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1.
Health Res Policy Syst ; 19(1): 13, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33546707

RESUMO

BACKGROUND: Implementing evidence-informed population health interventions in new contexts often requires adaptations. While the need to adapt interventions to better fit new contexts is recognised, uncertainties remain regarding why and when to adapt (or not), and how to assess the benefits (or not) of adaptation. The ADAPT Study aims to develop comprehensive guidance on adaptation. This scoping review informs guidance development by mapping and exploring how adaptation has been undertaken in practice, in public health and health services research. METHODS: We searched seven databases from January 2000 and October 2018 to identify eligible studies for this scoping review and a related systematic review of adaptation guidance. We mapped the studies of adaptation by coding data from all eligible studies describing the methods, contexts, and interventions considered for adaptation. From this map, we selected a sample of studies for in-depth examination. Two reviewers extracted data independently into seven categories: description, key concepts, types, rationale, processes, evaluation methods, evaluation justification, and accounts of failures and successes. RESULTS: We retrieved 6694 unique records. From 429 records screened at full text, we identified 298 eligible studies for mapping and selected 28 studies for in-depth examination. The majority of studies in our map focused on micro- (i.e., individual-) level interventions (84%), related to transferring an intervention to a new population group within the same country (62%) and did not report using guidance (73%). Studies covered a range of topic areas, including health behaviour (24%), mental health (19%), sexual health (16%), and parenting and family-centred interventions (15%). Our in-depth analysis showed that adaptation is seen to save costs and time relative to developing a new intervention, and to enhance contextual relevance and cultural compatibility. It commonly follows a structured process and involves stakeholders to help with decisions on what to adapt, when, and how. CONCLUSIONS: Adaptation has been undertaken on a range of health topics and largely in line with existing guidance. Significant gaps relate to adaptation of macro- (e.g., national-) level interventions, consideration of programme theories, mechanisms and contexts (i.e., a functional view of interventions), nuances around stakeholder involvement, and evaluation of the adapted interventions. Registration Open Science Framework, 2019, osf.io/udzma.


Assuntos
Saúde da População , Atenção à Saúde , Pesquisa sobre Serviços de Saúde , Humanos
2.
Gynecol Oncol ; 156(3): 530-534, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31937450

RESUMO

OBJECTIVES: Intraperitoneal (IP) chemotherapy following neoadjuvant chemotherapy (NACT) and interval tumor reductive surgery (TRS) for advanced ovarian cancer is feasible, however, the impact on disease outcomes remains unclear. We compare outcomes of patients treated with IP chemotherapy versus intravenous (IV) chemotherapy following NACT and interval TRS. METHODS: In this retrospective review, patients with advanced ovarian cancer were included if they received NACT followed by optimal interval TRS between 1/2004 and 4/2017. Patients were excluded if they had an ECOG PS >1, received >6 cycles of NACT or postoperative chemotherapy, and/or received bevacizumab during primary therapy. Primary outcomes were progression free survival (PFS) and overall survival (OS). RESULTS: There were 134 patients included in this study, 37 (28%) received IP and 97 (72%) received IV chemotherapy postoperatively. Patients in the IV group were older (median 66.3 vs 59.7 years, p = 0.0039) though there were no differences in BMI, race, BRCA status, stage, or histology. Median PFS was 3 months longer in the IP group (14.5 versus 11.5 months, p = 0.028) however there was no significant difference in OS. On univariate analysis, increasing number of NACT cycles (HR 1.914, 95% CI 1.024-3.497) and residual disease at completion of TRS (HR 1.541, 95% CI 1.042-2.248) were associated with decreased PFS; IP chemotherapy was associated with increased PFS (HR 0.633, 95% CI 0.414-0.944). These associations remained on multivariate analysis. Toxicity was comparable between the groups. CONCLUSIONS: IP after NACT and optimal interval TRS was associated with in improved PFS compared to IV chemotherapy without significant differences in toxicity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/cirurgia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Epitelial do Ovário/patologia , Quimioterapia Adjuvante , Procedimentos Cirúrgicos de Citorredução , Feminino , Humanos , Infusões Intravenosas , Infusões Parenterais , Pessoa de Meia-Idade , Terapia Neoadjuvante , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Neoplasias Ovarianas/patologia , Intervalo Livre de Progressão , Estudos Retrospectivos , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Adulto Jovem
4.
Dis Esophagus ; 29(7): 747-751, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26455587

