RESUMO
Surgery is the standard of care for patients with primary renal cell carcinoma. Stereotactic body radiotherapy (SBRT) is a novel alternative for patients who are medically inoperable, technically high risk, or who decline surgery. Evidence for using SBRT in the primary renal cell carcinoma setting is growing, including several rigorously conducted prospective clinical trials. This systematic review was performed to assess the safety and efficacy of SBRT for primary renal cell carcinoma. Review results then formed the basis for the practice guidelines described, on behalf of the International Stereotactic Radiosurgery Society. 3972 publications were screened and 36 studies (822 patients) were included in the analysis. Median local control rate was 94·1% (range 70·0-100), 5-year progression-free survival was 80·5% (95% CI 72-92), and 5-year overall survival was 77·2% (95% CI 65-89). These practice guidelines addressed four key clinical questions. First, the optimal dose fractionation was 25-26 Gy in one fraction, or 42-48 Gy in three fractions for larger tumours. Second, routine post-treatment biopsy is not recommended as it is not predictive of patient outcome. Third, SBRT for primary renal cell carcinoma in a solitary kidney is safe and effective. Finally, guidelines for post-treatment follow-up are described, which include cross-axial imaging of the abdomen including both kidneys, adrenals, and surveillance of the chest initially every 6 months. This systematic review and practice guideline support the practice of SBRT for primary renal cell carcinoma as a safe and effective standard treatment option. Randomised trials with surgery and invasive ablative therapies are needed to further define best practice.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Radiocirurgia , Humanos , Carcinoma de Células Renais/radioterapia , Carcinoma de Células Renais/cirurgia , Rim , Neoplasias Renais/radioterapia , Neoplasias Renais/cirurgia , Estudos Prospectivos , Radiocirurgia/efeitos adversosRESUMO
BACKGROUND: Obesity and type 2 diabetes (T2DM) are associated with increased circulating free fatty acids and triacylglycerols. However, very little is known about specific molecular lipid species associated with these diseases. In order to gain further insight into this, we performed plasma lipidomic analysis in a rodent model of obesity and insulin resistance as well as in lean, obese and obese individuals with T2DM. METHODOLOGY/PRINCIPAL FINDINGS: Lipidomic analysis using liquid chromatography coupled to mass spectrometry revealed marked changes in the plasma of 12 week high fat fed mice. Although a number of triacylglycerol and diacylglycerol species were elevated along with of a number of sphingolipids, a particularly interesting finding was the high fat diet (HFD)-induced reduction in lysophosphatidylcholine (LPC) levels. As liver, skeletal muscle and adipose tissue play an important role in metabolism, we next determined whether the HFD altered LPCs in these tissues. In contrast to our findings in plasma, only very modest changes in tissue LPCs were noted. To determine when the change in plasma LPCs occurred in response to the HFD, mice were studied after 1, 3 and 6 weeks of HFD. The HFD caused rapid alterations in plasma LPCs with most changes occurring within the first week. Consistent with our rodent model, data from our small human cohort showed a reduction in a number of LPC species in obese and obese individuals with T2DM. Interestingly, no differences were found between the obese otherwise healthy individuals and the obese T2DM patients. CONCLUSION: Irrespective of species, our lipidomic profiling revealed a generalized decrease in circulating LPC species in states of obesity. Moreover, our data indicate that diet and adiposity, rather than insulin resistance or diabetes per se, play an important role in altering the plasma LPC profile.
