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The purpose of this article is to describe the lessons learned in the course of a 5-year research study on a palliative care intervention for persons on a Phase 1 clinical trial. Patients who are participating in Phase 1 trials and the families who care for them may be especially vulnerable and require special attention. The patients are generally experiencing the effects of advanced disease, and they also may soon experience unknown side effects, intense treatment regimens, and the emotional stress of an uncertain future as a result of clinical trial participation. Oncology nurses in all roles including clinical trials/research nurses, clinicians, educators, and advanced practice registered nurses play a critical role in addressing the quality-of-life concerns in this population. Palliative care can provide better symptom control and information on treatment options and facilitate a better understanding of patient/family goals. Attending to these factors can ultimately mean improved survival for the advanced cancer patient, and support for these patients can assist in advancing the field of oncology as these investigational therapies hold the promise for enhancing survival.
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OBJECTIVE: The aim of our study was to analyze the dynamics of HIV-DNA levels in CD4 T-cell subsets in individuals starting successful dolutegravir-based regimens. DESIGN: Twenty-seven individuals with acute infection (AI, nâ=â8) or chronic infection (CI, nâ=â5) and patients in virological success (VS, nâ=â10) or virological failure (VF, nâ=â4) on antiretroviral therapy (ART) who initiated a dolutegravir-based regimen were enrolled (NCT02557997). METHODS: CD4 T-cells from baseline and week 48 of successful treatment were sorted into effector memory (TEM), transitional memory (TTM), central memory (TCM) and naïve (TN) cell groups for total HIV-DNA measurements by qPCR. Bayesian methods were used to estimate the posterior probability of a HIV-DNA decrease more than 0.25 log copies/10 cells at week 48. RESULTS: All patients achieved HIV-RNA suppression at 48 weeks. At baseline and week 48, the highest contributions to the HIV-DNA-infected pool from CD4 T cells were observed in TTM cells in the AI group (62.4 and 60.2%, respectively), but in TCM cells for the CI, VS and VF groups (54.6 and 59.4%, 58.2 and 62.9%, 62.4 and 67.2%), respectively. HIV-DNA burden declined in all subsets after 48 weeks of treatment in the AI (probability (Pr) > 91%), CI (Pr > 52%) and VF (Pr > 52%) groups, but only in TEM cells in the VS group (Prâ=â95%). CONCLUSION: Our study showed that dolutegravir-based treatment reduced the HIV-DNA cellular burden in individuals from the AI, CI and VF groups, though the reduction levels differed between the patient subgroups. Early treated patients had the highest probability of HIV-DNA reduction. Interestingly, in the aviremic VS group, HIV-DNA reduction was limited to TEM cells.
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Fármacos Anti-HIV/administração & dosagem , Linfócitos T CD4-Positivos/virologia , DNA Viral/análise , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Subpopulações de Linfócitos T/virologia , Adulto , Idoso , Terapia Antirretroviral de Alta Atividade/métodos , Feminino , Seguimentos , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Oxazinas , Piperazinas , Estudos Prospectivos , Piridonas , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: Patients in phase 1 clinical trials often have significant symptom burdens and quality-of-life concerns that increase as they progress along the cancer trajectory and experience drug toxicities from the clinical trial. â©. OBJECTIVES: The interdisciplinary intervention described is aimed at providing optimum palliative care to support patients with solid tumors participating in a phase 1 clinical trial.â©. METHODS: The intervention includes a baseline evaluation using quantitative surveys, a comprehensive palliative care assessment by a research nurse based on patient baseline evaluation, and a goals-of-care discussion by the treating oncologist. The second component includes an interdisciplinary meeting where palliative care recommendations are made, followed by two patient education sessions.â©. FINDINGS: The initial experience with the palliative care intervention suggests a need for support for this population, as well as potential benefits from integrating palliative care for patients enrolled in phase 1 clinical trials.
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Ensaios Clínicos Fase I como Assunto , Neoplasias/tratamento farmacológico , Cuidados Paliativos , Educação de Pacientes como Assunto , Qualidade de Vida , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias/enfermagem , Neoplasias/fisiopatologiaRESUMO
BACKGROUND: The combination of low-dose radiation therapy with PARP inhibition enhances anti-tumor efficacy through potentiating DNA damage. We combined low-dose fractionated whole abdominal radiation (LDFWAR) with ABT-888 in patients with peritoneal carcinomatosis with a dose escalation in ovarian and fallopian cancer patients (OV). METHODS: Patients were treated with veliparib, 40-400mg orally BID on days 1-21 of 3 28-day cycles on 6 dose levels. Dose levels 5 and 6 included only OV patients. LDFWAR consisted of 21.6Gy in 36 fractions, 0.6Gy twice daily on days 1 and 5 for weeks 1-3 of each cycle. Circulating tumor material and quality of life were serially assessed. RESULTS: 32pts were treated. Median follow-up was 45months (10-50). The most common treatment-related grade 3 and 4 toxicities were lymphopenia (59%), anemia (9%), thrombocytopenia (12%), neutropenia (6%), leukopenia (6%), nausea (6%), diarrhea (6%), anorexia (6%), vomiting (6%) and fatigue (6%). The maximum tolerated dose was determined to be 250mg PO BID. Median PFS was 3.6months and median OS was 9.1months. In OV patients, OS was longer for platinum-sensitive patients (10.9mo) compared to platinum-resistant patients (5.8mo). QoL decreased for all groups during treatment. Germline BRCA status was known for 14/18 patients with OV cancers, 5 of whom were BRCA mutation carriers. One objective response (3%) was observed. CONCLUSION: ABT-888 plus LDFWAR is tolerable with gastrointestinal symptoms, fatigue and myelosuppression as the most common toxicities. The single observed objective response was in a germline BRCA mutated, platinum-sensitive patient.
