RESUMO
The purpose of this study was to quantitate motor performance in 196 genetically confirmed steroid-naïve boys with Duchenne muscular dystrophy (DMD), to evaluate the test-retest reliability of measures of motor performance in young DMD boys, and to assess correlations among the different functional outcomes including timed tests. Boys aged 4-7 years were recruited in the FOR-DMD study, a comparative effectiveness study of different steroid regimens in DMD. Eligible boys had to be able to rise from the floor independently and to perform pulmonary function testing consistently. The boys were evaluated with standardized assessments at the screening and baseline visits at 32 sites in 5 countries (US, UK, Canada, Italy, Germany). Assessments included timed rise from floor, timed 10â¯m walk/run, six-minute walk distance, North Star Ambulatory Assessment (NSAA) and forced vital capacity (FVC). Mean age at baseline was 5.9 years (range 4.1-8.1 years). Test-retest reliability was high for functional assessments, regardless of time lag between assessments (up to 90 days) and for the majority of age groups. Correlations were strong among the functional measures and timed tests, less so with FVC. Physiotherapy measures are reliable in a young, steroid-naïve population and rise from floor velocity appears to be a sensitive measure of strength in this population.
Assuntos
Distrofia Muscular de Duchenne , Criança , Pré-Escolar , Humanos , Masculino , Avaliação de Resultados em Cuidados de Saúde , Reprodutibilidade dos Testes , Esteroides , CaminhadaRESUMO
BACKGROUND: The NeuroNEXT SMA Infant Biomarker Study, a two year, longitudinal, multi-center study of infants with SMA type 1 and healthy infants, presented a unique opportunity to assess multi-site rater reliability on three infant motor function tests (MFTs) commonly used to assess infants with SMA type 1. OBJECTIVE: To determine the effect of prospective MFT rater training and the effect of rater experience on inter-rater and intra-rater reliability for the Test of Infant Motor Performance Screening Items (TIMPSI), the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) and the Alberta Infant Motor Scale (AIMS). METHODS: Training was conducted utilizing a novel set of motor function test (MFT) videos to optimize accurate MFT administration and reliability for the study duration. Inter- and intra-rater reliability of scoring for the TIMPSI and inter-rater reliability of scoring for the CHOP INTEND and the AIMS was assessed using intraclass correlation coefficients (ICC). Effect of rater experience on reliability was examined using ICC. Agreement with 'expert' consensus scores was examined using Pearson's correlation coefficients. RESULTS: Inter-rater reliability on all MFTs was good to excellent. Intra-rater reliability for the primary MFT, the TIMPSI, was excellent for the study duration. Agreement with 'expert' consensus was within predetermined limits (≥85%) after training. Evaluator experience with SMA and MFTs did not affect reliability. CONCLUSIONS: Reliability of scores across evaluators was demonstrated for all three study MFTs and scores were reproducible on repeated administration. Evaluator experience had no effect on reliability.
Assuntos
Competência Clínica , Atividade Motora/fisiologia , Fisioterapeutas , Atrofias Musculares Espinais da Infância/diagnóstico , Biomarcadores/análise , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Reprodutibilidade dos Testes , Atrofias Musculares Espinais da Infância/fisiopatologiaRESUMO
Purpose: In breast cancer models, combination epigenetic therapy with a DNA methyltransferase inhibitor and a histone deacetylase inhibitor led to reexpression of genes encoding important therapeutic targets, including the estrogen receptor (ER). We conducted a multicenter phase II study of 5-azacitidine and entinostat in women with advanced hormone-resistant or triple-negative breast cancer (TNBC).Experimental Design: Patients received 5-azacitidine 40 mg/m2 (days 1-5, 8-10) and entinostat 7 mg (days 3, 10) on a 28-day cycle. Continuation of epigenetic therapy was offered with the addition of endocrine therapy at the time of progression [optional continuation (OC) phase]. Primary endpoint was objective response rate (ORR) in each cohort. We hypothesized that ORR would be ≥20% against null of 5% using Simon two-stage design. At least one response was required in 1 of 13 patients per cohort to continue accrual to 27 per cohort (type I error, 4%; power, 90%).Results: There was one partial response among 27 women with hormone-resistant disease (ORR = 4%; 95% CI, 0-19), and none in 13 women with TNBC. One additional partial response was observed in the OC phase in the hormone-resistant cohort (n = 12). Mandatory tumor samples were obtained pre- and posttreatment (58% paired) with either up- or downregulation of ER observed in approximately 50% of posttreatment biopsies in the hormone-resistant, but not TNBC cohort.Conclusions: Combination epigenetic therapy was well tolerated, but our primary endpoint was not met. OC phase results suggest that some women benefit from epigenetic therapy and/or reintroduction of endocrine therapy beyond progression, but further study is needed. Clin Cancer Res; 23(11); 2691-701. ©2016 AACR.
