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1.
Neurology ; 77(10): 973-9, 2011 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-21813790

RESUMO

OBJECTIVE: To use a historical placebo control design to determine whether lithium carbonate slows progression of amyotrophic lateral sclerosis (ALS). METHODS: A phase II trial was conducted at 10 sites in the Western ALS Study Group using similar dosages (300-450 mg/day), target blood levels (0.3-0.8 mEq/L), outcome measures, and trial duration (13 months) as the positive trial. However, taking riluzole was not a requirement for study entry. Placebo outcomes in patients matched for baseline features from a large database of recent clinical trials, showing stable rates of decline over the past 9 years, were used as historical controls. RESULTS: The mean rate of decline of the ALS Functional Rating Scale-Revised was greater in 107 patients taking lithium carbonate (-1.20/month, 95% confidence interval [CI] -1.41 to -0.98) than that in 249 control patients (-1.01/month, 95% CI -1.11 to -0.92, p = 0.04). There were no differences in secondary outcome measures (forced vital capacity, time to failure, and quality of life), but there were more adverse events in the treated group. CONCLUSIONS: The lack of therapeutic benefit and safety concerns, taken together with similar results from 2 other recent trials, weighs against the use of lithium carbonate in patients with ALS. The absence of drift over time and the availability of a large database of patients for selecting a matched historical control group suggest that use of historical controls may result in more efficient phase II trials for screening putative ALS therapeutic agents. CLASSIFICATION OF EVIDENCE: This study provided Class IV evidence that lithium carbonate does not slow the rate of decline of function in patients with ALS over 13 months.


Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/patologia , Progressão da Doença , Carbonato de Lítio/uso terapêutico , Programas de Rastreamento , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Programas de Rastreamento/tendências , Pessoa de Meia-Idade , Projetos de Pesquisa/tendências , Adulto Jovem
2.
Oncogene ; 26(43): 6269-79, 2007 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-17471242

RESUMO

An improved understanding of cell immortalization and its manifestation in clinical tumors could facilitate novel therapeutic approaches. However, only rare tumor cells, which maintain telomerase expression in vitro, immortalize spontaneously. By expression-profiling analyses of limited-life primary breast tumor cultures pre- and post-hTERT transduction, and spontaneously immortalized breast cancer cell lines, we identified a common signature characteristic of tumor cell immortalization. A predominant feature of this immortalization signature (ImmSig) was the significant overexpression of oxidoreductase genes. In contrast to epithelial cells derived from low histologic grade primary tumors, which required hTERT transduction for the acquisition of ImmSig, spontaneously immortalizing high-grade tumor cultures displayed similar molecular changes independent of exogenous hTERT. Silencing the hTERT gene reversed ImmSig expression, increased cellular reactive oxygen species levels, altered mitochondrial membrane potential and induced apoptotic and proliferation changes in immortalized cells. In clinical breast cancer samples, cell-proliferation-pathway genes were significantly associated with ImmSig. In these cases, ImmSig expression itself was inversely correlated with patient survival (P=0), and was particularly relevant to the outcome of estrogen receptor-positive tumors. Our data support the notion that ImmSig assists in surmounting normal barriers related to oxidative and replicative stress response. Targeting a subset of aggressive breast cancers by reversing ImmSig components could be a practical therapeutic strategy.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Estresse Oxidativo , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Sobrevivência Celular , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Interferência de RNA , Transdução de Sinais , Taxa de Sobrevida , Telomerase/genética , Telomerase/metabolismo , Resultado do Tratamento , Células Tumorais Cultivadas
3.
Cochrane Database Syst Rev ; (1): CD001447, 2007 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-17253460

RESUMO

BACKGROUND: Riluzole has been approved for treatment of patients with amyotrophic lateral sclerosis in most countries. Questions persist about its clinical utility because of high cost and modest efficacy. OBJECTIVES: To examine the efficacy of riluzole in prolonging survival, and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Register for randomized trials in December 2004 and made enquiries of authors of trials, Aventis (manufacturer of riluzole) and other experts in the field. We searched MEDLINE (January 1966 to August 25 2006) and EMBASE (January 1980 to September 30th 2006). SELECTION CRITERIA: Types of studies: randomized trials. TYPES OF PARTICIPANTS: adults with a diagnosis of amyotrophic lateral sclerosis. Types of interventions: treatment with riluzole or placebo. Types of outcome measures: Primary: pooled hazard ratio of tracheostomy-free survival over all time points with riluzole 100 mg. Secondary: per cent mortality with riluzole 50, 100 and 200 mg; neurologic function, muscle strength and adverse events. DATA COLLECTION AND ANALYSIS: We identified four eligible randomized trials. MAIN RESULTS: The four trials examining tracheostomy-free survival included a total of 974 riluzole treated patients and 503 placebo treated patients. The methodological quality was acceptable and three trials were easily comparable, although one trial included older patients in more advanced stages of amyotrophic lateral sclerosis and one had multiple primary endpoints. Riluzole 100 mg per day provided a benefit for the homogeneous group of patients in the first two trials (P value = 0.042, hazard ratio 0.80, 95% confidence interval 0.64 to 0.99) and there was no evidence of heterogeneity (P value = 0.33). When the third trial (which included older and more seriously affected patients) was added, there was evidence of heterogeneity (P value < 0.0001) and the random effects model, which takes this into account, resulted in the overall treatment effect estimate falling just short of significance (P value = 0.056, hazard ratio 0.84, 95% confidence interval 0.70 to 1.01). This represented a 9% gain in the probability of surviving one year (57% in the placebo and 66% in the riluzole group). There was a small beneficial effect on both bulbar and limb function, but not on muscle strength. A threefold increase in serum alanine transferase was more frequent in riluzole treated patients than controls (weighted mean difference 2.62, 95% confidence interval 1.59 to 4.31). AUTHORS' CONCLUSIONS: Riluzole 100 mg daily is reasonably safe and probably prolongs median survival by about two to three months in patients with amyotrophic lateral sclerosis.


Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Riluzol/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Humanos , Expectativa de Vida , Fármacos Neuroprotetores/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Riluzol/efeitos adversos
4.
J Perinatol ; 27(3): 141-6, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17036031

RESUMO

OBJECTIVE: To determine whether vaginal breech delivery is associated with increased morbidity in term breech singletons using strict selection criteria. This study encompasses our previous studies (in 1987 and 1995) and extends our experience to 21 years. STUDY DESIGN: Retrospective cohort study from 1980 to 2001 including term, non-anomalous singleton breech deliveries selected by strict criteria. Univariable and multivariable analyses were performed for neonatal and maternal outcomes. RESULTS: Five hundred and eleven women underwent cesarean section and 214 a trial of labor. We found greater overall maternal morbidity in the cesarean section group (odds ratio (OR) 1.89, 95% confidence interval (CI)=1.34-2.65). In the vaginal delivery group, neonates were more likely to have had >1 day of mechanical ventilation (OR 10.0, 95% CI=1.56-63.9). No maternal deaths occurred and no neonatal deaths or seizures occurred. CONCLUSION: Given our findings, offering a trial of vaginal breech delivery to well-counseled strictly selected patients remains an appropriate option.


Assuntos
Apresentação Pélvica , Cesárea , Parto Obstétrico , Resultado da Gravidez , Aconselhamento , Feminino , Hospitais Universitários , Humanos , Morbidade , Gravidez , Respiração Artificial/estatística & dados numéricos , Medição de Risco , São Francisco , Prova de Trabalho de Parto
5.
Cochrane Database Syst Rev ; (3): CD003218, 2006 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-16855999

RESUMO

BACKGROUND: Excessive daytime sleepiness is a common symptom of myotonic dystrophy. Psychostimulants are drugs increasingly used to treat hypersomnia in myotonic dystrophy. OBJECTIVES: To search systematically for, and combine all evidence from, randomised trials relating to the effects of psychostimulants in myotonic dystrophy patients with hypersomnia. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Trials Register (January 2006), MEDLINE (from January 1966 to January 2006) and EMBASE (from January 1980 to January 2006) for randomised trials concerning psychostimulants in myotonic dystrophy, checked the bibliographies of identified papers and made enquiries of the authors of the papers. The search for relevant studies was updated in January 2006. SELECTION CRITERIA: We considered all randomised or quasi randomised trials that have evaluated any type of psychostimulants (versus a placebo or no treatment) in children or adults with proven myotonic dystrophy and hypersomnia. DATA COLLECTION AND ANALYSIS: Potentially relevant papers were scrutinised by two authors and the selection of eligible studies was agreed by them and a third author. Data were extracted by one author and checked by a second author. MAIN RESULTS: Primary outcome. One trial using a modified maintenance of wakefulness test showed an improvement by 5.70 (95% confidence intervals 0.1 to 11.3) minutes more in the modafinil than the control group. Secondary outcomes. In a double-blind crossover study of 10 participants with myotonic dystrophy, there was no difference between the selegiline and placebo periods in mean improvement in the multiple sleep latency test. Two trials, involving 60 participants in total, evaluated the efficacy and safety of modafinil in adults with myotonic dystrophy-related daytime sleepiness. The weighted mean difference on the Epworth Sleepiness Scale was -1.59 (95% confidence intervals, -2.77 to -0.42) in favour of modafinil. AUTHORS' CONCLUSIONS: There is no evidence to support the routine use of psychostimulants to treat hypersomnia in myotonic dystrophy. There is some evidence from two studies that modafinil may improve daytime sleepiness. More randomised trials are needed to evaluate the efficacy and safety of psychostimulants.