Assuntos
Diabetes Mellitus Tipo 2/sangue , Lisofosfatidilcolinas/sangue , Obesidade/sangue , Tecido Adiposo/metabolismo , Adiposidade , Adulto , Animais , Estudos de Coortes , Gorduras na Dieta/farmacologia , Humanos , Resistência à Insulina , Fígado/metabolismo , Masculino , Camundongos , Músculo Esquelético/metabolismo , Fatores de TempoRESUMO
The objective of this paper is to measure health literacy in a representative sample of the Australian general population using three health literacy tools; to consider the congruency of results; and to determine whether these assessments were associated with socio-demographic characteristics. Face-to-face interviews were conducted in a stratified random sample of the adult Victorian population identified from the 2004 Australian Government Electoral Roll. Participants were invited to participate by mail and follow-up telephone call. Health literacy was measured using the Rapid Estimate of Adult Literacy in Medicine (REALM), Test of Functional Health Literacy in Adults (TOFHLA) and Newest Vital Sign (NVS). Of 1680 people invited to participate, 89 (5.3%) were ineligible, 750 (44.6%) were not contactable by phone, 531 (32%) refused and 310 (response rate 310/1591, 19.5%) agreed to participate. Compared with the general population, participants were slightly older, better educated and had a higher annual income. The proportion of participants with less than adequate health literacy levels varied: 26.0% (80/308) for the NVS, 10.6% (51 33/310) for the REALM and 6.8% (21/309) for the TOFHLA. A varying but significant proportion of the general population was found to have limited health literacy. The health literacy measures we used, while moderately correlated, appear to measure different but related constructs and use different cut offs to indicate poor health literacy.
Assuntos
Compreensão , Educação em Saúde , Conhecimentos, Atitudes e Prática em Saúde , Adulto , Idoso , Feminino , Nível de Saúde , Inquéritos Epidemiológicos , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , VitóriaRESUMO
OBJECTIVE: Neutral endopeptidase (NEP, EC 3.4.24.11) metabolises endogenous vasoactive peptides that may protect against atherogenesis. Since NEP is found in the adventitia of arteries, we investigated the anti-atherogenic effects of chronic adventitial NEP inhibition. METHODS: Intimal hyperplasia of rabbit carotid arteries was induced by placement of soft, non-occlusive, peri-arterial silastic collars. NEP localisation was studied with autoradiography 7 and 14 days after collar placement. Vascular NEP was inhibited in vivo by local superfusion of one collared carotid artery with Candoxatrilat (50 pmol/h), for 7 days (n = 7). The contralateral collar was filled with saline vehicle. After 7 days, ring segments of collared and normal (proximal to the collar) arteries were obtained and in vitro functional measurements, immunohistochemical determination of the pro-atherogenic factor plasminogen activator inhibitor-1 (PAI-1), localization of macrophages and morphometric analyses were carried out. RESULTS: Vascular NEP radiolabelled substrate binding, mainly in the media, was increased by approximately 50% after 7 days (n = 5; p < 0.05) and by approximately 300% after 14 days of collar placement (n = 5; p < 0.05). Compared with normal artery segments from the same animal, vehicle-filled collared sections displayed significantly impaired vasorelaxation to acetylcholine (endothelium-independent vasodilatation was preserved), increased PAI-1 immunostaining, macrophage accumulation and intimal thickening. In Candoxatrilat-treated collared arteries, vasorelaxation to acetylcholine was improved, along with reductions in PAI-1 levels, macrophage numbers and intimal area (all p < 0.05). CONCLUSION: Enhancing the activity of local, endogenous peptides by adventitial inhibition of vascular NEP may protect against early atherogenesis. This is of particular relevance to using adventitial therapies to prevent intimal hyperplasia leading to restenosis.
Assuntos
Estenose das Carótidas/enzimologia , Ácidos Cicloexanocarboxílicos/uso terapêutico , Células Endoteliais/enzimologia , Neprilisina/antagonistas & inibidores , Inibidores de Proteases/uso terapêutico , Túnica Íntima/enzimologia , Acetilcolina/farmacologia , Animais , Autorradiografia , Biomarcadores/análise , Artérias Carótidas , Estenose das Carótidas/imunologia , Estenose das Carótidas/patologia , Células Endoteliais/imunologia , Células Endoteliais/patologia , Hiperplasia , Imuno-Histoquímica/métodos , Macrófagos/patologia , Masculino , Modelos Animais , Inibidor 1 de Ativador de Plasminogênio/análise , Coelhos , Túnica Íntima/imunologia , Túnica Íntima/patologia , Vasodilatadores/farmacologiaRESUMO
