite Reumatoide/diagnóstico , Medidas de Resultados Relatados pelo Paciente , Inquéritos e Questionários , Exacerbação dos Sintomas , Traduções , Artrite Reumatoide/fisiopatologia , Comparação Transcultural , Feminino , Humanos , Itália , Idioma , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Tamanho da Amostra , Estatísticas não Paramétricas , TraduçãoRESUMO
Systemic sclerosis (SSc)-related Raynaud's phenomenon (RP) and digital ulcers (DU) can impair health-related quality of life (HRQoL). The aim of our study was to estimate HRQoL in SSc patients treated with two different intravenous (IV) iloprost (ILO) regimens and in patients not treated with IV ILO. 96 consecutive SSc patients were enrolled in a pragmatic, prospective and non-randomized study, and divided into 3 groups: not requiring therapy with IV ILO (N=52), IV ILO once monthly (N=24) or IV ILO for 5 consecutive days every 3 months (N=20). Patients were followed up for three months. We assessed HRQoL using the generic preference-based questionnaire EQ-5D-5L. We conducted multiple regression analyses to estimate, in each treatment group, the mean general health (GH) and the mean utility index of the EQ-5D-5L, adjusting for possible confounders. The mean adjusted utility index and GH score, after three months' follow-up, were not different in the three groups: IV ILO was able to make patients requiring IV ILO similar to those not requiring it. Moreover, there was no difference in this model between the two ILO regimens (1 day monthly vs 5 consecutive days every 3 months). The two different IV ILO regimens (the most appropriate regimen was decided according to patients' characteristics and needs) were able to stabilize HRQoL in RP secondary to SSc non-adequately controlled by oral therapy.
Assuntos
Iloprosta/administração & dosagem , Qualidade de Vida , Escleroderma Sistêmico/tratamento farmacológico , Administração Intravenosa , Efeitos Psicossociais da Doença , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
OBJECTIVES: Chemerin and interleukin (IL)-8 are pro-inflammatory mediators whose role in joint inflammation and cartilage degradation has been demonstrated in in-vitro findings. Studies on their presence in synovial fluid (SF) samples may offer further information on their pathogenic role. The aim of this study was to investigate SF chemerin and IL-8 levels in patients with different joint diseases. METHODS: 37 patients were enrolled: 18 with rheumatoid arthritis (RA), 8 with psoriatic arthritis (PsA) and 11 with osteoarthritis (OA). 41 SF samples were obtained by arthrocentesis in case of knee synovitis. Serum samples were obtained from 13 patients (4 with RA, 6 with PsA and 3 with OA) at the time of arthrocentesis. Chemerin, IL-8, TNF-α and IL-6 levels were measured using commercially available ELISA kits. Immunohistochemical analysis of synovial RA specimens was also performed. RESULTS: No difference in chemerin SF levels emerged between patients with immune-mediated inflammatory arthritides and those with OA (p=0.0656), while subjects with inflammatory arthritis displayed significantly higher levels of SF IL-8 compared to OA (p=0.0020). No significant difference emerged across the three conditions in the serum levels of both chemerin and IL-8. IL-8 strongly correlated with inflammatory markers as ESR, CRP, IL-6 and TNF-α. CONCLUSIONS: We observed similar chemerin SF and serum levels in the three conditions. Although flawed by some limitations, our findings support the emerging concept of OA as an inflammatory disorder. However the increased IL-8 levels we described in patients with inflammatory arthritis suggest a selective involvement of this pro-inflammatory and angiogenic cytokine in these conditions.
