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1.
Oncologist ; 28(1): 59-71, 2023 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-35881028

RESUMO

BACKGROUND: Preserving health-related quality of life (HRQOL) is an important goal during renal cell carcinoma treatment. We report HRQOL outcomes from a phase II trial (NCT03173560). PATIENTS AND METHODS: HRQOL data were collected during a multicenter, randomized, open-label phase II study comparing the safety and efficacy of 2 different starting doses of lenvatinib (18 mg vs. 14 mg daily) in combination with everolimus (5 mg daily), following one prior vascular endothelial growth factor-targeted treatment. HRQOL was measured using 3 different instruments-FKSI-DRS, EORTC QLQ-C30, and EQ-5D-3L-which were all secondary endpoints. Change from baseline was assessed using linear mixed-effects models. Deterioration events for time to deterioration (TTD) analyses were defined using established thresholds for minimally important differences in the change from baseline for each scale. TTD for each treatment arm was estimated using the Kaplan-Meier method. RESULTS: Baseline characteristics of the 343 participants randomly assigned to 18 mg lenvatinib (n = 171) and 14 mg lenvatinib (n = 172) were well balanced. Least-squares mean estimates for change from baseline were favorable for the 18 mg group over the 14 mg group for the FKSI-DRS and most EORTC QLQ-C30 scales, but differences between treatments did not exceed the minimally important thresholds. Median TTD was longer among participants in the 18 mg group than those in the 14 mg group for most scales. CONCLUSIONS: Participants who received an 18 mg lenvatinib starting dose had favorable HRQOL scores and longer TTD on most scales compared with those who received a 14 mg starting dose.


Assuntos
Antineoplásicos , Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Everolimo/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Qualidade de Vida , Fator A de Crescimento do Endotélio Vascular , Antineoplásicos/administração & dosagem
2.
Lancet Oncol ; 23(6): 768-780, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35489363

RESUMO

BACKGROUND: Results from the phase 3 CLEAR study showed that lenvatinib plus pembrolizumab improved progression-free survival and overall survival compared with sunitinib in patients with advanced renal cell carcinoma. We aimed to assess the health-related quality-of-life (HRQOL) outcomes from the CLEAR study. METHODS: This open-label, randomised, phase 3 study was done across 200 hospitals and cancer centres in 20 countries. Patients were required to be 18 years or older, with advanced clear-cell renal cell carcinoma, and a Karnofsky performance status of 70% or higher. Patients who had received previous systemic anticancer therapy for renal cell carcinoma were not eligible. Patients were randomly assigned (1:1:1) to lenvatinib (oral 20 mg per day) plus pembrolizumab (intravenous 200 mg every 21 days), lenvatinib (oral 18 mg per day) plus everolimus (oral 5 mg per day) in 21-day cycles, or sunitinib (oral 50 mg per day, 4 weeks on followed by 2 weeks off). Patients were assigned to treatments with a computer-generated randomisation scheme and were stratified by geographical region and Memorial Sloan Kettering Cancer Center prognostic groups. The primary endpoint, previously reported, was progression-free survival, and HRQOL was a secondary endpoint. Most HRQOL analyses were done in patients who underwent randomisation, received at least one dose of study treatment, and had any HRQOL data. Completion and compliance analyses were done in the full analysis set. Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease-Related Symptoms (FKSI-DRS), European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), and the EQ-5D-3 Level (EQ-5D-3L) preference questionnaire were administered at baseline and on day 1 of each subsequent 21-day cycle. This study is registered with ClinicalTrials.gov, NCT02811861, and is closed to new participants. FINDINGS: Between Oct 13, 2016, and July 24, 2019, 355 patients were randomly assigned to the lenvatinib plus pembrolizumab group, 357 to the lenvatinib plus everolimus group, and 357 to the sunitinib group. Median follow-up for HRQOL analyses was 12·9 months (IQR 5·6-22·3). Because of the promising efficacy and safety results of lenvatinib plus pembrolizumab in the first-line setting, we focus the HRQOL results in this report on that combination versus sunitinib. Mean change from baseline in the lenvatinib plus pembrolizumab group compared with the sunitinib group was -1·75 (SE 0·59) versus -2·19 (0·66) for FKSI-DRS, -5·93 (0·86) versus -6·73 (0·94) for EORTC QLQ-C30 global health status/quality of life (GHS/QOL), and -4·96 (0·85) versus -6·64 (0·94) for the EQ-5D visual analogue scale (VAS). Median time to first deterioration in the lenvatinib plus pembrolizumab group compared with the sunitinib group was 9·14 weeks (95% CI 6·43-12·14) versus 12·14 weeks (9·14-15·29; HR 1·13 [95% CI 0·94-1·35], log-rank p=0·20) for FKSI-DRS, 12·00 weeks (7·29-15·14) versus 9·14 weeks (6·29-12·14; 0·88 [0·74-1·05], log-rank p=0·17) for EORTC QLQ-C30 GHS/QOL, and 9·43 weeks (6·43-12·29) versus 9·14 weeks (6·29-12·00; 0·83 [0·70-0·99], log-rank p=0·041) for the EQ-5D VAS. Median time to definitive deterioration in the lenvatinib plus pembrolizumab group compared with the sunitinib group was 134·14 weeks (95% CI 120·00-not estimable) versus 117·43 weeks (90·14-131·29; HR 0·70 [95% CI 0·53-0·92], log-rank p=0·0081) for FKSI-DRS, 114·29 weeks (102·14-153·29) versus 75·14 weeks (57·29-105·14; 0·60 [0·47-0·77], log-rank p<0·0001) for EORTC QLQ-C30 GHS/QOL, and 124·86 weeks (94·71-134·57) versus 74·86 weeks (54·14-96·00; 0·67 [0·53-0·85], log-rank p=0·0012) for the EQ-5D VAS. No outcomes on any of the instruments significantly favoured sunitinib over lenvatinib plus pembrolizumab. Most HRQOL comparisons of lenvatinib plus everolimus versus sunitinib were similar or favoured sunitinib. INTERPRETATION: These HRQOL results demonstrate that patients given lenvatinib plus pembrolizumab treatment had similar or favourable scores compared with patients given sunitinib, particularly with respect to time to definitive deterioration. These results support the efficacy and safety profile of lenvatinib plus pembrolizumab as first-line therapy for patients with advanced renal cell carcinoma. FUNDING: Eisai (Nutley, NJ, USA) and Merck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA).


