RESUMO
OBJECTIVES: Renal cancer is resistant to most DNA and DNA repair targeted chemotherapy; although moderate response rates to nucleotide analog based therapy have been reported. Bevacizumab also has activity. We thus performed a phase II trial of gemcitabine, capecitabine, and bevacizumab in patients with metastatic renal cancer. METHODS: Following significant hematotoxicity, dosing was modified to gemcitabine 1000 mg/m (Days 1, 8), capecitabine 1000 mg twice daily (Days 1-14), and bevacizumab 15 mg/kg (Day 1) on a 21-day cycle with evaluation every 3 cycles. Primary end point was objective response rate. RESULTS: Twenty-nine patients were enrolled between March 2005 and May 2008. Most patients had been previously treated with a vascular endothelial growth factor receptor tyrosine kinase inhibitor. Seven patients (24%) had a partial response. Median overall and progression-free survival were 9.8 months (95% confidence interval: 6.2, 14.9) and 5.3 months (95% confidence interval: 3.9, 9.9), respectively. The regimen was well tolerated with hematologic toxicity, fatigue, and rash being most common. CONCLUSION: The trial was terminated early despite not meeting criteria for success or futility because of slow accrual and because the historical response rate became irrelevant with emerging data using sequential vascular endothelial growth factor therapies. Nevertheless, the observed progression-free and overall survival compare favorably to other phase II trials in this heavily pretreated population.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Terapia de Alvo Molecular , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Capecitabina , Chicago , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/análogos & derivados , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/efeitos adversos , Metástase Neoplásica , Análise de Sobrevida , GencitabinaRESUMO
STUDY OBJECTIVE: To investigate whether anesthesiologists' decisions to request preoperative cardiac evaluation (cardiologist consultation, echocardiography, and cardiac stress testing) before vascular surgery were influenced by patient comorbidity and magnitude of surgery; and to explore whether factors unrelated to the American College of Cardiology/American Heart Association (ACC/AHA) guidelines influence these decisions. DESIGN: Survey instrument. SETTING: University medical center. SUBJECTS: 2,000 U.S. anesthesiologists who were mailed a survey. MEASUREMENTS: Six factors in a hypothetical patient presenting for vascular surgery [gender, race (white vs. black), age (65 yrs vs. 85 yrs), comorbidities (sick vs. healthy), functional status, and magnitude of surgical stress] were evaluated. Respondents were asked about their demographics, practice patterns, and how they would manage the hypothetical patient. MAIN RESULTS: Of 2,000 mailed surveys, 439 U.S. anesthesiologists responded (22%). Multivariate ordinal logistic regression analysis showed that anesthesiologists were more likely to recommend preoperative cardiology consultation for patients with more comorbidities [odds ratio = 5.53; 95% confidence interval (CI) = 3.76, 8.15], for those with poorer functional status (odds ratio = 1.45; 95% CI = 1.02, 2.07), for those undergoing a more significant surgery (odds ratio = 1.61; 95% CI = 1.13, 2.30), as the clinicians' estimated risk of perioperative myocardial infarction increased (P < 0.001), or if they only infrequently anesthetized patients such as the one described in the scenario (P = 0.05). They also would request a preoperative echocardiogram for patients with more comorbidities (odds ratio = 2.58; 95% CI = 1.80, 3.68) and for those undergoing a more significant surgery (odds ratio = 1.59; 95% CI = 1.12, 2.25). A preoperative stress test was recommended for patients with more comorbidities (odds ratio = 3.01; 95% CI = 2.06, 4.38) and for those with a more significant surgery (odds ratio = 1.74; 95% CI = 1.15, 2.63). Other factors associated with request for a preoperative stress test were female gender of the anesthesiologist (odds ratio = 1.79; 95% CI = 1.11, 2.87), those with less experience with such patients (P = 0.05), and those from New England (odds ratio = 2.16; 95% CI = 1.01, 4.62). CONCLUSIONS: Anesthesiologists' preferences for preoperative cardiac evaluation are generally consistent with evidence-based and expert-based AHA/ACC guidelines. However, other physician factors (ie, gender, years in practice, and familiarity with the surgical procedure) also influenced these decisions.