RESUMO

In the past 30 years, the incidence of esophageal adenocarcinoma (EAC) has increased more rapidly than any other cancer in the United States. The prevalence of obesity and diabetes mellitus has drastically increased as well. We explored the potential association between obesity, diabetes mellitus, and EAC. By means of retrospective interrogation of an administrative database from fiscal year 2005-2009, we identified two cohorts. The cancer cohort was defined as patients with adenocarcinoma of the distal esophagus or gastric cardia. The comparison cohort contained patients with gastroesophageal reflux disorder (GERD; diagnosis coupled with a procedure code for fundoplication). Patient data, including demographic measures, diagnoses of obesity, diabetes mellitus, dyslipidemia, alcohol abuse, and nicotine dependence were examined. A logistic regression model identified risk factors for development of EAC. The sample included 2,836 patients identified as having either EAC (1,704) or fundoplication with GERD (1,132). Although slightly higher percentages of the benign cohort were obese, the cancer cohort had more diabetics (30.8% vs. 14.8%; chi-square = 94.5; P < 0.0001). In a logistic regression analysis adjusting for comorbidity and lifestyle factors, diagnosis of diabetes mellitus was significantly associated with esophageal cancer as opposed to GERD without cancer (OR = 2.2; 95% confidence interval [CI] 1.7-2.8). Nicotine dependence was also identified as a risk factor (OR = 1.7; 95% CI 1.4-2.0). We identified a potential association between diabetes mellitus and adenocarcinoma of the esophagus or gastric cardia. This association appears to be independent of obesity. Additionally, nicotine dependence was identified as a risk factor for EAC.


Assuntos
Adenocarcinoma/etiologia , Cárdia , Diabetes Mellitus Tipo 2/complicações , Neoplasias Esofágicas/etiologia , Refluxo Gastroesofágico/complicações , Obesidade/complicações , Neoplasias Gástricas/etiologia , Adenocarcinoma/epidemiologia , Idoso , Distribuição de Qui-Quadrado , Bases de Dados Factuais , Neoplasias Esofágicas/epidemiologia , Esôfago , Feminino , Fundoplicatura , Refluxo Gastroesofágico/terapia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Neoplasias Gástricas/epidemiologia , Tabagismo/complicações , Estados Unidos/epidemiologia , United States Department of Veterans Affairs/estatística & dados numéricos
5.
Gynecol Oncol ; 129(1): 103-6, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23369942

RESUMO

OBJECTIVE: The objective of this study was to evaluate peri-operative and survival outcomes of ovarian cancer patients undergoing percutaneous upper gastrointestinal decompression for malignant bowel obstruction (MBO). METHODS: Retrospective chart review was used to identify patients with ovarian, peritoneal, or fallopian tube cancer who underwent palliative decompressive treatment for MBO from 1/2002 to 12/2010. Kaplan-Meier methods were used to estimate the median survival (MS) and multivariate analysis used to determine if any variables were associated with the hazard of death. RESULTS: Fifty-three patients met inclusion criteria. Median length of diagnosis prior to intervention was 21 months. Fifteen (28.3%) patients experienced complications and 9 required revision. Forty-nine (92.5%) experienced relief of symptoms after placement, and 91% tolerated some form of oral intake. Following placement, 19 (36%) patients received additional chemotherapy and 21(41%) patients received total parental nutrition (TPN). Thirty-five patients were discharged home/outpatient facility, 16 to hospice care, and 2 died prior to discharge. MS for all patients was 46 days. Patients who received chemotherapy had a MS of 169 days compared to 33 days (p<0.001). We failed to find an association between survival and TPN or performance status. CONCLUSIONS: Malignant bowel obstruction is a common complication of ovarian cancer. Management is palliative; risks and benefits of any therapy must be considered. Percutaneous decompressive therapy provides relief from associated symptoms, and allows patients to be discharged home. Median survival in this group is limited, and decisions regarding aggressive therapy should be individualized.


