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The novel circumstance-driven bivariate integer-valued autoregressive (CuBINAR) model for non-stationary count time series is proposed. The non-stationarity of the bivariate count process is defined by a joint categorical sequence, which expresses the current state of the process. Additional cross-dependence can be generated via cross-dependent innovations. The model can also be equipped with a marginal bivariate Poisson distribution to make it suitable for low-count time series. Important stochastic properties of the new model are derived. The Yule-Walker and conditional maximum likelihood method are adopted to estimate the unknown parameters. The consistency of these estimators is established, and their finite-sample performance is investigated by a simulation study. The scope and application of the model are illustrated by a real-world data example on sales counts, where a soap product in different stores with a common circumstance factor is investigated.
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Common count distributions, such as the Poisson (binomial) distribution for unbounded (bounded) counts considered here, can be characterized by appropriate Stein identities. These identities, in turn, might be utilized to define a corresponding goodness-of-fit (GoF) test, the test statistic of which involves the computation of weighted means for a user-selected weight function f. Here, the choice of f should be done with respect to the relevant alternative scenario, as it will have great impact on the GoF-test's performance. We derive the asymptotics of both the Poisson and binomial Stein-type GoF-statistic for general count distributions (we also briefly consider the negative-binomial case), such that the asymptotic power is easily computed for arbitrary alternatives. This allows for an efficient implementation of optimal Stein tests, that is, which are most powerful within a given class F $\mathcal {F}$ of weight functions. The performance and application of the optimal Stein-type GoF-tests is investigated by simulations and several medical data examples.
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Modelos Estatísticos , Distribuição BinomialRESUMO
Time series are sequentially observed data in which important information about the phenomenon under consideration is contained not only in the individual observations themselves, but also in the way these observations follow one another [...].
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In a time series context, the study of the partial autocorrelation function (PACF) is helpful for model identification. Especially in the case of autoregressive (AR) models, it is widely used for order selection. During the last decades, the use of AR-type count processes, i.e., which also fulfil the Yule-Walker equations and thus provide the same PACF characterization as AR models, increased a lot. This motivates the use of the PACF test also for such count processes. By computing the sample PACF based on the raw data or the Pearson residuals, respectively, findings are usually evaluated based on well-known asymptotic results. However, the conditions for these asymptotics are generally not fulfilled for AR-type count processes, which deteriorates the performance of the PACF test in such cases. Thus, we present different implementations of the PACF test for AR-type count processes, which rely on several bootstrap schemes for count times series. We compare them in simulations with the asymptotic results, and we illustrate them with an application to a real-world data example.
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Ordinal patterns can be used to construct non-parametric hypothesis tests that aim to discover (possibly non-linear) serial dependence in a real-valued time series. We derive the asymptotic distribution of the vector of sample frequencies of ordinal patterns and that of various corresponding tests statistics such that the targeted tests for serial dependence are easily implemented based on asymptotic approximations. Simulations are used to check the finite-sample performance of these tests as well as their power properties with respect to various alternative scenarios. The application and interpretation of the tests in practice are illustrated by an environmental data example.
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In real applications, time series often exhibit missing observations such that standard analytical tools cannot be applied. While there are approaches of how to handle missing data in quantitative time series, the case of categorical time series seems not to have been treated so far. Both for the case of ordinal and nominal time series, solutions are developed that allow to analyze their marginal and serial properties in the presence of missing observations. This is achieved by adapting the concept of amplitude modulation, which allows to obtain closed-form asymptotic expressions for the derived statistics' distribution (assuming that missingness happens independently of the actual process). The proposed methods are investigated with simulations, and they are applied in a project on migraine patients, where the monitored qualitative time series are often incomplete.