Assuntos
Carcinoma de Células Renais , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Everolimo , Humanos , Compostos de Fenilureia , Qualidade de Vida , Quinolinas , Sunitinibe
3.
Nicotine Tob Res ; 21(2): 241-248, 2019 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29370401

RESUMO

Introduction: Cue reactivity (CR) research has reliably demonstrated robust cue-induced responding among smokers exposed to common proximal smoking cues (eg, cigarettes, lighter). More recent work demonstrates that distal stimuli, most notably the actual environments in which smoking previously occurred, can also gain associative control over craving. In the real world, proximal cues always occur within an environment; thus, a more informative test of how cues affect smokers might be to present these two cue types simultaneously. Methods: Using a combined-cue counterbalanced CR paradigm, the present study tested the impact of proximal (smoking and neutral) + personal environment (smoking and nonsmoking places) pictorial cues, on smokers' subjective and behavioral CR; as well as the extent to which cue-induced craving predicts immediate subsequent smoking in a within-subjects design. Results: As anticipated, the dual smoking cue combination (ProxS + EnvS) led to the greatest cue-induced craving relative to the other three cue combinations (ProxS + EnvN, ProxN + EnvS, and ProxN ± EnvN), ps < .004. Dual smoking cues also led to significantly shorter post-trial latencies to smoke, ps < .01. Overall CR difference score (post-trial craving minus baseline craving) was predictive of subsequent immediate smoking indexed by: post-trial latency to smoke [B = -2.69, SE = 9.02; t(143) = -2.98, p = .003]; total puff volume [B = 2.99, SE = 1.13; t(143) = 2.65, p = .009]; and total number of puffs [B = .053, SE = .027; t(143) = 1.95, p = .05]. Conclusions: The implications of these findings for better understanding the impact of cues on smoking behavior and cessation are discussed. Implications: This novel cue reactivity study examined smokers' reactivity to combined proximal and distal smoking cues. Exposure to a combination of two smoking cues (proximal and environment) led to the greatest increases in cue-induced craving and smoking behavior compared to all other cue combinations. Further, the overall magnitude of cue-induced craving was found to significantly predict immediate subsequent smoking. This work provides new insight on how exposure to various cues and cue combinations directly affect smokers' craving and actual smoking behavior, as well as the relationship between those two indices of reactivity.


Assuntos
Condicionamento Psicológico , Sinais (Psicologia) , Abandono do Hábito de Fumar/métodos , Abandono do Hábito de Fumar/psicologia , Fumar/psicologia , Fumar/terapia , Adulto , Condicionamento Psicológico/fisiologia , Feminino , Previsões , Humanos , Masculino , Pessoa de Meia-Idade , Fumantes/psicologia , Fumar Tabaco/psicologia , Fumar Tabaco/terapia , Adulto Jovem
4.
Cephalalgia ; 37(14): 1384-1397, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28758415

RESUMO

Objective To examine treatment utilization patterns and safety of onabotulinumtoxinA for the prophylactic treatment of chronic migraine in routine clinical practice. Background Clinical trials support onabotulinumtoxinA for the prophylaxis of headache in patients with chronic migraine, but real-world data are limited. Design/methods A prospective, observational, post-authorization study in adult patients with chronic migraine treated with onabotulinumtoxinA. Data were collected at the first study injection and approximately every three months for ≤52 weeks for utilization and ≤64 weeks for safety data, and summarized using descriptive statistics. Results Eighty-five physicians (81% neurologists) at 58 practices in the United Kingdom, Germany, Spain, and Sweden participated and recruited 1160 patients (84.2% female, median age 46.6 years). At baseline, 85.8% of patients had physician diagnoses of chronic migraine/transformed migraine and reported an average of 11.3 (SD = 6.9) severe headache days per 28 days; 50.6% had previously used onabotulinumtoxinA for chronic migraine. A total of 4017 study treatments were observed. The median number of injection sites (n = 31) and total dose (155 U) were consistent across all treatment sessions, with a median 13.7 weeks observed between sessions. At least one treatment-related adverse event was reported by 291 patients (25.1%); the most frequently reported treatment-related adverse event was neck pain (4.4%). Most patients (74.4%) were satisfied/extremely satisfied with onabotulinumtoxinA treatment. Conclusions Patient demographics/characteristics are consistent with published data on the chronic migraine population. Utilization of onabotulinumtoxinA treatment for chronic migraine appears to be consistent with the Summary of Product Characteristics and published PREEMPT injection paradigm. No new safety signals were identified.


