942 resultados para Advanced age


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Having determined in a phase I study the maximum tolerated dose of high-dose ifosfamide combined with high-dose doxorubicin, we now report the long-term results of a phase II trial in advanced soft-tissue sarcomas. Forty-six patients with locally advanced or metastatic soft-tissue sarcomas were included, with age <60 years and all except one in good performance status (0 or 1). The chemotherapy treatment consisted of ifosfamide 10 g m(-2) (continuous infusion for 5 days), doxorubicin 30 mg m(-2) day(-1) x 3 (total dose 90 mg m(-2)), mesna and granulocyte-colony stimulating factor. Cycles were repeated every 21 days. A median of 4 (1-6) cycles per patient was administered. Twenty-two patients responded to therapy, including three complete responders and 19 partial responders for an overall response rate of 48% (95% CI: 33-63%). The response rate was not different between localised and metastatic diseases or between histological types, but was higher in grade 3 tumours. Median overall survival was 19 months. Salvage therapies (surgery and/or radiotherapy) were performed in 43% of patients and found to be the most significant predictor for favourable survival (exploratory multivariate analysis). Haematological toxicity was severe, including grade > or =3 neutropenia in 59%, thrombopenia in 39% and anaemia in 27% of cycles. Three patients experienced grade 3 neurotoxicity and one patient died of septic shock. This high-dose regimen is toxic but nonetheless feasible in multicentre settings in non elderly patients with good performance status. A high response rate was obtained. Prolonged survival was mainly a function of salvage therapies.

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Introduction: Preoperative chemoradiotherapy is generally recommended for locally advanced esophageal cancer (clinical stage T3 or T4 or nodal positive disease) but not for early cancer (clinical stage T0 to T2, N0). EUS has been described as the most accurate method to distinguish between early and locally advanced stage in several studies. Recently however, the high accuracy of EUS (90% or higher) was questioned by some investigators. This raises the issue whether the results of studies focused on EUS accuracy may be directly translated into daily clinical practice. Aim & Methods: The aim of this retrospective analysis was to assess the accuracy of preoperative EUS to distinguish between early and locally advanced esophageal cancer in daily clinical practice outside a study setting. EUS was performed by several investigators, including trainees in one university hospital. For this purpose, EUS reports and patient files (medical and surgical) including histological reports of 300 consecutive pts with esophageal tumors were reviewed. In pts with adenocarcinoma or squamous cell cancer and surgical resection without previous radio-/chemotherapy, EUS tumor staging was compared with histological diagnosis. Results: Out of the 300 consecutive pts with esophageal tumor and EUS 102 pts had esophageal surgery after EUS-staging without any radio-/chemotherapy. In 93 pts oesophageal cancer was confirmed, whereas 9 had other tumors. The mean age was 65 years (range 27-89), sex ratio female:male was 1:3.2. To distinguish between early and late tumor stage, the accuracy was 85%. The sensitivity and specificity for early cancer was 59%, and 93%, respectively. The diagnostic accuracy for local tumor spread was 90%, 90%, 68%, 69%, 89% for pT0, pT1, pT2, pT3 and pT4 lesions, respectively. The overall accuracy for T-stage was 74%. For pN-positive staging the accuracy of EUS was 73%. Conclusion: In daily clinical practice, the accuracy of EUS in assessing esophageal tumor staging is lower than in specific studies focusing on EUS accuracy. Mainly early esophageal cancer stages were overstaged. Thus, the implementation of recommendations for diagnostic work-up of esophageal cancer patients resulting from highly specific studies should consider the appropriate clinical setting.