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The family of cumulative paired Ï-entropies offers a wide variety of ordinal dispersion measures, covering many well-known dispersion measures as a special case. After a comprehensive analysis of this family of entropies, we consider the corresponding sample versions and derive their asymptotic distributions for stationary ordinal time series data. Based on an investigation of their asymptotic bias, we propose a family of signed serial dependence measures, which can be understood as weighted types of Cohen's κ, with the weights being related to the actual choice of Ï. Again, the asymptotic distribution of the corresponding sample κÏ is derived and applied to test for serial dependence in ordinal time series. Using numerical computations and simulations, the practical relevance of the dispersion and dependence measures is investigated. We conclude with an environmental data example, where the novel Ï-entropy-related measures are applied to an ordinal time series on the daily level of air quality.
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Time series consist of data observed sequentially in time, and they are assumed to stem from an underlying stochastic process [...].
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For the modeling of categorical time series, both nominal or ordinal time series, an extension of the basic discrete autoregressive moving-average (ARMA) models is proposed. It uses an observation-driven regime-switching mechanism, leading to the family of RS-DARMA models. After having discussed the stochastic properties of RS-DARMA models in general, we focus on the particular case of the first-order RS-DAR model. This RS-DAR ( 1 ) model constitutes a parsimoniously parameterized type of Markov chain, which has an easy-to-interpret data-generating mechanism and may also handle negative forms of serial dependence. Approaches for model fitting are elaborated on, and they are illustrated by two real-data examples: the modeling of a nominal sequence from biology, and of an ordinal time series regarding cloudiness. For future research, one might use the RS-DAR ( 1 ) model for constructing parsimonious advanced models, and one might adapt techniques for smoother regime transitions.
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BACKGROUND: The aim of this study was to evaluate the efficacy and safety of chemoradiotherapy (RCT) combined with regional deep hyperthermia (RHT) of high-risk bladder cancer after transurethral resection of bladder tumor (TUR-BT). MATERIALS AND METHODS: Between 1982 and 2016, 369 patients with pTa, pTis, pT1, and pT2 cN0-1 cM0 bladder cancer were treated with a multimodal treatment after TUR-BT. All patients received radiotherapy (RT) of the bladder and regional lymph nodes. RCT was administered to 215 patients, RCT + RHT was administered to 79 patients, and RT was used in 75 patients. Treatment response was evaluated 4-6 weeks after treatment with TUR-BT. RESULTS: Complete response (CR) overall was 83% (290/351), and in treatment groups was RT 68% (45/66), RCT 86% (178/208), and RCT + RHT 87% (67/77). CR was significantly improved by concurrent RCT compared with RT (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.05-5.12; p = .037), less influenced by hyperthermia (OR, 2.56; 95% CI, 0.88-8.00; p = .092). Overall survival (OS) after RCT was superior to RT (hazard ratio [HR], 0.7; 95% CI, 0.50-0.99; p = .045). Five-year OS from unadjusted Kaplan-Meier estimates was RCT 64% versus RT 45%. Additional RHT increased 5-year OS to 87% (HR, 0.32; 95% CI, 0.18-0.58; p = .0001). RCT + RHT compared with RCT showed a significantly better bladder-preservation rate (HR, 0.13; 95% CI, 0.03-0.56; p = .006). Median follow-up was 71 months. The median number of RHT sessions was five. CONCLUSION: The multimodal treatment consisted of a maximal TUR-BT followed by RT; concomitant platinum-based chemotherapy combined with RHT in patients with high-grade bladder cancer improves local control, bladder-preservation rate, and OS. It offers a promising alternative to surgical therapies like radical cystectomy. IMPLICATIONS FOR PRACTICE: Radical cystectomy with appropriate lymph node dissection has long represented the standard of care for muscle-invasive bladder cancer in medically fit patients, despite many centers reporting excellent long-term results for bladder preserving strategies. This retrospective analysis compares different therapeutic modalities in bladder-preservation therapy. The results of this study show that multimodal treatment consisting of maximal transurethral resection of bladder tumor followed by radiotherapy, concomitant platinum-based chemotherapy combined with regional deep hyperthermia in patients with Ta, Tis, T1-2 bladder carcinomas improves local control, bladder-preservation rate, and survival. More importantly, these findings offer a promising alternative to surgical therapies like radical cystectomy. The authors hope that, in the future, closer collaboration between urologists and radiotherapists will further improve treatments and therapies for the benefit of patients.