Assuntos
Inibidores da Liberação da Acetilcolina/administração & dosagem , Toxinas Botulínicas Tipo A/administração & dosagem , Internacionalidade , Transtornos de Enxaqueca/epidemiologia , Transtornos de Enxaqueca/prevenção & controle , Profilaxia Pré-Exposição/métodos , Inibidores da Liberação da Acetilcolina/efeitos adversos , Adulto , Blefaroptose/induzido quimicamente , Toxinas Botulínicas Tipo A/efeitos adversos , Doença Crônica , Europa (Continente)/epidemiologia , Feminino , Humanos , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/diagnóstico , Cervicalgia/induzido quimicamente , Estudos Prospectivos , Resultado do Tratamento
5.
Cancer ; 119(10): 1908-15, 2013 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-23504821

RESUMO

BACKGROUND: The randomized, controlled BOLERO-2 (Breast Cancer Trials of Oral Everolimus) trial demonstrated significantly improved progression-free survival with the use of everolimus plus exemestane (EVE + EXE) versus placebo plus exemestane (PBO + EXE) in patients with advanced breast cancer who developed disease progression after treatment with nonsteroidal aromatase inhibitors. This analysis investigated the treatment effects on health-related quality of life (HRQOL). METHODS: Using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) questionnaire, HRQOL was assessed at baseline and every 6 weeks thereafter until disease progression and/or treatment discontinuation. The 30 items in 15 subscales of the QLQ-C30 include global health status wherein higher scores (range, 0-100) indicate better HRQOL. This analysis included a protocol-specified time to definitive deterioration (TDD) analysis at a 5% decrease in HRQOL versus baseline, with no subsequent increase above this threshold. The authors report additional sensitivity analyses using 10-point minimal important difference decreases in the global health status score versus baseline. Treatment arms were compared using the stratified log-rank test and Cox proportional hazards model adjusted for trial stratum (visceral metastases, previous hormone sensitivity), age, sex, race, baseline global health status score and Eastern Cooperative Oncology Group performance status, prognostic risk factors, and treatment history. RESULTS: Baseline global health status scores were found to be similar between treatment groups (64.7 vs 65.3). The median TDD in HRQOL was 8.3 months with EVE + EXE versus 5.8 months with PBO + EXE (hazard ratio, 0.74; P = .0084). At the 10-point minimal important difference, the median TDD with EVE + EXE was 11.7 months versus 8.4 months with PBO + EXE (hazard ratio, 0.80; P = .1017). CONCLUSIONS: In patients with advanced breast cancer who develop disease progression after treatment with nonsteroidal aromatase inhibitors, EVE + EXE was associated with a longer TDD in global HRQOL versus PBO + EXE.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Qualidade de Vida , Adulto , Idoso , Androstadienos/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/patologia , Neoplasias da Mama/psicologia , Progressão da Doença , Método Duplo-Cego , Esquema de Medicação , Everolimo , Feminino , Nível de Saúde , Humanos , Pessoa de Meia-Idade , Razão de Chances , Pós-Menopausa , Modelos de Riscos Proporcionais , Sirolimo/administração & dosagem , Sirolimo/análogos & derivados , Inquéritos e Questionários , Resultado do Tratamento
6.
Int J Colorectal Dis ; 26(2): 173-81, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21190026

RESUMO

PURPOSE: Panitumumab monotherapy is approved for chemotherapy-refractory wild-type KRAS metastatic colorectal cancer (mCRC). Patient-reported outcomes-although important in the palliative setting-have not been reported in this patient population. METHODS: In a phase 3 trial (n = 463), patients with chemotherapy-refractory mCRC were randomized 1:1 to panitumumab plus best supportive care (BSC) or BSC alone. Patient-reported outcomes were assessed using the NCCN/FACT CRC Symptom Index (FCSI) and EQ-5D Index. KRAS tumor status was analyzed in a prospectively defined, retrospective analysis. Average difference in change from baseline between treatment groups was evaluated using linear mixed and pattern-mixture models. RESULTS: KRAS tumor status and post-baseline patient-reported outcomes were available for 363 patients. Linear mixed models indicated significant differences in the FCSI score (difference in least-squares [LS] adjusted means [95% CI]; 5.62 [2.38, 8.86]) and the EQ-5D Index (difference in LS adjusted means [95% CI]; 0.22 [0.12, 0.32]) favoring panitumumab over BSC in patients with wild-type KRAS mCRC. By pattern-mixture analysis, the advantage of panitumumab over BSC was more pronounced in those patients with wild-type KRAS mCRC who did not drop out of the study early. In patients with mutant KRAS mCRC, no differences were observed between groups. CONCLUSIONS: Panitumumab-treated patients with wild-type KRAS mCRC maintained better control of CRC symptoms and quality of life compared with BSC alone, extending our understanding of the benefits of panitumumab treatment beyond improvements in progression-free survival.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos , Saúde , Qualidade de Vida , Neoplasias Colorretais/genética , Humanos , Análise dos Mínimos Quadrados , Modelos Lineares , Metástase Neoplásica , Panitumumabe , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Proteínas ras/genética
7.
J Patient Rep Outcomes ; 5(1): 82, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34491454