Assuntos
Anestesiologia/métodos , Padrões de Prática Médica/estatística & dados numéricos , Cuidados Pré-Operatórios/métodos , Procedimentos Cirúrgicos Vasculares/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/diagnóstico , Coleta de Dados , Ecocardiografia/métodos , Medicina Baseada em Evidências , Teste de Esforço/métodos , Feminino , Fidelidade a Diretrizes , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Complicações Pós-Operatórias/prevenção & controle , Guias de Prática Clínica como Assunto , Fatores de Risco , Estados Unidos , Procedimentos Cirúrgicos Vasculares/efeitos adversosRESUMO
PURPOSE: Hepatobiliary cancers respond poorly to cytotoxic chemotherapy. We evaluated the activity and safety of ixabepilone, an epothilone B analogue which stabilizes microtubules, in a phase II trial in patients with advanced cancers of the gallbladder, bile duct, and liver. METHODS: Eligible patients had previously-untreated, histologically-proven unresectable hepatobiliary cancer. Ixabepilone, 40 mg/m(2), was administered intravenously over 3 h every 21 days. RESULTS: Between January 2002 and April 2005, 54 patients (19 hepatocelluar carcinoma, 13 cholangiocarcinomas, 22 gallbladder carcinomas) were enrolled; 47 patients were evaluable for efficacy. The objective response rate was 8.5%; 51% had stable disease. Median overall survival was 7.0 months (95% CI, 5.0 to 10.8 months) and median progression-free survival was 2.6 months (95% CI, 1.4 to 4.1 months). Grade 3/4 toxicities included neutropenia (39%), fatigue (9%), allergic/hypersensitivity reaction (4%) and sensory neuropathy (4%). CONCLUSION: Single agent ixabepilone has limited activity in advanced hepatobiliary cancers.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/patologia , Epotilonas/metabolismo , Epotilonas/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Epotilonas/efeitos adversos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Resultado do Tratamento , Universidades , Adulto JovemRESUMO
OBJECTIVES: To determine what findings on postchemoradiation (post-CRT) neck computed tomography (CT) may predict removal of the internal jugular vein (IJV) or sternocleidomastoid muscle (SCM) and to examine whether pretreatment CT had any bearing on the ultimate posttreatment neck dissection with regard to the IJV and SCM. DESIGN: Retrospective review of CT, intraoperative, and pathologic findings. SETTING: Tertiary care academic medical center. PATIENTS: Thirty-four patients who underwent 43 planned post-CRT hemi-neck dissections for pretreatment N2 or greater disease. RESULTS: Of the 43 neck dissections, 39 (91%) were selective neck dissections, 2 (5%) were modified radical dissections, and 2 (5%) were radical neck dissections. The IJV was removed in 6 of the 39 selective neck dissections (15%), in 1 of the 2 modified radical dissections, and in both of the 2 radical neck dissections. The SCM was removed in the 2 modified radical dissections and 2 radical neck dissections. The IJV was removed in 7 of the 9 dissections (78%) in which the IJV was abnormal on preoperative CT (filling defect or thrombosed) vs 2 of the 34 dissections (6%) with a normal IJV on CT (P < .001; positive predictive value, 78%; negative predictive value, 94%). The SCM was removed in 4 of the 11 dissections (36%) in which the tissue plane between the carotid sheath and the SCM was indistinct on CT vs 0 of the 32 dissections with a radiographically normal SCM tissue plane (P = .003; positive predictive value, 36%; negative predictive value, 100%). In 27 patients with pre-CRT CTs for comparison, the IJV normalized in 3 of the 8 patients (38%) with an abnormal IJV on pre-CRT CT, and the tissue plane around the SCM normalized in 15 of the 24 patients (63%) with an indistinct tissue plane on pre-CRT CT. CONCLUSIONS: Filling defects or thrombosis of the IJV is highly predictive of need for removal intraoperatively, which may affect planning especially in bilateral neck dissections in which an effort may be made to preserve at least 1 vein. Presence of a clear tissue plane between the SCM and carotid sheath predicts the ability to preserve this muscle. Changes in the status of the IJV and SCM seen on CT that occur as a result of CRT may make preservation of these structures more feasible, even in patients with advanced neck disease.
Assuntos
Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/terapia , Esvaziamento Cervical/métodos , Terapia Neoadjuvante/métodos , Invasividade Neoplásica/patologia , Tomografia Computadorizada por Raios X/métodos , Adulto , Idoso , Quimioterapia Adjuvante , Estudos de Coortes , Meios de Contraste , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Cuidados Pós-Operatórios , Valor Preditivo dos Testes , Cuidados Pré-Operatórios/métodos , Radioterapia Adjuvante , Estudos Retrospectivos , Medição de Risco , Análise de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: Hypertension is a mechanism-based toxicity of sorafenib and other cancer therapeutics that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. This prospective, single-center, cohort study characterized ambulatory blood pressure monitoring as an early pharmacodynamic biomarker of VEGF signaling pathway inhibition by sorafenib. EXPERIMENTAL DESIGN: Fifty-four normotensive advanced cancer patients underwent 24-hour ambulatory blood pressure monitoring before and between days 6 and 10 of sorafenib therapy. After blood pressure changes were detected among the first cohort within 10 days, ambulatory blood pressure monitoring was done during the first 24 hours of treatment for the second cohort. RESULTS: For the entire patient population, the blood pressure increase [mean systolic, +10.8 mm Hg; 95% confidence interval (95% CI), 8.6-13.0; range, -5.2 to +28.7 mm Hg; mean diastolic, +8.0 mm Hg; 95% CI, 6.3-9.7; range, -4.4 to +27.1 mm Hg] was detected between days 6 and 10 (P < 0.0001 for both) and plateaued thereafter. Variability in blood pressure change did not associate with: age, body size, sex, self-reported race, baseline blood pressure, or steady-state sorafenib plasma concentrations. In the second cohort, the blood pressure elevation was detected during the first 24 hours (mean systolic, +8.2 mm Hg; 95% CI, 5.0-11.3; mean diastolic, +6.5 mm Hg; 95% CI, 4.7-8.3; P < 0.0001 for both). CONCLUSIONS: Ambulatory blood pressure monitoring detects the blood pressure response to VEGF signaling pathway inhibition by sorafenib during the first 24 hours of treatment. The magnitude of blood pressure elevation is highly variable and unpredictable but could be important in optimizing the therapeutic index of VEGF signaling pathway inhibitor therapy.