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OBJECTIVES: An optimized, longitudinal in vivo magnetic resonance vessel wall-imaging protocol was evaluated regarding its capability of detecting differences in the time-dependent atherosclerotic lesion progression in the aortic arch between ApoE(-/-) and double-deficient ApoE(-/-)/TNF(-/-) mice at comparatively early plaque development stages. MATERIALS AND METHODS: Seven ApoE(-/-) and seven ApoE(-/-)/TNF(-/-) female mice underwent MRI at 11.75 teslas at four stages up to 26 weeks of age. A double-gated spin-echo MRI sequence was used with careful perpendicular slice positioning to visualize the vessel wall of the ascending aortic arch. RESULTS: Wall-thickness progression measured with MRI was significant at 11 weeks of age in ApoE(-/-) mice, but only at 26 weeks in ApoE(-/-)/TNF(-/-) mice. A significant correlation was found between MRI wall-thickness and lesion area determined on histology. CONCLUSION: MRI was shown to be sensitive enough to reveal subtle genetically-induced differences in lesion progression at ages earlier than 25 weeks.

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The study of advanced materials aimed at improving human life has been performed since time immemorial. Such studies have created everlasting and greatly revered monuments and have helped revolutionize transportation by ushering the age of lighter–than–air flying machines. Hence a study of the mechanical behavior of advanced materials can pave way for their use for mankind’s benefit. In this school of thought, the aim of this dissertation is to broadly perform two investigations. First, an efficient modeling approach is established to predict the elastic response of cellular materials with distributions of cell geometries. Cellular materials find important applications in structural engineering. The approach does not require complex and time-consuming computational techniques usually associated with modeling such materials. Unlike most current analytical techniques, the modeling approach directly accounts for the cellular material microstructure. The approach combines micropolar elasticity theory and elastic mixture theory to predict the elastic response of cellular materials. The modeling approach is applied to the two dimensional balsa wood material. Predicted properties are in good agreement with experimentally determined properties, which emphasizes the model’s potential to predict the elastic response of other cellular solids, such as open cell and closed cell foams. The second topic concerns intraneural ganglion cysts which are a set of medical conditions that result in denervation of the muscles innervated by the cystic nerve leading to pain and loss of function. Current treatment approaches only temporarily alleviate pain and denervation which, however, does not prevent cyst recurrence. Hence, a mechanistic understanding of the pathogenesis of intraneural ganglion cysts can help clinicians understand them better and therefore devise more effective treatment options. In this study, an analysis methodology using finite element analysis is established to investigate the pathogenesis of intraneural ganglion cysts. Using this methodology, the propagation of these cysts is analyzed in their most common site of occurrence in the human body i.e. the common peroneal nerve. Results obtained using finite element analysis show good correlation with clinical imaging patterns thereby validating the promise of the method to study cyst pathogenesis.

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OBJECT: The goal of this study was to investigate the efficacy of long-term deep brain stimulation (DBS) of the posteroventral lateral globus pallidus internus (GPi) accomplished using a single-contact monopolar electrode in patients with advanced Parkinson disease (PD). METHODS: Sixteen patients suffering from severe PD and levodopa-induced side effects such as dyskinesias and on-off fluctuations were enrolled in a prospective study protocol. There were six women and 10 men and their mean age at surgery was 65 years. All patients underwent implantation of a monopolar electrode in the posteroventral lateral GPi. Initially, nine patients received unilateral stimulation. Three of these patients underwent contralateral surgery at a later time. Ten patients received bilateral stimulation (contemporaneous bilateral surgery was performed in seven patients and staged bilateral surgery in the three patients who had received unilateral stimulation initially). Formal assessments were performed during both off-medication and on-medication (levodopa) periods preoperatively, and at 3 and 12 months postoperatively. There were no serious complications related to surgery or to DBS. Two transient adverse events occurred: in one patient a small pallidal hematoma developed, resulting in a prolonged micropallidotomy effect, and in another patient a subcutaneous hemorrhage occurred at the site of the pacemaker. In patients who received unilateral DBS, the Unified Parkinson's Disease Rating Scale activities of daily living (ADL) score during the off-levodopa period decreased from 30.8 at baseline to 20.4 at 3 months (34% improvement) and 20.6 at 12 months (33% improvement) postoperatively. The motor score during the off period improved from 57.2 at baseline to 35.2 at 3 months (38% improvement) and 35.3 at 12 months (38% improvement) postoperatively. Bilateral DBS resulted in a reduction in the ADL score during the off period from 34.9 at baseline to 22.3 at 3 months (36% improvement) and 22.9 at 12 months (34% improvement). The motor score for the off period changed from 63.4 at baseline to 40.3 at 3 months (36% improvement) and 37.5 at 12 months (41% improvement). In addition, there were significant improvements in patients' symptoms during the on period and in on-off motor fluctuations. CONCLUSIONS: Pallidal DBS accomplished using a monopolar electrode is a safe and effective procedure for treatment of advanced PD. Compared with pallidotomy, the advantages of pallidal DBS lie in its reversibility and the option to perform bilateral surgery in one session. Comparative studies in which DBS is applied to other targets are needed.

