A phase II multi-institutional study assessing simultaneous in-field boost helical tomotherapy for 1-3 brain metastases

<p>Abstract</p> <p>Background</p> <p>Our research group has previously published a dosimetric planning study that demonstrated that a 60 Gy/10 fractions intralesional boost with whole-brain radiotherapy (WBRT) to 30 Gy/10 fractions was biologically equivalent with a stereotactic radiosurgery (SRS) boost of 18 Gy/1 fraction with 30 Gy/10 fractions WBRT. Helical tomotherapy (HT) was found to be dosimetrically equivalent to SRS in terms of target coverage and superior to SRS in terms of normal tissue tolerance. A phase I trial has been now completed at our institution with a total of 60 enrolled patients and 48 evaluable patients. The phase II dose has been determined to be the final phase I cohort dose of 60 Gy/10 fractions.</p> <p>Methods/Design</p> <p>The objective of this clinical trial is to subject the final phase I cohort dose to a phase II assessment of the endpoints of overall survival, intracranial control (ICC) and intralesional control (ILC). We hypothesize HT would be considered unsuitable for further study if the median OS for patients treated with the HT SIB technique is degraded by 2 months, or the intracranial progression-free rates (ICC and ILC) are inferior by 10% or greater compared to the expected results with treatment by whole brain plus SRS as defined by the RTOG randomized trial. A sample size of 93 patients was calculated based on these parameters as well as the statistical assumptions of alpha = 0.025 and beta = 0.1 due to multiple statistical testing. Secondary assessments of toxicity, health-related quality-of-life, cognitive changes, and tumor response are also integrated into this research protocol.</p> <p>Discussion</p> <p>To summarize, the purpose of this phase II trial is to assess this non-invasive alternative to SRS in terms of central nervous system (CNS) control when compared to SRS historical controls. A follow-up phase III trial may be required depending on the results of this trial in order to definitively assess non-inferiority/superiority of this approach. Ultimately, the purpose of this line of research is to provide patients with metastatic disease to the brain a shorter course, dose intense, non-invasive radiation treatment with equivalent or improved CNS control/survival and health-related quality-of-life/toxicity profile when compared to SRS radiotherapy.</p> <p>Trial registration</p> <p>Clinicaltrials.gov - <a href="http://www.clinicaltrials.gov/ct2/show/NCT01543542">NCT01543542</a>.</p

The Search for Invariance: Repeated Positive Testing Serves the Goals of Causal Learning

Positive testing is characteristic of exploratory behavior, yet it seems to be at odds with the aim of information seeking. After all, repeated demonstrations of one’s current hypothesis often produce the same evidence and fail to distinguish it from potential alternatives. Research on the development of scientific reasoning and adult rule learning have both documented and attempted to explain this behavior. The current chapter reviews this prior work and introduces a novel theoretical account—the Search for Invariance (SI) hypothesis—which suggests that producing multiple positive examples serves the goals of causal learning. This hypothesis draws on the interventionist framework of causal reasoning, which suggests that causal learners are concerned with the invariance of candidate hypotheses. In a probabilistic and interdependent causal world, our primary goal is to determine whether, and in what contexts, our causal hypotheses provide accurate foundations for inference and intervention—not to disconfirm their alternatives. By recognizing the central role of invariance in causal learning, the phenomenon of positive testing may be reinterpreted as a rational information-seeking strategy

Tear fluid biomarkers in ocular and systemic disease: potential use for predictive, preventive and personalised medicine

In the field of predictive, preventive and personalised medicine, researchers are keen to identify novel and reliable ways to predict and diagnose disease, as well as to monitor patient response to therapeutic agents. In the last decade alone, the sensitivity of profiling technologies has undergone huge improvements in detection sensitivity, thus allowing quantification of minute samples, for example body fluids that were previously difficult to assay. As a consequence, there has been a huge increase in tear fluid investigation, predominantly in the field of ocular surface disease. As tears are a more accessible and less complex body fluid (than serum or plasma) and sampling is much less invasive, research is starting to focus on how disease processes affect the proteomic, lipidomic and metabolomic composition of the tear film. By determining compositional changes to tear profiles, crucial pathways in disease progression may be identified, allowing for more predictive and personalised therapy of the individual. This article will provide an overview of the various putative tear fluid biomarkers that have been identified to date, ranging from ocular surface disease and retinopathies to cancer and multiple sclerosis. Putative tear fluid biomarkers of ocular disorders, as well as the more recent field of systemic disease biomarkers, will be shown