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Benzimidazóis/administração & dosagem , Neoplasias das Tubas Uterinas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/radioterapia , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/radioterapia , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Idoso , Benzimidazóis/efeitos adversos , Quimiorradioterapia , Fracionamento da Dose de Radiação , Relação Dose-Resposta a Droga , Feminino , Humanos , Pessoa de Meia-Idade , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversosRESUMO
BACKGROUND: Salvage high-dose (HD) chemotherapy with autologous stem cell transplant (ASCT), consisting of 2 to 3 sequential cycles of HD carboplatin and etoposide (CE) can achieve durable remissions in approximately half of patients with relapsed germ cell tumors. To improve on these results and based on success with paclitaxel, ifosfamide, and cisplatin (TIP) as salvage conventional-dose chemotherapy, we conducted a phase I/II trial of HD paclitaxel with ifosfamide (TI), substituting carboplatin for cisplatin to allow dose escalation. PATIENTS AND METHODS: Treatment consisted of 1 to 2 cycles of TI and granulocyte colony-stimulating factor for stem cell mobilization followed by 3 cycles of HD TI with carboplatin (TIC) with ASCT every 21 to 28 days. Twenty-six patients were enrolled. For phase I, a standard 3+3 dose-escalation design was used. RESULTS: With no dose-limiting toxicities observed, the maximum tolerated dose (MTD) was not reached and the highest prespecified dose level (paclitaxel 250 mg/m(2), ifosfamide 9990 mg/m(2), carboplatin area under the curve 24) was considered the MTD. In phase II, a Simon 2-stage design was used to estimate the complete response (CR) rate at the MTD. With 7 of 11 phase II patients who achieved a CR, efficacy was demonstrated. However, 3 patients developed delayed chronic kidney disease, resulting in premature trial closure. CONCLUSION: TI-TIC was active in relapsed germ cell tumors but treatment-emergent chronic renal impairment, possibly from overlapping ifosfamide and carboplatin, preclude its further use. TI-CE, consisting of 2 cycles of TI with 3 cycles of HD CE remains the standard of care HD chemotherapy regimen at Memorial Sloan Kettering Cancer Center.
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Carboplatina/administração & dosagem , Ifosfamida/administração & dosagem , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Neoplasias Embrionárias de Células Germinativas/cirurgia , Paclitaxel/administração & dosagem , Adulto , Carboplatina/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Ifosfamida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Estudos Prospectivos , Terapia de Salvação , Transplante de Células-Tronco , Transplante Autólogo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Proven strategies to reduce right ventricular (RV) dysfunction after continuous-flow left ventricular assist device (CF-LVAD) implantation are lacking. We sought to evaluate the tolerability, feasibility, efficacy, and pharmacokinetics of inhaled milrinone (iMil) delivery after CF-LVAD implantation. METHODS AND RESULTS: We prospectively evaluated fixed-dose nebulized iMil delivered into a ventilator circuit for 24 hours in 10 postoperative CF-LVAD (Heartmate-II) patients. Tolerability (arrhythmias, hypotension, and hypersensitivity reaction), efficacy (hemodynamics), pharmacokinetics (plasma milrinone levels), and cost data were collected.Mean age was 56 ± 9 years, 90% were male, and mean INTERMACS profile was 2.5 ± 0.8. No new atrial arrhythmia events occurred, although 3 (30%) ventricular tachycardia (1 nonsustained, 2 sustained) events occurred. Sustained hypotension, drug hypersensitivity, death, or need for right ventricular assist device were not observed. Invasive mean pulmonary arterial pressure from baseline to during iMil therapy was improved (P = .017). Mean plasma milrinone levels (ng/mL) at baseline, and 1, 4, 8, 12, and 24 hours were 74.2 ± 35.4, 111.3 ± 70.9, 135.9 ± 41.5, 205.0 ± 86.7, 176.8 ± 61.3 187.6 ± 105.5, respectively. Reduced institutional cost was observed when iMil was compared with nitric oxide therapy over 24 hours ($165.29 vs $1,944.00, respectively). CONCLUSIONS: iMil delivery after CF-LVAD implantation was well tolerated, feasible, and demonstrated favorable hemodynamic, pharmacokinetic, and cost profiles. iMil therapy warrants further study in larger clinical trials.