Assuntos
Benzenossulfonatos/efeitos adversos , Monitorização Ambulatorial da Pressão Arterial , Hipertensão/induzido quimicamente , Hipertensão/diagnóstico , Neoplasias/fisiopatologia , Piridinas/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Benzenossulfonatos/farmacocinética , Benzenossulfonatos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Ritmo Circadiano , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/farmacocinética , Piridinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Sorafenibe , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/fisiologiaRESUMO
INTRODUCTION: Retrospective recall of smoking during pregnancy is assumed to be substantially biased, but this has rarely been tested empirically. METHODS: We examined the validity of an interview-based retrospective recall more than a decade after pregnancy, in a cohort with repeated, multimethod characterization of pregnancy smoking (N = 245). Retrospective smoking patterns were examined in relation to prospective reported and biological estimates of overall and trimester-specific smoking status and intensity. We also compared characteristics of women whose smoking status was misclassified by either prospective or retrospective measures with women whose status was congruent for nonsmoking across timepoints. RESULTS: In general, sensitivity and specificity of recalled smoking were excellent relative to both prospective self-reported and cotinine-validated smoking status and trimester-specific intensity. However, measures were less congruent for amount smoked for women who recalled being heavy smokers. Further, retrospective measures captured some smokers not identified prospectively due to smoking that occurred prior to assessments. Women who would have been misclassified as nonsmokers based on either prospective or retrospective assessment differed significantly from congruently classified nonsmokers in a number of maternal, family, and neighborhood, but not child behavior, characteristics. DISCUSSION: When epidemiological studies of the impact of smoking in pregnancy use retrospective methods, misclassification may not be a significant problem if prenatal smoking is assessed in terms of the pattern across pregnancy. This type of interview-based recall of pregnancy smoking may be relatively accurate, although optimal measurement should combine retrospective and prospective self-report and biological assays, as each provide unique information and sources of error.
Assuntos
Memória , Complicações na Gravidez/psicologia , Fumar/psicologia , Adulto , Criança , Comportamento Infantil , Família , Feminino , Humanos , Pessoa de Meia-Idade , Gravidez , Prevalência , Estudos Prospectivos , Características de Residência , Estudos RetrospectivosRESUMO
Single agent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have demonstrated reproducible response rates of 5-15% in treatment of squamous cell carcinomas of the head and neck (SCCHN). The subset of patients that benefits most from these agents remains unknown. We reviewed individual patient data from five clinical trials of erlotinib, lapatinib, or gefitinib to determine if there are clinical characteristics that are associated with clinical benefit defined as complete response (CR), partial response (PR), and stable disease (SD) >4months. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Three-hundred and nineteen subjects were included. Observed responses were: 1% CR, 6% PR, 24% SD >4months, 18% SD <4months, 45% progressive disease (PD), 7% not evaluable (NE). The median OS was 6.4months and the median PFS was 2.7months. The most common toxicities observed were rash (grade 1 in 37%, grade 2 in 33%, grade 3+ in 6%) and diarrhea (grade 1 in 30%, grade 2 in 10%, grade 3+ in 5%). Performance status (PS) (p=0.04), older age (p=0.02), and development of rash (p<0.01), diarrhea (p=0.03), or oral side effects (p=0.02) were independently associated with clinical benefit. Older age, better PS, and development of rash were associated with longer PFS and OS. Clinical parameters that appear to predict response to EGFR TKI include PS and age. EGFR mechanistic toxicities that develop during therapy are also highly associated with benefit and suggest a relationship between drug exposure and outcome.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Fatores Etários , Idoso , Carcinoma de Células Escamosas/secundário , Intervalo Livre de Doença , Cloridrato de Erlotinib , Feminino , Gefitinibe , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Lapatinib , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Tirosina Quinases/antagonistas & inibidores , Quinazolinas/uso terapêutico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Despite numerous advances, the 5-year survival rate for head and neck squamous cell cancer (HNSCC) has remained largely unchanged. This poor outcome is due to several variables, including the development of multiple primary tumors. Therefore, it is essential to supplement early detection with preventive strategies. Using the 4-nitroquinoline 1-oxide (4-NQO) mouse model, we sought to define an appropriate dose and duration of administration that would predict the histologic timeline of HNSCC progression. Additionally, we sought to determine the timing of the onset of the angiogenic phenotype. Finally, using ABT-510 as a proof-of-principle drug, we tested the hypothesis that inhibitors of angiogenesis can slow/delay the development of HNSCC. We determined that 8 weeks of 100 microg/mL 4-NQO in the drinking water was the optimal dosage and duration to cause a sufficient incidence of hyperkeratoses, dysplasias, and HNSCC over a period of 32 weeks with minimal morbidity and mortality. Increased microvessel density and vascular endothelial growth factor expression in hyperkeratotic lesions provided evidence that the initiation of the angiogenic phenotype occurred before the development of dysplasia. Importantly, ABT-510 significantly decreased the overall incidence of HNSCC from 37.3% to 20.3% (P = 0.021) as well as the combined incidence of dysplasia and HNSCC from 82.7% to 50.6% (P < 0.001). These findings suggest that our refinement of the 4-NQO model allows for the investigation of the histologic, molecular, and biological alterations that occur during the premalignant phase of HNSCC. In addition, these data support the hypothesis that inhibitors of angiogenesis may be promising chemopreventive agents.