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Hipertermia Induzida/métodos , Preservação de Órgãos/métodos , Neoplasias da Bexiga Urinária/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/radioterapiaRESUMO
Aims: The aim of this study was to investigate the effect of contact-to-balloon time on mortality in ST-segment elevation myocardial infarction (STEMI) patients with and without haemodynamic instability. Methods and results: Using data from the prospective, multicentre Feedback Intervention and Treatment Times in ST-Elevation Myocardial Infarction (FITT-STEMI) trial, we assessed the prognostic relevance of first medical contact-to-balloon time in n = 12 675 STEMI patients who used emergency medical service transportation and were treated with primary percutaneous coronary intervention (PCI). Patients were stratified by cardiogenic shock (CS) and out-of-hospital cardiac arrest (OHCA). For patients treated within 60 to 180 min from the first medical contact, we found a nearly linear relationship between contact-to-balloon times and mortality in all four STEMI groups. In CS patients with no OHCA, every 10-min treatment delay resulted in 3.31 additional deaths in 100 PCI-treated patients. This treatment delay-related increase in mortality was significantly higher as compared to the two groups of OHCA patients with shock (2.09) and without shock (1.34), as well as to haemodynamically stable patients (0.34, P < 0.0001). Conclusions: In patients with CS, the time elapsing from the first medical contact to primary PCI is a strong predictor of an adverse outcome. This patient group benefitted most from immediate PCI treatment, hence special efforts to shorten contact-to-balloon time should be applied in particular to these high-risk STEMI patients. Clinical Trial Registration: NCT00794001.
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Angioplastia Coronária com Balão , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Tempo para o Tratamento , Idoso , Idoso de 80 Anos ou mais , Serviços Médicos de Emergência , Feminino , Alemanha , Hemodinâmica , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Parada Cardíaca Extra-Hospitalar/mortalidade , Parada Cardíaca Extra-Hospitalar/fisiopatologia , Parada Cardíaca Extra-Hospitalar/cirurgia , Estudos Prospectivos , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Choque Cardiogênico/etiologia , Choque Cardiogênico/mortalidade , Choque Cardiogênico/fisiopatologia , Choque Cardiogênico/cirurgiaRESUMO
BACKGROUND: In heart failure (HF) patients with implantable cardioverter defibrillators (ICD) or cardiac resynchronisation therapy defibrillators (CRT-D), remote monitoring has been shown to result in at least non-inferior outcomes relative to in-clinic visits. We aimed to provide further evidence for this effect, and to assess whether adding telephone follow-ups to remote follow-ups influenced outcomes. METHODS: InContact was a prospective, randomised, multicentre study. Subjects receiving quarterly automated follow-up only (telemetry group) were compared to those receiving personal physician contact. Personal contact patients were further divided into those receiving automated follow-up plus a telephone call (remote+phone subgroup) or in-clinic visits only. RESULTS: Two hundred and ten patients underwent randomisation (telemetry n = 102; personal contact n = 108 [remote+phone: n = 53; visit: n = 55]). Baseline characteristics were comparable between groups and subgroups. Over 12 months, 34.8% of patients experienced deterioration of their Packer Clinical Composite Response, with no significant difference between the telemetry group and personal care (p > 0.999), remote+phone (p = 0.937) or visit (p = 0.940) patients; predefined non-inferiority criteria were met. Mortality rates (5.2% overall) were comparable between groups and subgroups (p = 0.832/p = 0.645), as were HF-hospitalisation rates (11.0% overall; p = 0.605/p = 0.851). The proportion of patients requiring ≥1 unscheduled follow-up was nominally higher in telemetry and remote+phone groups (42.2 and 45.3%) compared to the visit group (29.1%). Overall, ≥ 1 ICD therapy was delivered to 15.2% of patients. CONCLUSION: In HF patients with ICDs/CRT-Ds, quarterly remote follow-up only over 12 months was non-inferior to regular personal contact. Addition of quarterly telephone follow-ups to remote monitoring does not appear to offer any clinical advantage. TRIAL REGISTRATION: clinicaltrials.gov: NCT01200381 (retrospectively registered on September 13th 2010).