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Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/cirurgia , Coração Auxiliar/tendências , Milrinona/administração & dosagem , Administração por Inalação , Idoso , Análise Custo-Benefício , Feminino , Insuficiência Cardíaca/diagnóstico , Ventrículos do Coração , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Milrinona/economia , Cuidados Pós-Operatórios/economia , Cuidados Pós-Operatórios/métodos , Resultado do Tratamento , Vasodilatadores/administração & dosagem , Vasodilatadores/economia , Disfunção Ventricular Direita/prevenção & controleRESUMO
BACKGROUND AND OBJECTIVES: Labetalol is frequently prescribed for the treatment of hypertension during pregnancy; however, the influence of pregnancy on labetalol pharmacokinetics is uncertain, with inconsistent findings reported by previous studies. This study examined the population pharmacokinetics of oral labetalol during and after pregnancy in women receiving labetalol for hypertension. METHODS: Data were collected from 57 women receiving the drug for hypertension from the 12th week of pregnancy through 12 weeks postpartum using a prospective, longitudinal design. A sparse sampling strategy guided collection of plasma samples. Samples were assayed for labetalol by high-performance liquid chromatography. Estimation of population pharmacokinetic parameters and covariate effects was performed by nonlinear mixed effects modeling using NONMEM. The final population model was validated by bootstrap analysis and visual predictive check. Simulations were performed with the final model to evaluate the appropriate body weight to guide labetalol dosing. RESULTS: Lean body weight (LBW) and gestational age, i.e. weeks of pregnancy, were identified as significantly influencing oral clearance (CL/F) of labetalol, with CL/F ranging from 1.4-fold greater than postpartum values at 12 weeks' gestational age to 1.6-fold greater at 40 weeks. Doses adjusted for LBW provide more consistent drug exposure than doses adjusted for total body weight. The apparent volumes of distribution for the central compartment and at steady-state were 1.9-fold higher during pregnancy. CONCLUSIONS: Gestational age and LBW impact the pharmacokinetics of labetalol during pregnancy and have clinical implications for adjusting labetalol doses in these women.
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Anti-Hipertensivos/farmacocinética , Peso Corporal/fisiologia , Idade Gestacional , Labetalol/farmacocinética , Adolescente , Adulto , Anti-Hipertensivos/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Humanos , Hipertensão Induzida pela Gravidez/tratamento farmacológico , Labetalol/uso terapêutico , Estudos Longitudinais , Gravidez , Estudos Prospectivos , Adulto JovemRESUMO
INTRODUCTION: Research has been limited in circadian activity rhythms and their relationship with health status in early-stage breast cancer survivors. Maintaining strong circadian parameters may reduce symptoms and improve physical functioning and disease-free survival. METHODS: This is a descriptive, correlational, secondary analysis of data from a randomized controlled trial collected 1 year after the first chemotherapy treatment; n = 156 cases with 7 days of wrist actigraph data of six circadian activity rhythm parameters; measures of function, fatigue, sleep, and anxiety/depression; and demographic/medical data including body mass index (BMI). RESULTS: In the total sample and three BMI categories, acrophase was the only circadian parameter that reached means established in healthy adults. In the total sample, phase-delayed acrophase was associated with higher depression (r = 0.180, p = 0.025) and lower morning energy (r = -0.194, p = 0.016) and trended for higher fatigue (r = 0.153, p = 0.057). Lower morning energy was also associated with a lower circadian quotient (r = 0.158, p = 0.05). As BMI increased, weaker circadian parameters were recorded consistently. When compared with women in normal BMI categories, obese women's amplitude and 24-h autocorrelation coefficient were significantly weaker (p = 0.011-0.015). In obese women, phase-delayed acrophase was correlated with higher fatigue and anxiety and with lower morning energy and physical functioning. DISCUSSION/CONCLUSIONS: Amplitude and 24-h autocorrelation parameters were significantly weaker, and phase-delayed acrophase was linked to several more intense symptoms and lower physical functioning in obese women. IMPLICATIONS FOR CANCER SURVIVORS: Clinicians need to target high-risk women with phase-delayed rhythms, higher symptoms, and lower physical functioning for intervention.