Assuntos
Descompressão Cirúrgica , Obstrução Intestinal/cirurgia , Neoplasias Ovarianas/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Obstrução Intestinal/mortalidade , Pessoa de Meia-Idade , Cuidados Paliativos , Nutrição Parenteral Total , Estudos Retrospectivos , Resultado do Tratamento
6.
Gynecol Oncol ; 124(2): 221-4, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22055764

RESUMO

INTRODUCTION: Hematologic, gastrointestinal, and neurologic complications are common side effects of the platinum and taxane-based chemotherapy used in the primary treatment of epithelial ovarian cancer (EOC). These side effects and the impact of the resultant chemotherapy dose modification on disease free interval have not been extensively studied. The goal of this study was to determine the effect of chemotherapy delays and dose reductions on progression free survival (PFS) and overall survival (OS). METHODS: A review of patients with primary epithelial ovarian, peritoneal, and fallopian tube carcinoma treated between 1/2000 and 12/2007 was performed. Inclusion criteria were advanced stage disease and first line chemotherapy with a platinum and taxane regimen. Cox proportional hazard models were used to determine the effect of chemotherapy reductions and delays on PFS and OS. RESULTS: One hundred and fifty seven patients met the inclusion criteria. Patients were divided into four groups: no delays or reductions (48%), delay only (27%), reduction only (8%), and both delay and reduction (18%). The mean number of delays/reductions per patient was 1.1 (range=0-5) and therapy was delayed a mean of 8 days. The most common reasons for delays/reductions were neutropenia (n=51), thrombocytopenia (n=45), and neuropathy (n=18). There were no differences detected in PFS or OS between groups. CONCLUSIONS: There were no differences detected in survival between patients who required dose adjustments and treatment delays and those who did not. The lack of association between survival and chemotherapy alterations suggests that in specific circumstances patients with advanced ovarian cancer should have individualized treatment plans.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Epitelial do Ovário , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
7.
Scott Med J ; 57(1): 38-42, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22408214

RESUMO

In Scotland, deaths in drug users are known to be higher than in the rest of the UK and most of Europe. Reducing drug-related deaths is currently a national priority for the Scottish Government.  This study aimed to present a description of the life histories of a group of injecting drug users who have recently died, with a view to highlighting areas for further research. The Edinburgh Addiction Cohort study recently carried out 432 follow-up interviews between the years 2005 and 2007. Thirty-three cases who completed this extensive interview detailing early life, education, employment, drug use, opiate substitution treatment, criminal history, mental health problems and overdose have subsequently died, leaving this source of rich information about their lives. The design of the interview used the life grid approach. Information was also compiled from full primary care records and General Register Office death certificates. Early life adversity was apparent for many cases, with a steady progression into early criminal behaviour and drug misuse. Poor adult life outcomes illustrated the lifelong damaging effects of drug injecting. Death occurred significantly earlier than in the general population or those living in deprived communities who did not use drugs. In conclusion, a clearer understanding of the life histories of problem drug users would be advantageous for health-care professionals and policy-makers. More qualitative research studies are needed to highlight areas which might require early intervention and also complement the existing secondary data studies.


Assuntos
Overdose de Drogas/mortalidade , Soropositividade para HIV/mortalidade , Hepatite C/mortalidade , Mortalidade Prematura , Abuso de Substâncias por Via Intravenosa/mortalidade , Abuso de Substâncias por Via Intravenosa/prevenção & controle , Adulto , Idade de Início , Estudos de Coortes , Atestado de Óbito , Overdose de Drogas/prevenção & controle , Usuários de Drogas , Feminino , Seguimentos , Hepatite C/prevenção & controle , Humanos , Masculino , Mortalidade Prematura/tendências , Fatores de Risco , Escócia/epidemiologia , Fatores Socioeconômicos , Transtornos Relacionados ao Uso de Substâncias/mortalidade , Transtornos Relacionados ao Uso de Substâncias/prevenção & controle
8.
Eur Respir J ; 36(4): 751-7, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20413535

RESUMO

Recent studies suggest that use of inhaled corticosteroids (ICS) in chronic obstructive pulmonary disease (COPD) may be associated with a higher incidence of pneumonia. However, it is unclear whether COPD subjects on ICS who develop pneumonia have worse outcomes. Therefore, our aim was to examine the association of prior outpatient ICS therapy with mortality in hospitalised COPD subjects with pneumonia. We included subjects ≥64 yrs of age, hospitalised with pneumonia in US Veterans Affairs hospitals, and assessed the association of ICS exposure with mortality for hospitalised COPD subjects with pneumonia in a covariate-adjusted regression model. We identified 6,353 subjects with a diagnosis of pneumonia and prior COPD, of whom 38% were on ICS. Mortality was 9% at 30 days and 16% at 90 days. In regression analyses, outpatient ICS therapy was associated with lower mortality at both 30 days (OR 0.76, 95% CI 0.70-0.83), and 90 days (OR 0.80, 95% CI 0.75-0.86). Outpatient therapy with ICS was associated with a significantly lower 30- and 90-day mortality in hospitalised COPD patients with pneumonia.