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Desfibriladores Implantáveis , Cardioversão Elétrica/instrumentação , Insuficiência Cardíaca/terapia , Tecnologia de Sensoriamento Remoto/instrumentação , Telemetria/instrumentação , Idoso , Cardioversão Elétrica/efeitos adversos , Cardioversão Elétrica/mortalidade , Alemanha , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Pessoa de Meia-Idade , Visita a Consultório Médico , Valor Preditivo dos Testes , Estudos Prospectivos , Telefone , Fatores de Tempo , Resultado do TratamentoRESUMO
We propose a compressed sampling and dictionary learning framework for fiber-optic sensing using wavelength-tunable lasers. A redundant dictionary is generated from a model for the reflected sensor signal. Imperfect prior knowledge is considered in terms of uncertain local and global parameters. To estimate a sparse representation and the dictionary parameters, we present an alternating minimization algorithm that is equipped with a preprocessing routine to handle dictionary coherence. The support of the obtained sparse signal indicates the reflection delays, which can be used to measure impairments along the sensing fiber. The performance is evaluated by simulations and experimental data for a fiber sensor system with common core architecture.
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As the detection rate of HPV-DNA in anal carcinoma commonly exceeds 90%, a comparison between sole HPV-positive and HPV-negative cancers with respect to treatment response following chemoradiotherapy (CRT) and long-term oncological outcome is challenging. Against this background, we aimed to assess HPV types and HPV DNA load in formalin-fixed paraffin-embedded tissue (FFPE) of 95 patients treated with standard CRT for anal cancer to correlate viral load (≤/> median) with local failure, distant metastases, cancer-specific (CSS) and overall survival (OS) rates. Various clinicopathologic parameters and the immunohistochemical marker p16(INK4a) were evaluated for any correlation with HPV16 DNA load and were included in uni- and multivariate analyses. The overall prevalence of HPV DNA was 95.8% with HPV16 monoinfection being the most commonly encountered HPV type (78.9%), followed by HPV16 and 31, 35, 39, 44, 58, 66 and 81 dual infection in 9 patients (9.5%). HPV16 DNA load was significantly associated with p16(INK4a) expression (p = 0.001). Patients with HPV16 DNA load ≤ median and low p16(INK4a) expression showed significantly worse local control (HPV16 DNA load: univariate p = 0.023, multivariate p = 0.042; p16(INK4a): univariate p = 0.021), and OS (HPV16 DNA load: univariate p = 0.02, multivariate p = 0.03). Moreover, a combined HPV16 DNA load and p16(INK4a) variable revealed a significant correlation to decreased local failure, and increased CSS and OS (p = 0.019, p = 0.04 and p = 0.031). In conclusion, these data indicate that HPV16 DNA load and p16(INK4a) expression are significant prognostic factors for local tumor control and overall survival of patients with anal SCC following CRT.