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Atividades Cotidianas , Sintomas Afetivos , Neoplasias da Mama/psicologia , Ritmo Circadiano , Qualidade de Vida , Sobreviventes , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ansiedade/fisiopatologia , Índice de Massa Corporal , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Depressão/fisiopatologia , Docetaxel , Doxorrubicina/administração & dosagem , Fadiga/fisiopatologia , Feminino , Humanos , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Sono/fisiologia , Taxoides/administração & dosagemRESUMO
BACKGROUND: Simultaneous inhibition of the vascular epithelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathway may improve treatment response in advanced renal cell carcinoma (RCC). Everolimus, an oral mTOR inhibitor, and sunitinib, an oral tyrosine kinase inhibitor targeting VEGF, are standard agents in the management of metastatic RCC. METHODS: Sequential cohorts of 3 to 6 patients with advanced RCC received dose-escalated combinations of sunitinib (37.5 or 50 mg daily, 4 weeks on/2 weeks off) with everolimus (2.5-5 mg daily or 20-30 mg weekly). Dose-limiting toxicities (DLTs) were assessed in the first 6-week cycle to determine maximum tolerated dose (MTD). Pharmacokinetic profiles were obtained. RESULTS: Twenty patients (13 clear cell and 7 nonclear cell RCC) were enrolled in 5 cohorts. Daily everolimus was not tolerated when combined with sunitinib; the first 2 patients on the second cohort suffered DLTs. With weekly everolimus, the MTD was 30 mg everolimus on days 7, 14, 21, and 28, plus 37.5 mg sunitinib on days 1 to 28 of a 42-day cycle; however, chronic treatment was associated with grade 3 and 4 toxicities. A schedule of 20 mg everolimus weekly/37.5 mg sunitinib was tolerated as chronic therapy. Five patients (25%) had confirmed partial responses, and 3 had nonclear cell RCC. No unexpected accumulation of everolimus, sunitinib, or N-desethyl sunitinib was observed. CONCLUSIONS: The combination of everolimus and sunitinib is associated with significant acute and chronic toxicities and is only tolerated at attenuated doses. Responses were observed in nonclear cell and clear cell RCC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Indóis/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Pirróis/administração & dosagem , Sirolimo/análogos & derivados , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Renais/secundário , Everolimo , Feminino , Humanos , Indóis/farmacocinética , Neoplasias Renais/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Pirróis/farmacocinética , Sirolimo/administração & dosagem , Sirolimo/farmacocinética , SunitinibeRESUMO
Women of childbearing age commonly receive azithromycin for the treatment of community-acquired infections, including during pregnancy. This study determined azithromycin pharmacokinetics in pregnant and nonpregnant women and identified covariates contributing to pharmacokinetic variability. Plasma samples were collected by using a sparse-sampling strategy from pregnant women at a gestational age of 12 to 40 weeks and from nonpregnant women of childbearing age receiving oral azithromycin for the treatment of an infection. Pharmacokinetic data from extensive sampling conducted on 12 healthy women were also included. Plasma samples were assayed for azithromycin by high-performance liquid chromatography. Population data were analyzed by nonlinear mixed-effects modeling. The population analysis included 53 pregnant and 25 nonpregnant women. A three-compartment model with first-order absorption and a lag time provided the best fit of the data. Lean body weight, pregnancy, ethnicity, and the coadministration of oral contraceptives were covariates identified as significantly influencing the oral clearance of azithromycin and, except for oral contraceptive use, intercompartmental clearance between the central and second peripheral compartments. No other covariate relationships were identified. Compared to nonpregnant women not receiving oral contraceptives, a 21% to 42% higher dose-adjusted azithromycin area under the plasma concentration-time curve (AUC) occurred in non-African American women who were pregnant or receiving oral contraceptives. Conversely, azithromycin AUCs were similar between pregnant African American women and nonpregnant women not receiving oral contraceptives. Although higher levels of maternal and fetal azithromycin exposure suggest that lower doses be administered to non-African American women during pregnancy, the consideration of azithromycin pharmacodynamics during pregnancy should guide any dose adjustments.
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Azitromicina/farmacocinética , Peso Corporal/fisiologia , Anticoncepcionais Orais/farmacologia , Etnicidade/etnologia , Gravidez/metabolismo , Adolescente , Adulto , Área Sob a Curva , Azitromicina/administração & dosagem , Cromatografia Líquida de Alta Pressão , Anticoncepcionais Orais/administração & dosagem , Feminino , Idade Gestacional , Humanos , Pessoa de Meia-Idade , Gravidez/sangue , Adulto JovemRESUMO
PURPOSE: In April 2009, an expert group of 11 physicians and clinical nurses met to discuss the management of selected adverse events associated with the use of everolimus for the treatment of metastatic renal cell carcinoma (mRCC). Everolimus is an orally administered inhibitor of the mammalian target of rapamycin that recently received approval from the European Medicines Agency for the treatment of advanced RCC that has progressed on or after treatment with vascular endothelial growth factor (VEGF)-targeted therapy, and from the United States Food and Drug Administration for treatment of advanced RCC after failure of sorafenib or sunitinib. Before the approval of everolimus, no standard therapy existed for the treatment of mRCC after failure of VEGF-targeted therapy. RECORD-1 (Renal Cell cancer treatment with Oral RAD001 given Daily) was the pivotal multicenter, phase III, randomised, double-blind, placebo-controlled trial of everolimus that led to approval for patients with disease progression on or after treatment with VEGF-targeted agents. Safety data from RECORD-1 were reviewed by these clinicians, all of whom had experience using everolimus in patients with mRCC. Adverse events discussed were non-infectious pneumonitis, infections, stomatitis and metabolic abnormalities. RESULTS: The outcome of this discussion is summarised here. Guidance for management of these adverse events is provided. Both clinicians and patients should be aware of the potential side-effects of everolimus and understand that these side-effects are manageable with standard care to optimise patient benefit.