Assuntos
Corticosteroides/uso terapêutico , Pneumonia/complicações , Pneumonia/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/mortalidade , Administração por Inalação , Corticosteroides/administração & dosagem , Adulto , Comorbidade , Feminino , Hospitalização , Hospitais de Veteranos , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
9.
Mol Psychiatry ; 14(5): 537-45, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-18180759

RESUMO

Converging evidence suggests that patients with panic disorder have a metabolic disturbance that may influence the regulation of arousal systems and confer vulnerability to 'spontaneous' panic attacks. The consistent finding of elevated brain lactate responses to various metabolic challenges in panic disorder appears to support this model, although the mechanism of this effect is not understood. Several mechanisms have been proposed to account for elevated brain lactate responses in panic disorder, including (1) brain hypoxia due to excessive cerebral vasoconstriction, and (2) a metabolic disturbance affecting lactate metabolism. Recent studies have shown that neural activation (for example, sensory stimulation) causes local lactate accumulation in the presence of increased oxygen availability. The current study used proton magnetic resonance spectroscopic measures of visual cortex lactate changes during visual stimulation in 15 untreated patients with panic disorder and 15 matched volunteers to critically test these two proposed mechanisms of elevated brain lactate responses in panic disorder. Visual cortex lactate/N-acetylaspartate increased during visual stimulation in both groups. The increase was significantly greater in the panic patients than in the comparison group. There were no group differences in end-tidal pCO(2). The finding that visual stimulation leads to significantly greater visual cortex lactate responses in panic patients is not predicted by the hypoxia model. These results suggest that a metabolic disturbance affecting the production or clearance of lactate is the cause of the elevated brain lactate responses consistently observed in panic disorder and provide further support for metabolic models of vulnerability to this illness.


Assuntos
Encéfalo/metabolismo , Encéfalo/patologia , Ácido Láctico/metabolismo , Espectroscopia de Ressonância Magnética , Neurônios/metabolismo , Transtorno de Pânico/patologia , Adulto , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Mapeamento Encefálico , Estudos de Casos e Controles , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Estimulação Luminosa/métodos , Prótons , Análise Espectral , Adulto Jovem
10.
Gynecol Oncol ; 118(1): 47-51, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20382413

RESUMO

BACKGROUND: Increased rates of bowel perforation in patients with recurrent epithelial ovarian cancer (EOC) treated with bevacizumab have been reported, but the risk factors for this association are uncertain. We sought to identify factors associated with bowel perforation and fistula formation in recurrent EOC patients treated with bevacizumab. METHODS: A chart review of all patients treated with bevacizumab for recurrent EOC at a single institution was performed. Pertinent patient characteristics and treatment information were collected. Univariate logistic regression was performed to analyze multiple variables. RESULTS: One hundred twelve patients who were treated with 160 different bevacizumab regimens were identified. The median age was 60 years (range, 29-78 years). Patients had received a median of 4 prior chemotherapy regimens (range, 1-10). The median number of cycles was 4 (range, 0.5-31). Ten patients (9%) were diagnosed with bowel perforations, and another 2 patients (1.8%) were diagnosed with fistulas. The 30-day mortality following perforation was 50%, with 30% of patients dying within 1 week. Patients with rectovaginal nodularity were more likely to develop a bowel perforation or fistula than those who did not have this finding, OR=3.64 (95% CI=1.1 to 12.1, p=0.04). None of the other variables were significantly associated with bowel perforations or fistula formation. CONCLUSIONS: Rectovaginal nodularity is associated with an increased risk of bowel perforation or fistula formation for patients with recurrent EOC treated with bevacizumab. Careful consideration should be given prior to initiating bevacizumab treatment in EOC patients with rectovaginal nodularity since the mortality rate with bevacizumab associated bowel perforations is 50%.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Perfuração Intestinal/induzido quimicamente , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab , Células Epiteliais/patologia , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias das Tubas Uterinas/patologia , Feminino , Humanos , Perfuração Intestinal/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/patologia , Estudos Retrospectivos , Fatores de Risco
11.
Indoor Air ; 20(5): 380-91, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20590919