Assuntos
Inibidores da Angiogênese/farmacologia , Carcinoma de Células Escamosas/prevenção & controle , Modelos Animais de Doenças , Neoplasias Bucais/prevenção & controle , Oligopeptídeos/farmacologia , 4-Nitroquinolina-1-Óxido/toxicidade , Animais , Carcinógenos/toxicidade , Carcinoma de Células Escamosas/induzido quimicamente , Carcinoma de Células Escamosas/patologia , Imuno-Histoquímica , Antígeno Ki-67/biossíntese , Antígeno Ki-67/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos CBA , Microvasos/efeitos dos fármacos , Neoplasias Bucais/induzido quimicamente , Neoplasias Bucais/patologia , Neovascularização Patológica/tratamento farmacológico , Lesões Pré-Cancerosas/induzido quimicamente , Lesões Pré-Cancerosas/tratamento farmacológico , Lesões Pré-Cancerosas/patologia , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator A de Crescimento do Endotélio Vascular/efeitos dos fármacosRESUMO
While there is a burgeoning body of research linking smoking during pregnancy to problem behaviour in offspring, a major criticism of this work has been the crude measurement of exposure in these studies (e.g. retrospective, self-reported only) that could lead to biased estimates. To address this issue, we used a pregnancy cohort with repeated prospective measures of exposure as well as biological assays to generate estimates of exposure patterns using a range of modelling techniques. In this paper we report on the analytical approaches we have developed, including patterns of exposure over time and best-estimate approaches that combine self-report and cotinine measures, and compare their predictive value in relation to different dimensions of fetal growth as a first step towards examining the utility of greater precision of exposure measurement. Surprisingly, in this sample the more complex assessments of exposure, including biological measures, generally did not perform better than simple indicators of exposure based on repeated self-report measures, with one exception: a combined self-report cotinine 'best estimate' of third trimester exposure was uniquely associated with lower brain : body ratio. Further study is needed using more sophisticated cotinine assays and testing prediction of a range of outcomes to ascertain whether these findings represent true differences or are specific to the sample, methods and outcomes used. Such research will inform the development of guidelines for adequate exposure characterisation in developmental studies.
Assuntos
Cotinina/urina , Desenvolvimento Fetal/fisiologia , Efeitos Tardios da Exposição Pré-Natal , Fumar/efeitos adversos , Poluição por Fumaça de Tabaco/efeitos adversos , Biomarcadores/urina , Peso ao Nascer , Tamanho Corporal , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Exposição Materna , Modelos Biológicos , Valor Preditivo dos Testes , GravidezRESUMO
Carboplatin is a chemotherapeutic agent used in the management of many cancers, yet treatment is limited by resistance and toxicities. To achieve a better understanding of the genetic contribution to carboplatin resistance or toxicities, lymphoblastoid cell lines from 34 large Centre d'Etude du Polymorphisme Humain pedigrees were utilised to evaluate interindividual variation in carboplatin cytotoxicity. Significant heritability, ranging from 0.17-0.36 (p = 1 x 10(-7) to 9 x 10(-4)), was found for cell growth inhibition following 72-hour treatment at each carboplatin concentration (10, 20, 40 and 80 microM) and IC(50) (concentration for 50 per cent cell growth inhibition). Linkage analysis revealed 11 regions with logarithm of odds (LOD) scores greater than 1.5. The highest LOD score on chromosome 11 (LOD = 3.36, p = 4.2 x 10(-5)) encompasses 65 genes within the 1 LOD confidence interval for the carboplatin IC 50 . We further analysed the IC(50) phenotype with a linkage-directed association analysis using 71 unrelated HapMap and Perlegen cell lines and identified 18 single nucleotide polymorphisms within eight genes that were significantly associated with the carboplatin IC(50) (p < 3.6 x 10(-5); false discovery rate <5 per cent). Next, we performed linear regression on the baseline expression and carboplatin IC(50) values of the eight associated genes, which identified the most significant correlation between CD44 expression and IC(50) (r(2)= 0.20; p = 6 x 10(-4)). The quantitative real-time polymerase chain reaction further confirmed a statistically significant difference in CD44 expression levels between carboplatin-resistant and -sensitive cell lines (p = 5.9 x 10(-3)). Knockdown of CD44 expression through small interfering RNA resulted in increased cellular sensitivity to carboplatin (p < 0.01). Our whole-genome approach using molecular experiments identified CD44 as being important in conferring cellular resistance to carboplatin.