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Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Sirolimo/análogos & derivados , Idoso , Ensaios Clínicos como Assunto , Progressão da Doença , Everolimo , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Placebos , Pneumonia/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Risco , Sirolimo/efeitos adversos , Estomatite/induzido quimicamente , Fatores de Tempo , Resultado do TratamentoRESUMO
PURPOSE: We previously reported a dose-finding and phase II trial of the TI-CE regimen (paclitaxel [T] plus ifosfamide [I] followed by high-dose carboplatin [C] plus etoposide [E] with stem-cell support) in germ cell tumor (GCT) patients predicted to have a poor prognosis with conventional-dose salvage therapy. We now report the efficacy of TI-CE with prognostic factors for disease-free survival (DFS) and overall survival (OS) in our full data set of 107 patients. PATIENTS AND METHODS: Eligible patients had advanced GCTs with progressive disease following chemotherapy and unfavorable prognostic features (extragonadal primary site, incomplete response [IR] to first-line therapy, or relapse/IR to ifosfamide-cisplatin-based conventional-dose salvage). Univariate and multivariate analyses (MVAs) of prognostic factors were performed. The predictive ability of the Einhorn and Beyer prognostic models was assessed. RESULTS: Most patients were platinum refractory and had an IR to first-line chemotherapy. There were 54 (5%) complete and eight (8%) partial responses with negative markers; 5-year DFS was 47% and OS was 52% (median follow-up, 61 months). No relapses occurred after 2 years. Five (24%) of 21 primary mediastinal nonseminomatous GCTs are continuously disease free. On MVA, primary mediastinal site (P < .001), two or more lines of prior therapy (P < .001), baseline human chorionic gonadotropin > or = 1,000 U/L (P = .01), and lung metastases (P = .02) significantly predicted adverse DFS. Poor-risk patients did worse than good- or intermediate-risk patients according to both Beyer (P < .002) and Einhorn (P < .05) models. CONCLUSION: TI-CE is effective salvage therapy for GCT patients with poor prognostic features. Mediastinal primary site and two or more lines of prior therapy were most predictive of adverse DFS. Beyer and Einhorn models can assist in predicting outcome.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Embrionárias de Células Germinativas/tratamento farmacológico , Adolescente , Adulto , Carboplatina/administração & dosagem , Terapia Combinada , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Ifosfamida/administração & dosagem , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Prognóstico , Retratamento , Terapia de SalvaçãoRESUMO
One of the most important conservation issues in ecology is the imperiled state of grassland ecosystems worldwide due to land conversion, desertification, and the loss of native populations and species. The Janos region of northwestern Mexico maintains one of the largest remaining black-tailed prairie dog (Cynomys ludovicianus) colony complexes in North America and supports a high diversity of threatened and endangered species. Yet, cattle grazing, agriculture, and drought have greatly impacted the region. We evaluated the impact of human activities on the Janos grasslands, comparing changes in the vertebrate community over the last two decades. Our results reveal profound, rapid changes in the Janos grassland community, demonstrating large declines in vertebrate abundance across all taxonomic groups. We also found that the 55,000 ha prairie dog colony complex has declined by 73% since 1988. The prairie dog complex has become increasingly fragmented, and their densities have shown a precipitous decline over the years, from an average density of 25 per ha in 1988 to 2 per ha in 2004. We demonstrated that prairie dogs strongly suppressed woody plant encroachment as well as created open grassland habitat by clearing woody vegetation, and found rapid invasion of shrubland once the prairie dogs disappeared from the grasslands. Comparison of grasslands and shrublands showed markedly different species compositions, with species richness being greatest when both habitats were considered together. Our data demonstrate the rapid decline of a grassland ecosystem, and documents the dramatic loss in biodiversity over a very short time period concomitant with anthropogenic grassland degradation and the decline of a keystone species.