Assuntos
Artrite Psoriásica/metabolismo , Artrite Reumatoide/metabolismo , Quimiocinas/análise , Interleucina-8/análise , Osteoartrite/metabolismo , Líquido Sinovial/metabolismo , Idoso , Artrite Psoriásica/diagnóstico , Artrite Psoriásica/fisiopatologia , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/fisiopatologia , Biomarcadores/metabolismo , Sedimentação Sanguínea , Proteína C-Reativa/análise , Cartilagem Articular/metabolismo , Cartilagem Articular/fisiopatologia , Diagnóstico Diferencial , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Articulações/metabolismo , Articulações/fisiopatologia , Masculino , Pessoa de Meia-Idade , Osteoartrite/diagnóstico , Osteoartrite/fisiopatologia , Estatística como Assunto , Líquido Sinovial/química , Fator de Necrose Tumoral alfa/análiseRESUMO
BACKGROUND: Anaemia is a risk factor for death, adverse cardiovascular outcomes and poor quality of life in patients with chronic kidney disease (CKD). Erythropoietin Stimulating Agents (ESA) are the most used treatment option. In observational studies, higher haemoglobin (Hb) levels (around 11-13 g/dL) are associated with improved survival and quality of life compared to Hb levels around 9-10 g/dL. Randomized studies found that targeting higher Hb levels with ESA causes an increased risk of death, mainly due to adverse cardiovascular outcomes. It is possible that this is mediated by ESA dose rather than haemoglobin concentration, although this hypothesis has never been formally tested. METHODS: We present the protocol of the Clinical Evaluation of the Dose of Erythropoietins (C.E. DOSE) trial, which will assess the benefits and harms of a high versus a low ESA dose therapeutic strategy for the management of anaemia of end stage kidney disease (ESKD). This is a randomized, prospective open label blinded end-point (PROBE) design trial due to enroll 900 haemodialysis patients. Patients will be randomized 1:1 to 4000 UI/week i. v. versus 18000 UI/week i. v. of epoetin alfa, beta or any other epoetin in equivalent doses. The primary outcome of the trial is a composite of cardiovascular events. In addition, quality of life and costs of these two strategies will be assessed. The study has been approved and funded by the Italian Agency of Drugs (Agenzia Italiana del Farmaco (AIFA)) within the 2006 funding plan for independent research on drugs (registered at www.clinicaltrials.gov (NCT00827021)).
Assuntos
Anemia/tratamento farmacológico , Hematínicos/administração & dosagem , Diálise Renal , Anemia/economia , Anemia/etiologia , Nefropatias Diabéticas/complicações , Gerenciamento Clínico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Hematínicos/efeitos adversos , Hematínicos/economia , Hematínicos/farmacologia , Hematínicos/uso terapêutico , Hemoglobinas/análise , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Metanálise como Assunto , Pessoa de Meia-Idade , Estudos Observacionais como Assunto , Avaliação de Resultados em Cuidados de Saúde , Qualidade de Vida , Diálise Renal/efeitos adversos , Diálise Renal/economia , Projetos de Pesquisa , RiscoRESUMO
BACKGROUND: Human immune system (HIS)-engrafted mice are new tools to investigate human immune responses. Here, we used HIS mice to study human immune responses against human HER-2-positive cancer cells and their ability to control tumour growth and metastasis. METHODS: BALB/c Rag2(-/-), Il2rg(-/-) mice were engrafted with CD34(+) or CD133(+) human cord blood hematopoietic stem cells (HSC) and vaccinated with human HER-2-positive cancer cells SK-OV-3 combined to human IL-12. RESULTS: Both CD34(+) or CD133(+) human HSC gave long-term engraftment and differentiation, both in peripheral blood and in lymphoid organs, and production of human antibodies. Vaccinated mice produced specific anti-HER-2 human IgG. An s.c. SK-OV-3 challenge was significantly inhibited (but not abolished) in both vaccinated and non-vaccinated HIS mice. Tumours were heavily infiltrated with human and murine cells, mice showed NK cells and production of human interferon-γ, that could contribute to tumour growth inhibition. Vaccinated HIS mice showed significantly inhibited lung metastases when compared with non-vaccinated HIS mice and to non-HIS mice, along with higher levels of tumour-infiltrating human dendritic cells. CONCLUSION: Anti-HER-2 responses were elicited through an adjuvanted allogeneic cancer cell vaccine in HIS mice. Human immune responses elicited in HIS mice effectively inhibited lung metastases.