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We investigated if the MET-activating point mutation Y1253D influences clinical outcomes in patients with advanced squamous cell carcinoma of the head and neck (HNSCC). The study population consisted of 152 HNSCC patients treated by hyperfractionated radiotherapy alone or concomitant with chemotherapy between September 1994 and July 2000. Tumors were screened for the presence of the MET-activating point mutation Y1253D. Seventy-eight patients (51%) received radiotherapy alone, 74 patients (49%) underwent radiotherapy concomitant with chemotherapy. Median patient age was 54 years and median follow-up was 5.5 years. Distant metastasis-free survival, local relapse-free survival and overall survival were compared with MET Y1253D status. During follow-up, 29 (19%) patients developed distant metastasis. MET Y1253D was detected in tumors of 21 out of 152 patients (14%). Distant metastasis-free survival (P = 0.008) was associated with MET Y1253D. In a multivariate Cox regression model, adjusted for T-category, only presence of MET Y1253D was associated with decreased distant metastasis-free survival: hazard ratio = 2.5 (95% confidence interval: 1.1, 5.8). The observed association between MET Y1253D-activating point mutation and decreased distant metastasis-free survival in advanced HNSCC suggests that MET may be a potential target for specific treatment interventions.

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Advanced glycation end products (AGEs) may play a role in the pathogenesis of diabetic nephropathy, by modulating extracellular matrix turnover. AGEs are known to activate specific membrane receptors, including the receptor for AGE (RAGE). In the present study, we analyzed the various receptors for AGEs expressed by human mesangial cells and we studied the effects of glycated albumin and of carboxymethyl lysine on matrix protein and remodelling enzyme synthesis. Membrane RAGE expression was confirmed by FACS analysis. Microarray methods, RT-PCR, and Northern blot analysis were used to detect and confirm specific gene induction. Zymographic analysis and ELISA were used to measure the induction of tPA and PAI-1. We show herein that cultured human mesangial cells express AGE receptor type 1, type 2 and type 3 and RAGE. AGEs (200 microg/ml) induced at least a 2-fold increase in mRNA for 10 genes involved in ECM remodelling, including tPA, PAI-1 and TIMP-3. The increase in tPA synthesis was confirmed by fibrin zymography. The stimulation of PAI-1 synthesis was confirmed by ELISA. AGEs increased PAI-1 mRNA through a signalling pathway involving reactive oxygen species, the MAP kinases ERK-1/ERK-2 and the nuclear transcription factor NF-kappaB, but not AP-1. Carboxymethyl lysine (CML, 5 microM), which is a RAGE ligand, also stimulated PAI-1 synthesis by mesangial cells. In addition, a blocking anti-RAGE antibody partially inhibited the AGE-stimulated gene expression and decreased the PAI-1 accumulation induced by AGEs and by CML. Inhibition of AGE receptors or neutralization of the protease inhibitors TIMP-3 and PAI-1 could represent an important new therapeutic strategy for diabetic nephropathy.