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Conservação dos Recursos Naturais , Ecossistema , Poaceae , Animais , Biodiversidade , México , SciuridaeRESUMO
PURPOSE: The purpose of this study was to examine patterns of circadian activity rhythms and their relationship with fatigue, anxiety/depression, and demographic/medical variables in women receiving breast cancer adjuvant therapy treatments (Tx) at three times within a randomized clinical trial (RCT) designed to improve sleep and modify fatigue. METHODS: A RCT enrolled 219 women with stage I-IIIA breast cancer who were randomized 2 days prior to starting chemotherapy to a behavioral therapy sleep intervention or healthy eating control group. All cases with available data (n = 190) were included in a descriptive, correlational, repeated measures analysis. Activity data were collected continuously by wrist actigraphy for 7 days at three times: the start (Tx 1), continuation (Tx 3), and recovery (30 days after last Tx) of chemotherapy. Circadian activity rhythm parameters were generated using Action4 software (Ambulatory Monitoring, Inc.). Measures collected simultaneously included Piper Fatigue Scale, Hospital Anxiety and Depression Scale, and demographic/medical variables. RESULTS: Circadian activity rhythm parameters at three times in both groups were disrupted compared to healthy adults, but similar to values of cancer patients. Significant changes in mesor, amplitude, peak activity, and 24 h autocorrelation values were found over time in both groups. The intervention group's amplitude and circadian quotient values were significantly more robust. More robust activity rhythms were associated with lower fatigue, depressive symptoms, body mass index, and higher performance status in both groups. CONCLUSIONS: Disrupted patterns of circadian activity rhythms were prevalent and associated with distressing fatigue and depressive symptoms during chemotherapy and at recovery. The intervention resulted in more robust rhythms.
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Antineoplásicos/efeitos adversos , Ansiedade/etiologia , Neoplasias da Mama/fisiopatologia , Ritmo Circadiano/efeitos dos fármacos , Depressão/etiologia , Fadiga/etiologia , Atividade Motora/efeitos dos fármacos , Actigrafia , Adulto , Idoso , Antraciclinas/uso terapêutico , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante/efeitos adversos , Feminino , Humanos , Modelos Lineares , Pessoa de Meia-Idade , Sono/efeitos dos fármacosRESUMO
PURPOSE: Both bevacizumab and sunitinib target the vascular endothelial growth factor pathway and demonstrate activity against advanced renal cell carcinoma (RCC). In this phase I study, the maximum-tolerated dose (MTD) and safety of sunitinib in combination with bevacizumab were examined in patients with advanced RCC. PATIENTS AND METHODS: Three cohorts of three to six patients were treated with escalated doses of daily oral sunitinib (ie, 25 mg, 37.5 mg, 50 mg) for 4 weeks followed by a 2-week break and with fixed doses of bevacizumab (10 mg/kg) intravenously once every 2 weeks. Dose-limiting toxicities (DLTs) were assessed during the first cycle to determine the MTD, and an expanded cohort was treated to obtain additional safety information. RESULTS: Of 26 study participants, 25 received treatment at one of three dose levels. Grade 4 hemorrhage, identified as a DLT, occurred in one patient in each of cohorts 2 and 3. The MTD was determined to be sunitinib 50 mg/bevacizumab 10 mg/kg, but chronic therapy at this dose level frequently resulted in grades 3 to 4 hypertension and hematologic and vascular toxicities. Overall, 48% of patients discontinued treatment because of adverse events. One complete and 12 partial responses were observed, which provided an objective response rate of 52%. CONCLUSION: In this phase I trial of patients with metastatic RCC, the combination of sunitinib and bevacizumab caused a high degree of hypertension and vascular and hematologic toxicities at the highest dose level. We do not plan to pursue additional study of this regimen at these doses in patients with RCC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab , Carcinoma de Células Renais/sangue , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Neoplasias Renais/sangue , Masculino , Pessoa de Meia-Idade , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Sunitinibe , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
BACKGROUND: Nonmodulating (NMHT) is a high-renin subtype of salt sensitive hypertension, which additionally develops insulin resistance and oxidative stress. Conversely, modulating hypertensives (MHT) normally regulates renal hemodynamics after high sodium intake without metabolic impairment. We postulate that telmisartan, an angiotensin receptor blocker with partial peroxisome proliferators-activated receptorgamma partial agonist, may improve insulin resistance compared with ramipril, an angiotensin-converting enzyme inhibitor (ACEI) in NMHT. METHODS: We studied 18 NMTH (32 +/- 5y nine men, BMI 29 +/- 3 kg/m2) and 16 MHT (34 +/- 4, 10 men, BMI 28 +/- 5 kg/m2) before and after the crossover administration of ramipril 10 mg (3 months) or telmisartan 80 mg (3 months). In each patient studied we measured, before and after each treatment period, office blood pressure, glycemia and insulinemia before and 60 and 120 min after a glucose overload (75 g), total cholesterol, high-density