RESUMO

BACKGROUND: Long-acting somatostatin analogs (LA SSAs) are approved and recommended for the treatment of patients with advanced neuroendocrine tumors (NETs). Given the long duration of therapy and differences in administration routes, it is important to understand patients' experiences with receiving LA SSA injections. METHODS: We conducted a serial survey, informed by qualitative interviews with eight patients treated with LA SSAs and two nurses who administer LA SSA injections, among patients undergoing LA SSA treatment over a 28-day period (administered at baseline and 14 days and 28 days after injection). Eligible patients, recruited by the Carcinoid Cancer Foundation, self-reported having received an LA SSA injection for physician-diagnosed NET within the 5 days before the survey. RESULTS: 202 patients completed the survey at baseline (82 receiving lanreotide and 120 receiving octreotide), 148 at day 14, and 124 at day 28. Patients reported consistently high satisfaction levels with their most recent LA SSA injection (91.1% at baseline, 85.1% at day 14, and 85.5% at day 28); 68.8% reported that their injection experience differed based on the nursing staff administering the injection. CONCLUSIONS: Satisfaction with LA SSA injections is high among patients in this population, and specific experiences with LA SSA injections varied based on the nursing staff administering the injection. Evaluations of patients' experiences and satisfaction with treatment are increasingly important as patients take more active roles in decision-making for their treatment pathways.

8.
Lancet Gastroenterol Hepatol ; 6(8): 649-658, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34087115

RESUMO

BACKGROUND: Hepatocellular carcinoma is the third-leading cause of cancer-related death worldwide. Preservation of health-related quality of life (HRQOL) during treatment is an important therapeutic goal. The aim of this study was to evaluate the effect of treatment with lenvatinib versus sorafenib on HRQOL. METHODS: REFLECT was a previously published multicentre, randomised, open-label, non-inferiority phase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib as a first-line systemic treatment for unresectable hepatocellular carcinoma. Eligible patients were aged 18 years or older with unresectable hepatocellular carcinoma and one or more measurable target lesion per modified Response Evaluation Criteria in Solid Tumors criteria, Barcelona Clinic Liver Cancer stage B or C categorisation, Child-Pugh class A, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or lower, and adequate organ function. Patients were randomly assigned (1:1) via an interactive voice-web response system; stratification factors for treatment allocation included region; macroscopic portal vein invasion, extrahepatic spread, or both; ECOG performance status; and bodyweight. Patient-reported outcomes (PROs), collected at baseline, on day 1 of each subsequent cycle, and at the end of treatment, were evaluated in post-hoc analyses of secondary and exploratory endpoints in the analysis population, which was the subpopulation of patients with a PRO assessment at baseline. A linear mixed-effects model evaluated change from baseline in PROs, including European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and hepatocellular carcinoma-specific QLQ-HCC18 scales (both secondary endpoints of the REFLECT trial). Time-to-definitive-deterioration analyses were done based on established thresholds for minimum differences for worsening in PROs. Responder analyses explored associations between HRQOL and clinical response. This study is registered with ClinicalTrials.gov, NCT01761266. FINDINGS: Of 954 eligible patients randomly assigned to lenvatinib (n=478) or sorafenib (n=476) between March 14, 2013, and July 30, 2015, 931 patients (n=468 for lenvatinib; n=463 for sorafenib) were included in this analysis. Baseline PRO scores reflected impaired HRQOL and functioning and considerable symptom burden relative to full HRQOL. Differences in overall mean change from baseline estimates in most PRO scales generally favoured the lenvatinib over the sorafenib group, although the differences were not nominally statistically or clinically significant. Patients treated with lenvatinib experienced nominally statistically significant delays in definitive, meaningful deterioration on the QLQ-C30 fatigue (hazard ratio [HR] 0·83, 95% CI 0·69-0·99), pain (0·80, 0·66-0·96), and diarrhoea (0·52, 0·42-0·65) domains versus patients treated with sorafenib. Significant differences in time to definitive deterioration were not observed for other QLQ-C30 domains, and there was no difference in time to definitive deterioration on the global health status/QOL score (0·89, 0·73-1·09). For most PRO scales, differences in overall mean change from baseline estimates favoured responders versus non-responders. Across all scales, HRs for time to definitive deterioration were in favour of responders; median time to definitive deterioration for responders exceeded those for non-responders by a range of 4·8 to 14·6 months. INTERPRETATION: HRQOL for patients undergoing treatment for unresectable hepatocellular carcinoma is an important therapeutic consideration. The evidence of HRQOL benefits in clinically relevant domains support the use of lenvatinib compared with sorafenib to delay functional deterioration in advanced hepatocellular carcinoma. FUNDING: Eisai and Merck Sharp & Dohme.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Estadiamento de Neoplasias , Medidas de Resultados Relatados pelo Paciente , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Sorafenibe/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/diagnóstico , Humanos , Neoplasias Hepáticas/diagnóstico , Resultado do Tratamento
10.
J Affect Disord ; 90(2-3): 217-21, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16360216

RESUMO

BACKGROUND: Research has shown that lack of treatment adherence is a serious problem, especially among patients with psychiatric disorders. The current study was conducted to assess adherence and patient preference among individuals taking Wellbutrin SR (bupropion) for depression, as well as their interest in a once-daily formulation of bupropion. METHODS: A 20-item web-based survey was administered to 527 individuals (276 men and 251 women) recruited through an online panel. All participants were at least 18 years of age, diagnosed with major depressive disorder, and had been taking Wellbutrin SR for at least 6 weeks. Survey items addressed treatment regimen, adherence, satisfaction with Wellbutrin SR, and interest in a once-daily formulation of bupropion. RESULTS: The majority of respondents reported taking Wellbutrin SR twice a day (67%). Only 15% of once-daily users were nonadherent compared to 37% of twice-daily users and 65% of thrice-daily users. The most common reason reported for missing a dose of Wellbutrin SR was simply forgetting to take it (49% of twice-daily users and 65% of thrice-daily users). Results indicated that 77% of twice-daily users and 94% of thrice-daily users were interested in a once-daily formula. CONCLUSIONS: A reduction in dosing frequency is favored by Wellbutrin SR users and likely to improve their adherence to treatment. Because greater adherence has been shown to facilitate symptom relief, improvements in quality of life, and reductions in healthcare expenses, the results of this study support the value of the recently released once-daily formulation, Wellbutrin XL.