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The exact mechanism for capillary occlusion in diabetic retinopathy is still unclear, but increased leukocyte-endothelial cell adhesion has been implicated. We examined the possibility that posttranslational modification of surface O-glycans by increased activity of core 2 transferase (UDP-Glc:Galbeta1-3GalNAcalphaRbeta-N-acetylglucoaminyltr ansferase) is responsible for increased adhesion of leukocytes to vascular endothelium in diabetes. The mean activity of core 2 transferase in polymorphonuclear leukocytes isolated from type 1 and type 2 diabetic patients was higher compared with age-matched control subjects (1,638 +/- 91 [n = 42] vs. 249 +/- 35 pmol x h(-1) x mg(-1) protein [n = 24], P = 0.00013; 1,459 +/- 194 [n = 58] vs. 334 +/- 86 [n = 11], P = 0.01). As a group, diabetic patients with retinopathy had significantly higher mean activity of core 2 transferase compared with individuals with no retinopathy. There was a significant association between enzyme activity and severity of retinopathy in type 1 and type 2 diabetic patients. There was a strong correlation between activity of core 2 transferase and extent of leukocyte adhesion to cultured retinal capillary endothelial cells for diabetic patients but not for age-matched control subjects. Results from transfection experiments using human myelocytic cell line (U937) demonstrated a direct relationship between increased activity of core 2 transferase and increased binding to cultured endothelial cells. There was no relationship between activity of core 2 transferase and HbA(1c) (P = 0.8314), serum advanced glycation end product levels (P = 0.4159), age of the patient (P = 0.7896), and duration of diabetes (P = 0.3307). On the basis that branched O-glycans formed by the action of core 2 transferase participate in leukocyte adhesion, the present data suggest the involvement of this enzyme in increased leukocyte-endothelial cell adhesion and the pathogenesis of capillary occlusion in diabetic retinopathy.

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Background: Inflammation is implicated in the development of cancer related fatigue (CRF). However there is limited literature on the mediators of inflammation (namely), cytokines and their receptors, associated with clinically significant fatigue and response to treatment. Methods: We reviewed 37 advanced cancer patients with fatigue (≥4/10), who participated in two Randomized Controlled Trials, of anti-inflammatory agents (Thalidomide and Dexamethasone) for CRF. Responders showed improvement in FACIT-F subscale at the end of study (Day 15). Baseline patient characteristics and symptoms were assessed by FACIT-F, ESAS; serum cytokines [IL-1β and receptor antagonist (IL-1RA), IL-6, IL-6R, TNF-α and sTNF-R1 and R2, IL-8, IL-10, IL-17] levels measured by Luminex. Data were analyzed using principal component analysis (PCA) [reporting cumulative variance (variance) for the first four components] to determine their association with fatigue and response to treatment. Results: Females were 54%. Mean (SD) was as follows for age, 61(14); baseline FACIT (F) scores, 21.4(8.6); ESAS Fatigue item, 6.5(1.9); and FACIT-F change, 6.4(9.7); ESAS (fatigue) change, -2 (2.41). Baseline median in pg/mL for IL-6, TNF-α, IL-1β were 31.9; 18.9; 0.55, respectively. Change in IL-6 negatively correlated with change in FACIT-F scores (p=0.02). Baseline CRF (FACIT-F score) was associated with IL-6, IL-6R and IL-17, Variance = 78% whereas IL-10, IL-1RA, TNF-α and IL-1β were associated with improvement of CRF, Variance=74%. Conversely, IL-6 and IL-8 were associated with no improvement or worsening of CRF, Variance= 93%. Conclusions: Change in IL-6 negatively correlated with change in FACIT-F scores. IL-6, IL-6R and IL-17 are associated with CRF while IL-6 and IL-8 were associated with no improvement of CRF. Further studies are warranted confirm our findings.