RESUMO

UNLABELLED: A report by the Institute of Medicine suggested that more research is needed to better understand mold effects on allergic disease, particularly asthma development. We compared the ability of the fungal Penicillium chrysogenum (PCE) and house dust mite (HDM) extracts to induce allergic responses in BALB/c mice. The extracts were administered by intratracheal aspiration (IA) at several doses (0, 2.5, 5, 10, 20, 40, and 80 µg) four times over a 4-week period. Three days after the last IA exposure, serum and bronchoalveolar lavage fluid (BALF) were collected. The relative allergenicity of the extracts was evaluated based on the lowest dose able to induce a significant response compared to control (0 µg) and the robustness of the response. PCE induced the most robust response at the lowest dose for most endpoints examined: BALF total, macrophage, neutrophil, and eosinophil cell counts, and antigen-specific IgE. Taken together, our data suggest that PCE may induce a more robust allergic and inflammatory response at lower doses than HDM. PRACTICAL IMPLICATIONS: Our data suggest that Penicillium chrysogenum is a robust allergen and may be a more potent allergen source than house dust mite (HDM) in this mouse model. Two critical factors in the development of human allergic disease, exposure levels and sensitization thresholds, are unknown for most allergens including molds/fungi. Human exposure levels are not within the scope of this article. However, the data presented suggest a threshold dose for the induction of allergic responsiveness to P. chrysogenum. Additionally, P. chrysogenum as well as other molds may play an important role in asthma development in our society.


Assuntos
Hipersensibilidade/imunologia , Penicillium chrysogenum/imunologia , Pyroglyphidae/imunologia , Animais , Lavagem Broncoalveolar , Líquido da Lavagem Broncoalveolar/imunologia , Modelos Animais de Doenças , Relação Dose-Resposta Imunológica , Hipersensibilidade/etiologia , Imunoglobulina E/análise , Intubação Intratraqueal , L-Lactato Desidrogenase/análise , Cloreto de Metacolina/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Pyroglyphidae/patogenicidade
12.
Gynecol Oncol ; 115(3): 396-400, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19804901

RESUMO

OBJECTIVE: To determine efficacy, toxicity, and survival in patients with recurrent epithelial ovarian cancer (EOC) receiving combination of weekly paclitaxel and biweekly bevacizumab (PB). METHODS: We reviewed chemotherapy logs identifying all patients receiving combination PB. Toxicities were graded using CTCAEv3.0 criteria. Response rates (RR) were measured using RECIST criteria or by CA-125 levels per modified Rustin criteria. RR and progression-free survival (PFS) were determined and plotted using Kaplan-Meier survival analysis. RESULTS: Fifty-one patients receiving at least two cycles of chemotherapy were evaluable for survival and 55 patients receiving one cycle of PB were evaluable in toxicity analysis. The mean number of previous regimens was four. The overall median PFS was 7 months and median OS was 12 months. The overall response rate (ORR) was 60% (CR 25% and PR 35%). Median PFS for complete and partial responders were 14 and 5 months respectively. Stable disease was seen in 26% with median PFS of 6 months. Thirteen experienced treatment delays for a variety of factors. The most G3/4 toxicities were fatigue (16%), hematologic (9%) and neurotoxicity (7%). Three patients (5%) experienced bowel perforations. CONCLUSIONS: Combination of paclitaxel and bevacizumab is feasible and demonstrates an acceptable toxicity profile and a high response rate. These observations should be useful in planning future clinical trials with this combination therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Estudos Retrospectivos , Taxa de Sobrevida
13.
Cell Death Differ ; 14(9): 1700-10, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17599100

RESUMO

The respective pro- and antiapoptotic functions of the transcription factors p53 and nuclear factor kappaB (NF-kappaB), and their potential impact on tumorigenesis and response to tumor therapy are well recognized. The capacity of the RelA(p65) subunit of NF-kappaB to specify a pro-apoptotic outcome in response to some stimuli is less well recognized, but needs to be understood if rational manipulation of the NF-kappaB pathway is to be deployed in cancer therapy. In this report, we provide evidence that the growth-responsive nuclear protein, proenkephalin (Penk), is required, in part, for apoptosis induction, in response to activation or overexpression of p53 and RelA(p65). We describe UV-C-inducible physical associations between endogenous Penk and p53 and RelA(p65) in mammalian cell lines. Depletion of Penk by RNA interference (RNAi) substantially preserves viable cell number following exposure to UV-C irradiation or hydrogen peroxide and confers transient protection in cells exposed to the genotoxin etoposide. In virally transformed and human tumor cell lines, overexpression of nuclear Penk with overabundant or activated p53, or RelA(p65) even in the absence of p53, enhances apoptosis to the point of synergy. We have further shown that Penk depletion by RNAi substantially derepresses transcription of a range of antiapoptotic gene targets previously implicated in repression-mediated apoptosis induction by NF-kappaB and p53. Physical association of endogenous Penk with the transcriptional co-repressor histone deacetylase suggests that it may be a component of a transcriptional repression complex that contributes to a pro-apoptotic outcome, following activation of the NF-kappaB and p53 pathways, and could therefore help to facilitate an antitumor response to a broad range of agents.