Assuntos
Antidepressivos de Segunda Geração/administração & dosagem , Bupropiona/administração & dosagem , Transtorno Depressivo/tratamento farmacológico , Cooperação do Paciente/psicologia , Satisfação do Paciente , Adulto , Idoso , Antidepressivos de Segunda Geração/efeitos adversos , Bupropiona/efeitos adversos , Preparações de Ação Retardada , Transtorno Depressivo/psicologia , Esquema de Medicação , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida/psicologia
11.
Mol Cancer Res ; 1(4): 300-11, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12612058

RESUMO

Tamoxifen is a widely used breast cancer therapeutic and preventative agent. Although functioning as an estrogen antagonist at the cellular level, transcriptional profiling revealed that at the molecular level, tamoxifen functions largely as an agonist, virtually recapitulating the gene expression profile induced in breast cancer cells by estrogen. Remarkably, tamoxifen induces transcription factors and genes involved in promoting cell cycle progression including fos, myc, myb, cdc25a, cyclins E and A2, and stk15 with kinetics that paralleled that of cells cycling in response to estrogen, even though tamoxifen-treated cells are not transiting through the cell cycle. Induction of cell cycle-associated genes was specific for tamoxifen, and did not occur with raloxifene. However, cyclin D1 was a key estrogen-induced gene not expressed in response to tamoxifen or raloxifene but constitutively expressed in tamoxifen-resistant cells.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Genes cdc/fisiologia , Tamoxifeno/análogos & derivados , Tamoxifeno/farmacologia , Neoplasias da Mama/patologia , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Estrogênios/metabolismo , Estrogênios/farmacologia , Perfilação da Expressão Gênica , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tamoxifeno/metabolismo , Fatores de Tempo
12.
Mol Endocrinol ; 16(6): 1215-29, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12040010

RESUMO

The steroid hormone estrogen can stimulate mitogenesis in hormone-responsive breast cancer epithelial cells. This action is attributed to the transcriptional activity of the ER, a ligand-dependent transcription factor. However, the exact molecular mechanism underlying estrogen-induced proliferation has yet to be completely elucidated. Using custom cDNA microarrays containing many genes implicated in cell cycle progression and DNA replication, we examined the gene expression of a hormone-responsive breast cancer cell line (MCF-7) treated with a mitogenic dose of estrogen in the absence of confounding growth factors found in serum. Gene expression changes were monitored 1, 4, 12, 24, 36, and 48 h after estrogen stimulation so that RNA levels at critical times throughout cell cycle progression could be monitored. Significant changes include the altered transcript levels of genes implicated in transcription, cellular signaling, and cell cycle checkpoints. At time points during which increased numbers of cells were progressing through S phase, a majority of the genes associated with the DNA replication fork were also found to be induced. The coexpression of DNA replication fork genes by estrogen without the support of serum growth factors indicates an important estrogen regulatory component of the molecular mechanism driving estrogen-induced mitogenesis.


Assuntos
Replicação do DNA/efeitos dos fármacos , Estradiol/farmacologia , Divisão Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Receptor alfa de Estrogênio , Receptor beta de Estrogênio , Etanol/farmacologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , RNA Mensageiro/genética , Receptores de Estrogênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas
13.
Environ Health Perspect ; 112(4): 465-79, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15033597

RESUMO

This study, designed and conducted as part of the International Life Sciences Institute working group on the Application of Genomics and Proteomics, examined the changes in the expression profile of genes associated with the administration of three different nephrotoxicants--cisplatin, gentamicin, and puromycin--to assess the usefulness of microarrays in the understanding of mechanism(s) of nephrotoxicity. Male Sprague-Dawley rats were treated with daily doses of puromycin (5-20 mg/kg/day for 21 days), gentamicin (2-240 mg/kg/day for 7 days), or a single dose of cisplatin (0.1-5 mg/kg). Groups of rats were sacrificed at various times after administration of these compounds for standard clinical chemistry, urine analysis, and histological evaluation of the kidney. RNA was extracted from the kidney for microarray analysis. Principal component analysis and gene expression-based clustering of compound effects confirmed sample separation based on dose, time, and degree of renal toxicity. In addition, analysis of the profile components revealed some novel changes in the expression of genes that appeared to be associated with injury in specific portions of the nephron and reflected the mechanism of action of these various nephrotoxicants. For example, although puromycin is thought to specifically promote injury of the podocytes in the glomerulus, the changes in gene expression after chronic exposure of this compound suggested a pattern similar to the known proximal tubular nephrotoxicants cisplatin and gentamicin; this prediction was confirmed histologically. We conclude that renal gene expression profiling coupled with analysis of classical end points affords promising opportunities to reveal potential new mechanistic markers of renal toxicity.