Assuntos
Antineoplásicos/farmacologia , Carboplatina/farmacologia , Genoma Humano , Receptores de Hialuronatos/genética , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/genética , Expressão Gênica , Humanos , Receptores de Hialuronatos/metabolismo , Locos de Características Quantitativas , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismoRESUMO
BACKGROUND: Short sleep is associated with obesity and may alter the endocrine regulation of hunger and appetite. OBJECTIVE: We tested the hypothesis that the curtailment of human sleep could promote excessive energy intake. DESIGN: Eleven healthy volunteers [5 women, 6 men; mean +/- SD age: 39 +/- 5 y; mean +/- SD body mass index (in kg/m(2)): 26.5 +/- 1.5] completed in random order two 14-d stays in a sleep laboratory with ad libitum access to palatable food and 5.5-h or 8.5-h bedtimes. The primary endpoints were calories from meals and snacks consumed during each bedtime condition. Additional measures included total energy expenditure and 24-h profiles of serum leptin and ghrelin. RESULTS: Sleep was reduced by 122 +/- 25 min per night during the 5.5-h bedtime condition. Although meal intake remained similar (P = 0.51), sleep restriction was accompanied by increased consumption of calories from snacks (1087 +/- 541 compared with 866 +/- 365 kcal/d; P = 0.026), with higher carbohydrate content (65% compared with 61%; P = 0.04), particularly during the period from 1900 to 0700. These changes were not associated with a significant increase in energy expenditure (2526 +/- 537 and 2390 +/- 369 kcal/d during the 5.5-h and 8.5-h bedtime periods, respectively; P = 0.58), and we found no significant differences in serum leptin and ghrelin between the 2 sleep conditions. CONCLUSIONS: Recurrent bedtime restriction can modify the amount, composition, and distribution of human food intake, and sleeping short hours in an obesity-promoting environment may facilitate the excessive consumption of energy from snacks but not meals.
Assuntos
Ingestão de Energia/fisiologia , Grelina/sangue , Leptina/sangue , Obesidade/etiologia , Privação do Sono/sangue , Privação do Sono/fisiopatologia , Adulto , Apetite/fisiologia , Composição Corporal/fisiologia , Peso Corporal/fisiologia , Estudos Cross-Over , Ingestão de Alimentos/fisiologia , Metabolismo Energético/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/sangueRESUMO
OBJECTIVE: To test the hypothesis that FYN, a member of the SRC family of kinases (SFKs), is up-regulated in prostate cancer, as FYN is functionally distinct from other SFKs, and interacts with FAK and paxillin (PXN), regulators of cell morphology and motility. MATERIALS AND METHODS: Through data-mining in Oncomine (http://www.oncomine.org), cell-line profiling with immunoblotting, quantitative reverse transcription and polymerase chain reaction (RT-PCR) and immunohistochemical analysis, we described FYN expression in prostate cancer. The analysis included 32 cases of prostate cancer, nine of prostatic intraepithelial neoplasia (PIN) and 19 normal prostates. Samples were scored for the percentage of stained glands and intensity of staining (from 0 to 3). Each sample was assigned a composite score generated by multiplying percentage and intensity. RESULTS: Data-mining showed an eight times greater FYN expression in prostate cancer than in normal tissue; this was specific to FYN and not present for other SFKs. Expression of FYN in prostate cancer cell lines (LNCaP, 22Rv1, PC3, DuPro) was detected using quantitative RT-PCR and immunoblotting. Expression of FYN and its signalling partners FAK and PXN was detected in human tissue. Comparing normal with cancer samples, there was a 2.1-fold increase in median composite score for FYN (P < 0.001) 1.7-fold increase in FAK (P < 0.001), and a doubling in PXN (P < 0.05). There was a 1.7-fold increase in FYN (P < 0.05) and a 1.6-fold increase in FAK (P < 0.01) in cancer compared with PIN. CONCLUSIONS: These studies support the hypothesis that FYN and its related signalling partners are up-regulated in prostate cancer, and support further investigation into the role of the FYN as a therapeutic target.
Assuntos
Neoplasia Prostática Intraepitelial/metabolismo , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Adulto , Idoso , Western Blotting , Estudos de Casos e Controles , Quinase 1 de Adesão Focal/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Paxilina/metabolismo , Neoplasia Prostática Intraepitelial/genética , Neoplasias da Próstata/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Regulação para CimaRESUMO
Copper transporters have been proposed to be involved in cellular import and export of platinating agents. Expression of the human copper transporter 1 (hCtr1) is thought to result in increased sensitivity to cisplatin, whereas expression of ATP7A and ATP7B are thought to be involved in resistance to cisplatin either by sequestering drug away from its targets (ATP7A) or by exporting the drug from the cell (ATP7B). In this study, we evaluated the sensitivity of cells expressing copper transporters to cisplatin, carboplatin and oxaliplatin. We also examined whether O (6)-benzylguanine, a modulator of platinating agent cytotoxicity, enhanced sensitivity of cells with or without the transporters to cisplatin. Overexpression of hCtr1 in the HEK293 cell line did not result in increased sensitivity to cisplatin, either alone or following treatment with O (6)-benzylguanine. In contrast, overexpression of ATP7A and ATP7B in Me32a fibroblasts resulted in increased resistance to cisplatin, but not to carboplatin or oxaliplatin. ATP7A-expressing cells (MeMNK) showed a significant enhancement of cisplatin cytotoxicity following O (6)-benzylguanine treatment, but ATP7B-expressing cells (MeWND) did not. Notably, expression of either ATP7A or ATP7B did not result in a change in total cytoplasmic platinum levels following treatment with BG plus cisplatin. The mechanism of BG enhancement of cisplatin cytotoxicity is not likely through regulation of copper transporters.