Assuntos
Distúrbios do Sono por Sonolência Excessiva/tratamento farmacológico , Distrofia Miotônica/complicações , Psicotrópicos/uso terapêutico , Compostos Benzidrílicos/efeitos adversos , Compostos Benzidrílicos/uso terapêutico , Distúrbios do Sono por Sonolência Excessiva/etiologia , Humanos , Modafinila , Inibidores da Monoaminoxidase/efeitos adversos , Inibidores da Monoaminoxidase/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Selegilina/efeitos adversos , Selegilina/uso terapêutico
6.
Int J Gynecol Cancer ; 16(2): 496-500, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16681717

RESUMO

The objective of this study was to evaluate the ability of a preoperative serum CA125 to predict whether optimal debulking (OD) could be achieved for patients with stage III and IV epithelial ovarian cancer (EOC). The records of consecutive patients who underwent primary surgery for EOC at Indiana University Hospital between January 1997 and January 2003 were reviewed. Eligibility criteria included FIGO stage III/IV disease, surgery by gynecologic oncology faculty, preoperative CA125, and an operative note clearly defining volume of residual disease. The Medcalc software statistical package was used to generate a receiver-operating characteristic (ROC) curve. Two hundred and eighty-nine cases of stage III/IV EOC were identified, of which 164 met the eligibility criteria. Serum CA125 /=75% of the time. Conversely, OD was achieved in /=4500. The area under the ROC curve for CA125 was .670. The OD rate for those with and without ascites was 49% and 79%, respectively (P < 0.001). In a multivariate analysis using CA125, age, and ascites, the area under the curve was 0.686. We conclude that preoperative serum CA125 did not reliably predict OD in patients with stage III-IV EOC.


Assuntos
Antígeno Ca-125/sangue , Neoplasias Epiteliais e Glandulares/sangue , Neoplasias Ovarianas/sangue , Adenocarcinoma/sangue , Adenocarcinoma/cirurgia , Adenocarcinoma de Células Claras/sangue , Adenocarcinoma de Células Claras/cirurgia , Adenocarcinoma Mucinoso/sangue , Adenocarcinoma Mucinoso/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Quimioterapia Adjuvante , Cistadenocarcinoma Papilar/sangue , Cistadenocarcinoma Papilar/cirurgia , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Epiteliais e Glandulares/cirurgia , Neoplasias Ovarianas/cirurgia , Neoplasias Peritoneais/sangue , Neoplasias Peritoneais/cirurgia , Curva ROC , Sistema de Registros , Sensibilidade e Especificidade
7.
Mol Hum Reprod ; 11(4): 253-60, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15734895

RESUMO

Angiopoietin (Ang)-2, the natural antagonist of the Ang1/Tie2 receptor is a complex regulator of blood vessel plasticity that plays a pivotal role in both vessel sprouting [in the presence of vascular endothelial growth factor (VEGF)-A] and vessel regression (in the absence of VEGF-A). Based on the spatial and temporal expression of Ang2 throughout human gestation, we recently suggested that the Ang2 may play a pivotal role in placental angiogenesis. Further, to examine this tenet we have developed a novel murine model system in which in utero Ang2 gene delivery via a non-replicating adenoviral expression vector has the potential to manipulate the blood vessel phenotype in vivo during pregnancy. Ang2 overexpression selectively and rapidly remodels the labyrinth perivascular extracellular matrix, subsequently promoting plasticity of the maternal and fetal vessels, which appear honeycombed due to a 2-fold increase in blood vessel luminal area. High levels of Ang2 impair endothelial cell adhesiveness, leading to vascular leakiness with perivascular oedema, which increases placental weight. These observations suggest that the Ang2 overexpression may play a key role in placental vascular remodelling. Furthermore, we suggest a novel new model to study the pathobiology of placental vascularization and the effect of placental blood vessels on fetal phenotype.


Assuntos
Angiopoietina-2/fisiologia , Neovascularização Fisiológica , Placenta/irrigação sanguínea , Angiopoietina-2/análise , Angiopoietina-2/genética , Animais , Vasos Sanguíneos/citologia , Vasos Sanguíneos/crescimento & desenvolvimento , Endotélio Vascular/química , Matriz Extracelular/química , Feminino , Vetores Genéticos , Humanos , Camundongos , Modelos Animais , Neovascularização Fisiológica/fisiologia , Fenótipo , Placenta/química , Placentação , Gravidez , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Transcrição Gênica , Ativação Transcricional , Transfecção
9.
Neurology ; 62(10): 1845-7, 2004 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-15159491

RESUMO

Two double-blind, randomized, placebo-controlled feasibility trials of minocycline in ALS were conducted. In Trial 1, 19 subjects received 200 mg/day or placebo for 6 months; there were no significant differences in adverse events (AE). In Trial 2, 23 subjects received up to 400 mg/day in an 8-month crossover trial. The mean tolerated dose was 387 mg/day, there was a trend toward more gastrointestinal AE (p = 0.057), and blood urea nitrogen and liver enzymes became elevated (p < 0.05). Using these data, the authors have designed and launched a phase III trial.


Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Minociclina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Adulto , Idoso , Doença Hepática Induzida por Substâncias e Drogas , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Gastroenteropatias/induzido quimicamente , Força da Mão , Humanos , Nefropatias/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Minociclina/administração & dosagem , Minociclina/efeitos adversos , Minociclina/farmacologia , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/farmacologia , Músculos Respiratórios/efeitos dos fármacos , Riluzol/administração & dosagem , Riluzol/uso terapêutico , Resultado do Tratamento
10.
Int J Gynecol Cancer ; 14(1): 104-9, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-14764037

RESUMO

A functional and widely accepted definition of microinvasive cervical adenocarcinoma remains elusive. The purpose of this study was to determine at which depth of invasion the likelihood of lymph node metastasis or disease recurrence was so small that conservative surgery could be considered appropriate. Charts of patients with adenocarcinoma of the cervix (ACC) who underwent radical hysterectomy and pelvic lymphadenectomy (n = 98) at Indiana University Medical Center from 1987 to 1998 were retrospectively reviewed. Patients with stage IA1-IB1 lesions were included in the study. Patients treated with preoperative radiotherapy were excluded. Pathologic parameters evaluated included histologic type, depth of stromal invasion (DOI), and the presence of lymphatic vascular space invasion, or lymph node metastases. The patient median age was 39 years (20-65). The median time of follow-up was 30 months (4-124). Lymph node metastases were found in ten patients and 11 developed recurrences. The precise DOI could be measured in 84 patients. Of the 48 patients with cancers with a DOI 5 mm had nodal metastases (P = 0.00069). None of these 48 patients with a tumor DOI 5 mm developed recurrent disease (P = 0.0048). The risk of nodal metastases and recurrence is so low in patients with ACC and DOI

Assuntos
Adenocarcinoma/secundário , Recidiva Local de Neoplasia/epidemiologia , Neoplasias do Colo do Útero/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Feminino , Humanos , Indiana/epidemiologia , Excisão de Linfonodo , Linfonodos/cirurgia , Metástase Linfática , Prontuários Médicos , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Pelve , Estudos Retrospectivos , Fatores de Risco , Neoplasias do Colo do Útero/cirurgia
11.
Artigo em Inglês | MEDLINE | ID: mdl-13129806

RESUMO

BACKGROUND: Riluzole 100 mg probably prolongs survival in patients with amyotrophic lateral sclerosis by about two months and the safety of the drug is not a major concern. The evidence from randomized controlled trials indicates that patients taking riluzole probably survive longer than patients taking placebo. The beneficial effects are very modest and the drug is expensive. Adverse effects from riluzole are relatively minor and for the most part reversible after stopping the drug. Riluzole has been approved for treatment of patients with amyotrophic lateral sclerosis in many countries but not all. Questions persist about its clinical utility because of high cost, modest efficacy and concern over adverse effects. OBJECTIVES: To examine the efficacy of riluzole in prolonging survival, and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival. SEARCH STRATEGY: Search of the Cochrane Neuromuscular Disease Group Register for randomized trials and enquiry from authors of trials, Aventis (manufacturer of riluzole) and other experts in the field. The most recent search was November 2002. SELECTION CRITERIA: Randomized trials of adults with diagnosis of amyotrophic lateral sclerosis (ALS), treated with riluzole or placebo. Types of outcome measures: Primary: pooled hazard ratio of tracheostomy-free survival over all time points with riluzole 100 mg. Secondary: per cent mortality as a function of time with riluzole 100 mg and other doses of riluzole; neurologic function, quality of life, muscle strength and adverse events. DATA COLLECTION & ANALYSIS: We identified four eligible randomized trials. Each reviewer graded them for methodological quality. Data extraction was performed by a single reviewer and checked by two others. We obtained some missing data from investigators and regulatory agencies. We performed meta-analyses with Review Manager 4.1 software using a fixed effects model. A test of drug efficacy was based on the Parmar pooled hazard ratio. RESULTS: The three trials examining tracheostomy-free survival included a total of 876 riluzole treated patients and 406 placebo treated patients. The data for tracheostomy-free survival was not available from the fourth trial. The methodological quality was acceptable and the three trials were easily comparable, although one trial included older patients in more advanced stages of amyotrophic lateral sclerosis. Riluzole 100 mg per day provided a benefit for the homogeneous group of patients in the first two trials (p=0.039, hazard ratio 0.80, 95% confidence interval 0.64 to 0.99) and there was no evidence of heterogeneity (p=0.33). When the third trial (which included older and more seriously affected patients) is added, there is evidence of heterogeneity (p<0.0001) and the random effects model, which takes this into account results in the overall treatment effect estimate falling just short of significance (p=0.056, hazard ratio 0.84, 95% confidence interval 0.70 to 1.01). This represents a 9% gain in the probability of surviving one year (57% in the placebo and 66% in the riluzole group). In secondary analyses of survival at separate time points, there was a significant survival advantage with riluzole 100 mg at six, nine, 12 and 15 months, but not at three or 18 months. There was a small beneficial effect on both bulbar and limb function, but not on muscle strength. There were no data on quality of life, but patients treated with riluzole remained in a more moderately affected health state significantly longer than placebo-treated patients (weighted mean difference 35.5 days, 95% confidence interval 5.9 to 65.0). A threefold increase in serum alanine transferase was more frequent in riluzole treated patients than controls (weighted mean difference 2.69, 95% confidence interval 1.65 to 4.38). CONCLUSIONS: Riluzole 100 mg daily is reasonably safe and probably prolongs survival by about two months in patients with ALS. More studies are needed, especially to clarify its effect in older patients (over 75 years), and those with more advanced disease.


Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Riluzol/uso terapêutico , Adulto , Bases de Dados como Assunto , Método Duplo-Cego , Avaliação de Medicamentos , Humanos , Doença dos Neurônios Motores/classificação , Doença dos Neurônios Motores/tratamento farmacológico , Doença dos Neurônios Motores/epidemiologia , Doença dos Neurônios Motores/fisiopatologia , Estudos Multicêntricos como Assunto , Músculos/fisiopatologia , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Riluzol/efeitos adversos , Risco , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento
12.
Cochrane Database Syst Rev ; (2): CD001447, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12076411

RESUMO

BACKGROUND: Riluzole has been approved for treatment of patients with amyotrophic lateral sclerosis in many countries but not all. Questions persist about its clinical utility because of high cost, modest efficacy and concern over adverse effects. OBJECTIVES: To examine the efficacy of riluzole in prolonging survival, and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival. SEARCH STRATEGY: Search of the Cochrane Neuromuscular Disease Group Register for randomized trials and enquiry from authors of trials, Aventis (manufacturer of riluzole) and other experts in the field. The most recent search was May, 2001 SELECTION CRITERIA: Types of studies: randomized trials TYPES OF PARTICIPANTS: adults with a diagnosis of amyotrophic lateral sclerosis Types of interventions: treatment with riluzole or placebo Types of outcome measures: Primary: pooled hazard ratio of tracheostomy-free survival over all time points with riluzole 100 mg. Secondary: per cent mortality as a function of time with riluzole 100 mg and other doses of riluzole; neurologic function, quality of life, muscle strength and adverse events. DATA COLLECTION AND ANALYSIS: We identified four eligible randomized trials. Each reviewer graded them for methodological quality. Data extraction was performed by a single reviewer and checked by two others. We obtained some missing data from investigators and regulatory agencies. We performed meta-analyses with Review Manager 4.1 software using a fixed effects model. A test of drug efficacy was based on the Parmar pooled hazard ratio. MAIN RESULTS: The three trials examining tracheostomy-free survival included a total of 876 riluzole treated patients and 406 placebo treated patients. The data for tracheostomy-free survival was not available from the fourth trial. The methodological quality was acceptable and the three trials were easily comparable, although one trial included older patients in more advanced stages of amyotrophic lateral sclerosis. Riluzole 100 mg per day provided a benefit for the homogeneous group of patients in the first two trials (p=0.039, hazard ratio 0.80, 95% confidence interval 0.64 to 0.99) and there was no evidence of heterogeneity (p=0.33). When the third trial (which included older and more seriously affected patients) is added, there is evidence of heterogeneity (p<0.0001) and the random effects model, which takes this into account results in the overall treatment effect estimate falling just short of significance (p=0.056, hazard ratio 0.84, 95% confidence interval 0.70 to 1.01). This represents a 9% gain in the probability of surviving one year (57% in the placebo and 66% in the riluzole group). In secondary analyses of survival at separate time points, there was a significant survival advantage with riluzole 100 mg at six, nine, 12 and 15 months, but not at three or 18 months. There was a small beneficial effect on both bulbar and limb function, but not on muscle strength. There were no data on quality of life, but patients treated with riluzole remained in a more moderately affected health state significantly longer than placebo-treated patients (weighted mean difference 35.5 days, 95% confidence interval 5.9 to 65.0). A threefold increase in serum alanine transferase was more frequent in riluzole treated patients than controls (weighted mean difference 2.69, 95% confidence interval 1.65 to 4.38). REVIEWER'S CONCLUSIONS: Riluzole 100 mg daily is reasonably safe and probably prolongs survival by about two months in patients with amyotrophic lateral sclerosis. More studies are needed, especially to clarify its effect in older patients (over 75 years), and those with more advanced disease.


Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Riluzol/uso terapêutico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
13.
Cochrane Database Syst Rev ; (4): CD001447, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11687111