Assuntos
Antígenos CD34/imunologia , Antígenos CD/imunologia , Vacinas Anticâncer/imunologia , Glicoproteínas/imunologia , Neoplasias Pulmonares/imunologia , Peptídeos/imunologia , Receptor ErbB-2/imunologia , Antígeno AC133 , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Células-Tronco Hematopoéticas/imunologia , Humanos , Isotipos de Imunoglobulinas/imunologia , Neoplasias Pulmonares/secundário , Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos BALB CRESUMO
The highly aggressive cancer syndrome of female mice carrying a p53 knockout allele and a rat HER-2/neu (Neu) transgene (BALB-p53Neu) can be prevented by a cell vaccine presenting three components: Neu, interleukin (IL)-12 production, and allogeneic major histocompatibility complex (MHC) alleles (Triplex cell vaccine). Here we tested a second-generation Triplex DNA-based vaccine (Tri-DNA), consisting of the combination of three gene components (a transmembrane-extracellular domain fragment of the Neu gene, IL-12 genes, and the H-2D(q) allogeneic MHC gene), carried by separate plasmids. The Tri-DNA vaccine was at least as effective as the Triplex cell vaccine for cancer immunoprevention, giving a similar delay in the onset of mammary cancer and complete protection from salivary cancer. Both vaccines induced anti-Neu antibodies of the murine IgG2a isotype at similar levels. The Tri-DNA vaccine gave more restricted immunostimulation, consisting of a fully helper T cell type 1 (Th1)-polarized response, with effective production of interferon (IFN)-gamma in response to the vaccine but no spontaneous production, and no induction of anti-Neu IgG3 antibodies. On the other hand, the Triplex cell vaccine induced both Th1 and Th2 cytokines, a strong increase in spontaneous IFN-gamma production, and high levels of IgG3 antibodies recognizing Neu-positive syngeneic cells. In conclusion, the Tri-DNA vaccine is as effective as Triplex cell vaccine, exploiting a more restricted immune stimulation.
Assuntos
Vacinas Anticâncer/imunologia , Interleucina-12/imunologia , Síndromes Neoplásicas Hereditárias/prevenção & controle , Receptor ErbB-2/genética , Proteína Supressora de Tumor p53/genética , Vacinas de DNA/imunologia , Animais , Citocinas/biossíntese , Citocinas/imunologia , Citotoxicidade Imunológica , Feminino , Terapia Genética , Imunoglobulina G/sangue , Imunoterapia , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-12/metabolismo , Complexo Principal de Histocompatibilidade/imunologia , Glândulas Mamárias Animais/imunologia , Glândulas Mamárias Animais/patologia , Camundongos , Síndromes Neoplásicas Hereditárias/terapia , Ratos , Receptor ErbB-2/imunologia , Receptor ErbB-2/metabolismo , Glândulas Salivares/imunologia , Glândulas Salivares/patologia , Transfecção , Proteína Supressora de Tumor p53/imunologia , Proteína Supressora de Tumor p53/metabolismoRESUMO
Metastatic melanoma cells express a number of protein tyrosine kinases (PTKs) that are considered to be targets for imatinib. We conducted a phase II trial of imatinib in patients with metastatic melanoma expressing at least one of these PTKs. Twenty-one patients whose tumours expressed at least one PTK (c-kit, platelet-derived growth factor receptors, c-abl, or abl-related gene) were treated with 400 mg of imatinib twice daily. One patient with metastatic acral lentiginous melanoma, containing the highest c-kit expression among all patients, had dramatic improvement on positron emission tomographic scan at 6 weeks and had a partial response lasting 12.8 months. The responder had a substantial increase in tumour and endothelial cell apoptosis at 2 weeks of treatment. Imatinib was fairly well tolerated: no patient required treatment discontinuation because of toxicity. Fatigue and oedema were the only grade 3 or 4 toxicities that occurred in more than 10% of the patients. Imatinib at the studied dose had minimal clinical efficacy as a single-agent therapy for metastatic melanoma. However, based on the characteristics of the responding tumour in our study, clinical activity of imatinib, specifically in patients with melanoma with certain c-kit aberrations, should be examined.