Assuntos
Apoptose , Encefalinas/metabolismo , NF-kappa B/metabolismo , Precursores de Proteínas/metabolismo , Fator de Transcrição RelA/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Animais , Linhagem Celular , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Sobrevivência Celular , Encefalinas/genética , Etoposídeo/farmacologia , Humanos , Precursores de Proteínas/genética , Interferência de RNA , Proteínas Repressoras/metabolismo , Transcrição Gênica
14.
Eur Respir J ; 31(3): 611-7, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17959631

RESUMO

Recent studies suggest that statins and angiotensin-converting enzyme (ACE) inhibitors may have beneficial effects for some types of infections. The present study aimed to examine the association of outpatient use of these medications on 30-day mortality for subjects aged >65 yrs and hospitalised with community-acquired pneumonia. A retrospective national cohort study was conducted using the Department of Veterans Affairs administrative data including subjects aged >/=65 yrs hospitalised with community-acquired pneumonia, and having >/=1 yr of prior Veterans Affairs outpatient care. In total, 8,652 subjects were identified with a mean age of 75 yrs, 98.6% were male, and 9.9% of subjects died within 30 days of presentation. In this cohort, 18.1% of subjects were using statins and 33.9% were using ACE inhibitors. After adjusting for potential confounders, current statin use (odds ratio (OR) 0.54, 95% confidence interval (CI) 0.42-0.70) and ACE inhibitor use (OR 0.80, 95% CI 0.68-0.89) were significantly associated with decreased 30-day mortality. Use of statins and angiotensin-converting enzyme inhibitors prior to admission is associated with decreased mortality in subjects hospitalised with community-acquired pneumonia. Randomised controlled trials are needed to examine whether the use of these medications in patients hospitalised with community-acquired pneumonia may be beneficial.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pneumonia/mortalidade , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Infecções Comunitárias Adquiridas/mortalidade , Feminino , Mortalidade Hospitalar , Hospitais de Veteranos/estatística & dados numéricos , Humanos , Masculino , Razão de Chances , Pneumonia/complicações , Estudos Retrospectivos , Estados Unidos/epidemiologia
15.
Int J Gynecol Cancer ; 18(1): 136-40, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-17466051

RESUMO

The objective is to determine the relationship between obesity and defects in DNA mismatch repair (MMR) in women with endometrial cancer and to establish whether our previous finding of a higher rate of previous malignancy in thinner women with endometrial cancer is related to these factors. Specimens from 109 patients with primary uterine cancer were used to create a tissue microarray, which was stained with antibodies against MMR genes MLH1, MSH2, MSH6, and PMS2. Genotyping of normal and tumor tissues for microsatellite instability (MSI) was performed. Patients were stratified by body mass index (BMI) and correlated with a history of previous malignancy and defects in MMR. The average BMI of the overall population was 33 kg/m(2). Defective MMR was seen in 22% of tumors. The mean BMI in patients with tumors with MSI was 30.5, compared with 33.8 in microsatellite stable (MSS) tumors (P= 0.06); MSS tumors were more commonly seen in patients with a BMI more than 40 (25% vs 5% in patients with tumors with MSI, P= 0.07). Prior to their diagnosis of endometrial cancer, 16/109 (15%) patients reported having a prior malignancy, 11 (69%) had breast cancer, and 1 had colorectal cancer. Patients with tumors with MSI had previous cancer in 17% of cases, compared with 14% of patients with MSS tumors (P= 0.75). Our previous finding of an increased rate of prior malignancy in thinner patients with endometrial cancer does not appear to be due to alterations in MMR, and hereditary nonpolyposis colorectal cancer-associated cancers are rarely the prior malignancy.


