A phase-I trial of pre-operative, margin intensive, stereotactic body radiation therapy for pancreatic cancer: the 'SPARC' trial protocol.

BACKGROUND: Standard therapy for borderline-resectable pancreatic cancer in the UK is surgery with adjuvant chemotherapy, but rates of resection with clear margins are unsatisfactory and overall survival remains poor. Meta-analysis of single-arm studies shows the potential of neo-adjuvant chemo-radiotherapy but the relative radio-resistance of pancreatic cancer means the efficacy of conventional dose schedules is limited. Stereotactic radiotherapy achieves sufficient accuracy and precision to enable pre-operative margin-intensive dose escalation with the goal of increasing rates of clear resection margins and local disease control. METHODS/DESIGN: SPARC is a "rolling-six" design single-arm study to establish the maximum tolerated dose for margin-intensive stereotactic radiotherapy before resection of pancreatic cancer at high risk of positive resection margins. Eligible patients will have histologically or cytologically proven pancreatic cancer defined as borderline-resectable per National Comprehensive Cancer Network criteria or operable tumour in contact with vessels increasing the risk of positive margin. Up to 24 patients will be recruited from up to 5 treating centres and a 'rolling-six' design is utilised to minimise delays and facilitate ongoing recruitment during dose-escalation. Radiotherapy will be delivered in 5 daily fractions and surgery, if appropriate, will take place 5-6 weeks after radiotherapy. The margin-intense radiotherapy concept includes a systematic method to define the target volume for a simultaneous integrated boost in the region of tumour-vessel infiltration, and up to 4 radiotherapy dose levels will be investigated. Maximum tolerated dose is defined as the highest dose at which no more than 1 of 6 patients or 0 of 3 patients experience a dose limiting toxicity. Secondary endpoints include resection rate, resection margin status, response rate, overall survival and progression free survival at 12 and 24 months. Translational work will involve exploratory analyses of the cytological and humoral immunological responses to stereotactic radiotherapy in pancreatic cancer. Radiotherapy quality assurance of target definition and radiotherapy planning is enforced with pre-trial test cases and on-trial review. Recruitment began in April 2015. DISCUSSION: This prospective multi-centre study aims to establish the maximum tolerated dose of pre-operative margin-intensified stereotactic radiotherapy in pancreatic cancer at high risk of positive resection margins with a view to subsequent definitive comparison with other neoadjuvant treatment options

An Assessment of the Effectiveness of High Definition Cameras as Remote Monitoring Tools for Dolphin Ecology Studies.

Research involving marine mammals often requires costly field programs. This paper assessed whether the benefits of using cameras outweighs the implications of having personnel performing marine mammal detection in the field. The efficacy of video and still cameras to detect Indo-Pacific bottlenose dolphins (Tursiops aduncus) in the Fremantle Harbour (Western Australia) was evaluated, with consideration on how environmental conditions affect detectability. The cameras were set on a tower in the Fremantle Port channel and videos were perused at 1.75 times the normal speed. Images from the cameras were used to estimate position of dolphins at the water’s surface. Dolphin detections ranged from 5.6 m to 463.3 m for the video camera, and from 10.8 m to 347.8 m for the still camera. Detection range showed to be satisfactory when compared to distances at which dolphins would be detected by field observers. The relative effect of environmental conditions on detectability was considered by fitting a Generalised Estimation Equations (GEEs) model with Beaufort, level of glare and their interactions as predictors and a temporal auto-correlation structure. The best fit model indicated level of glare had an effect, with more intense periods of glare corresponding to lower occurrences of observed dolphins. However this effect was not large (-0.264) and the parameter estimate was associated with a large standard error (0.113).The limited field of view was the main restraint in that cameras can be only applied to detections of animals observed rather than counts of individuals. However, the use of cameras was effective for long term monitoring of occurrence of dolphins, outweighing the costs and reducing the health and safety risks to field personal. This study showed that cameras could be effectively implemented onshore for research such as studying changes in habitat use in response to development and construction activities

Technical report on the Bottlenose dolphin (Tursiops aduncus) unusual mortality event within the Swan Canning Riverpark, June-October 2009

This technical report reviews findings from an investigation into the mortalities of six bottlenose dolphins (Tursiops aduncus) in the Swan Canning Riverpark in 2009. The report: (a) describes the epidemiology and pathology of these mortalities; (b) presents background information on the ecology of dolphins in the Swan Canning Riverpark and factors known to affect dolphin health; and (c) discusses the potential role of chemical contaminants in the mortalities. These mortalities were investigated in context of dolphin deaths in the Swan Canning Riverpark prior to 2009 and a series of mortalities of dolphins in the Bunbury area between 2008-10, as well as marine mammal mortality events in other locations

The Emerging Picture of Human Breast Cancer as a Stem Cell-based Disease

13 páginas, 2 figuras.There are increasing data supporting the existence of a cell hierarchy within the mammary gland. At the top or this hierarchy a small population of cells with self-renewal properties maintains the tissue architecture and remodeling, and they are known as stem cells. Also, recent evidences indicate that breast cancer is originated and maintained by its own cancer stem cells reminding the normal mammary gland. The existence of this small population of cells with self-renewal capability has important biological and clinical significances. So, the interpretation of tumors as hierarchical cellular structures has changed our vision of the breast cancer scenario. Here, we review the current knowledge about normal and breast cancer stem cells, and their implications in cancer development, together with their consequences in breast cancer susceptibility, dissemination and treatment response.I.S.G.’s research is supported partially by FEDER and by MEC (SAF2006-03726 and PETRI Nº 95-0913.OP), Junta de Castilla y León (CSI03A05), FIS (PI050087, PI050116), Fundación de Investigación MMA, Federación de Cajas de Ahorro Castilla y León (I Convocatoria de Ayudas para Proyectos de Investigación Biosanitaria con Células Madre), CDTEAM project (CENIT-Ingenio 2010) and MEC Consolider-Ingenio 2010 (Ref. CSD2007-0017). J.J.C., R.G.S. and I.S.G. belong to the GR15 group sponsored by JCyL.Peer reviewe

Guidelines for the use and interpretation of assays for monitoring autophagy

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Guidelines for the use and interpretation of assays for monitoring autophagy

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field