Circulating and imaging markers for angiogenesis

Abundant preclinical and indirect clinical data have for several decades convincingly supported the notion that anti-angiogenesis is an effective strategy for the inhibition of tumor growth. The recent success achieved in patients with metastatic colon carcinoma using a neutralizing antibody directed against vascular endothelial growth factor (VEGF) has translated preclinical optimism into a clinical reality.With this transformation in the field of angiogenesis has come a need for reliable surrogate markers. A surrogate marker by definition serves as a substitute for the underlying process in question, and in the case of angiogenesis, microvessel density (usually in so-called “hot-spots”) has until now been the most widely used parameter. However, this parameter is more akin to a static “snap-shot” and does not lend itself either to the dynamic in situ assessment of the status of the tumor microvasculature or to the molecular factors that regulate its growth and involution. This has led to an acute need for developing circulating and imaging markers of angiogenesis that can be monitored in vivo at repeated intervals in large number of patients with a variety of tumors in a non-invasive manner. Such markers of angiogenesis are the subject of this review.     

Méta-analyses d’essais randomisés sur données individuelles dans le traitement des cancers ORL non métastatiques : principes,résultats,perspectives

Meta-analyses are considered as an important pillar of evidence-based medicine. The aim of this review is to describe the main principles of a meta-analysis and to use examples of head and neck oncology to demonstrate their clinical impact and methodological interest. The major role of individual patient data is outlined, as well as the superiority of individual patient data over meta-analyses based on published summary data. The major clinical breakthrough of head and neck meta-analyses are summarized, regarding concomitant chemotherapy, altered fractionated chemotherapy, new regimens of induction chemotherapy or the use of radioprotectants. Recent methodological developments are described, including network meta-analyses, the validation of surrogate markers. Lastly, the future of meta-analyses is discussed in the context of personalized medicine.     

Legal developments in assisted reproduction.

Courts have been quite consistent in allowing ex-partners in marriages or similar relationships, usually men, to veto the other partner's reproductive use of jointly-created IVF embryos. This supports the principle of voluntary parenthood. In contrast, child custody disputes following surrogate motherhood may favor the commissioning couple or the surrogate. Decisive are the best interests of the child, which a court may find favorable to the former or the latter, or custody shared between them. Preimplantation genetic diagnosis (PGD) may be restricted by governmental licensing regulations, and raises concerns about diagnosis showing noninheritance of a feared disorder, but not other conditions harming a subsequently born child. Travel abroad raises concerns of legality. Some countries explicitly allow nationals to go to other countries for services legally barred in their own, but others would bind nationals by their prohibitive laws if they were to receive, or counsel, services abroad that are lawful where delivered.     

Isocyanate and VOC exposure analysis using Flexane®

Flexane® 80 is a trowelable urethane product used in combination with cleaners and primers to effect rubber conveyor belt repairs. These products are of concern due to the potential for worker exposure to isocyanates and volatile organic compounds (VOCs). Small chamber experiments were used to identify chemicals liberated to the ambient air from each of the Flexane®-related products. A new sample collection method using treated cotton sleeves as a surrogate skin surface to assess potential dermal exposure to isocyanates during mixing and application of the Flexane® product was validated. Six simulations of a worst case scenario were performed by an experienced belt repair technician in a walk-in laboratory exposure chamber. Analysis of air samples from the large chamber simulations did not detect airborne isocyanates. The average airborne VOC concentrations were below established occupational exposure levels. Dermal sleeve samples detected intermittent and low levels of isocyanates from self-application while wearing gloves having surface residues of uncured Flexane®. The data strongly suggest that the normal and intended use of Flexane® putty, and its associated products under worst case or typical working conditions is not likely to result in worker VOC or isocyanate exposure levels sufficient to produce adverse health effects.     