Assuntos
Índice de Massa Corporal , Neoplasias da Mama/genética , Reparo de Erro de Pareamento de DNA , Neoplasias do Endométrio/genética , Magreza , Proteínas Adaptadoras de Transdução de Sinal/genética , Adenosina Trifosfatases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Peso Corporal , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Feminino , Genótipo , Humanos , Técnicas Imunoenzimáticas , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Endonuclease PMS2 de Reparo de Erro de Pareamento , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS/genética , Proteínas Nucleares/genética , Análise Serial de Tecidos
16.
J Clin Oncol ; 5(10): 1621-3, 1987 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-3655859

RESUMO

Twenty-four patients with recurrent or widespread adenocarcinoma of the cervix were treated with combination chemotherapy. The drugs used were 5-fluorouracil (5-FU) (500 to 800 mg/m2), doxorubicin (40 to 50 mg/m2), and cisplatin (50 to 60 mg/m2). The chemotherapy was administered as a 76-hour continuous infusion via a silastic central venous catheter and repeated every 28 days. The total response rate was 42% (25% complete and 17% partial). Median duration of response was 7 months. Areas of response were usually lung and lymph node metastases. Toxicity, mainly neutropenia, was acceptable. All patients relapsed. This combination chemotherapy results in a modest response rate for a malignancy about which there is little information regarding the treatment of disseminated disease. Future studies should determine the activity of this combination administered in a bolus fashion.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico , Adenocarcinoma/secundário , Adulto , Assistência Ambulatorial/economia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/administração & dosagem , Doxorrubicina/administração & dosagem , Avaliação de Medicamentos , Feminino , Fluoruracila/administração & dosagem , Hospitalização/economia , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico
17.
J Clin Oncol ; 5(4): 618-21, 1987 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-3559652

RESUMO

Eighteen patients with metastatic mixed mesodermal sarcoma of the uterus received cisplatin therapy at the University of Texas (UT) M.D. Anderson Hospital and Tumor Institute at Houston. The dose of cisplatin varied from 75 mg/m2 to 100 mg/m2. Previous therapy included surgery in 11 patients, radiotherapy in two patients, and surgery plus radiotherapy in four patients. One patient had no prior therapy. Seven patients had also received prior chemotherapy with doxorubicin. Of 12 patients with measurable disease, one (8%) had a complete response and four (33%) had a partial response for an overall response rate of 42%. The median progression-free survival of patients treated with cisplatin as first- and second-line therapy was 4.5 and 5.5 months, respectively. Cisplatin demonstrated moderate activity with mild toxicity in this group of patients with metastatic mixed mesodermal uterine sarcomas. Further studies including cisplatin-containing combination regimens seem to be warranted.


Assuntos
Cisplatino/uso terapêutico , Mesenquimoma/tratamento farmacológico , Neoplasias Uterinas/tratamento farmacológico , Idoso , Cisplatino/efeitos adversos , Feminino , Humanos , Mesenquimoma/mortalidade , Pessoa de Meia-Idade , Metástase Neoplásica , Sarcoma/tratamento farmacológico , Neoplasias Uterinas/mortalidade
18.
J Clin Oncol ; 19(4): 1021-9, 2001 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-11181665

RESUMO

PURPOSE: The primary objective of this phase I trial was to determine the feasibility of administering a combination of paclitaxel, cisplatin, and doxorubicin with or without granulocyte colony-stimulating factor (G-CSF) in patients with advanced endometrial and other gynecologic cancers. PATIENTS AND METHODS: Patients were chemotherapy-naive. Doxorubicin was administered as a brief infusion, paclitaxel for 3 hours, and cisplatin for 60 minutes. Treatments were repeated every 3 weeks. For most dose levels, the cisplatin and doxorubicin were fixed at 60 mg/m(2) and 45 mg/m(2), whereas the paclitaxel was escalated in successive cohorts from 90 to 250 mg/m(2). Patients who had received previous radiotherapy to the whole pelvis were escalated separately from those who had not. RESULTS: Eighty patients received 320 cycles of therapy. When G-CSF was not used, myelosuppression prevented escalation beyond the starting dose for patients with or without previous pelvic radiotherapy. When G-CSF was added, neurotoxicity became dose-limiting for both groups. Ten patients were removed from the study for asymptomatic declines in ejection fraction, but no symptomatic congestive heart failure was observed. Major antitumor responses occurred in 46% of patients (six of 13) with measurable endometrial carcinoma and 50% of patients (eight of 16) with measurable cervical carcinoma. CONCLUSION: The combination of paclitaxel, doxorubicin, and cisplatin at relevant single-agent doses is active and feasible with the addition of G-CSF. A regimen of cisplatin 60 mg/m(2), doxorubicin 45 mg/m(2), and paclitaxel 160 mg/m(2) with G-CSF support is recommended for further testing.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias dos Genitais Femininos/tratamento farmacológico , Adulto , Idoso , Medula Óssea/efeitos dos fármacos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Esquema de Medicação , Estudos de Viabilidade , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Coração/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Nervos Periféricos/efeitos dos fármacos
19.
Scott Med J ; 50(2): 64-8, 2005 May.
Artigo em Inglês | MEDLINE | ID: mdl-15977518