RESUMO

BACKGROUND: Riluzole has been approved for treatment of patients with amyotrophic lateral sclerosis (ALS) in some countries but not others. Questions persist about its clinical utility because of high cost, modest efficacy and concern over adverse effects. OBJECTIVES: To examine the efficacy of riluzole in prolonging survival, and in delaying the use of surrogates (tracheostomy and mechanical ventilation) to sustain survival. SEARCH STRATEGY: Search of the Cochrane Neuromuscular Disease Group Register for randomized trials and enquiry from authors of trials and other experts in the field. The most recent search was conducted in June 1999. SELECTION CRITERIA: Types of studies: randomized trials TYPES OF PARTICIPANTS: adults with a diagnosis of ALS Types of interventions: treatment with riluzole or placebo Types of outcome measures: Primary: per cent mortality at 12 months with riluzole 100 mg Secondary: per cent mortality as a function of time with 100 mg and with all doses of riluzole, scales of neurologic function, quality of life, muscle strength and adverse events. DATA COLLECTION AND ANALYSIS: We identified two randomized trials. Each reviewer graded them for methodological quality. Data extraction was performed by a single reviewer and checked by the other two. We obtained some missing data from investigators. We performed meta-analyses with RevMan software using a fixed effects model. MAIN RESULTS: The two eligible trials included a total of 794 riluzole treated patients and 320 placebo treated patients. The methodological quality was acceptable and the trials were easily comparable. There were significant differences between the riluzole and placebo groups of both trials, in terms of the primary outcome measure, which was per cent mortality at 12 months with the 100 mg dose of riluzole. The odds ratio for the combined studies was 0.57 (95%CI 0.41 to 0.80) at 12 months. In the secondary outcome measures, there was a survival advantage with riluzole 100 mg at six, nine, 12 and 15 months, but not at three or 18 months. Pooled data from the 50, 100 and 200mg dose groups in the larger trial showed a lower per cent mortality with riluzole compared to placebo only at 12 months (odds ratio (OR) 0.64, 95% CI 0.47 to 0.88). There was no beneficial effect on bulbar function, or muscle strength. There were scant data on quality of life, but patients treated with riluzole remained in a more moderately affected health state significantly longer than placebo-treated patients (weighted mean difference (WMD) 35.5 days, 95% CI 5.9 to 65.0). A threefold increase in serum alanine transferase was more frequent in riluzole treated patients than controls (WMD 2.65, 95% CI 1.51 to 4.65). REVIEWER'S CONCLUSIONS: Riluzole 100 mg per day appears to be modestly effective in prolonging survival for patients with ALS.


Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Riluzol/uso terapêutico , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto
14.
J Neurol Sci ; 191(1-2): 75-8, 2001 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-11676995

RESUMO

There is still no consensus as to which physiologic marker should be used as a trigger for the initiation of non-invasive positive pressure ventilation (NPPV) in patients with amyotrophic lateral sclerosis (ALS). Current practice parameters recommend that the decision to begin treatment be based upon forced vital capacity (FVC) measurements. A prospective, randomized study was performed in 20 ALS patients who had an FVC of 70-100%. Patients received baseline assessments including: ALS functional rating scale-respiratory version (ALSFRS-R), pulmonary symptom scale, Short form 36 (SF-36), FVC%, maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), and nocturnal oximetry. Patients were randomized to receive NPPV based upon nocturnal oximetry studies suggesting oxygen desaturation <90% for one cumulative minute ("early intervention") or a FVC <50% ("standard of care"). At enrollment, there was no significant correlation between FVC% and the ALSFRS-R, symptom score, MEP, MIP, or duration of nocturnal desaturation <90%. An increase in the vitality subscale of the SF-36 was demonstrated in 5/6 patients randomized to "early intervention" with NPPV. Our data indicate that FVC% correlates poorly with respiratory symptoms and suggests that MIP and nocturnal oximetry may be more sensitive measures of early respiratory insufficiency. In addition, intervention with NPPV earlier than our current standard of care may result in improved quality of life.


Assuntos
Hipoventilação/diagnóstico , Hipoventilação/fisiopatologia , Doença dos Neurônios Motores/fisiopatologia , Testes de Função Respiratória , Progressão da Doença , Humanos , Hipoventilação/etiologia , Doença dos Neurônios Motores/complicações , Doença dos Neurônios Motores/terapia , Oximetria , Respiração com Pressão Positiva , Valor Preditivo dos Testes , Estudos Prospectivos , Qualidade de Vida , Índice de Gravidade de Doença , Método Simples-Cego , Inquéritos e Questionários , Capacidade Vital
15.
J Neurol Sci ; 191(1-2): 127-31, 2001 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-11677003

RESUMO

OBJECTIVE: To evaluate the efficacy of gabapentin in increasing muscle strength of patients with spinal muscular atrophy (SMA). BACKGROUND: Preclinical data in experimental models of motor neuron disease suggest a neuroprotective effect of gabapentin. METHODS: Gabapentin (1200 mg), or placebo, was administered three times daily in a randomized, double-blind trial for 12 months. The primary outcome measure was the average percent change from baseline, based on the measurement of strength in four muscles (elbow flexion and hand grip bilaterally) for each patient. Drug efficacy was examined by comparing the percent change in strength for patients on drug vs. placebo. Secondary efficacy variables included: forced vital capacity (FVC), SMA functional rating scale (SMAFRS), and mini-Sickness Impact Profile (SIP). RESULTS: Eighty-four patients, with type II or III SMA, were enrolled at eight sites across the United States. There were no differences in baseline features. There was no difference between the placebo and drug groups in any outcome measure. CONCLUSIONS: This study demonstrates the feasibility of this trial design and provides data for the design of future clinical trials in SMA.