Clinical symptoms and microbiological outcomes in tuberculosis treatment trials

During a recent Food and Drug Administration workshop on clinical trials to evaluate new TB drugs, questions were raised regarding the use of bacteriologic endpoints such as treatment failure and relapse as measures of improvement in health status and long term outcome after treatment. FDA scientists asked how patients' clinical signs and symptoms changed during therapy, noting that while such information is usually collected during clinical trials, it is not often reported. We analyzed data from an international phase 3 TB treatment trial that included systematic assessments of symptoms. The percentage of subjects with self-reported symptoms at baseline ranged from 30% for dyspnea to 81% for cough, with 51% reporting fever. During therapy, fever, sweats, and dyspnea decreased most rapidly, with near resolution by the end of therapy. Chest pain and cough resolved more slowly; 13% of subjects reported cough at six months. Symptom resolution during treatment did not differ between those who relapsed and those who did not. Among those with microbiological relapse, symptoms returned with significant increases in the proportion with fever, cough, and chest pain. At the time of relapse, cough was the most frequent symptom, occurring in 75% of subjects who relapsed but only 12% of those who did not. Our data support the continued use of bacteriologic endpoints based on sputum culture as surrogate measures of the relief of symptoms, improvement in health status and favorable long term treatment outcome in TB drug trials.     

Design of clinical trials of gene therapy in Parkinson disease

No current therapy for Parkinson disease has been shown to slow or reverse the progressive course of the disease. As a departure from traditional treatments, gene therapy approaches provide a new hope for realizing this long-sought goal; but before they can be widely employed for use in patients, they must first be submitted to the rigorous safety and efficacy standards of the clinical trial. Some of the challenges of gene therapy clinical trial design are similar to those in studies of conventional pharmacological agents and include addressing the heterogeneity of the disease, the need for clinical and surrogate endpoints, and the issue of distinguishing "symptomatic" from "neuroprotective" effects. Gene therapy trials also raise the issues of the risks of viral therapy, issues of dose-response, the need for sham surgery, and the long duration of risks and benefits. We conclude that the most feasible designs are for those treatments that are expected to produce a rapid improvement in directly observable symptoms. Trials of agents which are expected to produce only a slowing of progression and not a reversal of the disease course are likely to take much longer and will require the development of methods to assess quality of life and other non-motor aspects of the disease.     

Imaging readouts as biomarkers or surrogate parameters for the assessment of therapeutic interventions

Surrogate markers and biomarkers based on imaging readouts providing predictive information on clinical outcome are of increasing importance in the preclinical and clinical evaluation of novel therapies. They are primarily used in studies designed to establish evidence that the therapeutic principle is valid in a representative patient population or in an individual. A critical step in the development of (imaging) surrogates is validation: correlation with established clinical endpoints must be demonstrated. Biomarkers must not fulfill such stringent validation criteria; however, they should provide insight into mechanistic aspects of the therapeutic intervention (proof-of-mechanism) or document therapy efficacy with prognostic quality with regard to the long-term clinical outcome (proof of concept). Currently used imaging biomarkers provide structural, physiological and metabolic information. Novel imaging approaches annotate structure with molecular signatures that are tightly linked to the pathophysiology or to the therapeutic principle. These cellular and molecular imaging methods yield information on drug biodistribution, receptor expression and occupancy, and/or intra- and intercellular signaling. The design of novel target-specific imaging probes is closely related to the development of the therapeutic agents and should be considered early in the discovery phase. Significant technical and regulatory hurdles have to be overcome to foster the use of imaging biomarkers for clinical drug evaluation.     

本科护生人工辅助生殖技术认同度的调查与分析

目的探讨本科护生对人工辅助生殖技术的认同度及相关影响因素,分析本科护生思想中存在的伦理误区。方法自行设计人工辅助生殖技术认同度调查问卷,包括学生的一般资料、一个典型案例及所附带的6个伦理问题,对372名本科护生进行问卷调查。结果本科护生对人工辅助生殖技术伦理问题持较为宽容的态度;70%的本科护生对"名人精子库"持否定态度;16.3%的本科护生对"名人精子库"诞生的孩子必然成为名人的说法持否定态度;54.1%的本科护生对告知由人工辅助技术出生的孩子其真实身世的态度上是否定的。不同性别本科护生在"名人精子库"、"单身母亲"、"代孕母亲"等问题的态度上存在显著差异(p﹤0.05);不同家庭收入的本科护生在"单身母亲"态度上存在显著差异(p﹤0.05)。结论大部分本科护生对人工辅助生殖技术持有较为理性的态度,少数本科护生存在伦理误区,教学中要开展有针对性的教育,同时需健全和完善相关法律法规。