Assuntos
Perfilação da Expressão Gênica , Marcadores Genéticos , Rim/efeitos dos fármacos , Rim/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Animais , Antibacterianos/toxicidade , Antimetabólitos Antineoplásicos/toxicidade , Antineoplásicos/toxicidade , Cisplatino/toxicidade , Relação Dose-Resposta a Droga , Determinação de Ponto Final , Gentamicinas/toxicidade , Masculino , Puromicina/toxicidade , Ratos , Ratos Sprague-Dawley
14.
Radiat Res ; 160(3): 273-90, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12926986

RESUMO

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by progressive cerebellar degeneration, immunodeficiencies, telangiectasias, sensitivity to ionizing radiation, and high predisposition for malignancies. The ataxia telangiectasia mutated (ATM) gene encodes a protein (ATM) with serine/threonine kinase activity. DNA-double strand breaks are known to increase its kinase activity. While cells from individuals with AT are attenuated in their G(1)-, S- and G(2)-phase cell cycle checkpoint functions in response to gamma irradiation and oxidative stress, their response to UV irradiation appears to be equivalent to that of wild-type cells. In this study, we investigated changes in gene expression in response to gamma irradiation, oxidative stress, and UV irradiation, focusing on the dependence on ATM. Doses for all three treatments were selected that resulted in roughly an equivalent induction of a G(1) checkpoint response and inhibition of progression through S phase. To investigate gene expression changes, logarithmically growing wild-type and AT dermal diploid fibroblasts were exposed to either gamma radiation (5 Gy), oxidative stress (75 micro M t-butyl-hydroperoxide), or UV radiation (7.5 J/m(2)), and RNA was harvested 6 h after treatment. Gene expression analysis was performed using the NIEHS Human ToxChip 2.0 with approximately 1900 cDNA clones representing known genes and ESTs. All three treatments resulted in distinct patterns of gene expression changes, as shown previously. ATM-dependent and ATM-independent components were detected within these patterns, as were novel indications of involvement of ATM in regulation of transcription factors such as SP1, AP1 and MTF1.


Assuntos
Raios gama , Regulação da Expressão Gênica , Estresse Oxidativo , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Serina-Treonina Quinases/genética , Raios Ultravioleta , Algoritmos , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular , Linhagem Celular , Células Cultivadas , Ciclina E/metabolismo , Dano ao DNA , DNA Complementar/metabolismo , Proteínas de Ligação a DNA , Regulação para Baixo , Etiquetas de Sequências Expressas , Fibroblastos/metabolismo , Fase G1 , Fase G2 , Histonas/metabolismo , Humanos , Modelos Biológicos , Família Multigênica , Análise de Sequência com Séries de Oligonucleotídeos , RNA/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fase S , Fatores de Transcrição/metabolismo , Transcrição Gênica , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor , Regulação para Cima
15.
Toxicol Sci ; 67(2): 219-31, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12011481

RESUMO

The application of gene expression profiling technology to examine multiple genes and signaling pathways simultaneously promises a significant advance in understanding toxic mechanisms to ultimately aid in protection of public health. Public and private efforts in the new field of toxicogenomics are focused on populating databases with gene expression profiles of compounds where toxicological and pathological endpoints are well characterized. The validity and utility of a toxicogenomics is dependent on whether gene expression profiles that correspond to different chemicals can be distinguished. The principal hypothesis underlying a toxicogenomic or pharmacogenomic strategy is that chemical-specific patterns of altered gene expression will be revealed using high-density microarray analysis of tissues from exposed organisms. Analyses of these patterns should allow classification of toxicants and provide important mechanistic insights. This report provides a verification of this hypothesis. Patterns of gene expression corresponding to liver tissue derived from chemically exposed rats revealed similarity in gene expression profiles between animals treated with different agents from a common class of compounds, peroxisome proliferators [clofibrate (ethyl-p-chlorophenoxyisobutyrate), Wyeth 14,643 ([4-chloro-6(2,3-xylidino)-2-pyrimidinylthio]acetic acid), and gemfibrozil (5-2[2,5-dimethylphenoxy]2-2-dimethylpentanoic acid)], but a very distinct gene expression profile was produced using a compound from another class, enzyme inducers (phenobarbital).


Assuntos
Perfilação da Expressão Gênica/métodos , Expressão Gênica , Genômica , Proliferadores de Peroxissomos/toxicidade , Fenobarbital/toxicidade , Animais , Clofibrato/química , Clofibrato/toxicidade , Biologia Computacional , DNA Complementar/análise , Genfibrozila/química , Genfibrozila/toxicidade , Perfilação da Expressão Gênica/classificação , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Reconhecimento Automatizado de Padrão , Proliferadores de Peroxissomos/química , Fenobarbital/química , Pirimidinas/química , Pirimidinas/toxicidade , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Relação Estrutura-Atividade
16.
Toxicol Sci ; 67(2): 232-40, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12011482