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Cachexia is very common among patients with advanced pancreatic cancer and is a marker of poor prognosis. Weight loss in cachexia is due to both adipose and muscle compartments, and sarcopenia (severe muscle depletion) is associated with worse outcomes. Curcumin has shown a myriad of biological effects, including anti-cancer and anti-inflammatory. The ability of curcumin to attenuate cachexia and muscle loss has been tested in animal models, with conflicting results so far. The hypothesis of this study was that patients with advanced pancreatic cancer treated with curcumin for two months have less fat and muscle loss as compared to matched controls not treated with this compound. A matched 1:2 case-control retrospective study was conducted with 22 patients with pancreatic cancer who were treated with curcumin on a previous protocol and 44 untreated controls with the same diagnosis matched by age, gender, time from advanced cancer, body mass index, and number of prior therapies. Data was collected regarding oncologic treatment, medication use, weights, heights, and survival. Body composition was determined by computerized tomography analyses at two timepoints separated by 60±20 days. For treated patients, the first image was at the beginning of treatment and for controls it was determined by the matching time from advanced cancer. The evolution of body composition over time was quantitatively analyzed comparing both groups. All patients lost weight both due to fat and muscle losses, and patients treated with curcumin presented greater losses both in lean adipose body mass. Use of medications, chemotherapy, age, time from advanced cancer, baseline albumin, performance status, and number of prior therapies were not independently correlated with changes in body composition variables. Patients treated with curcumin had borderline shorter survival when compared with untreated patients. Sarcopenic treated patients had significantly shorter survival than non-sarcopenic counterparts, and sarcopenia status was not associated with survival among the controls. Treated patients with shorter survival showed a tendency to lose more lean and especially fat body mass as compared to untreated patients, maybe suggesting an effect of curcumin on shifting weight loss towards the end of life by impacting its mechanisms.

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We examined outcomes and trends in surgery and radiation use for patients with locally advanced esophageal cancer, for whom optimal treatment isn't clear. Trends in surgery and radiation for patients with T1-T3N1M0 squamous cell or adenocarcinoma of the mid or distal esophagus in the Surveillance, Epidemiology, and End Results database from 1998 to 2008 were analyzed using generalized linear models including year as predictor; Surveillance, Epidemiology, and End Results doesn't record chemotherapy data. Local treatment was unimodal if patients had only surgery or radiation and bimodal if they had both. Five-year cancer-specific survival (CSS) and overall survival (OS) were analyzed using propensity-score adjusted Cox proportional-hazard models. Overall 5-year survival for the 3295 patients identified (mean age 65.1 years, standard deviation 11.0) was 18.9% (95% confidence interval: 17.3-20.7). Local treatment was bimodal for 1274 (38.7%) and unimodal for 2021 (61.3%) patients; 1325 (40.2%) had radiation alone and 696 (21.1%) underwent only surgery. The use of bimodal therapy (32.8-42.5%, P = 0.01) and radiation alone (29.3-44.5%, P < 0.001) increased significantly from 1998 to 2008. Bimodal therapy predicted improved CSS (hazard ratios [HR]: 0.68, P < 0.001) and OS (HR: 0.58, P < 0.001) compared with unimodal therapy. For the first 7 months (before survival curve crossing), CSS after radiation therapy alone was similar to surgery alone (HR: 0.86, P = 0.12) while OS was worse for surgery only (HR: 0.70, P = 0.001). However, worse CSS (HR: 1.43, P < 0.001) and OS (HR: 1.46, P < 0.001) after that initial timeframe were found for radiation therapy only. The use of radiation to treat locally advanced mid and distal esophageal cancers increased from 1998 to 2008. Survival was best when both surgery and radiation were used.

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BACKGROUND & AIMS: Age is frequently discussed as negative host factor to achieve a sustained virological response (SVR) to antiviral therapy of chronic hepatitis C. However, elderly patients often show advanced fibrosis/cirrhosis as known negative predictive factor. The aim of this study was to assess age as an independent predictive factor during antiviral therapy. METHODS: Overall, 516 hepatitis C patients were treated with pegylated interferon-α and ribavirin, thereof 66 patients ≥60 years. We analysed the impact of host factors (age, gender, fibrosis, haemoglobin, previous hepatitis C treatment) and viral factors (genotype, viral load) on SVR per therapy course by performing a generalized estimating equations (GEE) regression modelling, a matched pair analysis and a classification tree analysis. RESULTS: Overall, SVR per therapy course was 42.9 and 26.1%, respectively, in young and elderly patients with hepatitis C virus (HCV) genotypes 1/4/6. The corresponding figures for HCV genotypes 2/3 were 74.4 and 84%. In the GEE model, age had no significant influence on achieving SVR. In matched pair analysis, SVR was not different in young and elderly patients (54.2 and 55.9% respectively; P = 0.795 in binominal test). In classification tree analysis, age was not a relevant splitting variable. CONCLUSIONS: Age is not a significant predictive factor for achieving SVR, when relevant confounders are taken into account. As life expectancy in Western Europe at age 60 is more than 20 years, it is reasonable to treat chronic hepatitis C in selected elderly patients with relevant fibrosis or cirrhosis but without major concomitant diseases, as SVR improves survival and reduces carcinogenesis.