Assuntos
Azacitidina/administração & dosagem , Benzamidas/administração & dosagem , Epigênese Genética/genética , Piridinas/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Idoso , Azacitidina/efeitos adversos , Benzamidas/efeitos adversos , Biomarcadores Tumorais/sangue , Terapia Combinada , Intervalo Livre de Doença , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Pessoa de Meia-Idade , National Cancer Institute (U.S.) , Estadiamento de Neoplasias , Piridinas/efeitos adversos , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Estados UnidosRESUMO
UNLABELLED: Epigenetic modifiers, including the histone deacetylase inhibitor vorinostat, may sensitize tumors to chemotherapy and enhance outcomes. We conducted a multicenter randomized phase II neoadjuvant trial of carboplatin and nanoparticle albumin-bound paclitaxel (CP) with vorinostat or placebo in women with stage II/III, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, in which we also examined whether change in maximum standardized uptake values corrected for lean body mass (SUL(max)) on (18)F-FDG PET predicted pathologic complete response (pCR) in breast and axillary lymph nodes. METHODS: Participants were randomly assigned to 12 wk of preoperative carboplatin (area under the curve of 2, weekly) and nab-paclitaxel (100 mg/m(2) weekly) with vorinostat (400 mg orally daily, days 1-3 of every 7-d period) or placebo. All patients underwent (18)F-FDG PET and research biopsy at baseline and on cycle 1 day 15. The primary endpoint was the pCR rate. Secondary objectives included correlation of change in tumor SUL(max) on (18)F-FDG PET by cycle 1 day 15 with pCR and correlation of baseline and change in Ki-67 with pCR. RESULTS: In an intent-to-treat analysis (n = 62), overall pCR was 27.4% (vorinostat, 25.8%; placebo, 29.0%). In a pooled analysis (n = 59), we observed a significant difference in median change in SUL(max) 15 d after initiating preoperative therapy between those achieving pCR versus not (percentage reduction, 63.0% vs. 32.9%; P = 0.003). Patients with 50% or greater reduction in SUL(max) were more likely to achieve pCR, which remained statistically significant in multivariable analysis including estrogen receptor status (odds ratio, 5.1; 95% confidence interval, 1.3-22.7; P = 0.023). Differences in baseline and change in Ki-67 were not significantly different between those achieving pCR versus not. CONCLUSION: Preoperative CP with vorinostat or placebo is associated with similar pCR rates. Early change in SUL(max) on (18)F-FDG PET 15 d after the initiation of preoperative therapy has potential in predicting pCR in patients with HER2-negative breast cancer. Future studies will further test (18)F-FDG PET as a potential treatment-selection biomarker.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Fluordesoxiglucose F18/metabolismo , Tomografia por Emissão de Pósitrons , Receptor ErbB-2/metabolismo , Adulto , Idoso , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Transporte Biológico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/cirurgia , Carboplatina/efeitos adversos , Carboplatina/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Paclitaxel/efeitos adversos , Paclitaxel/uso terapêutico , Período Pré-Operatório , Segurança , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: Agents that target the epigenome show activity in breast cancer models. In preclinical studies, the histone deacetylase inhibitor vorinostat induces cell-cycle arrest, apoptosis, and differentiation. We evaluated biomarker modulation in breast cancer tissues obtained from women with newly diagnosed invasive disease who received vorinostat and those who did not. EXPERIMENTAL DESIGN: Tumor specimens were collected from 25 women who received up to 6 doses of oral vorinostat 300 mg twice daily and from 25 untreated controls in a