Assuntos
Antineoplásicos/farmacologia , Proteínas de Transporte de Cátions/metabolismo , Resistencia a Medicamentos Antineoplásicos , Regulação da Expressão Gênica , Guanina/análogos & derivados , Adenosina Trifosfatases/genética , Antineoplásicos/farmacocinética , Transporte Biológico , Carboplatina/farmacocinética , Carboplatina/farmacologia , Proteínas de Transporte de Cátions/genética , Linhagem Celular , Cisplatino/farmacocinética , Cisplatino/farmacologia , Transportador de Cobre 1 , ATPases Transportadoras de Cobre , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fibroblastos/metabolismo , Guanina/farmacologia , Humanos , Compostos Organoplatínicos/farmacocinética , Compostos Organoplatínicos/farmacologia , OxaliplatinaRESUMO
BACKGROUND: Worldwide, approximately two billion people are chronically infected with Toxoplasma gondii with largely unknown consequences. METHODS: To better understand long-term effects and pathogenesis of this common, persistent brain infection, mice were infected at a time in human years equivalent to early to mid adulthood and studied 5-12 months later. Appearance, behavior, neurologic function and brain MRIs were studied. Additional analyses of pathogenesis included: correlation of brain weight and neurologic findings; histopathology focusing on brain regions; full genome microarrays; immunohistochemistry characterizing inflammatory cells; determination of presence of tachyzoites and bradyzoites; electron microscopy; and study of markers of inflammation in serum. Histopathology in genetically resistant mice and cytokine and NRAMP knockout mice, effects of inoculation of isolated parasites, and treatment with sulfadiazine or alphaPD1 ligand were studied. RESULTS: Twelve months after infection, a time equivalent to middle to early elderly ages, mice had behavioral and neurological deficits, and brain MRIs showed mild to moderate ventricular dilatation. Lower brain weight correlated with greater magnitude of neurologic abnormalities and inflammation. Full genome microarrays of brains reflected inflammation causing neuronal damage (Gfap), effects on host cell protein processing (ubiquitin ligase), synapse remodeling (Complement 1q), and also increased expression of PD-1L (a ligand that allows persistent LCMV brain infection) and CD 36 (a fatty acid translocase and oxidized LDL receptor that mediates innate immune response to beta amyloid which is associated with pro-inflammation in Alzheimer's disease). Immunostaining detected no inflammation around intra-neuronal cysts, practically no free tachyzoites, and only rare bradyzoites. Nonetheless, there were perivascular, leptomeningeal inflammatory cells, particularly contiguous to the aqueduct of Sylvius and hippocampus, CD4+ and CD8+ T cells, and activated microglia in perivascular areas and brain parenchyma. Genetically resistant, chronically infected mice had substantially less inflammation. CONCLUSION: In outbred mice, chronic, adult acquired T. gondii infection causes neurologic and behavioral abnormalities secondary to inflammation and loss of brain parenchyma. Perivascular inflammation is prominent particularly contiguous to the aqueduct of Sylvius and hippocampus. Even resistant mice have perivascular inflammation. This mouse model of chronic T. gondii infection raises questions of whether persistence of this parasite in brain can cause inflammation or neurodegeneration in genetically susceptible hosts.
Assuntos
Encéfalo/parasitologia , Encefalite/parasitologia , Degeneração Neural/parasitologia , Neurônios/parasitologia , Toxoplasmose Cerebral/fisiopatologia , Fatores Etários , Animais , Atrofia/parasitologia , Atrofia/patologia , Atrofia/fisiopatologia , Comportamento Animal/fisiologia , Biomarcadores/análise , Biomarcadores/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/parasitologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/parasitologia , Doença Crônica , Modelos Animais de Doenças , Encefalite/patologia , Encefalite/fisiopatologia , Feminino , Ventrículos Laterais/patologia , Imageamento por Ressonância Magnética , Camundongos , Microglia/imunologia , Microglia/parasitologia , Degeneração Neural/patologia , Degeneração Neural/fisiopatologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/patologia , Toxoplasma/citologia , Toxoplasma/fisiologia , Toxoplasmose Cerebral/patologiaRESUMO
O6-Benzylguanine (BG) enhances cisplatin [cis-diammine dichloroplatinum (II)]-induced cytotoxicity and apoptosis in head and neck cancer cell lines by an unknown mechanism. We investigated the effect of cisplatin with and without BG on two targets of damage: DNA and the endoplasmic reticulum (ER). We chose three cancer cell lines to ascertain the mechanism of BG-enhanced cytotoxicity: SQ20b head and neck and SKOV-3x ovarian cancer cell lines, where BG enhanced cisplatin cytotoxicity, and A549 nonsmall cell lung cancer line, where BG did not enhance cisplatin cytotoxicity. All three lines had an increase in DNA damage when BG was added to cisplatin treatment, as evidenced by increased platination and phosphorylated histone H2AX formation. The increase in cisplatin-induced DNA damage after treatment with BG plus cisplatin is not sufficient to increase cytotoxicity or apoptosis in A549 cells. We evaluated the effect of cisplatin on the ER and observed increased caspase 12 cleavage in SQ20b and SKOV-3x cells, but not in A549 cells, after treatment with BG plus cisplatin versus cisplatin alone. Growth arrest and DNA damage inducible (GADD) 153, an ER stress-response gene, is up-regulated after treatment with BG plus cisplatin compared with cisplatin alone in SQ20b and SKOV-3x cells, but not in A549 cells. ER stress-induced apoptosis is an integral part of the mechanism by which BG enhances cisplatin. Inhibition of ER stress in the SQ20b cell line by salubrinal, an inhibitor of eIF2alpha dephosphorylation, or GADD153 small interfering RNA, abrogated BG-enhancement of cisplatin cytotoxicity and apoptosis through caspase 3 and 12 cleavage. These data indicate GADD153 up-regulation plays an important role in BG-enhanced cisplatin cytotoxicity and apoptosis.
Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Retículo Endoplasmático/metabolismo , Guanina/análogos & derivados , Caspase 12/metabolismo , Caspase 3/metabolismo , Linhagem Celular Tumoral , DNA/metabolismo , Quebras de DNA de Cadeia Dupla , Sinergismo Farmacológico , Guanina/farmacologia , Humanos , Platina/metabolismo , RNA Mensageiro/análise , Fator de Transcrição CHOP/antagonistas & inibidores , Fator de Transcrição CHOP/biossíntese , Fator de Transcrição CHOP/genéticaRESUMO
There is a need to develop early biomarkers of acute kidney injury following cardiac surgery, where morbidity and mortality are increased by its presence. Plasma cystatin C (CyC) and plasma and urine Neutrophil Gelatinase Associated Lipocalin (NGAL) have been shown to detect kidney injury earlier than changes in plasma creatinine in critically ill patients. In order to determine the utility of urinary CyC levels as a measure of kidney injury, we prospectively collected plasma and urine from 72 adults undergoing elective cardiac surgery for analysis. Acute kidney injury was defined as a 25% or greater increase in plasma creatinine or renal replacement therapy within the first 72 hours following surgery. Plasma CyC and NGAL were not useful predictors of acute kidney injury within the first 6 hours following surgery. In contrast, both urinary CyC and NGAL were elevated in the 34 patients who later developed acute kidney injury, compared to those with no injury. The urinary NGAL at the time of ICU arrival and the urinary CyC level 6 hours after ICU admission were most useful for predicting acute kidney injury. A composite time point consisting of the maximum urinary CyC achieved in the first 6 hours following surgery outperformed all individual time points. Our study suggests that urinary CyC and NGAL are superior to conventional and novel plasma markers in the early diagnosis of acute kidney injury following adult cardiac surgery.
Assuntos
Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Cistatina C/urina , Nefropatias/diagnóstico , Proteínas de Fase Aguda/urina , Biomarcadores/urina , Procedimentos Cirúrgicos Eletivos , Nefropatias/etiologia , Lipocalina-2 , Lipocalinas/urina , Estudos Prospectivos , Proteínas Proto-Oncogênicas/urina , Fatores de TempoRESUMO
PURPOSE: To determine the incidence of new chorioretinal lesions in children with toxoplasmosis diagnosed after, and therefore not treated during, their first year. DESIGN: Prospective longitudinal cohort study. METHODS: Thirty-eight children were evaluated in Chicago between 1981 and 2005 for new chorioretinal lesions. Thirty-eight children and mothers had serum IgG antibody to Toxoplasma gondii. RESULTS: Twenty-eight of 38 children had one of the following: diagnosis with serum antibody to T. gondii indicative of chronic infection at age 24 months, central nervous system calcifications, hydrocephalus, illness compatible with congenital toxoplasmosis perinatally but not diagnosed at that time. Twenty-five returned for follow-up during 1981 to 2005. Their mean (range) age at last exam was 10.9 +/- 5.7 (range, 3.5 to 27.2) years and mean follow-up was 5.7 +/- 2.9 years. Eighteen (72%) children developed at least one new lesion. Thirteen (52%) had new central lesions, 11 (44%) had new peripheral lesions, and six (24%) had both. Thirteen (52%) had new lesions diagnosed at age > or =10 years. New lesions were found at more than one visit in four (22%), and bilateral new lesions developed in seven (39%) of 18 children who developed new lesions. Of 10 additional children with eye findings and serologic tests indicative of chronic infection, six returned for follow-up, four (67%) developing new lesions at > or =10 years of age. CONCLUSIONS: More than 70% developed new chorioretinal lesions. New lesions were commonly diagnosed after the first decade of life.