RESUMO

DNA microarrays, used to measure the gene expression of thousands of genes simultaneously, hold promise for future application in efficient screening of therapeutic drugs. This will be aided by the development and population of a database with gene expression profiles corresponding to biological responses to exposures to known compounds whose toxicological and pathological endpoints are well characterized. Such databases could then be interrogated, using profiles corresponding to biological responses to drugs after developmental or environmental exposures. A positive correlation with an archived profile could lead to some knowledge regarding the potential effects of the tested compound or exposure. We have previously shown that cDNA microarrays can be used to generate chemical-specific gene expression profiles that can be distinguished across and within compound classes, using clustering, simple correlation, or principal component analyses. In this report, we test the hypothesis that knowledge can be gained regarding the nature of blinded samples, using an initial training set comprised of gene expression profiles derived from rat liver exposed to clofibrate, Wyeth 14,643, gemfibrozil, or phenobarbital for 24 h or 2 weeks of exposure. Highly discriminant genes were derived from our database training set using approaches including linear discriminant analysis (LDA) and genetic algorithm/K-nearest neighbors (GA/KNN). Using these genes in the analysis of coded liver RNA samples derived from 24-h, 3-day, or 2-week exposures to phenytoin, diethylhexylpthalate, or hexobarbital led to successful prediction of whether these samples were derived from livers of rats exposed to enzyme inducers or to peroxisome proliferators. This validates our initial hypothesis and lends credibility to the concept that the further development of a gene expression database for chemical effects will greatly enhance the hazard identification processes.


Assuntos
Bases de Dados Factuais , Perfilação da Expressão Gênica/métodos , Genômica , Biossíntese de Proteínas , Xenobióticos/toxicidade , Algoritmos , Animais , Biologia Computacional , DNA Complementar/análise , Dietilexilftalato/toxicidade , Análise Discriminante , Relação Dose-Resposta a Droga , Perfilação da Expressão Gênica/classificação , Hexobarbital/toxicidade , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Reconhecimento Automatizado de Padrão , Fenitoína/toxicidade , Valor Preditivo dos Testes , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Padrões de Referência , Método Simples-Cego , Relação Estrutura-Atividade , Xenobióticos/química
17.
Toxicology ; 181-182: 555-63, 2002 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-12505366

RESUMO

Assessment of the impact of xenobiotic exposure on human health and disease progression is complex. Knowledge of mode(s) of action, including mechanism(s) contributing to toxicity and disease progression, is valuable for evaluating compounds. Toxicogenomics, the subdiscipline which merges genomics with toxicology, holds the promise to contributing significantly toward the goal of elucidating mechanism(s) by studying genome-wide effects of xenobiotics. Global gene expression profiling, revolutionized by microarray technology and a crucial aspect of a toxicogenomic study, allows measuring transcriptional modulation of thousands of genes following exposure to a xenobiotic. We use our results from previous studies on compounds representing two different classes of xenobiotics (barbiturate and peroxisome proliferator) to discuss the application of computational approaches for analyzing microarray data to elucidate mechanism(s) underlying cellular responses to toxicants. In particular, our laboratory demonstrated that chemical-specific patterns of gene expression can be revealed using cDNA microarrays. Transcript profiling provides discrimination between classes of toxicants, as well as, genome-wide insight into mechanism(s) of toxicity and disease progression. Ultimately, the expectation is that novel approaches for predicting xenobiotic toxicity in humans will emerge from such information.


Assuntos
Farmacogenética/métodos , Xenobióticos/toxicidade , Biologia Computacional , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , National Institutes of Health (U.S.) , Análise de Sequência com Séries de Oligonucleotídeos , Estados Unidos
18.
Curr Med Res Opin ; 29(11): 1463-73, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23962028

RESUMO

OBJECTIVE: Everolimus (EVE)+exemestane (EXE; n = 485) more than doubled median progression-free survival versus placebo (PBO) + EXE (n = 239), with a manageable safety profile and no deterioration in health-related quality-of-life (HRQOL) in patients with hormone-receptor-positive (HR(+)) advanced breast cancer (ABC) who recurred or progressed on/after nonsteroidal aromatase inhibitor (NSAI) therapy. To further evaluate EVE + EXE impact on disease burden, we conducted additional post-hoc analyses of patient-reported HRQOL. RESEARCH DESIGN AND METHODS: HRQOL was assessed using EORTC QLQ-C30 and QLQ-BR23 questionnaires at baseline and every 6 weeks thereafter until treatment discontinuation because of disease progression, toxicity, or consent withdrawal. Endpoints included the QLQ-C30 Global Health Status (QL2) scale, the QLQ-BR23 breast symptom (BRBS), and arm symptom (BRAS) scales. Between-group differences in change from baseline were assessed using linear mixed models with selected covariates. Sensitivity analysis using pattern-mixture models determined the effect of study discontinuation on/before week 24. Treatment arms were compared using differences of least squares mean (LSM) changes from baseline and 95% confidence intervals (CIs) at each timepoint and overall. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT00863655. MAIN OUTCOME MEASURES: Progression-free survival, survival, response rate, safety, and HRQOL. RESULTS: Linear mixed models (primary model) demonstrated no statistically significant overall difference between EVE + EXE and PBO + EXE for QL2 (LSM difference = -1.91; 95% CI = -4.61, 0.78), BRBS (LSM difference = -0.18; 95% CI = -1.98, 1.62), or BRAS (LSM difference = -0.42; 95% CI = -2.94, 2.10). Based on pattern-mixture models, patients who dropped out early had worse QL2 decline on both treatments. In the expanded pattern-mixture model, EVE + EXE-treated patients who did not drop out early had stable BRBS and BRAS relative to PBO + EXE. KEY LIMITATIONS: HRQOL data were not collected after disease progression. CONCLUSIONS: These analyses confirm that EVE + EXE provides clinical benefit without adversely impacting HRQOL in patients with HR(+) ABC who recurred/progressed on prior NSAIs versus endocrine therapy alone.