nonrandomized study. Candidate gene expression was analyzed by reverse transcription PCR (RT-PCR) using the Oncotype DX 21-gene assay, and by immunohistochemistry for Ki-67 and cleaved caspase-3. Matched samples from treated women were analyzed for gene methylation by quantitative multiplex methylation-specific PCR (QM-MSP). Wilcoxon nonparametric tests were used to compare changes in quantitative gene expression levels pre- and post-vorinostat with changes in expression in untreated controls, and changes in gene methylation between pre- and post-vorinostat samples. RESULTS: Vorinostat was well tolerated and there were no study-related delays in treatment. Compared with untreated controls, there were statistically significant decreases in the expression of proliferation-associated genes Ki-67 (P = 0.003), STK15 (P = 0.005), and Cyclin B1 (P = 0.03) following vorinostat, but not in other genes by the Oncotype DX assay, or in expression of Ki-67 or cleaved caspase-3 by immunohistochemistry. Changes in methylation were not observed. CONCLUSIONS: Short-term vorinostat administration is associated with a significant decrease in expression of proliferation-associated genes in untreated breast cancers. This demonstration of biologic activity supports investigation of vorinostat in combination with other agents for the management of breast cancer.
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Antineoplásicos/uso terapêutico , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Ácidos Hidroxâmicos/uso terapêutico , Antígeno Ki-67/metabolismo , Adulto , Idoso , Antineoplásicos/farmacocinética , Aurora Quinase A/genética , Aurora Quinase A/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/cirurgia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Terapia Combinada , Ciclina B1/genética , Ciclina B1/metabolismo , Feminino , Humanos , Ácidos Hidroxâmicos/farmacocinética , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Antígeno Ki-67/genética , Pessoa de Meia-Idade , Estudos Prospectivos , Survivina , Transativadores/genética , Transativadores/metabolismo , Transcriptoma , VorinostatRESUMO
PURPOSE: We sought to evaluate the feasibility of detecting PIK3CA mutations in circulating tumor DNA (ctDNA) from plasma of patients with metastatic breast cancer using a novel technique called BEAMing. EXPERIMENTAL DESIGN: In a retrospective analysis, 49 tumor and temporally matched plasma samples from patients with breast cancer were screened for PIK3CA mutations by BEAMing. We then prospectively screened the ctDNA of 60 patients with metastatic breast cancer for PIK3CA mutations by BEAMing and compared the findings with results obtained by screening corresponding archival tumor tissue DNA using both sequencing and BEAMing. RESULTS: The overall frequency of PIK3CA mutations by BEAMing was similar in both patient cohorts (29% and 28.3%, respectively). In the retrospective cohort, the concordance of PIK3CA mutation status by BEAMing between formalin-fixed, paraffin-embedded (FFPE) samples and ctDNA from temporally matched plasma was 100% (34 of 34). In the prospective cohort, the concordance rate among 51 evaluable cases was 72.5% between BEAMing of ctDNA and sequencing of archival tumor tissue DNA. When the same archival tissue DNA was screened by both sequencing and BEAMing for PIK3CA mutations (n = 41 tissue samples), there was 100% concordance in the obtained results. CONCLUSIONS: Analysis of plasma-derived ctDNA for the detection of PIK3CA mutations in patients with metastatic breast cancer is feasible. Our results suggest that PIK3CA mutational status can change upon disease recurrence, emphasizing the importance of reassessing PIK3CA status on contemporary (not archival) biospecimens. These results have implications for the development of predictive biomarkers of response to targeted therapies.
