Designs of Early Phase Cancer Trials with Drug Combinations

We discuss several innovative phase I and phase I--II designs for early phase cancer clinical trial with drug combinations focusing on continuous dose levels of both agents. For phase I trials with drug combinations, the main objective is to estimate the maximum tolerated dose (MTD) curve in the two-dimensional Cartesian plane. A parametric model is used to describe the relationship between the doses of the two agents and the probability of dose-limiting toxicity (DLT). Trial design proceeds using cohorts of two patients receiving doses according to univariate escalation with overdose control (EWOC) or continual reassessment method (CRM). At the end of the trial, the MTD is estimated as a function of Bayes estimates of the model parameters. Furthermore, we present the model where a fraction of DLTs can be attributed to one or both agents, and show how the parametric designs can be adapted to account for an unknown fraction of attributable DLTs. We also consider the inclusion of a binary baseline covariate to describe sub-groups with different frailty levels. In phase I--II trials, it may not be possible to evaluate efficacy in a short window of time. In this case, two-stage designs are frequently employed. First, a set of maximum tolerated dose combinations is selected. Next, the selected set is then tested for efficacy, sometimes in a different patient population than that used in the first stage. We discuss binary and time-to-event endpoints to identify dose combinations along the MTD curve with maximum probability of efficacy in the second stage

Teoria do direito: estudos em homenagem a Arnaldo Vasconcelos

- Divulgação dos SUMÁRIOS das obras recentemente incorporadas ao acervo da Biblioteca Ministro Oscar Saraiva do STJ. Em respeito à Lei de Direitos Autorais, não disponibilizamos a obra na íntegra.- Localização na estante: 34.01 T314d- Coordenado por: Hugo de Brito Machado Segundo e Marcio Augusto de Vasconcelos Diniz

The Lowest Prevalence of Cholelithiasis in the Americas - An Autopsy-based Study

OBJECTIVES: This study used autopsy to evaluate the prevalence of cholelithiasis and its associated risk factors in a population of healthy, young subjects who suffered a violent or natural death. METHODS: This study is a prospective evaluation of autopsies of 446 individuals from 2011 to 2013 in Brazil. Of that sample, 330 (74%) subjects died from violent deaths and 116 (26%) died naturally. The presence of biliary calculi, previous cholecystectomy, gender, age, ethnicity, body mass index (BMI) and alcohol use were evaluated. RESULTS: In the natural death group, 6.9% (95% CI 3.39 to 13.28) (3.08% of the male subjects and 11.76% of the female subjects) exhibited evidence of gallbladder disease. In the violent death group, only 2.12% (95% CI 0.96 to 4.43) (2.17% of the male subjects and 1.85% of the female subjects) of the subjects exhibited evidence of gallbladder disease. Age was correlated with the prevalence of gallbladder disease, but BMI was correlated with only gallbladder disease in the natural death group. CONCLUSIONS: This population has the lowest prevalence of cholelithiasis in the Americas. Dietary habits, physical activity, ethnicity, alcohol consumption and genetic factors may be responsible for this low prevalence

An analysis of tacrolimus-related complications in the first 30 days after liver transplantation

OBJECTIVES: Orthotopic liver transplantation has improved survival in patients with end-stage liver disease; however, therapeutic strategies that achieve ideal immunosuppression and avoid early complications are lacking. To correlate the dose and level of Tacrolimus with early complications, e.g., rejection, infection and renal impairment, after liver transplantation. From November 2011 to May 2013, 44 adult liver transplant recipients were studied in this retrospective comparative study. RESULTS: The most frequent indication for liver transplantation was hepatitis C cirrhosis (47.7%), with a higher prevalence observed in male patients (68.18%). The ages of the subjects ranged from 19-71 and the median age was 55.5 years. The mean length of the hospital stay was 16.1±9.32 days and the mean Model for End-stage Liver Disease score was 26.18±4.28. There were five cases of acute cellular rejection (11.37%) and 16 cases of infection (36.37%). The blood samples that were collected and analyzed over time showed a significant correlation between the Tacrolimus blood level and the deterioration of glomerular filtration rate and serum creatinine (

Early and Late Pathogenic Events of Newborn Mice Encephalitis Experimentally Induced by Itacaiunas and Curionópolis Bracorhabdoviruses Infection

In previous reports we proposed a new genus for Rhabdoviridae and described neurotropic preference and gross neuropathology in newborn albino Swiss mice after Curionopolis and Itacaiunas infections. In the present report a time-course study of experimental encephalitis induced by Itacaiunas and Curionopolis virus was conducted both in vivo and in vitro to investigate cellular targets and the sequence of neuroinvasion. We also investigate, after intranasal inoculation, clinical signs, histopathology and apoptosis in correlation with viral immunolabeling at different time points. Curionopolis and Itacaiunas viral antigens were first detected in the parenchyma of olfactory pathways at 2 and 3 days post-inoculation (dpi) and the first clinical signs were observed at 4 and 8 dpi, respectively. After Curionopolis infection, the mortality rate was 100% between 5 and 6 dpi, and 35% between 8 and 15 dpi after Itacaiunas infection. We identified CNS mice cell types both in vivo and in vitro and the temporal sequence of neuroanatomical olfactory areas infected by Itacaiunas and Curionopolis virus. Distinct virulences were reflected in the neuropathological changes including TUNEL immunolabeling and cytopathic effects, more intense and precocious after intracerebral or in vitro inoculations of Curionopolis than after Itacaiunas virus. In vitro studies revealed neuronal but not astrocyte or microglial cytopathic effects at 2 dpi, with monolayer destruction occurring at 5 and 7 dpi with Curionopolis and Itacaiunas virus, respectively. Ultrastructural changes included virus budding associated with interstitial and perivascular edema, endothelial hypertrophy, a reduced and/or collapsed small vessel luminal area, thickening of the capillary basement membrane, and presence of phagocytosed apoptotic bodies. Glial cells with viral budding similar to oligodendrocytes were infected with Itacaiunas virus but not with Curionopolis virus. Thus, Curionopolis and Itacaiunas viruses share many pathological and clinical features present in other rhabdoviruses but distinct virulence and glial targets in newborn albino Swiss mice brain

Estado social e princípio da solidariedade

O presente trabalho analisa o tema da solidariedade a partir de uma evolução histórica, buscando revelar a sua importância na construção do ideal de solidariedade e bem comum. Tais elementos são centrais na perspectiva da ética, na medida em que o indivíduo ético, consciente também reconhece a autonomia e a diferença, próprias de cada um. A presente investigação busca conhecer os pressupostos do Estado Social, levando em consideração os valores acima mencionados, vez que o Estado constitucional que pretenda exercer o papel de Estado Social, não pode afastar a eficácia primordial do princípio da dignidade humana

Estado social e princípio da solidariedade

O presente trabalho analisa o tema da solidariedade a partir de uma evolução histórica, buscando revelar a sua importância na construção do ideal de solidariedade e bem comum. Tais elementos são centrais na perspectiva da ética, na medida em que o indivíduo ético, consciente também reconhece a autonomia e a diferença, próprias de cada um. A presente investigação busca conhecer os pressupostos do Estado Social, levando em consideração os valores acima mencionados, vez que o Estado constitucional que pretenda exercer o papel de Estado Social, não pode afastar a eficácia primordial do princípio da dignidade humana

Direitos fundamentais e retórica política. Doi: 10.5020/2317-2150.1996.v04n1p171

Examina-se nessa monografia a teoria dos direitos fundamentais sob o prisma da teoria dos sistemas, bem como sua aplicação aos sistemas constitucionais dos Países periféricos