Assuntos
Androstadienos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Qualidade de Vida , Sirolimo/análogos & derivados , Adulto , Idoso , Androstadienos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/metabolismo , Progressão da Doença , Intervalo Livre de Doença , Everolimo , Feminino , Nível de Saúde , Humanos , Imunossupressores/uso terapêutico , Pessoa de Meia-Idade , Placebos/uso terapêutico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Sirolimo/efeitos adversos , Sirolimo/uso terapêutico , Inquéritos e Questionários , Resultado do Tratamento
19.
J Womens Health (Larchmt) ; 18(4): 461-8, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19361312

RESUMO

OBJECTIVE: The objective was to describe the healthcare and information-seeking behavior of women with self-reported sexual problems and accompanying sexually related personal distress identified from a large, population-based U.S. survey. METHODS: Women (n = 3,239) aged > or =18 years with self-reported sexual problems of desire, arousal, and/or orgasm accompanied by sexually related personal distress were identified from a cross-sectional mailed survey of 50,002 U.S. households sampled from a national research panel. Healthcare and information-seeking behavior was examined as four ordered categories: sought formal medical advice, sought informal advice, sought information from anonymous sources, and did not seek help or information. Correlates of help seeking for each type of distressing sexual problem were modeled with multivariable proportional odds regression. RESULTS: Just over a third of women with any distressing sexual problems had sought formal care, most often from a gynecologist or primary care physician; about 80% of the time, the woman, rather than the physician, initiated the conversation. Only 6% of women who sought medical advice scheduled a visit specifically for a sexual problem. Factors related to help seeking were having a current partner and interacting with the healthcare system. Barriers were poor self-perceived health and embarrassment about discussing sexual topics with a physician. CONCLUSIONS: Our results suggest inadequacies in the U.S. medical care system in addressing sexual problems in women. Gynecologists and primary care physicians, by including discussions about sexual health during routine visits, can increase the likelihood that adequate care can be offered.


Assuntos
Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Educação de Pacientes como Assunto , Disfunções Sexuais Fisiológicas , Adolescente , Idoso , Estudos Transversais , Feminino , Ginecologia , Inquéritos Epidemiológicos , Humanos , Serviços de Informação , Pessoa de Meia-Idade , Atenção Primária à Saúde , Disfunções Sexuais Fisiológicas/diagnóstico , Disfunções Sexuais Fisiológicas/terapia , Estresse Psicológico , Estados Unidos , Adulto Jovem
20.
Am J Physiol Heart Circ Physiol ; 287(3): H1404-9, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15165988

RESUMO

Previous studies have provided evidence of a non-noradrenergic contributor to reflex cutaneous vasoconstriction in humans but did not identify the transmitter responsible. To test whether neuropeptide Y (NPY) has a role, in two series of experiments we slowly reduced whole body skin temperature (TSK) from 34.5 to 31.7 degrees C. In protocol 1, Ringer solution and the NPY receptor antagonist BIBP-3226 alone were delivered intradermally via microdialysis. In protocol 2, yohimbine plus propranolol (Yoh + Pro), Yoh + Pro in combination with BIBP-3226, and Ringer solution were delivered to antagonize locally the vasomotor effects of NPY and norepinephrine. Blood flow was measured by laser Doppler flowmetry (LDF). Mean arterial blood pressure (MAP) was monitored at the finger (Finapres). In protocol 1, cutaneous vascular conductance (CVC) fell by 45%, to 55.1 +/- 5.6% of baseline at control sites (P < 0.05). At BIBP-3226-treated sites, CVC fell by 34.1% to 65.9 +/- 5.0% (P < 0.05; P < 0.05 between sites). In protocol 2, during body cooling, CVC at control sites fell by 32.6%, to 67.4 +/- 4.3% of baseline; at sites treated with Yoh + Pro, CVC fell by 18.7%, to 81.3 +/- 4.4% of baseline (P < 0.05 vs. baseline; P < 0.05 vs. control) and did not fall significantly at sites treated with BIBP-3226 + Yoh + Pro (P > 0.05; P < 0.05 vs. other sites). After cooling, exogenous norepinephrine induced vasoconstriction at control sites (P < 0.05) but not at sites treated with Yoh + Pro + BIBP-3226 (P > 0.05). These results indicate that NPY participates in sympathetically mediated cutaneous vasoconstriction in humans during whole body cooling.


Assuntos
Arginina/análogos & derivados , Neuropeptídeo Y/fisiologia , Reflexo/fisiologia , Fenômenos Fisiológicos da Pele , Pele/irrigação sanguínea , Vasoconstrição/fisiologia , Adulto , Arginina/farmacologia , Vasos Sanguíneos/efeitos dos fármacos , Temperatura Baixa , Combinação de Medicamentos , Dedos , Humanos , Soluções Isotônicas , Masculino , Neuropeptídeo Y/antagonistas & inibidores , Norepinefrina/antagonistas & inibidores , Norepinefrina/farmacologia , Norepinefrina/fisiologia , Propranolol/farmacologia , Fluxo Sanguíneo Regional/efeitos dos fármacos , Solução de Ringer , Pele/inervação , Temperatura Cutânea , Sistema Nervoso Simpático/fisiologia , Vasoconstritores/antagonistas & inibidores , Vasoconstritores/metabolismo , Vasoconstritores/farmacologia , Vasodilatadores/farmacologia , Sistema Vasomotor/efeitos dos fármacos , Sistema Vasomotor/fisiologia , Ioimbina/farmacologia
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