Assuntos
Acetatos/uso terapêutico , Aminas , Ácidos Cicloexanocarboxílicos , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Atrofias Musculares Espinais da Infância/tratamento farmacológico , Ácido gama-Aminobutírico , Adulto , Braço/fisiopatologia , Método Duplo-Cego , Estudos de Viabilidade , Feminino , Gabapentina , Força da Mão , Humanos , Masculino , Contração Muscular/efeitos dos fármacos , Índice de Gravidade de Doença , Perfil de Impacto da Doença , Atrofias Musculares Espinais da Infância/fisiopatologia , Resultado do Tratamento , Estados Unidos , Capacidade Vital/efeitos dos fármacos
16.
Cancer ; 93(4): 263-8, 2001 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-11507700

RESUMO

BACKGROUND: Fine-needle aspiration biopsy (FNAB) has been used with variable success as a diagnostic test for benign and malignant breast lesions. The goal of this study was to examine the effects of training physicians in the fine-needle aspiration sampling-technique on the diagnostic accuracy of FNAB of palpable breast masses. The settings for this study were private physicians' offices and university clinics of primary care physicians, surgeons, and cytopathologists. METHODS: We reviewed 1043 consecutive FNAB specimens of the breast obtained during 1 year (1992): 729 FNABs were performed by formally trained physicians (at least 150 FNABs performed previously under supervision during fellowship training or the equivalent) who had done at least 100 FNABs during the year; 314 FNABs were performed by physicians without formal training who had done a median of only 2 FNABs during the year (range, 1-43 FNABs). All FNAB specimens were reviewed microscopically and evaluated for cellularity and type of material present, for diagnostic accuracy, and for the rate of surgical intervention. A minimum of 2 years of follow-up was obtained by matching all cases to the population-based Northern California Cancer Registry. FNAB specimens were correlated with histologic specimens when they were available. RESULTS: Using FNAB, the formally trained physicians missed 2% of cancers, whereas the physicians without formal training missed 25%. Among the patients with benign lesions seen by the formally trained physicians, 8% went on to surgery, whereas 30% of those seen by physicians without formal training did so. Specimens obtained by the formally trained physicians were significantly more cellular and were significantly less likely to be nondiagnostic. CONCLUSIONS: FNAB, when performed by physicians who are well trained in the technique, is a highly accurate, cost-effective diagnostic method that carries minimal morbidity and could replace a large number of surgical biopsies. When performed by physicians without adequate training, FNAB is often misleading and potentially harmful.


Assuntos
Biópsia por Agulha/normas , Neoplasias da Mama/patologia , Competência Clínica/normas , Educação de Pós-Graduação em Medicina/normas , Patologia/educação , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha/métodos , Bolsas de Estudo , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Sensibilidade e Especificidade
17.
Clin Cancer Res ; 7(8): 2415-24, 2001 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-11489821

RESUMO

PURPOSE: erbB-2 and epidermal growth factor receptor (EGFR) may mediate motility via signaling that enables changes in the actin cytoskeleton. A physical basis for this motility may depend on the coexpression of gelsolin, a M(r) 80,000 actin-binding protein. EXPERIMENTAL DESIGN: The expression of erbB-2, EGFR, and gelsolin was analyzed in 790 archival invasive breast cancers. These data were compared with histological, clinical, and outcome data (median follow-up, 16.3 years). RESULTS: Protein overexpression was observed in overlapping subsets of breast cancers (38% of cases were erbB-2+; 15% of cases were EGFR+; and 56% of cases were gelsolin+). Tumor gelsolin was associated with overexpression of erbB-2 and EGFR, as well as with an aggressive tumor phenotype. By univariate and multivariate analyses, tumor gelsolin alone was not a prognostic factor. Overexpression of all three factors significantly predicted poor clinical outcome by univariate and multivariate analyses. For example, in node-positive patients, coexpression of all three markers was associated with a 3-year disease-specific survival (as compared with erbB-2+, EGFR+, gelsolin- patients, who had a median survival of 6 years). CONCLUSIONS: These data suggest that gelsolin coexpression may be an important additional prognostic factor in erbB-2+, EGFR+ breast cancer patients. We hypothesize that this is due to the role of gelsolin in mediating motility and invasion.