OBJECTIVE: Elevated vascular plasminogen activator inhibitor-1 (PAI-1) levels are associated with atherosclerosis. In vitro, C-type natriuretic peptide (CNP) has anti-proliferative effects and inhibits the production of PAI-1 in cultured vascular cells. Whether CNP can affect PAI-1 in vivo, particularly in the setting of atherosclerosis, has not been reported. METHODS: Using the rabbit carotid arterial collar model of intimal hyperplasia (collar in place for 7 days), PAI-1 protein was compared in normal, vehicle (saline)-collared, and CNP-treated-collared arteries from the same animal. PAI-1 levels were measured by immunohistochemistry and densitometry and by Western blot. CNP was either infused into the peri-arterial space within one collar (10 fmol/h) or infused directly into the arterial lumen under one collar (100 pmol/h). In some rabbits (n=8), superoxide production in collared and normal artery segments was measured in vitro by chemiluminescence. RESULTS: PAI-1 was present throughout the vascular wall. Endothelial PAI-1 was elevated in saline-collared arteries (approximately 16%, P<0.05; n=7 rabbits) compared with normal carotid segments. The collar induced both a neointima that contained PAI-1 and the accumulation of macrophages in the adventitia. Peri-arterial CNP reduced PAI-1 (P<0.05) in the endothelium (33%), adventitia (47%) and neointima (39%), compared with levels in the contralateral, saline-collared carotid artery, while macrophage infiltration was reduced. Elevated superoxide production in collared arteries was not altered by chronic in vivo treatment with CNP (n=8). Peri-arterial CNP treatment did not reduce intimal thickening. Intra-luminal CNP (n=6) reduced endothelial, neointimal and total vessel (Western blot) PAI-1, macrophage accumulation, and intimal thickening (all P<0.05). CONCLUSIONS: CNP treatment of collared carotid arteries in vivo for 1 week suppressed endothelial and neointimal PAI-1, independently of intimal thickening. The CNP effects were not via superoxide. This is the first evidence that CNP inhibits activated PAI-1, in vivo.
Assuntos
Doenças das Artérias Carótidas/tratamento farmacológico , Artéria Carótida Primitiva , Peptídeo Natriurético Tipo C/uso terapêutico , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Ativadores de Plasminogênio/uso terapêutico , Túnica Íntima/patologia , Animais , Western Blotting/métodos , Doenças das Artérias Carótidas/metabolismo , Doenças das Artérias Carótidas/patologia , Imuno-Histoquímica/métodos , Medições Luminescentes , Macrófagos/imunologia , Masculino , Modelos Animais , Inibidor 1 de Ativador de Plasminogênio/análise , Coelhos , Superóxidos/análise , Túnica Íntima/metabolismoRESUMO
BACKGROUND: Atrial and C-type natriuretic peptides (ANP and CNP), acting through different receptors, have antiproliferative effects in vitro. Beneficial effects of CNP in vivo on early atherosclerosis have been described, but it is not known if ANP is antiproliferative in vivo. In the present study, the effects of chronic in vivo ANP were tested and compared with CNP on endothelial dysfunction and intimal thickening caused by peri-arterial collars. METHODS: Non-occlusive collars were placed bilaterally around the common carotid arteries of rabbits. One collar was filled with saline vehicle. The contralateral collar was filled with ANP or CNP (1 or 10 microM, n = 5-7) with slow replacement of peptide via mini-pump (1 or 10 fmol/h). RESULTS: After 7 days, endothelium-dependent vasorelaxation in saline-collared arteries was 33 +/- 3% of maximum [averaged over 0.03-1 muM acetylcholine (ACh)] compared to 64 +/- 2% in normal (uncollared) arteries (p < 0.05, n = 23). In vivo ANP restored the ACh relaxation to normal (e.g., 57 +/- 6%, 1 microM ANP), similar to effects seen with CNP in vivo. Endothelium-independent vasorelaxation of collared-vessels was not altered by either peptide. Intimal hyperplasia induced by the collars was not prevented by peri-arterial natriuretic peptides. In additional rabbits (n = 6), CNP (100 pmol/h) given directly into the lumen of collared carotid arteries for 7 days reduced neointima formation by 16 +/- 5% (p < 0.05), whereas ANP given intraluminally (100 pmol/h; n = 6) did not. CONCLUSIONS: The more potent actions of CNP on vascular smooth muscle cell migration and proliferation (established in vitro) may explain differences between the peptides on intimal hyperplasia in vivo. The major hallmark of atherosclerosis and restenosis, endothelial dysfunction, was prevented by chronic, peri-arterial administration of ANP or CNP.