lipoprotein and low-density lipoprotein fractions, triglycerides and highly sensitive C-protein-reactive protein. After that, HOMA-IR Index was calculated. RESULTS: Plasma renin activity was higher in NMHT 4.4 +/- 0.5 than MHT 2.6 +/- 0.9 ng.ml.h; P < 0.01. Blood pressure was similarly reduced either in MHT or NMHT by ramipril (MHT: from 159 +/- 10/102 +/- 4 to 142 +/- 6/93 +/- 3 mmHg, P < 0.05; NMHT: from 162 +/- 12/97 +/- 4 to 139 +/- 7/89 +/- 2 mmHg, P < 0.05) or telmisartan (MHT: from 154 +/- 8/96 +/- 5 to 137 +/- 6/88 +/- 4 mmHg, P < 0.05; NMHT: from 161 +/- 9/96 +/- 5 to 137 +/- 5/86 +/- 3 mmHg, P < 0.05). In NMHT, fasting glycemia (99 +/- 10 mg%) and insulinemia (16 +/- 4 microU%) and 120 min glycemia (110 +/- 2 mg%) and insulinemia (57 +/- 9 microU%) were higher than in MHT (fasting: 92 +/- 8 mg% and 9.2 +/- 2 mU%; 120 min: 95 +/- 5 and 21 +/- 5 microU%, P < 0.05). In MHT, after 3 months treatment with either ramipril or telmisartan no changes were found in fasting and 120 min glycemia and insulinemia. In NMHT, telmisartan, after 3 months treatment, significantly reduced fasting and 120 min insulinemia (fasting: 8.4 +/- 2, 120 min: 25 +/- 10 microU%; P < 0.01) compared either to basal values or ramipril treatment. Similarly, only in NMHT, compared with basal values and ramipril treatment, telmisartan improved the HOMA-IR index in both MHT (2.76 +/- 0.16 to 2.24 +/- 0.18, P < 0.05) and NMHT (from: 4.4 +/- 1 to 2.3 +/- 0.7) and triglyceride plasma levels (MHT: from 139 +/- 1.85 to 122 +/- 2.4 mg%, P < 0.05; NMHT: from: 223 +/- 12 to 146 +/- 10 mg%, P < 0.01). Finally, highly sensitive C-protein-reactive protein values were higher in NMHT (0.33 +/- 0.07 mg.dl) than in MHT (0.14 +/- 0.06 mg.dl; P < 0.01). Both treatments reduced highly sensitive C-protein-reactive protein in NMHT. (ramipril from 0.32 +/- 0.05 mg.dl to 0.26 +/- 0.06 m.dl (P < 0.05) and telmisartan from 0.34 +/- 0.05+/- to 0.20 +/- 0.05 mg.dl (P < 0.01). CONCLUSION: Our data suggest that the improvement of the insulin sensitivity by telmisartan, instead of a similar effect on blood pressure shown by both drugs, could be ascribed to the PPAR agonistic action of telmisartan. This opens an interesting therapeutic approach for patients with hypertension and altered glycemic metabolism.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Benzimidazóis/farmacologia , Benzoatos/farmacologia , Hipertensão/sangue , Hipertensão/fisiopatologia , Resistência à Insulina/fisiologia , Renina/sangue , Tolerância ao Sal/fisiologia , Adulto , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Proteína C-Reativa/metabolismo , Estudos Cross-Over , Feminino , Humanos , Lipídeos/sangue , Masculino , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/agonistas , Ramipril/farmacologia , TelmisartanRESUMO
Actigraphy has become a valuable clinical and research tool to objectively evaluate sleep, daytime activity, and circadian activity rhythms in healthy individuals as well as persons with primary and comorbid insomnia. However, procedures used for sampling, data processing, and analysis are not consistently reported in the literature. The wide variability in how actigraphy is reported makes it difficult to compare findings across studies. The procedures and reporting methods from 21 studies that used actigraphs to assess sleep and wake in adult patients with cancer are reviewed to highlight the differences in reporting strategies. Patients with cancer were chosen to illustrate the methodological challenges related to procedures and reporting in one population. The aim of this article was to advance standards of information presented in publications to enable comparisons across research studies that use actigraphy. Specific methodological challenges when using actigraphy in research include instrumentation, selection of pertinent variables, sampling, and data processing and analysis. Procedural decisions are outlined and discussed, and suggestions are made for standardized actigraphy information to include in research reports. More consistent procedures and reporting will advance the science of sleep, daytime activity, and circadian activity rhythms and their association with other health-related variables.
Assuntos
Atividades Cotidianas , Algoritmos , Pesquisa Biomédica/métodos , Diagnóstico por Computador/métodos , Monitorização Ambulatorial/métodos , Atividade Motora , Polissonografia/métodos , Projetos de PesquisaRESUMO
Previous studies indicate that binding of alpha-synuclein to membranes is critical for its physiological function and the development of Parkinson's disease (PD). Here, we have investigated the association of fluorescence-labeled alpha-synuclein variants with different types of giant unilamellar vesicles using confocal microscopy. We found that alpha-synuclein binds with high affinity to anionic phospholipids, when they are embedded in a liquid-disordered as opposed to a liquid-ordered environment. This indicates that not only electrostatic forces but also lipid packing and hydrophobic interactions are critical for the association of alpha-synuclein with membranes in vitro. When compared to wild-type alpha-synuclein, the disease-causing alpha-synuclein variant A30P bound less efficiently to anionic phospholipids, while the variant E46K showed enhanced binding. This suggests that the natural association of alpha-synuclein with membranes is altered in the inherited forms of Parkinson's disease.