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Neoplasias do Ânus/terapia , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , DNA Viral/análise , Papillomaviridae/genética , Infecções por Papillomavirus/complicações , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/mortalidade , Neoplasias do Ânus/virologia , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/virologia , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Estadiamento de Neoplasias , Papillomaviridae/classificação , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/virologia , Prognóstico , Taxa de Sobrevida , Carga ViralRESUMO
BACKGROUND: We examined (a) the expression of the antioxidative factor glutathione peroxidase (GPx) and the transcription factor nuclear factor E2-related factor 2 (Nrf2) following low-dose X-irradiation in endothelial cells (ECs) and (b) the impact of reactive oxygen species (ROS) and Nrf2 on functional properties of ECs to gain further knowledge about the anti-inflammatory mode of action of low doses of ionizing radiation. MATERIAL AND METHODS: EA.hy926 ECs and primary human dermal microvascular ECs (HMVEC) were stimulated by tumor necrosis factor-α (TNF-α, 20 ng/ml) 4 h before irradiation with single doses ranging from 0.3 to 3 Gy. The expression and activity of GPx and Nrf2 were analyzed by flow cytometry, colorimetric assays, and real-time PCR. The impact of ROS and Nrf2 on peripheral blood mononuclear cell (PBMC) adhesion was assayed in the presence of the ROS scavenger N-acetyl-L-cysteine (NAC) and Nrf2 activator AI-1. RESULTS: Following a low-dose exposure, we observed in EA.hy926 EC and HMVECs a discontinuous expression and enzymatic activity of GPx concomitant with a lowered expression and DNA binding activity of Nrf2 that was most pronounced at a dose of 0.5 Gy. Scavenging of ROS by NAC and activation of Nrf2 by AI-1 significantly diminished a lowered adhesion of PBMC to EC at a dose of 0.5 Gy. CONCLUSION: Low-dose irradiation resulted in a nonlinear expression and activity of major compounds of the antioxidative system that might contribute to anti-inflammatory effects in stimulated ECs.
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Antioxidantes/metabolismo , Células Endoteliais/fisiologia , Células Endoteliais/efeitos da radiação , Inflamação/metabolismo , Inflamação/radioterapia , Espécies Reativas de Oxigênio/metabolismo , Adesão Celular/fisiologia , Adesão Celular/efeitos da radiação , Células Cultivadas , Relação Dose-Resposta à Radiação , Regulação da Expressão Gênica/fisiologia , Regulação da Expressão Gênica/efeitos da radiação , Humanos , Doses de RadiaçãoRESUMO
PURPOSE: Locoregional recurrence remains the main pattern of failure after primary combined modality treatment of squamous cell carcinoma of the head and neck (SCCHN). We compared the efficacy and toxicity of either cisplatin or cetuximab in combination with re-irradiation (ReRT) for recurrent unresectable SCCHN. Various clinicopathological factors were investigated to establish a prognostic score. PATIENTS AND METHODS: Between 2007 and 2014, 66 patients with recurrent SCCHN originating in a previously irradiated area received cetuximab (n = 33) or cisplatin-based chemotherapy (n = 33) concomitant with ReRT. Toxicity was evaluated weekly and at every follow-up visit. Physical examination, endoscopy, CT or MRI scans were used to evaluate response and disease control. RESULTS: With a mean follow-up of 18.3 months, the 1-year overall survival (OS) rates for Re-RT with cetuximab and cisplatin-based chemotherapy were 44.4 and 45.5% (p = 0.352), respectively. At 1 year, local control rates (LCR) were 46.4 and 54.2% (p = 0.625), freedom from metastases (FFM) rates 73.6 and 81% (p = 0.842), respectively. Haematological toxicity ≥ grade 3 occurred more often in the cisplatin group (p < 0.001), pain ≥ grade 3 was increased in the cetuximab group (p = 0.034). A physiological haemoglobin level and a longer interval between primary RT and ReRT, proved to be significant prognostic factors for OS (multivariate: p = 0.003, p = 0.002, respectively). Site of the recurrence and gross target volume (GTV) did not show a significant impact on OS in multivariate analysis (p = 0.160, p = 0.167, respectively). A prognostic-score (1-4 points) based on these four variables identified significantly different subgroups: 1-year OS for 0/1/2/3/4 prognostic points: 10, 38, 76, 80 and 100%, respectively (p < 0.001). CONCLUSION: Both cetuximab- and cisplatin-based ReRT of SCCHN recurrences are feasible and effective treatment options with comparable results in terms of tumour control and survival. Acute adverse events may differ slightly. Our prognostic score could help to identify appropriate patients for ReRT and stratify patients within future clinical trials.