Assuntos
Antineoplásicos/uso terapêutico , Melanoma/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Sequência de Bases , Benzamidas , Primers do DNA , Progressão da Doença , Feminino , Humanos , Mesilato de Imatinib , Masculino , Melanoma/irrigação sanguínea , Melanoma/diagnóstico por imagem , Melanoma/secundário , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Tomografia por Emissão de Pósitrons , Pirimidinas/efeitos adversos , Neoplasias Cutâneas/irrigação sanguínea , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
BACKGROUND: The purpose of this study was to evaluate the potential of noncytotoxic doses of suramin to reverse chemotherapy resistance in advanced chemonaive and chemoresistant non-small-cell lung cancer patients. PATIENTS AND METHODS: Patients received paclitaxel (Taxol) (200 mg/m(2)) and carboplatin (area under the concentration-time curve 6 mg/ml/min) every 3 weeks. The total suramin per cycle dose was calculated using a nomogram derived from the preceding phase I trial to obtain the desirable plasma concentration range of 10-50 microM. RESULTS: Thirty-nine response-assessable chemonaive patients (arm A) received 213 cycles. Thirty-eight cycles were administered to 15 patients with demonstrated resistance to paclitaxel and carboplatin (arm B). The pattern/frequency of toxic effects was similar to those expected for paclitaxel/carboplatin, and pharmacokinetic analyses (199 cycles) showed suramin plasma concentrations maintained between 10 and 50 microM in 94% of cycles. In arm A, response evaluation criteria in solid tumors (RECIST) response rate was 36% (95% confidence interval 22% to 54%; two complete, 12 partial); 15 patients (38%) had disease stabilization for > or =4 months; median progression-free survival (intention to treat) was 6.4 months; median overall survival (OS) 10.4 months and 1-year survival rate 38%. In arm B, no RECIST responses occurred; four patients had disease stabilization for > or =4 months; median OS was 132 days and 1-year survival rate 7%. Plasma basic fibroblast growth factor levels were higher in chemopretreated/refractory patients compared with chemonaive patients (P = 0.05). Sequence analysis of the EGFR tyrosine kinase domain in a long-term disease-free survivor revealed an ATP-binding pocket mutation (T790M). CONCLUSIONS: Noncytotoxic suramin did not increase paclitaxel/carboplatin's toxicity and the suramin dose was predicted from clinical parameters. No clinically significant reversal of primary resistance was documented, but a modulatory effect in chemotherapy-naive patients cannot be excluded. Controlled randomization is planned for further evaluation of this treatment strategy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carboplatina/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Feminino , Fator 1 de Crescimento de Fibroblastos/sangue , Fator 2 de Crescimento de Fibroblastos/sangue , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Paclitaxel/farmacocinética , Suramina/administração & dosagem , Suramina/efeitos adversos , Suramina/farmacocinéticaRESUMO
Arthroscopy is a mini-invasive technique that allows the direct observation of the joint cavity and the execution of diagnostic and therapeutic procedures; arthroscopy needs a very long learning-time curve as well as dedicated spaces and instruments. Ultrasonography is an imaging technique that enables to perform an immediate extension of the standard physical examination. The opportunity to visualize soft tissues, to obtain multiplanar and dynamic images in real time makes this practice easy repeatable at low costs. Ultrasonography allows to detect a variety of changes during inflammatory processes. The wide experience in arthroscopy of rheumatic patients acquired through the years by our team at the G. Pini Institute led us to study in vivo, during arthroscopy, the correspondence between arthroscopic and ultrasonographic images. Up to now three knee arthroscopies have been conducted with the double equipment (ultrasonographic and arthroscopic devices) in operating room. In our experience, the combination of the two methods in operating room may improve the validation of ultrasonography with arthroscopy as gold standard, helps to train the ultrasonographer to give immediate answers in order to clear the doubts aroused by ultrasonographic images; it also allows the arthroscopist to visualize the deeper layers of the synovial membrane making double guided targeted biopsies possible. Limits are the complexity of the procedure (instruments, operators, spaces, training of the doctors), the loose of power-doppler signal with the blood tourniquet and the always difficult evaluation of cartilage.