Assuntos
Neoplasias da Mama/patologia , Receptores ErbB/análise , Gelsolina/análise , Receptor ErbB-2/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Movimento Celular , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Análise de Sobrevida
18.
Liver Transpl ; 7(7): 581-7, 2001 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-11460224

RESUMO

The selection of patients with cirrhosis and the diagnosis of alcohol dependence or abuse who have a long-term high probability of abstinence after orthotopic liver transplantation (OLT) may enhance patient survival and outcomes. The aim of this study is to identify factors that would predict which patients would consume alcohol after OLT. Sixty-one patients with a history of alcohol dependence or abuse underwent OLT from June 1989 to June 1994 and were followed up monthly for a median of 6.9 years after OLT (range, 2.5 to 9.3 years). Survival analysis techniques (Cox proportional hazard model) were used to identify patients at high risk for recidivism. Recidivism occurred in 12 of 61 patients (20%) after OLT during follow-up. Noncompliance, with a relative hazard of 20.9 (95% confidence interval [CI], 5.6 to 78.3; P <.001), and personality disorder, with a relative hazard of 6.0 (95% CI, 1.9 to 18.7; P =.002), independently predicted recidivism among patients who underwent OLT. These data indicate that specific behaviors and psychiatric diagnoses can be used to select patients at high risk for drinking alcohol before and after OLT.


Assuntos
Alcoolismo/complicações , Hepatopatias Alcoólicas/cirurgia , Transplante de Fígado , Cooperação do Paciente , Adulto , Idoso , Feminino , Seguimentos , Humanos , Hepatopatias Alcoólicas/etiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Recidiva , Assunção de Riscos
19.
Clin Cancer Res ; 7(6): 1716-23, 2001 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11410511

RESUMO

Our objective was to investigate the prognostic significance of cell turnover (apoptosis and proliferation) in breast cancer patients. Apoptosis was microscopically quantitated on histological sections from 791 breast cancer patients with long-term follow-up (median, 16.3 years). Apoptotic counts were also compared with proliferation data (mitotic counts and MIB-1 labeling); apoptosis data derived from terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay; and pathobiological variables, including p53, erbB-2, and estrogen receptor (ER). High apoptotic counts were associated with increased cellular proliferation, ER negativity, immunopositivity of erbB-2 and p53 (P < 0.0001), and shortened disease-specific survival (DSS; P = 0.0009) and disease-free survival (DFS; P = 0.0006). Other factors associated with shortened DFS and DSS by univariate analysis were high tumor grade, nodal metastases, and large tumor size (P < 0.0001 for each). Multivariate analysis of data for all of the patients demonstrated that tumor size, nodal status, ER, histological grade, and erbB-2 showed independent prognostic value. In node-negative patients, tumor size and mitotic rate per 1000 cells independently predicted DFS (P = 0.0055). Tumor grade was the only independent predictor of DSS. For node-positive patients, tumor size, nodal status, ER, and erbB-2 were independent prognostic factors. The number of mitoses per 1000 was independently associated with DFS (P = 0.043) but not with DSS. Apoptosis data did not provide independent prognostic value in any, node-positive or node-negative, breast cancer patients.


Assuntos
Apoptose , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Prognóstico , Adulto , Idoso , Divisão Celular , Intervalo Livre de Doença , Feminino , Humanos , Marcação In Situ das Extremidades Cortadas , Pessoa de Meia-Idade , Mitose , Análise Multivariada , Receptor ErbB-2/biossíntese , Receptores de Estrogênio/biossíntese , Fatores de Tempo , Resultado do Tratamento , Proteína Supressora de Tumor p53/biossíntese
20.
J Clin Oncol ; 19(12): 2975-82, 2001 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-11408492

RESUMO

PURPOSE: A phase II study was conducted to determine the efficacy of paclitaxel and valspodar (PSC 833) in patients with advanced epithelial ovarian cancer. Valspodar, a nonimmunosuppressive cyclosporine D analogue that reverses P-glycoprotein-mediated multidrug resistance, in combination with paclitaxel might be active in paclitaxel-resistant and refractory ovarian cancer. PATIENTS AND METHODS: Patients received valspodar 5 mg/kg orally qid x 12 doses. Paclitaxel (70 mg/m(2) intravenously for 3 hours) was administered on day 2, 2 hours after the fifth or sixth dose of valspodar. This treatment was repeated every 21 days. One blood sample was collected before the sixth dose of valspodar for the first three cycles to evaluate valspodar trough concentration. Tumor tissue was obtained from patients for immunohistochemical staining of P-glycoprotein. RESULTS: Of 60 patients entered, 58 were assessable for response. There were five partial responses (8.6%; 90% confidence interval [CI], 3.8 to 20.0; median duration of response, 5.0 months [range, 1.9 to 10.5 months]). Median progression-free survival was 1.5 months (90% CI, 1.4 to 2.4). Grade 3 or 4 toxicities observed were neutropenia, anemia, nausea and vomiting, peripheral neuropathy, and cerebellar ataxia. The trough concentrations of valspodar were > or = 1,000 ng/mL in all but two of 40 patients in the first cycle. Immunohistochemical staining for P-glycoprotein was positive for one of two responding patients. CONCLUSION: Valspodar in combination with paclitaxel has limited activity in patients with paclitaxel-resistant ovarian carcinoma. An international randomized clinical trial of paclitaxel and carboplatin with or without valspodar as first-line therapy in advanced ovarian cancer is underway.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma/mortalidade , Carcinoma/patologia , Ciclosporinas/administração & dosagem , Intervalo Livre de Doença , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Taxa de Sobrevida
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