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Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia , Cisplatino/administração & dosagem , Recidiva Local de Neoplasia/terapia , Neoplasias Otorrinolaringológicas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Cetuximab , Cisplatino/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias Otorrinolaringológicas/mortalidade , Neoplasias Otorrinolaringológicas/patologia , Retratamento , Taxa de SobrevidaRESUMO
BACKGROUND: Stress related to surgery and critical illness depletes thiamine, essential in energy metabolism, and might result in high blood lactate concentrations and higher mortality. OBJECTIVES: We hypothesised that thiamine supplementation would increase blood concentration of thiamine and reduce blood lactate concentration postoperatively. Moreover, we aimed to identify the prevalence of, and risk factors for, high blood lactate concentrations. DESIGN: This was a double-blind, randomised controlled pilot study from February to July 2012 including 30 patients scheduled for cardiac surgery with cardiopulmonary bypass. INTERVENTIONS: Patients were assigned randomly to receive thiamine (300 mg in 0.9% Normal saline solution) or placebo (0.9% Normal saline) preoperatively. MAIN OUTCOME MEASURES: One arterial blood sample was taken preoperatively and another postoperatively to measure thiamine concentration, and multiple samples were taken during surgery and ICU stay to determine lactate concentrations. Twenty-four hour urine samples were collected to measure urinary thiamine concentration. Preoperatively, we assessed extracellular mass to body cell mass ratio (ECM/BCM). RESULTS: The mean (SD) age of the patients was 58 (12) years, 73% were overweight, 10% were malnourished and the prevalence of thiamine deficiency was 10%. Patients in the thiamine group had significantly higher blood thiamine concentrations 2 days postoperatively [805.2 ± 289.8 ng g(-1) haemoglobin (Hb)] than those in the placebo group (591.2 ± 100.7 ng g(-1) Hb, P < 0.01). The mean blood lactate concentration changed significantly over time, but did not differ significantly between the groups. Patients with ECM/BCM more than 1 had higher lactate concentrations on admission to ICU than those with ECM/BCM less than 1 (2.1 ± 0.7 vs. 1.7 ± 0.6, P = 0.09) and were at a significantly greater risk of having a higher lactate concentration on ICU admission [odds ratio (OR) 13.5, 95% confidence interval (95% CI) 1.0 to 179.4, P < 0.05]. On the basis of these results, a sample size calculation for a larger study has been facilitated. CONCLUSION: Thiamine supplementation caused normalisation of blood and urine concentrations postoperatively but without a significant reduction in lactate concentration or clinical outcome. Body composition played an important role in lactate formation. Further research focusing on preoperative screening and optimal treatment of high lactate concentrations in this specific population is warranted. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01524315.