Assuntos
Ânions/metabolismo , Fosfolipídeos/química , Fosfolipídeos/metabolismo , alfa-Sinucleína/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Membrana Celular/metabolismo , Ácidos Graxos/química , Corantes Fluorescentes/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Lipídeos/química , Microscopia de Fluorescência , Dados de Sequência Molecular , Peso Molecular , Mutação , Doença de Parkinson/genética , Ácidos Fosfatídicos/química , Fosfatidilcolinas/química , Fosfatidilcolinas/metabolismo , Fosfatidilgliceróis/química , Fosfatidilinositol 4,5-Difosfato/química , Fosfatidilserinas/química , Ligação Proteica , Conformação Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Rodaminas/metabolismo , Eletricidade Estática , Propriedades de Superfície , Lipossomas Unilamelares/química , Lipossomas Unilamelares/metabolismo , alfa-Sinucleína/química , alfa-Sinucleína/genética , alfa-Sinucleína/isolamento & purificaçãoRESUMO
BACKGROUND: Nonmodulating hypertension (NMHT) is a high-renin subtype of salt-sensitive hypertension due to renal hemodynamic alterations. AIMS: To evaluate, in NMHT, whether the increased oxidative stress, which interferes with endothelial function, could be the consequence of an elevated renin-angiotensin activity and insulin resistance. METHODS: Fourteen patients with NMHT and 12 with modulating hypertension (MHT) were included. Plasma renin activity (PRA) and glucose/insulin tolerance test were performed and homeostasis model assessment (HOMA) index and areas under the curves (AUC) calculated. Urinary nitrites and nitrates (NOx), urinary cyclic guanosine monophosphate (cGMP) activity, urinary isoprostanes and plasma nitrotyrosine levels were also measured. RESULTS: PRA was higher in NMHT than MHT. In addition, L-arginine infusion increased effective renal plasma flow in MHT but not in NMHT. Insulin levels were higher in NMHT both at fasting and at 120 min, as were HOMA and AUC values. In MHT, NOx and cGMP significantly increased when moving from low to high Na+ intake, while nitrotyrosine mass and isoprostanes failed to show any change. On the contrary, in NMHT under low Na+ intake, urinary NOx levels were significantly higher than MHT under high Na+ intake, and failed to show any change under high Na intake; cGMP also failed to show any change when patients moved from low to high Na+ intake. Nitrotyrosine mass and isoprostanes, like to NOx, were significantly higher in NMHT under both low and high Na+ intake. CONCLUSIONS: It is suggested that, in NMHT, a possible association between higher renin-angiotensin system activity, insulin resistance and endothelial dysfunction, showed for the first time in the same subjects, might result in systemic vascular and renal endothelial dysfunction, salt-sensitive hypertension and high cardiovascular risk.
Assuntos
Endotélio Vascular/fisiopatologia , Hipertensão/fisiopatologia , Resistência à Insulina/fisiologia , Renina/sangue , Adulto , Arginina/farmacologia , Endotélio Vascular/efeitos dos fármacos , Feminino , Humanos , Hipertensão/sangue , Masculino , Estresse Oxidativo , Fluxo Plasmático Renal Efetivo/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Sódio na Dieta/administração & dosagemRESUMO
Fatigue is the most prevalent and distressing symptom experienced by patients receiving adjuvant chemotherapy for early stage breast cancer. Higher fatigue levels have been related to sleep maintenance problems and low daytime activity in patients who have received chemotherapy, but knowledge describing these relationships prior to chemotherapy is sparse. The Piper Integrated Fatigue Model guided this study, which describes sleep/wake, activity/rest, circadian rhythms, and fatigue and how they interrelate in women with Stage I, II, or IIIA breast cancer during the 48 hours prior to the first adjuvant chemotherapy treatment. The present report describes these variables in 130 females, mean age=51.4 years; the majority were married and employed. Subjective sleep was measured by the Pittsburgh Sleep Quality Index and fatigue was measured by the Piper Fatigue Scale. Wrist actigraphy was used to objectively measure sleep/wake, activity/rest, and circadian rhythms. Mean Pittsburgh Sleep Quality Index score was 6.73+/-3.4, indicating poor sleep. Objective sleep/wake results were within normal limits established for healthy individuals, except for the number and length of night awakenings. Objective activity/rest results were within normal limits except for low mean daytime activity. Circadian rhythm mesor was 132.3 (24.6) and amplitude was 97.2 (22.8). Mean Piper Fatigue Scale score was 2.56+/-2, with 72% reporting mild fatigue. There were significant relationships between subjective and objective sleep, but no consistent patterns. Higher total and subscale fatigue scores were correlated with most components of poorer subjective sleep quality (r=0.25-0.42, P< or =0.005).