Assuntos
Coriorretinite/diagnóstico , Toxoplasmose Ocular/diagnóstico , Adolescente , Adulto , Animais , Anticorpos Antiprotozoários/sangue , Criança , Pré-Escolar , Coriorretinite/terapia , Feminino , Humanos , Imunoglobulina G/sangue , Incidência , Estudos Longitudinais , Masculino , Estudos Prospectivos , Toxoplasma/imunologia , Toxoplasmose Ocular/congênito , Toxoplasmose Ocular/terapiaRESUMO
OBJECTIVES: The objectives of this phase II trial were to assess the activity and tolerability of the combination of bevacizumab and erlotinib in patients with recurrent ovarian, primary peritoneal or fallopian tube cancer. METHODS: This was a single arm, multicenter phase II trial with overall objective response as the primary endpoint. Eligible patients had two or fewer prior chemotherapy regimens for recurrent or refractory disease and no prior anti-VEGF or anti-EGFR agents. Bevacizumab, 15 mg/kg, was administered intravenously every 21 days and erlotinib, 150 mg orally, was given daily. RESULTS: Between July and October 2005, 13 patients were enrolled. There were two major objective responses, one complete response of 16+ month duration and one partial response of 11 month duration, for a response rate of 15% (95% CI 1.9% to 45.4%). Seven patients had a best response of stable disease. The most common grade 3 or 4 toxicities included anemia (n=1), nausea (n=2), vomiting (n=1), hypertension (n=1), and diarrhea (n=2). One patient with an ileostomy was removed from the study secondary to grade 3 diarrhea. Two patients had fatal gastrointestinal perforations. CONCLUSION: There was no strong suggestion that this combination was superior to single agent bevacizumab, and the rate of gastrointestinal perforation was of concern. The study was therefore stopped. Identification of risk factors for gastrointestinal perforation will be of importance for the use of bevacizumab in the treatment of ovarian cancer.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Quinazolinas/uso terapêutico , Idoso , Inibidores da Angiogênese/toxicidade , Anticorpos Monoclonais/toxicidade , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab , Biomarcadores/sangue , Cloridrato de Erlotinib , Neoplasias das Tubas Uterinas/mortalidade , Neoplasias das Tubas Uterinas/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Seleção de Pacientes , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/patologia , Quinazolinas/toxicidade , Segurança , Taxa de Sobrevida , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangueRESUMO
OBJECTIVE: To identify predictors of comprehensive sex education in public schools. METHODS: Using a three-stage design, 335 sex education teachers from a probability sample of 201 schools in 112 Illinois school districts were surveyed regarding the 2003-2004 school year. Coverage of at least all of the following topics constituted "comprehensiveness": abstinence, human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), other sexually transmitted diseases (STDs), and contraception. A logistic regression model identified predictors of comprehensiveness. RESULTS: Representing 91.3% of sampled schools, the teacher survey response rate was 62.4%. The most frequently taught topics included HIV/AIDS (97%), STDs (96%), and abstinence-until-marriage (89%). The least frequently taught topics were emergency contraception (31%), sexual orientation (33%), condom (34%) and other contraceptive (37%) use, and abortion (39%). Abstinence-only curricula were used by 74% of teachers, but 33% of these teachers supplemented with "other" curricula. Overall, two thirds met comprehensiveness criteria based on topics taught. Curricular material availability was most commonly cited as having a "great deal" of influence on topics taught. Thirty percent had no training in sex education; training was the only significant predictor of providing comprehensive sex education in multivariable analysis. CONCLUSION: Illinois public school-based sex education emphasizes abstinence and STDs and is heavily influenced by the available curricular materials. Nearly one in three sex education teachers were not trained. Obstetrician-gynecologists caring for adolescents may need to fill gaps in adolescent knowledge and skills due to deficits in content, quality, and teacher training in sex education. LEVEL OF EVIDENCE: III.
Assuntos
Comportamento do Adolescente , Educação Sexual , Comportamento Sexual , Ensino/normas , Aborto Induzido , Adolescente , Preservativos/estatística & dados numéricos , Anticoncepção/métodos , Anticoncepção/psicologia , Feminino , Infecções por HIV/prevenção & controle , Infecções por HIV/psicologia , Humanos , Illinois , Modelos Logísticos , Masculino , Gravidez , Estupro/psicologia , Sexo Seguro/psicologia , Instituições Acadêmicas , Abstinência Sexual/psicologia , Infecções Sexualmente Transmissíveis/prevenção & controle , Infecções Sexualmente Transmissíveis/psicologia , Violência/psicologiaRESUMO
BACKGROUND: The aim of this study was to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), and determine the phase II dose for the combination of irinotecan-carboplatin-paclitaxel given as induction chemotherapy and with concomitant chest radiotherapy for patients with Stage III non-small cell lung cancer. METHODS: Patients with Cancer and Leukemia Group B performance status of 0 to 2, stage IIIA and IIIB NSCLC patients with resectable or unresectable disease were treated with induction chemotherapy (irinotecan 100 mg/m2, carboplatin AUC 5, and paclitaxel 175 mg/m2 days 1 and 22) followed by concomitant chemotherapy (irinotecan, carboplatin, and paclitaxel) and chest radiotherapy (66 Gy for unresectable and 50 Gy for resectable disease) beginning on week 7. The primary objective was to escalate the dose of irinotecan during chemoradiation in sequential cohorts to determine the DLT and MTD of the regimen. RESULTS: Thirty-eight patients were enrolled (median age 63 years, 57% male, 41% performance status 0, 30% resectable). Induction chemotherapy was tolerable and active (response rate 26%; stable disease 60%). Eight patients did not receive concurrent chemoradiotherapy because of progressive disease (5), death (1), hypersensitivity reaction to paclitaxel (1), and withdrawal of consent (1). Twenty-nine patients received concurrent chemoradiotherapy. The concomitant administration of chest radiotherapy with weekly irinotecan, carboplatin, and paclitaxel was not feasible at the first, second, and third dose levels. DLT was failure to achieve recovery to Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica
, Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico
, Carcinoma Pulmonar de Células não Pequenas/radioterapia
, Neoplasias Pulmonares/tratamento farmacológico
, Neoplasias Pulmonares/radioterapia
, Adulto
, Idoso
, Idoso de 80 Anos ou mais
, Antineoplásicos/administração & dosagem
, Antineoplásicos Fitogênicos/administração & dosagem
, Camptotecina/administração & dosagem
, Camptotecina/análogos & derivados
, Carboplatina/administração & dosagem
, Carcinoma Pulmonar de Células não Pequenas/patologia
, Terapia Combinada
, Relação Dose-Resposta a Droga
, Feminino
, Humanos
, Irinotecano
, Neoplasias Pulmonares/patologia
, Masculino
, Pessoa de Meia-Idade
, Estadiamento de Neoplasias
, Paclitaxel/administração & dosagem
, Análise de Sobrevida