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Ponte Cardiopulmonar/métodos , Suplementos Nutricionais , Ácido Láctico/sangue , Tiamina/administração & dosagem , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Projetos PilotoRESUMO
BACKGROUND: Advanced non-small cell lung cancer (NSCLC) represents a significant unmet medical need. Despite advances with targeted therapies in a small subset of patients, fewer than 20% of patients survive for more than two years after diagnosis. Cancer vaccines are a promising therapeutic approach that offers the potential for durable responses through the engagement of the patient's own immune system. CV9202 is a self-adjuvanting mRNA vaccine that targets six antigens commonly expressed in NSCLC (NY-ESO-1, MAGEC1, MAGEC2, 5 T4, survivin, and MUC1). METHODS/DESIGN: The trial will assess the safety and tolerability of CV9202 vaccination combined with local radiation designed to enhance immune responses and will include patients with stage IV NSCLC and a response or stable disease after first-line chemotherapy or therapy with an EGFR tyrosine kinase inhibitor. Three histological and molecular subtypes of NSCLC will be investigated (squamous and non-squamous cell with/without EGFR mutations). All patients will receive two initial vaccinations with CV9202 prior to local radiotherapy (5 GY per day for four successive days) followed by further vaccinations until disease progression. The primary endpoint of the study is the number of patients experiencing Grade >3 treatment-related adverse events. Pharmacodynamic analyses include the assessment of immune responses to the antigens encoded by CV9202 and others not included in the panel (antigen spreading) and standard efficacy assessments. DISCUSSION: RNActive self-adjuvanted mRNA vaccines offer the potential for simultaneously inducing immune responses to a wide panel of antigens commonly expressed in tumors. This trial will assess the feasibility of this approach in combination with local radiotherapy in NSCLC patients. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01915524/EudraCT No.: 2012-004230-41.
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Vacinas Anticâncer/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , RNA Mensageiro/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Quimioterapia Adjuvante , Terapia Combinada , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , RNA Mensageiro/efeitos adversos , RNA Mensageiro/uso terapêutico , Doses de Radiação , Radioterapia , Resultado do TratamentoRESUMO
INTRODUCTION: Renal cell carcinoma is counted among the most resistant tumors to chemotherapy and radiotherapy, respectively. However, therapeutic options expanded since the introduction of molecular agents, targeting specific pathways such as the vascular endothelial growth factor (VEGF)-α, the VEGF receptor (VEGFR), or the mammalian target of rapamycin (mTOR) pathway. These new agents almost doubled the time to tumor progression and in some trials even improved overall survival. Against this background, the role of local treatment strategies in metastasized or inoperable primary renal cell carcinoma has to be redefined. With the onset of new technical developments in radiotherapy and the possibility to precisely deliver higher doses per fraction, encouraging response and control rates have been reported for kidney cancer, supporting a possible role for irradiation in this setting. This overview summarizes the preclinical data and clinical experiences of modern radiotherapy with focus on possible synergies and toxicities when combined with molecular targeted agents. METHODS: The available literature on preclinical and clinical data comprising prospective trials, retrospective analyses and case reports was reviewed. CONCLUSION: With the recent developments in stereotactic and image-guided radiotherapy, encouraging data concerning local control in the treatment for metastasized renal cell carcinoma have been generated and are therefore recommended whenever possible. It seems that with these high- precision irradiation schedules, the combination with targeted agents is feasible with no increase in severe adverse events. Nevertheless, the addition of molecular targeted drugs to radiotherapy outside of approved regimens or clinical trials warrants careful consideration for every single case.
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Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/terapia , Neoplasias Renais/terapia , Terapia de Alvo Molecular , Radioterapia , Terapia Combinada , Relação Dose-Resposta à Radiação , Humanos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/radioterapia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
BACKGROUND: Public quality reports, based on new legislative regulations of 2008, were supposed to offer potential customers the possibility to make a well-informed choice of a care provider. AIM: This empirical study on marks for long-term care is based on the public quality reports of the Medical Service of the Health Insurance Companies (MDK), of 11 884 home care services and 10 310 nursing homes, which corresponds to a comprehensive survey of almost all care providers in Germany. METHOD: Descriptive statistical methods and discussion of the results concerning the customer benefit. RESULTS: The analysis of transparency reports reveals a limited value for customers, which is particularly caused by very good quality results with low scattering. In addition, a high amount of missing data - especially in the area of home care providers - leads to a growing influence of service criteria on the final grade. Though deficits in nursing might be compensated by good marks in service criteria, it rarely occurs. At present, a more detailed look at risk criteria hardly improves the customer benefit. CONCLUSION: The marks for nursing need to be improved to increase their informative value for the customer.