RESUMO

BACKGROUND AND AIMS: The high prevalence of smoking in disadvantaged communities gives serious cause for concern in terms of adverse effects on health and social outcomes. In Scotland, smoking -related lung cancer rates are particularly high and compare less favourably with the rest of the U.K. and Europe. GPs are increasingly being recognised as having an important role in smoking cessation and are allowed to prescribe NRT to those on a low income. This study aimed to follow up a group patientsfrom a disadvantaged area who had been prescribed nicotine patches by their GP. METHODS: An initial self-complete questionnaire gathered details on age, sex, motivation, marital status, employment history, contact with other smokers, concern about weight gain, and nicotine dependence. (Nicotine dependence was assessed by using the Fagerstrom Test). Follow up was carried out at three months after commencing NRT prescription. Data was also gathered from patient case notes as to whether the participant had a smoking-related diagnosis, periods of depression, drug and/or alcohol problems. Outcome was measured in terms of "smoke the same", "smoke less" and "stopped". The statistical methods used for testing each factor against smoking were Spearman rank correlation, chi-squared test for trend and Kruskal-Wallis test. Basic descriptive statistics were used to report general outcomes of the study. RESULTS: The study enrolled 120 patients but 19 were lost to follow up. Out of 101 who used their prescription, 35 were smoking the same, 46 were smoking less and 20 had stopped. The variables most strongly affecting outcome were age, with older smokers having more success (p < 0.001), and those who had a diagnosis of depression having a worse outcome in terms of smoking cessation (p < 0.05). CONCLUSION: This study's findings indicate that encouraging GPs to take a proactive approach in prescribing NRT is effective, even in an area of socio-economic deprivation, and particularly with older smokers.


Assuntos
Medicina de Família e Comunidade/métodos , Nicotina/administração & dosagem , Áreas de Pobreza , Abandono do Hábito de Fumar/métodos , Fumar/tratamento farmacológico , Tabagismo/tratamento farmacológico , Administração Cutânea , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Padrões de Prática Médica , Escócia/epidemiologia , Fumar/economia , Fumar/epidemiologia , Abandono do Hábito de Fumar/economia , Abandono do Hábito de Fumar/psicologia , Inquéritos e Questionários , Tabagismo/economia , Tabagismo/epidemiologia , Populações Vulneráveis
20.
Am J Psychiatry ; 156(4): 550-6, 1999 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-10200733

RESUMO

OBJECTIVE: Few studies have examined the course of coexisting dementia and depression. The purpose of this study was to compare elderly patients who had coexisting dementia and depression with elderly patients who had either disorder alone in terms of their utilization of inpatient and outpatient services. METHOD: The study group included 7,115 veterans aged 60 years or older who had been discharged from Department of Veterans Affairs inpatient units in 1992 with diagnoses of major depression, dementia, or both. Outcome measures were analyzed for a 2-year period following the index hospitalization for each diagnostic study group. RESULTS: Patients with coexisting dementia and depression had significantly more psychiatric inpatient days than the other two study groups and more medical inpatient days and nursing home readmissions than patients with depression alone. Patients with coexisting dementia and depression had significantly more total inpatient days than the other two groups. Notably, patients with coexisting dementia and depression did not utilize more outpatient resources than the other study groups; in fact, they had significantly fewer medical, psychiatric, and total visits than patients with depression alone. CONCLUSIONS: The findings suggest that patients with coexisting dementia and depression are high utilizers of inpatient services, with a course of illness that may resemble dementia in terms of nursing home and inpatient medical care utilization and depression in terms of inpatient psychiatric care utilization; however, these patients utilized significantly fewer outpatient resources than the group with depression alone. Aggressive outpatient treatment approaches might reduce utilization of inpatient care for patients with coexisting depression and dementia.


Assuntos
Demência/epidemiologia , Transtorno Depressivo/epidemiologia , Serviços de Saúde/estatística & dados numéricos , Fatores Etários , Idoso , Assistência Ambulatorial/estatística & dados numéricos , Comorbidade , Demência/diagnóstico , Transtorno Depressivo/diagnóstico , Feminino , Seguimentos , Avaliação Geriátrica , Hospitalização/estatística & dados numéricos , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Modelos Estatísticos , Casas de Saúde/estatística & dados numéricos , Readmissão do Paciente/estatística & dados numéricos
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