Intensity-modulated radiation therapy: emerging cancer treatment technology

The use of intensity-modulated radiation therapy (IMRT) is rapidly advancing in the field of radiation oncology. Intensity-modulated radiation therapy allows for improved dose conformality, thereby affording the potential to decrease the spectrum of normal tissue toxicities associated with IMRT. Preliminary results with IMRT are quite promising; however, the clinical data is relatively immature and overall patient numbers remain small. High-quality IMRT requires intensive physics support and detailed knowledge of three-dimensional anatomy and patterns of tumour spread. This review focuses on basic principles, and highlights the clinical implementation of IMRT in head and neck and prostate cancer

Cholesterol Pathways Affected by Small Molecules That Decrease Sterol Levels in Niemann-Pick Type C Mutant Cells

Niemann-Pick type C (NPC) disease is a genetically inherited multi-lipid storage disorder with impaired efflux of cholesterol from lysosomal storage organelles.The effect of screen-selected cholesterol lowering compounds on the major sterol pathways was studied in CT60 mutant CHO cells lacking NPC1 protein. Each of the selected chemicals decreases cholesterol in the lysosomal storage organelles of NPC1 mutant cells through one or more of the following mechanisms: increased cholesterol efflux from the cell, decreased uptake of low-density lipoproteins, and/or increased levels of cholesteryl esters. Several chemicals promote efflux of cholesterol to extracellular acceptors in both non-NPC and NPC1 mutant cells. The uptake of low-density lipoprotein-derived cholesterol is inhibited by some of the studied compounds.Results herein provide the information for prioritized further studies in identifying molecular targets of the chemicals. This approach proved successful in the identification of seven chemicals as novel inhibitors of lysosomal acid lipase (Rosenbaum et al, Biochim. Biophys. Acta. 2009, 1791:1155-1165)

Physics of Neutron Star Crusts

The physics of neutron star crusts is vast, involving many different research fields, from nuclear and condensed matter physics to general relativity. This review summarizes the progress, which has been achieved over the last few years, in modeling neutron star crusts, both at the microscopic and macroscopic levels. The confrontation of these theoretical models with observations is also briefly discussed.Comment: 182 pages, published version available at <http://www.livingreviews.org/lrr-2008-10

Increased classical endoplasmic reticulum stress is sufficient to reduce chondrocyte proliferation rate in the growth plate and decrease bone growth

Copyright: © 2015 Kung et al. Mutations in genes encoding cartilage oligomeric matrix protein and matrilin-3 cause a spectrum of chondrodysplasias called multiple epiphyseal dysplasia (MED) and pseudoachondroplasia (PSACH). The majority of these diseases feature classical endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) as a result of misfolding of the mutant protein. However, the importance and the pathological contribution of ER stress in the disease pathogenesis are unknown. The aim of this study was to investigate the generic role of ER stress and the UPR in the pathogenesis of these diseases. A transgenic mouse line (ColIITgcog) was generated using the collagen II promoter to drive expression of an ER stress-inducing protein (Tgcog) in chondrocytes. The skeletal and histological phenotypes of these ColIITgcog mice were characterised. The expression and intracellular retention of Tgcog induced ER stress and activated the UPR as characterised by increased BiP expression, phosphorylation of eIF2á and spliced Xbp1. ColIITgcog mice exhibited decreased long bone growth and decreased chondrocyte proliferation rate. However, there was no disruption of chondrocyte morphology or growth plate architecture and perturbations in apoptosis were not apparent. Our data demonstrate that the targeted induction of ER stress in chondrocytes was sufficient to reduce the rate of bone growth, a key clinical feature associated with MED and PSACH, in the absence of any growth plate dysplasia. This study establishes that classical ER stress is a pathogenic factor that contributes to the disease mechanism of MED and PSACH. However, not all the pathological features of MED and PSACH were recapitulated, suggesting that a combination of intra- and extra-cellular factors are likely to be responsible for the disease pathology as a whole