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Neoplasias da Mama/genética , DNA de Neoplasias/sangue , Fosfatidilinositol 3-Quinases/sangue , Fosfatidilinositol 3-Quinases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Classe I de Fosfatidilinositol 3-Quinases , Estudos de Coortes , Feminino , Marcadores Genéticos , Humanos , Pessoa de Meia-Idade , Mutação , Metástase Neoplásica , Estudos RetrospectivosRESUMO
Most breast cancers originate in the epithelial cells lining the breast ducts. Intraductal administration of cancer therapeutics would lead to high drug exposure to ductal cells and eliminate preinvasive neoplasms while limiting systemic exposure. We performed preclinical studies in N-methyl-N'-nitrosourea-treated rats to compare the effects of 5-fluorouracil, carboplatin, nanoparticle albumin-bound paclitaxel, and methotrexate to the previously reported efficacy of pegylated liposomal doxorubicin (PLD) on treatment of early and established mammary tumors. Protection from tumor growth was observed with all five agents, with extensive epithelial destruction present only in PLD-treated rats. Concurrently, we initiated a clinical trial to establish the feasibility, safety, and maximum tolerated dose of intraductal PLD. In each eligible woman awaiting mastectomy, we visualized one ductal system and administered dextrose or PLD using a dose-escalation schema (2 to 10 mg). Intraductal administration was successful in 15 of 17 women with no serious adverse events. Our preclinical studies suggest that several agents are candidates for intraductal therapy. Our clinical trial supports the feasibility of intraductal administration of agents in the outpatient setting. If successful, administration of agents directly into the ductal system may allow for "breast-sparing mastectomy" in select women.
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Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Animais , Carboplatina/administração & dosagem , Carboplatina/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Doxorrubicina/uso terapêutico , Vias de Administração de Medicamentos , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Humanos , Glândulas Mamárias Animais , Neoplasias Mamárias Animais/tratamento farmacológico , Metilnitrosoureia/uso terapêutico , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêutico , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/uso terapêutico , Ratos , Ratos Sprague-Dawley , Adulto JovemRESUMO
PURPOSE: Promoter methylation of tumor suppressor genes in histologically negative sentinel lymph nodes (HNSN) of early stage breast cancer patients has not been extensively studied. This study evaluates the methylation frequency and pattern in HNSN to determine if detection of hypermethylation of one or more genes is associated with an increased recurrence risk in node negative breast cancer. EXPERIMENTAL DESIGN: In 1998, a prospective study of patients with early stage breast cancer and HNSN was initiated in order to correlate sentinel node analysis with clinical outcome. Nodal tissue was selected from 120 HNSN patients for methylation analysis in at least one and up to six sentinel nodes using a panel of nine genes. Corresponding primary breast tumors from 79 patients were also evaluated for hypermethylation. Methylation analysis was performed using nested Methylation Sensitive PCR (n-MSP). Logistical regression was used to evaluate the relationship between clinical recurrence and methylation status. RESULTS: Over a median follow-up of 79 months, 13 of the 120 patients had clinical recurrence. Hypermethylation of genes was frequently observed in HNSN, but there was no correlation of methylation pattern and clinical recurrence. However, increased frequency of gene methylation of the primary tumor correlated with clinical recurrence. CONCLUSIONS: Although hypermethylation of multiple genes occurs frequently in HNSN of breast cancer patients, it is not associated with breast cancer recurrence in the first 7 years of clinical follow-up.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Metilação de DNA , Recidiva Local de Neoplasia/genética , Regiões Promotoras Genéticas/genética , Biópsia de Linfonodo Sentinela , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/secundário , Carcinoma Ductal de Mama/terapia , Carcinoma Lobular/genética , Carcinoma Lobular/secundário , Carcinoma Lobular/terapia , Feminino , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Reação em Cadeia da Polimerase , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Proteínas Supressoras de Tumor/genéticaRESUMO