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Objective Albeit clear advances in the treatment of SLE, many patients still present with refractory lupus nephritis requiring new treatment strategies for this disease. Here we determined whether reduced doses of the topoisomerase I inhibitor irinotecan, which is known as chemotherapeutic agent, were able to suppress SLE in NZB/W F1 mice. We further evaluated the potential mechanism how irinotecan influenced the course of SLE. Methods NZB/W F1 mice were treated with low dose irinotecan either from week 24 of age or from established glomerulonephritis defined by a proteinuria ≥grade 3+. Binding of anti-dsDNA antibodies was measured by ELISA; and DNA relaxation was visualized by gel electrophoresis. Results Significantly reduced irinotecan dosages improved lupus nephritis and prolonged survival in NZB/W F1 mice. The lowest dose successfully used for the treatment of established murine lupus nephritis was more than 50 times lower than the dose usually applied for chemotherapy in humans. As a mechanism, low dose irinotecan reduced B cell activity; however, the levels of B cell activity in irinotecan-treated mice were similar to those in Balb/c mice of the same age suggesting that irinotecan did not induce a clear immunosuppression. In addition, incubation of double-stranded (ds) DNA with topoisomerase I increased binding of murine and human anti-dsDNA antibodies showing for the first time that relaxed DNA is more susceptible to anti-dsDNA antibody binding. This effect was reversed by addition of the topoisomerase I inhibitor camptothecin. Conclusion Our results propose topoisomerase I inhibitors as a novel and targeted therapy for SLE. © 2014 American College of Rheumatology.

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Is numerical mimicry a third way of establishing truth? Kevin Heng received his M.S. and Ph.D. in astrophysics from the Joint Institute for Laboratory Astrophysics (JILA) and the University of Colorado at Boulder. He joined the Institute for Advanced Study in Princeton from 2007 to 2010, first as a Member and later as the Frank & Peggy Taplin Member. From 2010 to 2012 he was a Zwicky Prize Fellow at ETH Z¨urich (the Swiss Federal Institute of Technology). In 2013, he joined the Center for Space and Habitability (CSH) at the University of Bern, Switzerland, as a tenure-track assistant professor, where he leads the Exoplanets and Exoclimes Group. He has worked on, and maintains, a broad range of interests in astrophysics: shocks, extrasolar asteroid belts, planet formation, fluid dynamics, brown dwarfs and exoplanets. He coordinates the Exoclimes Simulation Platform (ESP), an open-source set of theoretical tools designed for studying the basic physics and chemistry of exoplanetary atmospheres and climates (www.exoclime.org). He is involved in the CHEOPS (Characterizing Exoplanet Satellite) space telescope, a mission approved by the European Space Agency (ESA) and led by Switzerland. He spends a fair amount of time humbly learning the lessons gleaned from studying the Earth and Solar System planets, as related to him by atmospheric, climate and planetary scientists. He received a Sigma Xi Grant-in-Aid of Research in 2006

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This study investigated the content, realism, stability, and coherence of the career aspirations of 262 students in seventh grade in Switzerland (ages 13-15 years). The content analysis revealed that 82% of the participants named at least one realistic career aspiration, and aspirations showed clear resemblance to existing opportunities in the environment. Quantitative analyses confirmed the hypotheses that realism and stability of aspirations over a 10-month period could better be predicted by individual degree of career adaptability as measured by planfulness and exploration than by chronological age when grade level was controlled for. Coherence of aspirations was not related to age or adaptability. Students attending basic scholastic requirements school tracks reported more adaptability but not more realistic, stable, or coherent aspirations compared to students in advanced requirements tracks.