Assuntos
Artroscopia , Artropatias/diagnóstico por imagem , Artropatias/patologia , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , UltrassonografiaAssuntos
Antirreumáticos/uso terapêutico , Isoxazóis/uso terapêutico , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Ensaios Clínicos como Assunto , Feminino , Humanos , Isoxazóis/efeitos adversos , Leflunomida , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Assessment of patient satisfaction is not performed routinely in many healthcare institutions. In this review, we discuss methodological aspects of assessment of patient satisfaction in hemodialysis. We also present a pilot study conducted in the Gambro Healthcare Italy dialysis clinics network. METHODS: Patient satisfaction was assessed in a network of hemodialysis units by using an internally validated Italian translation of the Choices for Healthy Outcomes in Caring for ESRD (CHOICE) questionnaire. A cross-sectional analytic study design was used and data analysed with univariate and multivariate hierarchical logistic regression to explore correlates of the risk of being unsatisfied with dialysis treatment. Covariates which were considered include a series of over 20 clinical, demographic, organizational and structural aspects. In addition, unexplained inter-centre residual variability due to 'case-mix' was explored and plotted. RESULTS: Seventeen dialysis units participated in this cross-sectional analysis and 758/1001 (75.7%) provided answers to the questionnaires. There was a statistically significant association on multivariate hierarchical analysis between the risk of being unsatisfied with dialysis treatment and interdialysis body weight gain (unit of increase: 1 kg, p=0.004). On the contrary, the risk of unsatisfaction with dialysis treatment was significantly lower in patients with higher dry weight (unit of increase: 1 kg, p=0.002). Our multivariate hierarchical analysis identified some residual variability between dialysis units (n=6 outliers) which may not be explained by any of over 20 potential confounding covariates which were explored. CONCLUSIONS: Assessment of ''customer satisfaction'' is standard practice in private for profit product companies in general but needs to be increasingly recognized as a standard in both public and private providers of healthcare services. Social research methods, which are used for this type of analysis, need to be fine tuned and actively implemented in order to better understand how we may influence the quality of service we provide to our patients and the level at which they rate it.
Assuntos
Satisfação do Paciente , Diálise Renal , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Projetos Piloto , Inquéritos e QuestionáriosRESUMO
By now many authors regard arthroscopic synovectomy an integral part of therapeutic treatment of many rheumatic diseases with favourable results on post operating course and clinical picture in the long term. The pathologic synovial tissue during articular inflammatory rheumatism is well known to have a damaging effect responsible of early cartilage injury, as well as symptomatic action (e.g. articular stiffness, effusion, pain, functional limitation). Therefore to value the removal of such a tissue you should think of the secondary prevention of cartilage injury, besides the symptomatic point of view. Since 1996 we performed 190 arthroscopic synovectomy, the adopted criteria of judgement were: pain (spontaneous, during active and passive movements), effusion or swelling presence, articular range and cartilage state (evaluated during arthroscopy according to Outerbridg's classification). 70% of the cases showed good results and six years later the beginning of this activity we retain arthroscopic synovectomy as a valid help in articular inflammatory rheumatism treatment.
Assuntos
Artrite/cirurgia , Artroscopia , Joelho/cirurgia , Sinovectomia , Adolescente , Adulto , Idoso , Artrite Psoriásica/cirurgia , Artrite Reumatoide/cirurgia , Condrocalcinose/cirurgia , Doença Crônica , Seguimentos , Humanos , Pessoa de Meia-Idade , Osteoartrite/cirurgia , Sinovite/cirurgia , Fatores de TempoRESUMO
BACKGROUND: Cephalotoxine esters, including homoharringtonine (HHT), have shown encouraging activity in leukemia in initial studies in China and in later studies in the U.S. METHODS: The authors conducted a review of the literature to examine the studies pertinent to HHT in relation to preclinical studies and Phase I-II trials in patients with hematologic malignancies and solid tumors. RESULTS: HHT and analogues appear to induce differentiation and apoptosis. Studies from China reported high response rates in patients with leukemia. Trials in the U.S. using short HHT infusions (3-4 mg/m(2) daily for 5 days) resulted in a high incidence of cardiovascular complications that were reduced using continuous infusion schedules of 3-7 mg/m(2) daily for 5-7 days initially, and later lower dose schedules of 2.5 mg/m(2) daily for 7-14 days. Results in solid tumors were negative. However encouraging results were reported in patients with acute myeloid leukemia, myelodysplastic syndrome, acute promyelocytic leukemia, and, most important, chronic myeloid leukemia (CML). In CML patients, HHT has been investigated alone and in combination with interferon-alpha and low-dose cytarabine in late and early chronic phases, with positive results. Additional areas of interest include the potential use of HHT for the treatment of central nervous system leukemia, polycythemia vera, and other nonmalignant conditions such as malaria. New semisynthetic preparations and HHT derivatives that bypass multidrug resistance may improve the efficacy and toxicity profiles, and broaden the range of antitumor efficacy. CONCLUSIONS: HHT and its derivatives appear to have promising activity in hematologic malignancies, a finding that needs to be pursued.
Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Harringtoninas/uso terapêutico , Neoplasias/tratamento farmacológico , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Previsões , Mepesuccinato de Omacetaxina , Humanos , Leucemia/tratamento farmacológico , PesquisaAssuntos
Antineoplásicos/uso terapêutico , Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores Enzimáticos/uso terapêutico , Neoplasias/tratamento farmacológico , Animais , Ciclo Celular/efeitos dos fármacos , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Neoplasias/enzimologiaRESUMO
Bryostatin 1, a macrocyclic lactone isolated from the marine bryozoan Bugula neritina, is a protein kinase C (PKC) modulator which has shown both preclinical and clinical activity in lymphoid malignancies. We conducted a phase II trial of bryostatin 1 administered at a dose of 120 microg/m2 by 72-h continuous infusion every 2 weeks in patients with relapsed multiple myeloma. Treatment was well tolerated with myalgias constituting the primaray toxicity. There were no responses in nine evaluable patients. The preclinical anti-lymphoid activity is strong enough to support further exploration of bryostatin 1 in different schedules and in combination therapy for multiple myeloma.
Assuntos
Antineoplásicos/uso terapêutico , Lactonas/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Briostatinas , Feminino , Humanos , Lactonas/efeitos adversos , Macrolídeos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Arsenic trioxide inhibits growth and promotes apoptosis in many different cancer cell lines. The National Cancer Institute is working cooperatively with research centers across the U.S. to evaluate its clinical activity in hematologic malignancies, such as acute promyelocytic leukemia, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, chronic lymphocytic leukemia, myelodysplastic syndrome, and multiple myeloma. It is also supporting research in solid tumors, such as advanced hormone-refractory prostate cancer and renal cell cancer and in cervical cancer and refractory transitional cell carcinoma of the bladder. The safety and pharmacokinetics of arsenic trioxide are also being evaluated in pediatric patients with refractory leukemia and lymphoma. The results of these ongoing studies should provide important insights into the clinical utility of arsenic trioxide in these diseases.
Assuntos
Antineoplásicos/uso terapêutico , Arsenicais/uso terapêutico , Ensaios Clínicos como Assunto , Neoplasias Hematológicas/tratamento farmacológico , Óxidos/uso terapêutico , Trióxido de Arsênio , Humanos , National Institutes of Health (U.S.) , Estados UnidosRESUMO
Irofulven (MGI 114, 6-hydroxymethylacylfulvene, HMAF) is a semisynthetic illudin analog with broad in vitro anti-neoplastic activity. In this leukemia phase I study, we investigated the toxicity profile and activity of Irofulven in patients with primary refractory or relapsed acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), or myelodysplastic syndromes (MDS). Irofulven was given as an intravenous infusion over five minutes daily for five days. The starting dose was 10 mg/m2/day (50 mg/m2/course). Courses were scheduled to be given every 3-4 weeks according to toxicity and antileukemic efficacy. Twenty patients [AML: 17 patients; MDS: one patient; ALL: one patient; mixed lineage acute leukemia: one patient] were treated. Nausea, vomiting, hepatic dysfunction, weakness, renal dysfunction, and pulmonary edema were dose limiting toxicities, occurring in two of five patients treated at 20 mg/m2/day and two of three patients treated at 12.5 mg/m2/day. The MTD was defined as 10 mg/m2/day for five days. One patient with primary resistant AML achieved complete remission. Proposed phase II studies will further define the activity of Irofulven in patients with better prognosis AML and in other hematological malignancies, both as a single agent and in combination regimens, particularly with topoisomerase 1 inhibitors.
Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Sesquiterpenos/administração & dosagem , Adolescente , Adulto , Idoso , Antineoplásicos Alquilantes/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Esquema de Medicação , Testes Hematológicos , Humanos , Infusões Intravenosas , Leucemia Mieloide Aguda/mortalidade , Dose Máxima Tolerável , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Sesquiterpenos/efeitos adversos , Taxa de SobrevidaRESUMO
PURPOSE: To define the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of the novel protein kinase inhibitor, UCN-01 (7-hydroxystaurosporine), administered as a 72-hour continuous intravenous infusion (CIV). PATIENTS AND METHODS: Forty-seven patients with refractory neoplasms received UCN-01 during this phase I trial. Total, free plasma, and salivary concentrations were determined; the latter were used to address the influence of plasma protein binding on peripheral tissue distribution. The phosphorylation state of the protein kinase C (PKC) substrate alpha-adducin and the abrogation of DNA damage checkpoint also were assessed. RESULTS: The recommended phase II dose of UCN-01 as a 72-hour CIV is 42.5 mg/m(2)/d for 3 days. Avid plasma protein binding of UCN-01, as measured during the trial, dictated a change in dose escalation and administration schedules. Therefore, nine patients received drug on the initial 2-week schedule, and 38 received drug on the recommended 4-week schedule. DLTs at 53 mg/m(2)/d for 3 days included hyperglycemia with resultant metabolic acidosis, pulmonary dysfunction, nausea, vomiting, and hypotension. Pharmacokinetic determinations at the recommended dose of 42.5 mg/m(2)/d for 3 days included mean total plasma concentration of 36.4 microM (terminal elimination half-life range, 447 to 1176 hours), steady-state volume of distribution of 9.3 to 14.2 L, and clearances of 0.005 to 0.033 L/h. The mean total salivary concentration was 111 nmol/L of UCN-01. One partial response was observed in a patient with melanoma, and one protracted period ( > 2.5 years) of disease stability was observed in a patient with alk-positive anaplastic large-cell lymphoma. Preliminary evidence suggests UCN-01 modulation of both PKC substrate phosphorylation and the DNA damage-related G(2) checkpoint. CONCLUSION: UCN-01 can be administered safely as an initial 72-hour CIV with subsequent monthly doses administered as 36-hour infusions.
Assuntos
Alcaloides/efeitos adversos , Antineoplásicos/efeitos adversos , Neoplasias/tratamento farmacológico , Adulto , Idoso , Alcaloides/administração & dosagem , Alcaloides/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Dano ao DNA , Relação Dose-Resposta a Droga , Esquema de Medicação , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Hiperglicemia/induzido quimicamente , Hipotensão/induzido quimicamente , Infusões Intravenosas , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neoplasias/patologia , Neoplasias Cutâneas/tratamento farmacológico , Estaurosporina/análogos & derivados , Vômito/induzido quimicamenteRESUMO
Few chemotherapy agents have demonstrated activity in patients with myelodysplastic syndromes (MDS) and supportive management remains the standard of care. An increasing number of new drugs in development are being directed at specific molecular or biological targets of these diseases. Topotecan, a topoisomerase I inhibitor, has shown single-agent activity and is now being combined with other agents, including cytarabine. The aminothiol amifostine induces responses in about 30% of patients; however, its role is still being clarified. Agents that inhibit histone deacetylase and target DNA hypermethylation, thus permitting derepression of normal genes, include 5-azacytidine, decitabine, phenylbutyrate, and depsipeptide. Arsenic trioxide has demonstrated impressive activity in acute promyelocytic leukemia and preclinical data suggest the potential for activity in MDS. UCN-01 is a novel agent that inhibits protein kinase C and other protein kinases important for progression through the G1 and G2 phases of the cell cycle. Dolastatin-10 has extremely potent in vitro activity against a variety of tumor cell lines. Since its dose-limiting toxicities include myelosuppression, it is being studied in acute myelogenous leukemia (AML) and MDS. Ras may play a role in MDS, and activation of this gene and its signaling pathways may require farnesylation. Several farnesyl transferase inhibitors are now available for study in patients with MDS. An increasing body of data suggests a possible role for angiogenesis in MDS, and several antiangiogenesis agents are in clinical trials, including thalidomide, SU5416, and anti-vascular endothelial growth factor (VEGF) antibodies. Development of new drugs and regimens will be facilitated by recently developed standardized response criteria. Future clinical trials should focus on rational combinations of these agents and others with the goal of curing patients with MDS.