PURPOSE: Aromatase inhibitors (AIs) are increasingly used as adjuvant treatment of postmenopausal women with hormone receptor-positive breast cancer. AIs are commonly associated with musculoskeletal symptoms. The primary objective of this study was to describe the musculoskeletal symptoms that developed in the first 100 subjects enrolled who had at least 6 months follow-up. METHODS: Women with early stage hormone receptor-positive breast cancer were recruited into a multicenter randomized clinical trial to study the pharmacogenomics of two AIs, exemestane, and letrozole. Patients completed the Health Assessment Questionnaire (HAQ) and Visual Analog Scale (VAS) at baseline, 1, 3, 6, and 12 months to assess changes in function and pain, respectively. Patients were referred for evaluation by a rheumatologist if their HAQ and/or VAS scores exceeded a predefined threshold. RESULTS: Forty-four of 97 eligible patients (45.4%) met criteria for rheumatologic referral. Three patients were ineligible because of elevated baseline HAQ (2) and failure to initiate AI therapy (1). No baseline characteristics were significantly associated with referral. Median time to onset of symptoms was 1.6 months (range 0.4-10 months). Clinical and laboratory evaluation of patients evaluated by rheumatology suggested that the majority developed either non-inflammatory musculoskeletal symptoms or inflammation localized to tenosynovial structures. Thirteen patients discontinued AI therapy because of musculoskeletal toxicity after a median 6.1 months (range 2.2-13 months). CONCLUSIONS: Musculoskeletal side effects were common in AI-treated patients, resulting in therapy discontinuation in more than 10% of patients. There are no identifiable pre-therapy indicators of risk, and the etiology remains elusive.
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Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Artropatias/induzido quimicamente , Doenças Musculares/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoimunidade , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos ProspectivosAssuntos
Coerção , Pesquisa Empírica , Comunicação Persuasiva , Ciências Sociais , Humanos , Estados UnidosRESUMO
This article argues that the concept of empowerment has been co-opted by health professionals and redefined as an intervention to produce compliance. Patients are considered empowered by health professionals only if they make the correct choices as defined by the health care provider. Patients are not informed about all possible choices and are not free to make their own choices for their own reasons. Empowerment is a coercive strategy that is justified by its outcomes and creates dependent populations.
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Cooperação do Paciente , Poder Psicológico , Relações Profissional-Paciente , Autoeficácia , Coerção , Diversidade Cultural , Tomada de Decisões , Humanos , Cuidados de Enfermagem , Papel Profissional , Estados UnidosRESUMO
The author presents a discourse analysis in three sections: a genealogy, a structural discourse analysis, and a power analytic. She concludes that the discourse of nursing diagnosis sustains conditions of social domination, limits autonomy and responsibility, and oppresses individuals and groups. The discourse of nursing diagnosis restricts what counts as evidence and limits acceptable input of voices, thus excluding, for example, the voices of the patient and his or herfamily. The discourse of nursing diagnosis appeals to the dominance of empirical analytic science and equates this dominance with professional social status. The author discusses potential discourses of resistance that provide speaking positions from which to articulate specific practices that resist oppressive effects of nursing diagnosis.
Assuntos
Relações Enfermeiro-Paciente , Diagnóstico de Enfermagem , Pesquisa Metodológica em Enfermagem , Poder Psicológico , Autonomia Profissional , Medicina Baseada em Evidências , Humanos , Cuidados de Enfermagem/psicologia , Defesa do Paciente , Autonomia Pessoal , Prática Profissional , Análise de Sistemas , Terminologia como AssuntoRESUMO
A survey of RNs in South Dakota was performed to determine their perceived level of competence, the extent to which their continuing nursing education (CNE) needs are being met, and their use of computers for CNE. Nationally certified nurses rated themselves significantly more competent than nurses who are not nationally certified. Fewer than half of the RNs reported their CNE needs were being met despite geographic access to CNE and programs available in their specialty. Three-fourths of nurses had computers at home while 76% had computers at work, yet fewer than 20% of nurses used these computers for CNE.